Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
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This achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
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We are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
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Thank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
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\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"5245",leadTitle:null,fullTitle:"Recent Advances in Robotic Systems",title:"Recent Advances in Robotic Systems",subtitle:null,reviewType:"peer-reviewed",abstract:"This book brings together some recent advances and development in robotics. In 12 chapters, written by experts and researchers in respective fields, the book presents some up-to-date research ideas and findings in a wide range of robotics, including the design, modeling, control, learning, interaction, and navigation of robots. From an application perspective, the book covers UAVs, USVs, mobile robots, humanoid robots, graspers, and underwater robots. The unique text offers practical guidance to graduate students and researchers in research and applications in the field of robotics.",isbn:"978-953-51-2571-6",printIsbn:"978-953-51-2570-9",pdfIsbn:"978-953-51-4180-8",doi:"10.5772/61677",price:119,priceEur:129,priceUsd:155,slug:"recent-advances-in-robotic-systems",numberOfPages:294,isOpenForSubmission:!1,isInWos:1,isInBkci:!0,hash:"f42dd7ed81a8b4ec4dd63428cc4b1904",bookSignature:"Guanghui Wang",publishedDate:"September 28th 2016",coverURL:"https://cdn.intechopen.com/books/images_new/5245.jpg",numberOfDownloads:22117,numberOfWosCitations:25,numberOfCrossrefCitations:15,numberOfCrossrefCitationsByBook:4,numberOfDimensionsCitations:23,numberOfDimensionsCitationsByBook:3,hasAltmetrics:1,numberOfTotalCitations:63,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 16th 2015",dateEndSecondStepPublish:"November 6th 2015",dateEndThirdStepPublish:"February 10th 2016",dateEndFourthStepPublish:"May 10th 2016",dateEndFifthStepPublish:"June 9th 2016",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7,8",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"178603",title:"Dr.",name:"Guanghui",middleName:null,surname:"Wang",slug:"guanghui-wang",fullName:"Guanghui Wang",profilePictureURL:"https://mts.intechopen.com/storage/users/178603/images/4910_n.jpg",biography:"Dr. Guanghui Wang is currently an assistant professor at the University of Kansas, USA. He is also with the National Laboratory of Pattern Recognition, Chinese Academy of Sciences, China, as an adjunct professor. His current research interests include computer vision, image analysis, machine learning, and robotics. He authored one book “Guide to Three Dimensional Structure and Motion Factorization” at Springer-Verlag, and has published over 80 papers in peer-reviewed journals and conferences. He served as associate editor or on the editorial board of four journals, as an area chair or TPC member of 20+ conferences, and as a reviewer of three research organizations, 20+ journals, and 20+ conferences.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"1",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1291",title:"Robotic System",slug:"robotic-system"}],chapters:[{id:"50884",title:"Autonomous Quadrocopter for Search, Count and Localization of Objects",doi:"10.5772/63568",slug:"autonomous-quadrocopter-for-search-count-and-localization-of-objects",totalDownloads:1728,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"This chapter describes and evaluates the design and implementation of a new fully autonomous quadrocopter, which is capable of self‐reliant search, count and localization of a predefined object on the ground inside a room.",signatures:"Nils Gageik, Christian Reul and Sergio Montenegro",downloadPdfUrl:"/chapter/pdf-download/50884",previewPdfUrl:"/chapter/pdf-preview/50884",authors:[{id:"168230",title:"Ph.D. Student",name:"Nils",surname:"Gageik",slug:"nils-gageik",fullName:"Nils Gageik"},{id:"168231",title:"Prof.",name:"Sergio",surname:"Montenegro",slug:"sergio-montenegro",fullName:"Sergio Montenegro"},{id:"181110",title:"MSc.",name:"Christian",surname:"Reul",slug:"christian-reul",fullName:"Christian Reul"}],corrections:null},{id:"51486",title:"Design, Implementation and Modeling of Flooding Disaster-Oriented USV",doi:"10.5772/64305",slug:"design-implementation-and-modeling-of-flooding-disaster-oriented-usv",totalDownloads:1899,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Although there exist some unmanned surface platforms, and parts of them have been applied in flooding disaster relief, the autonomy of these platforms is still so weak that most of them can only work under the control of operators. The primary reason is the difficulty of obtaining a dynamical model that is sufficient rich for model-based control and sufficient simple for model parameters identification. This makes them difficult to be used to achieve some high-performance autonomous control, such as robust control with respect to disturbances and unknown dynamics and trajectory tracking control in complicated and dynamical surroundings. In this chapter, a flooding disaster-oriented unmanned surface vehicle (USV) designed and implemented by Shenyang Institute of Automation, Chinese Academy of Sciences (SIA, CAS) is introduced first, including the hardware and software structures. Then, we propose a quasi-linear parameter varying (qLPV) model to approach the dynamics of the USV system. We first apply this to solve a structured modeling problem and then introduce model error to solve an unstructured modeling problem. Subsequently, the qLPV model identification results are analyzed and the superiority compared to two linear models is demonstrated. At last, extensive application experiments, including rescuing rope throwing using an automatic pneumatic and water sampling in a 2.5 m radius circle, are described in detail to show the performance of course keeping control and GPS point tracking control based on the proposed model.",signatures:"Junfeng Xiong, Feng Gu, Decai Li, Yuqing He and Jianda Han",downloadPdfUrl:"/chapter/pdf-download/51486",previewPdfUrl:"/chapter/pdf-preview/51486",authors:[{id:"9884",title:"Dr.",name:"Yuqing",surname:"He",slug:"yuqing-he",fullName:"Yuqing He"},{id:"9921",title:"Prof.",name:"Jianda",surname:"Han",slug:"jianda-han",fullName:"Jianda Han"},{id:"185358",title:"Dr.",name:"Junfeng",surname:"Xiong",slug:"junfeng-xiong",fullName:"Junfeng Xiong"},{id:"185359",title:"Dr.",name:"Feng",surname:"Gu",slug:"feng-gu",fullName:"Feng Gu"},{id:"185360",title:"Dr.",name:"Decai",surname:"Li",slug:"decai-li",fullName:"Decai Li"}],corrections:null},{id:"51357",title:"Muscle‐Like Compliance in Knee Articulations Improves Biped Robot Walkings",doi:"10.5772/63746",slug:"muscle-like-compliance-in-knee-articulations-improves-biped-robot-walkings",totalDownloads:1662,totalCrossrefCites:3,totalDimensionsCites:3,hasAltmetrics:0,abstract:"This chapter focuses on the compliance effect of dynamic humanoid robot walking. This compliance is generated with an articular muscle emulator system, which is designed using two neural networks (NNs). One NN models a muscle and a second learns to tune the proportional integral derivative (PID) of the articulation DC motor, allowing it to behave analogously to the muscle model. Muscle emulators are implemented in the knees of a three‐dimensional (3D) simulated biped robot. The simulation results show that the muscle emulator creates compliance in articulations and that the dynamic walk, even in walk‐halt‐stop transitions, improves. If an external thrust unbalances the biped during the walk, the muscle emulator improves the control and prevents the robot from falling. The total power consumption is significantly reduced, and the articular trajectories approach human trajectories.",signatures:"Hayssan Serhan and Patrick Henaff",downloadPdfUrl:"/chapter/pdf-download/51357",previewPdfUrl:"/chapter/pdf-preview/51357",authors:[{id:"184415",title:"Dr.",name:"Patrick",surname:"Henaff",slug:"patrick-henaff",fullName:"Patrick Henaff"},{id:"185026",title:"Dr.",name:"Hayssam",surname:"Serhan",slug:"hayssam-serhan",fullName:"Hayssam Serhan"}],corrections:null},{id:"52096",title:"Kinematic Analysis of the Triangle-Star Robot with Telescopic Arm and Three Kinematics Chains as T-S Robot (3-PRP)",doi:"10.5772/64556",slug:"kinematic-analysis-of-the-triangle-star-robot-with-telescopic-arm-and-three-kinematics-chains-as-t-s",totalDownloads:1853,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"In this chapter, the limitations and weaknesses of the motion geometry and the workspace of Triangle-Star Robot {T-S (3-PRP)} are diagnosed after research and consideration of the issues at hand. In addition, they are offered in index form. To remove the problems with the abovementioned cases, at first, a robot with telescopic arms and a similar kinematics chain is rendered to give a kinematics analysis approach like Hartenberg-Denavit. Furthermore, in order to increase the workspace, Reuleaux Triangle-Star Robot {RT-S (3-PRP)} with kinematics chains 3-PRP and Circle-Star Robot{C-S (3-PRP)} with kinematics chains 3-PRP and a new improved structure are introduced.",signatures:"Ahmad Zahedi, Hadi Behzadnia, Hassan Ghanbari and Seyed\nHamed Tabatabaei",downloadPdfUrl:"/chapter/pdf-download/52096",previewPdfUrl:"/chapter/pdf-preview/52096",authors:[{id:"184776",title:"Dr.",name:"Hadi",surname:"Behzadnia",slug:"hadi-behzadnia",fullName:"Hadi Behzadnia"},{id:"184777",title:"Dr.",name:"Ahmed",surname:"Zahedi",slug:"ahmed-zahedi",fullName:"Ahmed Zahedi"},{id:"184778",title:"Dr.",name:"Hassan",surname:"Ghanbari",slug:"hassan-ghanbari",fullName:"Hassan Ghanbari"},{id:"184779",title:"Dr.",name:"Hamed",surname:"Tabatabaei",slug:"hamed-tabatabaei",fullName:"Hamed Tabatabaei"}],corrections:null},{id:"51053",title:"Recent Developments in Monocular SLAM within the HRI Framework",doi:"10.5772/63820",slug:"recent-developments-in-monocular-slam-within-the-hri-framework",totalDownloads:1880,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"This chapter describes an approach to improve the feature initialization process in the delayed inverse-depth feature initialization monocular Simultaneous Localisation and Mapping (SLAM), using data provided by a robot’s camera plus an additional monocular sensor deployed in the headwear of the human component in a human-robot collaborative exploratory team. The robot and the human deploy a set of sensors that once combined provides the data required to localize the secondary camera worn by the human. The approach and its implementation are described along with experimental results demonstrating its performance. A discussion on the usual sensors within the robotics field, especially in SLAM, provides background to the advantages and capabilities of the system implemented in this research.",signatures:"Edmundo Guerra, Yolanda Bolea, Rodrigo Munguia and Antoni\nGrau",downloadPdfUrl:"/chapter/pdf-download/51053",previewPdfUrl:"/chapter/pdf-preview/51053",authors:[{id:"13038",title:"Prof.",name:"Antoni",surname:"Grau",slug:"antoni-grau",fullName:"Antoni Grau"},{id:"18024",title:"Dr.",name:"Yolanda",surname:"Bolea",slug:"yolanda-bolea",fullName:"Yolanda Bolea"},{id:"163432",title:"Dr.",name:"Rodrigo",surname:"Munguia",slug:"rodrigo-munguia",fullName:"Rodrigo Munguia"},{id:"165970",title:"Ph.D. Student",name:"Edmundo",surname:"Guerra",slug:"edmundo-guerra",fullName:"Edmundo Guerra"}],corrections:null},{id:"51618",title:"Validation and Experimental Testing of Observers for Robust GNSS-Aided Inertial Navigation",doi:"10.5772/63575",slug:"validation-and-experimental-testing-of-observers-for-robust-gnss-aided-inertial-navigation",totalDownloads:1687,totalCrossrefCites:2,totalDimensionsCites:3,hasAltmetrics:0,abstract:"This chapter is the study of state estimators for robust navigation. Navigation of vehicles is a vast field with multiple decades of research. The main aim is to estimate position, linear velocity, and attitude (PVA) under all dynamics, motions, and conditions via data fusion. The state estimation problem will be considered from two different perspectives using the same kinematic model. First, the extended Kalman filter (EKF) will be reviewed, as an example of a stochastic approach; second, a recent nonlinear observer will be considered as a deterministic case. A comparative study of strapdown inertial navigation methods for estimating PVA of aerial vehicles fusing inertial sensors with global navigation satellite system (GNSS)-based positioning will be presented. The focus will be on the loosely coupled integration methods and performance analysis to compare these methods in terms of their stability, robustness to vibrations, and disturbances in measurements.",signatures:"Jakob M. Hansen, Jan Roháč, Martin Šipoš, Tor A. Johansen and\nThor I. Fossen",downloadPdfUrl:"/chapter/pdf-download/51618",previewPdfUrl:"/chapter/pdf-preview/51618",authors:[{id:"132264",title:"Prof.",name:"Tor Arne",surname:"Johansen",slug:"tor-arne-johansen",fullName:"Tor Arne Johansen"},{id:"179630",title:"Prof.",name:"Thor",surname:"Fossen",slug:"thor-fossen",fullName:"Thor Fossen"},{id:"179647",title:"Dr.",name:"Martin",surname:"Šipoš",slug:"martin-sipos",fullName:"Martin Šipoš"},{id:"179649",title:"Associate Prof.",name:"Jan",surname:"Rohac",slug:"jan-rohac",fullName:"Jan Rohac"},{id:"181258",title:"Mr.",name:"Jakob Mahler",surname:"Hansen",slug:"jakob-mahler-hansen",fullName:"Jakob Mahler Hansen"}],corrections:null},{id:"51816",title:"Time-Energy Optimal Cluster Space Motion Planning for Mobile Robot Formations",doi:"10.5772/64615",slug:"time-energy-optimal-cluster-space-motion-planning-for-mobile-robot-formations",totalDownloads:1750,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The motions of a formation of mobile robots along predetermined paths are optimized according to a tunable time-energy cost function using the cluster space approach to multiagent system specification and control. Upon path-parameterizing cluster state variables describing the geometry and pose of a multirobot group, an optimal control problem is formulated that incorporates formation dynamics and state constraints. The optimal trajectory is derived numerically via a gradient search, iterating over the initial value of one costate. A multirobot formation control simulation is then used to demonstrate the effectiveness of the technique. Results indicate that a substantial tradeoff is made between energy expenditure and motion time when considered as minimization criteria in varying proportions, allowing the operator to tailor mission trajectories according to desired levels of each.",signatures:"Kyle Stanhouse, Chris Kitts and Ignacio Mas",downloadPdfUrl:"/chapter/pdf-download/51816",previewPdfUrl:"/chapter/pdf-preview/51816",authors:[{id:"13486",title:"Dr.",name:"Christopher",surname:"Kitts",slug:"christopher-kitts",fullName:"Christopher Kitts"}],corrections:null},{id:"51093",title:"Laser Graphics in Augmented Reality Applications for Real- World Robot Deployment",doi:"10.5772/63635",slug:"laser-graphics-in-augmented-reality-applications-for-real-world-robot-deployment",totalDownloads:1552,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Lasers are powerful light source. With their thin shafts of bright light and colours, laser beams can provide a dazzling display matching that of outdoor fireworks. With computer assistance, animated laser graphics can generate eye-catching images against a dark sky. Due to technology constraints, laser images are outlines without any interior fill or detail. On a more functional note, lasers assist in the alignment of components, during installation.",signatures:"Gerald Seet, Viatcheslav Iastrebov, Dinh Quang Huy and Pang Wee-\nChing",downloadPdfUrl:"/chapter/pdf-download/51093",previewPdfUrl:"/chapter/pdf-preview/51093",authors:[{id:"81562",title:"Prof.",name:"Gerald",surname:"Seet",slug:"gerald-seet",fullName:"Gerald Seet"},{id:"185583",title:"Dr.",name:"Viatcheslav",surname:"Iastrebov",slug:"viatcheslav-iastrebov",fullName:"Viatcheslav Iastrebov"},{id:"185584",title:"Ms.",name:"Wee-Ching",surname:"Pang",slug:"wee-ching-pang",fullName:"Wee-Ching Pang"},{id:"185585",title:"Mr.",name:"Quang Huy",surname:"Dinh",slug:"quang-huy-dinh",fullName:"Quang Huy Dinh"}],corrections:null},{id:"51155",title:"Dynamic Optimized Bandwidth Management for Teleoperation of Collaborative Robots",doi:"10.5772/63725",slug:"dynamic-optimized-bandwidth-management-for-teleoperation-of-collaborative-robots",totalDownloads:1530,totalCrossrefCites:1,totalDimensionsCites:0,hasAltmetrics:0,abstract:"A real-time dynamic and optimized bandwidth management algorithm is proposed and used in teleoperated collaborative swarms of robots. This method is effective in complex teleoperation tasks, where several robots rather than one are utilized and where an extensive amount of exchanged information between operators and robots is inevitable. The importance of the proposed algorithm is that it accounts for Interesting Events (IEs) occurring in the system's environment and for the change in the Quality of Collaboration (QoC) of the swarm of robots in order to allocate communication bandwidth in an optimized manner. A general dynamic optimized bandwidth management system for teleoperation of collaborative robots is formulated in this paper. The suggested algorithm is evaluated against two static algorithms applied to a swarm of two humanoid robots. The results demonstrate the advantages of dynamic optimization algorithm in terms of task and network performance. The developed algorithm outperforms two static bandwidth management algorithms, against which it was tested, for all performance parameters in 80% of the performed trials. Accordingly, it was demonstrated that the proposed dynamic bandwidth optimization and allocation algorithm forms the basis of a framework for algorithms applied to real-time highly complex systems.",signatures:"Chadi Mansour, Mohamad El Hariri, Imad H. Elhajj, Elie Shammas\nand Daniel Asmar",downloadPdfUrl:"/chapter/pdf-download/51155",previewPdfUrl:"/chapter/pdf-preview/51155",authors:[{id:"184287",title:"Dr.",name:"Mohamad",surname:"El Hariri",slug:"mohamad-el-hariri",fullName:"Mohamad El Hariri"}],corrections:null},{id:"51224",title:"Series Elastic Actuator: Design, Analysis and Comparison",doi:"10.5772/63573",slug:"series-elastic-actuator-design-analysis-and-comparison",totalDownloads:3451,totalCrossrefCites:4,totalDimensionsCites:11,hasAltmetrics:1,abstract:"In general, actuators are built to be as stiff as possible to increase the bandwidth. When a robot works in a structured environment, its automation is easier than in a non-structured environment in which case its modeling is quite difficult and presents a high computational effort. To overcome this difficulty, series elastic actuator (SEA) has been applied in compliant robotic grasping. Unlike rigid actuators, a SEA contains an elastic element in series with the mechanical energy source. Such an elastic element gives SEAs tolerance to impact loads, low mechanical output impedance, passive mechanical energy storage, and increased peak power output. The spring has to be able to support the loads, but it cannot be too stiff; otherwise, system impedance will be high. This chapter describes a comparison between two types of SEA, an electric series elastic actuator (ESEA) and a hydraulic series elastic actuator (HSEA), for four-legged dynamic robot application. The parameters employed in the comparison are bandwidth, output impedance, time response, power density, and dynamic range. The results indicate that HSEA is a better actuator than ESEA for a weight carrying four-legged dynamic robot because of its higher power density and dynamic ratio with desirable output impedance, time response, and bandwidth.",signatures:"Arnaldo Gomes Leal Junior, Rafhael Milanezi de Andrade and\nAntônio Bento Filho",downloadPdfUrl:"/chapter/pdf-download/51224",previewPdfUrl:"/chapter/pdf-preview/51224",authors:[{id:"182082",title:"Dr.",name:"Rafhael",surname:"Andrade",slug:"rafhael-andrade",fullName:"Rafhael Andrade"},{id:"185372",title:"Dr.",name:"Antônio",surname:"Bento Filho",slug:"antonio-bento-filho",fullName:"Antônio Bento Filho"},{id:"185373",title:"MSc.",name:"Arnaldo",surname:"Gomes Leal Junior",slug:"arnaldo-gomes-leal-junior",fullName:"Arnaldo Gomes Leal Junior"}],corrections:null},{id:"50812",title:"Fish-Like Robot Encapsulated by a Plastic Film",doi:"10.5772/63506",slug:"fish-like-robot-encapsulated-by-a-plastic-film",totalDownloads:1580,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Underwater robots are currently utilized to evaluate water quality and the undersea landscape. Small-sized underwater robots are especially useful in improving the spatial resolution of the measurements, yielding high-quality data. This chapter describes a small-sized fish-like robot, with its surface composed of a flexible thin plastic film. Its internal components, including an actuator, could be encapsulated in the plastic film using a vacuum packaging machine. To simplify the waterproofing and pressure resistance properties of the fish-like robot, its internal components can be filled with insulating fluid. The plastic film on the surface has electromagnetic-wave-transmitting properties, allowing sensors to be arranged within the device, enabling assessment of its autonomous locomotion using infrared sensors. Robot attitude can be altered, based on geography of its internal components, floating blocks, and insulating fluid. This attitude could be especially determined by the differences in densities between the floating block and insulating fluid. Evaluation of attitude control showed that an insulating fluid heavier than water allows a large variation.",signatures:"Mizuho Shibata",downloadPdfUrl:"/chapter/pdf-download/50812",previewPdfUrl:"/chapter/pdf-preview/50812",authors:[{id:"180106",title:"Dr.",name:"Mizuho",surname:"Shibata",slug:"mizuho-shibata",fullName:"Mizuho Shibata"}],corrections:null},{id:"51432",title:"CODA Algorithm: An Immune Algorithm for Reinforcement Learning Tasks",doi:"10.5772/63570",slug:"coda-algorithm-an-immune-algorithm-for-reinforcement-learning-tasks",totalDownloads:1546,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"This document presents the design of an algorithm that takes on its basis: reinforcement learning, learning from demonstration and most importantly Artificial Immune Systems. The main advantage of this algorithm named CODA (Cognition from Data). Is; it can learn from limited data samples- that is given a single example and the algorithm will create its own knowledge. The algorithm imitates from the Natural Immune System the clonal procedure for obtaining a repertoire of antibodies from a single antigen. It also uses the self-organised memory in order to reduce searching time in the whole action-state space by searching in specific clusters. CODA algorithm is presented and explained in detail in order to understand how these three principles are used. The algorithm is explained with pseudocode, flowcharts and block diagrams. The clonal/mutation results are presented with a simple example. It can be seen graphically how new data that has a completely new probability distribution. Finally, the first application where CODA is used, a humanoid hand is presented. In this application the algorithm created affordable grasping postures from limited examples, creates its own knowledge and stores data in memory data in memory in order to recognise whether it has been on a similar situation.",signatures:"Daniel R. Ramirez Rebollo, Pedro Ponce Cruz and Arturo Molina",downloadPdfUrl:"/chapter/pdf-download/51432",previewPdfUrl:"/chapter/pdf-preview/51432",authors:[{id:"181021",title:"Ph.D. Student",name:"Daniel",surname:"Ramirez Rebollo",slug:"daniel-ramirez-rebollo",fullName:"Daniel Ramirez Rebollo"},{id:"181149",title:"Dr.",name:"Pedro",surname:"Ponce",slug:"pedro-ponce",fullName:"Pedro Ponce"},{id:"181151",title:"Dr.",name:"Arturo",surname:"Molina",slug:"arturo-molina",fullName:"Arturo Molina"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. 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1. Introduction
The abundant serum protein alpha-1 antitrypsin (AAT) is the prototype chronic obstructive pulmonary disease (COPD) biomarker. AAT is an antiprotease which inhibits neutrophil-derived proteases and protects the fragile tissues of the lung. Absence of this key antiprotease renders the lung susceptible to proteolytic degradation. Alpha-1 antitrypsin deficiency (AATD) is a hereditary disorder characterised by low circulating levels of alpha-1 antitrypsin (AAT). The lung disease associated with the condition is characterized by neutrophil-dominated airway inflammation and elevated intra-pulmonary protease levels [1]. The SERPINA1 gene encodes for the AAT protein and the most common SERPINA1 mutation known to cause AATD is the Z mutation. The classic case of AATD is an individual homozygous for the Z mutation which causes a severe deficiency of circulating AAT. Intuitively, severe AATD is a proven genetic risk factor for the development of lung and less frequently, liver disease. The condition was previously estimated to play a causative role in approximately 1-2% of COPD cases [2]. However, when intermediate deficiency is included in any evaluation of the contribution of AATD to lung disease, we anticipate that this figure can rise to as high as 10%. Guidelines published by the World Health Organisation (WHO), the American Thoracic Society (ATS), and the European Respiratory Society (ERS) advocate a targeted screening approach for the detection of AATD. Together these organisations recommend testing for AATD in all individuals with COPD regardless of age or smoking history [3, 4]. Despite the clear and significant benefits of correct identification, AATD remains an under-diagnosed condition with the majority of cases undetected or misdiagnosed as COPD. Less than 10% of ZZ individuals have been correctly identified in Ireland and the same is true in many other countries [5]. In addition, long delays between the presentation of first symptoms and correct diagnosis are commonplace [6]. A diagnosis of AATD can present the doctor and the affected individual with a unique opportunity for early medical intervention and the prevention or postponement of COPD. This is an opportunity that, if seized, has enormous benefits for the affected individual and extended family relatives. This chapter aims to provide healthcare professionals with an overview of AATD and with clinically relevant information to assist them in the recognition, diagnosis, and management of this rarely diagnosed hereditary condition. It is our hope that this information can help counteract the nihilism related to AATD and the reluctance to test that can sometimes exist.
2. What is alpha-1 antitrypsin?
2.1. Clinical manifestations & presentation of AATD
To understand the deficiency, one must first understand the protein. Alpha-1 antitrypsin (AAT) is a 52 kDa glycosylated plasma protein. It belongs to a group of serine protease inhibitors and is encoded by the SERPINA1 gene on chromosome 14q32.1-32.3 [7]. Production of circulating AAT is predominantly the liver and the normal plasma concentration of AAT is 1.5 g/L (1.0-2.0 g/L) with a half-life of 4–5 days [8]. Production of AAT protein has also been shown in other cells such as monocytes, macrophages, pulmonary alveolar cells and intestinal epithelial cells [9-12], hinting at an important role in the local response to tissue inflammation. AAT is an acute phase protein and plasma levels can rise two to five fold in response to cytokine release (e.g. TNF-α, IL-1 and IL-6) during infection or inflammation [13, 14] with local concentrations at sites of inflammation reaching even higher levels [15].
The association of an absent alpha-globulin band on serum plasma electrophoresis with a possible hereditary form of pulmonary emphysema was first reported by Laurell and Eriksson in 1963 [16]. The observation that these individuals were susceptible to a severe form of hereditary emphysema led to a major breakthrough in our understanding of the role of protease-antiprotease imbalance in the pathogenesis of COPD [17]. Subsequently it was also discovered that people with AATD were also at risk of liver cirrhosis [18]. In the absence of familial or population screening for AATD the majority of people present with clinical symptoms, often at a stage where significant morbidity from the condition has already developed.
2.2. Pulmonary manifestations
Adults with AATD are susceptible to the premature development of lung diseases such as emphysema, chronic bronchitis, bronchiectasis, and asthma. Patients with AATD usually present with exertional breathlessness, wheeze, cough, and frequent pulmonary exacerbations often, but not exclusively with a background history of smoking [19]. Symptoms usually begin from the age of 30 and the clinical suspicion for underlying asthma or chronic obstructive pulmonary disease (COPD) prompts referral for spirometric assessment. The finding of reversibility on spirometry is common (approximately 50%) and often belies concomitant asthma and emphysema. Reversibility can be associated with a worse prognosis, possibly due to ongoing airway inflammation [19, 20]. The diagnosis of fixed airway obstruction in AATD, indicative of COPD, is often made at a much younger age (<40 years) than the general population. However, screening for AATD is recommended for all adults with COPD or incompletely reversible asthma [4]. Analysis of the Danish AATD registry data of index and non-index cases indicates that the median life expectancy in ZZ homozygotes is reduced dramatically from 69 years to 49 years in smokers compared to non-smokers, and baseline forced expiratory volume in 1 second (FEV1) was the single most important predictor of survival [21, 22]. Cigarette smoke exposure in AATD results in severe impairment of lung function and an accelerated decline in lung function, and affected individuals should be counselled to stop smoking immediately. Occupational exposure to chemicals and pollutants is also independently associated with a decline in lung function in AATD and patients should be advised of using personal protective respiratory equipment where necessary [23, 24].
Figure 1.
HRCT findings in ZZ individuals with emphysema (left) and bronchiectasis (right).
The classic pathological finding of bibasal panacinar emphysema can be now readily visualised with the widespread availability of high resolution computed tomography (HRCT) imaging, and the unexpected detection of these changes should prompt the clinician to screen for AATD. CT imaging with lung densitometry measurement facilitates monitoring of disease progression in AATD [25] and may be a superior outcome measure to change in FEV1 in clinical trials examining the effect of augmentation therapy in AATD [26]. CT imaging also permits the identification of bronchiectasis, which may or may not be clinically significant. The reported prevalence of bronchiectasis varies considerably but may occur independently of emphysema and can be severe [27, 28]. Symptoms of bronchiectasis are often difficult to distinguish from COPD and the prevalence and impact of this airway disease in AATD may be underestimated.
2.3. Liver manifestations
A small proportion of ZZ homozygotes present with a neonatal hepatitis syndrome, usually within the first 3-4 months of life. AATD is one of the commonest causes for neonatal hepatitis and can account for up to 29% of cases in some paediatric centres [29]. A large infant screening study of 200,000 newborns identified 120 with the ZZ phenotype, 22 (18.3%) had evidence of a hepatic abnormality. Of this cohort, 14 (11.7%) had prolonged obstructive jaundice and 9 (7.5%) had severe clinical liver disease [30]. The SZ phenotype is also associated with biochemical liver abnormalities, and can lead to end-stage liver disease requiring transplantation, although this is observed less frequently than in ZZ cohorts [31]. A number of risk factors for AATD associated liver disease in childhood have been identified including male gender, renal or pulmonary complications [29], and a first degree relative with AATD-related liver disease [32]. The reported outcomes of childhood liver disease are variable, with one study reporting mortality of 20/74 (27%) and persistent cirrhosis in a similar number [32], although most studies report complete clinical and biochemical recovery of liver function in the majority of cases [29].
Data from the Irish National AATD Registry allowed an investigation of the prevalence of liver abnormalities in a cohort of 115 ZZ individuals (Table 1). A total of 36% had liver function test (LFT) abnormalities on the first assessment, most commonly alanine aminotransferase (ALT), and this did not correlate with increasing age. A further 24% (30/115) were found to have abnormal liver findings by radiology. Fatty infiltration was the most common radiological finding (17%) after examination of abdominal ultrasound results, followed by cirrhosis, liver cysts, and haemangioma. No differences in body mass index (BMI) or alcohol consumption were observed in those with or without liver abnormalities which suggests the frequency of fatty liver was not due to increased obesity or alcohol but more likely to be attributable to the accumulation of Z AAT protein in the liver.
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t
\n\t\t\t\tTotal ZZ\n\t\t\t
\n\t\t\t
\n\t\t\t\tAbnormal Ultrasound\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
No. of subjects
\n\t\t\t
115
\n\t\t\t
30
\n\t\t
\n\t\t
\n\t\t\t
Gender (M/F)
\n\t\t\t
62/53
\n\t\t\t
20/10
\n\t\t
\n\t\t
\n\t\t\t
Age, years (mean +/- SD)
\n\t\t\t
52+/- 12
\n\t\t\t
44 +/- 11
\n\t\t
\n\t\t
\n\t\t\t
Mean FEV1 (% predicted)
\n\t\t\t
65 +/- 33
\n\t\t\t
50 +/- 28
\n\t\t
\n\t\t
\n\t\t\t
Mean BMI
\n\t\t\t
26.5
\n\t\t\t
27.4
\n\t\t
\n\t\t
\n\t\t\t
Alcohol (total respondents)
\n\t\t\t
80
\n\t\t\t
21
\n\t\t
\n\t\t
\n\t\t\t
Active
\n\t\t\t
61
\n\t\t\t
17
\n\t\t
\n\t\t
\n\t\t\t
Past
\n\t\t\t
4
\n\t\t\t
1
\n\t\t
\n\t\t
\n\t\t\t
Never
\n\t\t\t
15
\n\t\t\t
3
\n\t\t
\n\t
Table 1.
Liver abnormality findings in ZZ cohort on Irish National AATD Registry.
In adulthood, a strong relation between AATD and cirrhosis has been reported (OR=7.8; CI 2.4 to 24.7) and primary liver cancer (OR=20; CI 3.5 to 114.3), particularly affecting men [33]. Cirrhosis is usually complicated by portal hypertension, ascites, gastrointestinal bleeding, spontaneous bacterial peritonitis, hepatic encephalopathy, and hepatocellular carcinoma. The prevalence of liver cirrhosis increases with age and usually occurs in those who have never smoked, perhaps as a consequence of the prolonged survival in this group [4, 34]. Both genetic and environmental modifiers play a role in the pathogenesis of liver disease in AATD. Reports of putative candidate modifier genes for AATD-related liver disease have emerged [35-37], however, no specific gene or polymorphism has been conclusively demonstrated to have clinical utility and prognostic value. In addition, the high prevalence of MZ phenotypes in liver disease cohorts and the role of heterozygous AATD in worsening liver disease has been highlighted by several studies [38-40]. Thankfully, the natural history of those with fulminant AATD related liver disease has been dramatically altered by liver transplantation [41] and excellent survival rates have been achieved in adult and paediatric transplant recipients [31, 42].
2.4. Extra-pulmonary manifestations
The rare occurrence of recurrent panniculitis has been noted in individuals with AATD and is thought to relate to persistent neutrophilic inflammation at the affected sites [43]. A number of case reports have reported the panniculitis to be responsive to intravenous augmentation therapy [44-46]. AATD has been associated with a variety of other medical conditions, the best described being ANCA-associated vasculitis and in particular granulomatosis with polyangiitis (GPA). A recent genome wide association study identified the Z allele of SERPINA1 to be associated with Proteinase 3 (PR3)-ANCA positivity [47]. PR3 is inhibited by AAT and some case reports of PR3-ANCA vasculitis in ZZ homozygotes report a severe disease phenotype [48, 49]. The role of AAT in diseases of the circulatory system is incompletely understood. Oxidised AAT can bind to the Apolipoprotein B100 component of LDL in the circulation and may contribute to atherogenesis [50], additionally the cleaved C36 peptide fragment of AAT has been found complexed within atherosclerotic plaques indicating a role in monocyte recruitment within the intima of arterial walls [51]. AAT complexes with IgA were found in the joints and sera of patients with rheumatoid arthritis [52, 53] though there appears to be no strong link between the two conditions [54]. A recent development is the association of diabetes mellitus with low AAT levels [55] and the emerging scientific data demonstrating improved islet cell graft survival in mice transfected with human AAT [56]. However, it is too soon to determine if any sustained benefit can be achieved. Clinical trials are planned to investigate the efficacy of AAT augmentation therapy in diabetes (NCT01183455, NCT02093221).
2.5. AATD heterozygosity: A risk factor for COPD?
An accurate determination of the risk of COPD in AATD heterozygotes is vitally important given the large number of individuals who are potentially affected. We know MZ individuals have moderately reduced levels of AAT but clarifying the risk of COPD in this group has been controversial. The Irish National AATD Targeted Detection Programme has identified over 1,600 MZ individuals in the 12,000 individuals tested to date. While this heterozygote group does include cases identified through family screening, this means that approximately 1 in 8 individuals tested are MZ. Anecdotally, a significant number of MZ individuals from our AATD clinic, both smokers and non-smokers, develop COPD at a relatively young age. Approximately 250,000 individuals on the island of Ireland [5] and 6 million individuals in the United States possess the MZ genotype [57]. A deeper appreciation of the risk of COPD in heterozygotes could lead to the prevention or postponement of lung disease in this group, lessening the growing global healthcare burden of COPD.
During the past 40 years, over 100 studies have attempted to assess the risk of lung disease in MZ individuals. A meta-analysis by Hersh et al estimated that the combined odds ratio for COPD in MZ compared to MM individuals was 2.31. This risk was attenuated in studies which adjusted for cigarette smoke exposure [58]. An accurate determination of the risk of COPD has been fraught with difficulty. Many previous attempts to ascertain the contribution of MZ heterozygosity to the development of COPD have been met with various methodological and design flaws; most notably selection bias and inadequate control for cigarette smoke exposure. A recent study which aimed to clarify the risk of COPD in MZ heterozygotes has addressed many of the concerns which hampered an accurate risk estimate from previous attempts to answer this vitally important question. The issue of selection bias was addressed in the study design by using a family based approach. Index cases or probands were MZ individuals who had a confirmed diagnosis of COPD based on the following spirometric criteria: a post-bronchodilator FEV1/FVC ratio < 0.7 and an FEV1 (% predicted) < 80%. All first degree family members of the index case (probands) underwent AAT phenotyping, pre-and post-bronchodilator spirometry as well as completing the ATS‐DLD Epidemiology Questionnaire. For the final analysis, the probands were excluded and the risk of COPD in the MM and MZ first degree relatives was determined. While the main strength of this study was elimination of ascertainment bias, additional strengths included the use of a genetically homogenous population, a standardised criterion for the diagnosis of COPD and adequate control for covariates including age, sex and cigarette smoke exposure. The adjusted odds ratio (OR) for COPD in MZ compared with MM group was 5.18 and this was higher (OR, 10.65) in ever-smoking individuals [59].
A significant gene-by-environment interaction exists to influence the development of COPD in MZ individuals. MZ individuals who have a low exposure to cigarette smoke (< 20 pack-years) have more airflow obstruction compared to MM individuals [59] in addition to more emphysema on quantitative analysis of chest CT scans [60]. This indicates that MZ heterozygosity and cigarette smoke exposure are a potent combination of risk factors in the pathogenesis of COPD. While these studies focused on direct exposure to cigarette smoke, the effect of passive cigarette smoke exposure and occupational exposure are less well defined. The MZ genotype in conjunction with cigarette smoke exposure modifies a MZ heterozygote’s longitudinal decline in lung function following occupational exposure to vapours, dusts, fumes and gases [61]. An accurate estimate of the effect of passive cigarette smoke exposure on MZ individuals has yet to be determined but the harmful effect of environmental tobacco smoke was found to be greater in MZ schoolchildren [62].
The recent advances in our understanding of COPD risk in MZ individuals make it more important than ever to test individuals for AATD. Knowledge that the MZ genotype can significantly interact with environment to influence susceptibility to COPD is a powerful message and this should help deter heterozygotes from exposing themselves to potentially harmful environmental risk factors. The timely detection of at risk MZ individuals underpins the importance of diagnosing this condition early in order to reduce smoking initiation rates [63] and also increase smoking cessation [64].
2.6. AATD heterozygosity: A biological perspective
Analysis of sputum from non-smoking asymptomatic MZ individuals without evidence of airflow obstruction demonstrates increased neutrophil counts and IL-8 levels compared with MM individuals [65]. This indicates that the co-expression of the Z allele could have pro-inflammatory consequences. Harbouring the Z mutation may confer a survival advantage as the formation of polymers at sites of inflammation could potentially focus and amplify the immune response to aid the eradication of invading pathogens [66]. However, this advantage is abolished by environmental exposure to cigarette smoke via enhanced polymerization of the Z protein which potentiates a deleterious pro-inflammatory milieu in the AAT deficient lung, culminating in an increased risk of developing COPD [67].
The observed increased risk of COPD in MZ smokers challenges some of the underlying tenets of the protease-antiprotease theory. Given that MZ individuals have intermediate levels of circulating AAT, it is biologically plausible that an imbalance in pulmonary neutrophil elastase and a suboptimal protective level of AAT may be responsible for the observed increased risk of airflow obstruction and COPD in MZ heterozygotes. Reactive oxygen species in cigarette smoke can inactivate pulmonary AAT on the one hand and also promote a pro-inflammatory environment by increasing neutrophilic influx into the lung by the promotion of polymerisation of Z AAT on the other [68]. The biological mechanism by which cigarette smoke is presumed to enhance the risk of COPD in MZ heterozygotes is summarised in Figure 2.
Figure 2.
Pathogenesis of COPD in MZ heterozygotes. A normal protease/antiprotease balance exists in MM individuals (left panel). Non-smoking MZ individuals have intermediate levels of AAT and increased sputum IL-8 levels and neutrophil counts (middle panel). Reactive oxygen species in cigarette smoke inactivate AAT resulting in a protease/antiprotease imbalance with increased amounts of neutrophil elastase. Polymerisation of Z AAT protein and increased amounts of IL-8 increase neutrophil influx into the MZ lung. An overwhelmed anti-protease defence contributes to the development of COPD (right panel).
The increased risk of COPD in MZ heterozygotes should lead to a reconsideration of what is the true protective threshold. This has implications not only for our understanding of the pathogenesis of COPD but also for AAT replacement therapy. Plasma purified AAT has been administered for almost 30 years by intravenous infusion to severe AATD individuals [69] with the aim of maintaining the plasma levels of AAT above the 11 µM level (approximately 0.56 g/l) throughout the duration of therapy [70]. The conflicting results and the paucity of clinical evidence for AAT replacement therapy [71] in severe AAT deficiency (ZZ) may be the result of targeting a sub-therapeutic threshold and augmenting the threshold to a higher MZ level may lead to improved treatment efficacy. The original threshold was based on mean AAT plasma concentration in the SZ phenotype as these individuals were thought to rarely develop COPD [72]. The SZ phenotype is more common than ZZ but studies in this area have been relatively few [73, 74]. However, an accurate determination of this risk would be very difficult as it would require a similar family based approach to that employed to determine the risk in MZ individuals including rigorous control for cigarette smoke exposure and a number of different patient groups encompassing the Z, S and M alleles. Until such information is available it may be prudent to consider a new protective threshold as MZ individuals are not likely to develop lung disease in the absence of cigarette smoke exposure.
The emerging weight of evidence regarding the risk of COPD in MZ heterozygotes raises several important questions for further research. Firstly, what are the biological mechanisms by which cigarette smoking confers MZ heterozygotes with an increased risk of COPD? Secondly, in a longitudinal family based study, does the slope of lung function decline differ significantly between MZ and MM first degree relatives? What is the true protective threshold level of AAT and would increasing this threshold level result in greater therapeutic efficacy of AAT augmentation therapy?
2.7. When does AATD present – An Irish perspective
Trends in diagnosis and clinical presentation of severe AATD individuals in Ireland were recently investigated in a study of ZZ individuals enrolled in the Irish National AATD Registry. A total of 120 ZZ AATD individuals attending the national AATD centre completed a detailed questionnaire. For the entire group, the mean age of reported symptom onset was 37.8+/-1.6 years (range 0.03-80) while the mean age at diagnosis was 44.1+/-1.6 years (range 0.03-80). This leaves a mean interval between reported onset of first symptoms and diagnosis of AATD of 6.5+/-1.0 years (range 0 – 46). However, when subjects identified through family screening were excluded, the diagnostic delay increased to 8.5+/-1.2 years (range 1 – 46). In addition, the average number of physicians seen by the entire group prior to a diagnosis of AATD was 3 (range 1 – 13). The findings are similar to data from other registries and reflect the diagnostic odyssey that individuals are often subjected to before a correct diagnosis is reached [6, 28, 75]. This further highlights the under-recognition of AATD that persists.
2.8. Who should be tested?
Guidelines published by the World Health Organisation (WHO) and the American Thoracic Society/European Respiratory Society (ATS/ERS) recommend the establishment of targeted screening programmes for the detection of individuals with AATD [3, 4]. In comparison to general population screening which can be more difficult and expensive to perform, targeted detection programmes offer a much higher rate of detection and are significantly more cost effective. The Irish National AATD Targeted Detection Programme began in 2004 and follows the ATS/ERS and WHO guidelines for the diagnosis of AATD. The ATS/ERS guidelines recommend targeted screening of patients with COPD, non-responsive asthma, cryptogenic liver disease and also first-degree relatives of known AATD individuals, termed type A recommendations (Table 2).
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t\tATS/ERS Recommendations for Diagnostic Testing (Type A)\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
Adults with symptomatic emphysema or COPD (regardless of age or smoking history)
\n\t\t
\n\t\t
\n\t\t\t
Adults with asthma with airflow obstruction that is incompletely reversible after aggressive treatment with bronchodilators
\n\t\t
\n\t\t
\n\t\t\t
Asymptomatic individuals with persistent obstruction on pulmonary function tests with identifiable risk factors (e.g. cigarette smoking, occupational exposure)
\n\t\t
\n\t\t
\n\t\t\t
Adults with necrotising panniculitis
\n\t\t
\n\t\t
\n\t\t\t
Siblings of individuals with AATD
\n\t\t
\n\t\t
\n\t\t\t
Individuals with unexplained liver disease, including neonates, children, and adults, particularly the elderly
\n\t\t
\n\t
Table 2.
ATS/ERS recommendations for diagnostic testing for AATD (type A recommendations).
In addition to these groups, ATS/ERS guidelines also recommend testing should be considered in a number of other scenarios as outlined in table 3 (type B recommendations).
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t\tATS/ERS Recommendations for Diagnostic Testing (Type B)\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
Adults with bronchiectasis without evident etiology
\n\t\t
\n\t\t
\n\t\t\t
Adolescents with persistent airflow obstruction
\n\t\t
\n\t\t
\n\t\t\t
Asymptomatic individuals with persistent airflow obstruction and no risk factors
\n\t\t
\n\t\t
\n\t\t\t
Adults with C-ANCA-positive (anti-proteinase 3-positive) vasculitis
\n\t\t
\n\t
Table 3.
ATS/ERS recommendations for diagnostic testing for AATD (type B recommendations).
3. How do we test for AATD?
The laboratory diagnosis of AATD is usually performed by following two steps; determination of AAT concentration in serum or plasma (quantitative) and identification of allelic variants by phenotyping or genotyping (qualitative) [76-78]. Quantification of AAT is generally the first investigation and has the advantages of being quick and relatively inexpensive. Clinically, a simple rule of thumb is the lower the level of AAT, the higher the risk of COPD. AAT quantification is routinely performed in most clinical chemistry, biochemistry, and immunology hospital laboratories. If quantification of AAT reveals a level below a pre-determined cut-off point or threshold (for example 1.0 g/l or 100 mg/dl) the sample should be automatically reflexed to phenotyping [79, 80]. This is the most cost-efficient and prudent algorithm. If necessary, genotyping using allele-specific PCR (usually to Z and S) and/or direct sequencing of the AAT gene can be performed either as a further investigation or on a complementary basis. The choice of using phenotyping or genotyping depends on resources available and the type of sample being referred, and there are advantages and disadvantages associated with both qualitative methods.
Figure 3.
AATD diagnostic algorithm for whole blood, serum, and plasma in the Irish National AATD Targeted Detection Programme.
3.1. AAT quantification
AAT levels are measured routinely by immunoassay techniques such as nephelometry and turbidimetry, or less commonly by radial immunodiffusion [81, 82]. AAT levels measured in our centre are determined using immune turbidimetry on an Olympus AU540 analyser. The WHO and ATS/ERS guidelines recommend that AAT levels should be measured at least once in COPD patients. Although a substantial correlation between AAT phenotype and circulating AAT concentrations has been established by several groups [70, 80, 83], confounding factors include normal intra-individual variation, depression of AAT production in liver disease, malnutrition, and the fact that AAT is an acute phase protein [84, 85]. Potential analytical variation may also occur; however, this variation is generally not significant. The increasing availability of external quality assurance schemes and accreditation programmes has led to improvements in testing accuracy, sensitivity, and reproducibility. In terms of which type of blood sample to use for AATD testing, a study by Miles et al in 2004 [86] which compared results from serum and heparinised plasma samples for 45 different chemistry tests addressed this concern. No statistically significant difference was observed in AAT concentrations measured in serum compared to plasma.
As an acute phase reactant, AAT levels are increased during the acute phase response, for example during infection or surgery [13]. Therefore, markers of inflammation such as CRP should be considered when assessing the concentration of AAT, and this has been discussed comprehensively elsewhere [87]. If CRP is indeed elevated, the quantification of AAT should be repeated once the acute phase response has subsided. The acute phase response will however, not result in a significant increase in AAT level in severe AATD (e.g. ZZ, Z/null). In contrast, AAT levels in heterozygotes (e.g. MZ, SZ) can be falsely elevated to levels similar to those observed in MM individuals, masking the underlying deficiency. For this reason, quantification of AAT levels alone is not a definitive test, and is no substitute for phenotype or genotype analysis, neither of which is affected by the acute phase.
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t\tPhenotype\n\t\t\t
\n\t\t\t
\n\t\t\t\tCases\n\t\t\t
\n\t\t\t
Mean AAT(g/l +/- SEM)
\n\t\t\t
Range AAT(g/l)
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t\tMS\n\t\t\t
\n\t\t\t
1209
\n\t\t\t
1.23 +/- 0.01
\n\t\t\t
0.40 – 3.82
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t\tMZ\n\t\t\t
\n\t\t\t
1657
\n\t\t\t
0.91 +/- 0.01
\n\t\t\t
0.44 – 4.08
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t\tSS\n\t\t\t
\n\t\t\t
60
\n\t\t\t
0.91 +/- 0.01
\n\t\t\t
0.56 – 1.54
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t\tSZ\n\t\t\t
\n\t\t\t
165
\n\t\t\t
0.65 +/- 0.01
\n\t\t\t
0.35 – 1.17
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t\tZZ\n\t\t\t
\n\t\t\t
219
\n\t\t\t
0.25 +/- 0.001
\n\t\t\t
0.11 – 0.61
\n\t\t
\n\t
Table 4.
Mean AAT in deficient phenotypes identified in the Irish National AATD Targeted Detection Programme.
In the formulation of diagnostic algorithms for AATD the cut-off or threshold AAT value is critical to effective screening efforts and the identification of at risk individuals. A study by Donato et al in 2012 found a cut-off of 1.0 g/L was sufficient for the detection of severe (ZZ, Z/null) and intermediate AATD (e.g. MZ and SZ heterozygotes) [79]. Intermediate AATD has been an area of some controversy, with previous guidelines adopting stringently low cut-off values (for example 0.6 g/l) which would fail to detect large at risk populations of intermediate AATD. We know now that SZ and MZ individuals are also at risk of lung disease, particularly if they smoke [59, 74], and this knowledge has led to a change in diagnostic algorithms and increased the heterozygote detection rate. In light of the Donato study and our own data from screening 12,000 individuals we employ a cutoff point of 1.0 g/l at our centre as this is optimal for the detection of severe and intermediate AATD. Using this cut off value reduces laboratory costs and unnecessary testing, while maximising the detection of at risk individuals. An exception where a cut off value may not apply is when screening individuals due to a family history of AATD, as in this case it should be recommended the phenotype is checked regardless of AAT level.
3.2. AAT phenotyping
The ATS/ERS guidelines identify serum phenotyping as the ‘gold standard’ for the diagnosis of AATD. The qualitative detection and characterisation of AAT variants is carried out in our centre by isoelectric focusing followed by immunofixation using a kit which is the only FDA-approved method for AAT phenotype determination [88]. The isoelectric focusing (IEF) method on agarose gel has an added immunofixation step which utilises a specific antibody to AAT. This renders it superior to traditional IEF techniques due to its high resolution and reproducibility. IEF is also advantageous due to the fact it can easily detect rare and novel phenotypes. IEF identifies the various isoglycoforms and highlights the microheterogeneity of AAT in terms of carbohydrate side chains, but more importantly highlights the macroheterogeneity of AAT in terms of genetic variation. AAT phenotype is determined by comparison to three reference standards (e.g. MM, MS, and ZZ) and by visual inspection by a minimum of two independent observers. All IEF results are checked and correlated with the corresponding AAT levels. The recent publication of a reference compendium of known AAT phenotypes is a helpful resource for interpreting IEF migration patterns of AAT variants [89].
Figure 4.
IEF migration pattern of common (left) and rare (right) AAT phenotypes identified in Ireland.
There are some cases in which analytical errors may occur using the IEF technique. Patients who are on augmentation therapy receive intravenous administration of purified AAT (isolated from MM donor individuals). The M variant will be detected in samples obtained from individuals receiving therapy and could result in discordant or unidentifiable migration patterns (e.g. a ZZ individual on therapy may appear MZ). Another error is possible with the presence of null mutations, which are a class of mutations characterised by a total absence of AAT secretion. Therefore, heterozygote null cases such as M/null, Z/null, S/null will appear as homozygous MM, ZZ, SS respectively [90, 91]. M/null and S/null phenotypes can be identified by the lower than expected AAT level. More difficult to identify are the Z/null phenotypes as the AAT level in ZZ compared to Z/null phenotypes is so low as to be practically indistinguishable. Similarly, caution must be taken with samples from individuals following a blood transfusion; this may also result in an incorrect diagnosis due to the possibility of the phenotype of the donor being present. If necessary genotyping using PCR and/or direct sequencing of the SERPINA1 gene can be achieved either in a complementary investigation to investigate discordant results or to identify rare and novel phenotypic variants.
3.3. AAT genotyping and sequencing
The adoption of dried blood spot (DBS) samples in an attempt to increase testing rates by making sampling easier, coupled with advances in molecular diagnostics, has resulted in the development of genotyping assays for AATD. Genotyping assays are commonly performed by melt curve analysis on real-time PCR instruments with primers and probes designed for specific mutations or less frequently by PCR-based restriction fragment length polymorphism (RFLP) analysis [92, 93], although RFLP methods have been replaced by the faster and more efficient melt curve methods. Allowing for the fact the DBS method has the convenience of allowing home testing and easier transportation of samples [94], in our centre we encourage the collection of serum or plasma samples for phenotyping by isoelectric focusing. This is primarily due to the nature of the sample referral centres which are large hospitals with specialist respiratory clinics, and also due to cost and logistical reasons.
Genotyping has the advantage of facilitating the rapid screening of both dried blood spots and DNA isolated from blood and is arguably less prone to interpretation errors which may occur with phenotyping. A downside to the method is that many laboratories, generally for cost and logistical reasons, employ primers for selected mutations, often the most common Z and S. In some cases, this can lead to rare mutations such as I, F, and Mmalton not being detected and misclassified as normal [90]. For this reason, in certain laboratories the genotyping method is used on a complementary or a clarification basis, unless specific M primers are being used.
Figure 5.
Genotyping assay for the Z allele by melting curve analysis on a real-time PCR system [93].
For the precise identification of rare and unusual phenotypes observed in our centre we reflex to sequencing the gene for AAT (SERPINA1, RefSeq: NG_008290). This involves the isolation of DNA and sequencing the coding exons (II-V) of the SERPINA1 gene [95]. The detailed genetic analysis has led to the identification and characterisation of many rare and novel SERPINA1 alleles (Table 5).
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t\tVariant\n\t\t\t
\n\t\t\t
\n\t\t\t\tMechanism\n\t\t\t
\n\t\t\t
\n\t\t\t\tEffect\n\t\t\t
\n\t\t\t
\n\t\t\t\tDisease Risk\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
Z
\n\t\t\t
GAG – AAG, Glu342Lys
\n\t\t\t
Polymerisation, impaired secretion and severe deficiency
\n\t\t\t
Lung & liver \n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
S
\n\t\t\t
GAA – GTA, Glu264Val
\n\t\t\t
Impaired secretion and mild deficiency
\n\t\t\t
Lung & liver (in compound heterozygotes e.g. SZ)
\n\t\t
\n\t\t
\n\t\t\t
I
\n\t\t\t
CGC – TGC, Arg39Cys
\n\t\t\t
Impaired secretion and mild deficiency \n\t\t\t
\n\t\t\t
Lung & liver (case reports in compound heterozygotes e.g. IZ)
\n\t\t
\n\t\t
\n\t\t\t
F
\n\t\t\t
CGT – TGT, Arg223Cys
\n\t\t\t
Defective protease inhibition \n\t\t\t
\n\t\t\t
Lung (case reports in compound heterozygotes e.g. FZ)
\n\t\t
\n\t\t
\n\t\t\t
Null (Q0)
\n\t\t\t
Mutations causing gene deletion, premature stop codon or mRNA degradation
\n\t\t\t
No AAT produced
\n\t\t\t
Lung
\n\t\t
\n\t\t
\n\t\t\t
Mmalton\n\t\t\t
\n\t\t\t
ΔTTC, ΔPhe52
\n\t\t\t
Polymerisation, impaired secretion and severe deficiency
Common and rare pathological AATD variants detected in Ireland.
4. Why should we test?
There are clear benefits to a diagnosis of AATD for the clinician and the individual. Unfortunately, these benefits are often ignored to the detriment of the affected individual and the extended family.
4.1. Smoking cessation and occupational exposure considerations
The deleterious consequences of smoking on lung health in general and on the lungs of individuals with AATD in particular are well known and the origins of this can be traced back to the late 1960s. The twin discoveries of AATD and its association with COPD [16], and the induction of emphysema by the protease neutrophil elastase (NE) [96] led to an explosion in research surrounding proteolysis and lung disease. Importantly, NE was found to be exquisitely sensitive to inhibition by AAT by Aaron Janoff in 1968 [97]. The pathological effects of smoking were further elucidated when it was found products of cigarette smoke were able to destroy the anti-NE activity of AAT [98]. Despite being an excellent inhibitor of NE, the active site methionine residue at position 358 of the AAT molecule is easily oxidised by cigarette smoke and oxidants released by immune cells [99-101]. These studies provided the clear and irrefutable evidence that smoking causes a functional deficiency in the antiprotease screen. Therefore, in those individuals who develop COPD solely due to smoking, this functional deficiency contributes to the pathogenesis of disease. In individuals with AATD who develop COPD, the deficiency which contributes to the pathogenesis of disease is genetic.
So, we know that the small and precious quantity of AAT that does eventually reach the lung in ZZ individuals is knocked out by cigarette smoke. This is the reason why AAT deficient individuals who smoke develop early onset lung disease [102]. Cigarette smoke is by far the single most important risk factor for the development of COPD in AATD individuals [103-105]. In fact, smoking can reduce the life expectancy of a ZZ patient by up to 25 years [102]. Carpenter et al in a 2007 study revealed higher smoking cessation rates in individuals with a diagnosis of AATD compared to COPD individuals [64]. In this study severely deficient individuals (ZZ and SZ) had a 59% quit attempt rate, compared to a 26% quit attempt rate in unaffected MM individuals. This information is vital in the clinic as it shows that knowledge of AATD motivates the affected individual toward smoking cessation. Every ZZ, SZ, and MZ AATD individual should be educated about the incredibly harmful effects of cigarette smoke in AATD. Smoking cessation and the avoidance of occupational and environmental exposures (for example particulate matter, chemical vapours, and agricultural dusts) is paramount. AATD individuals without apparent lung disease should also be encouraged to quit smoking as this cohort offers the most realistic chance of delaying or possibly preventing the development of COPD. A decision to quit smoking is the most important decision a person with AATD can make. The decision to modify this behaviour is strongly influenced by the quality of the information provided and how this is communicated to at risk individuals.
Ireland is a leader in Europe in terms of anti-smoking measures with the introduction of the first ban on smoking in the workplace [106]. However, a 2007 Irish Government study (Slán 2007 Survey of Lifestyle, Attitudes and Nutrition in Ireland) found that 34% of Irish 30 – 44 year olds currently smoke and this is the age bracket that AATD individuals first begin to report deterioration in lung health. To assess the effect of smoking on lung health in AATD we analysed lung function data from 120 ZZ individuals enrolled in the Irish National AATD Registry and correlated this to smoking history. While the relative contribution of occupational exposures was not taken into account, the mean FEV1 (% predicted) and diffusion capacity of carbon monoxide (DLCO, % predicted) was significantly higher in ZZ subjects who never smoked compared to ZZ subjects who were past or active smokers (Figure 6). This clearly demonstrates the destructive consequences of smoking for ZZ individuals.
Figure 6.
FEV1 (% predicted) stratified by smoking in ZZ individuals enrolled in Irish National AATD Registry (***p < 0.0001, **p < 0.001, t-test).
Figure 7.
DLCO (% predicted) stratified by smoking in ZZ individuals enrolled in Irish National AATD Registry (***p < 0.0001, *p < 0.05, t-test).
Interestingly, smoking cessation rates were also analysed as part of this study. In the past smokers cohort 36% stopped smoking within the first 12 months after AATD diagnosis; 24% stopped smoking after the first 12 months post-AATD diagnosis and 40% had already stopped smoking prior to AATD diagnosis. This supports the findings of the earlier Carpenter study and demonstrates the positive effect of AATD diagnosis on smoking cessation rates.
4.2. Family screening
The area of family screening offers the greatest possibility for the prevention or at least postponement of COPD [107]. An early diagnosis of AATD provides tantalising opportunities for behaviour modification and lifestyle changes, the single most important of which is smoking cessation. Interim data from the Irish National AATD Registry demonstrates that ZZ individuals detected by family screening tend to have preserved lung function compared to those identified by symptomatic screening (Figure 8).
Figure 8.
FEV1 (% predicted) in ZZ individuals diagnosed by symptomatic screening versus those diagnosed by family screening enrolled in Irish National AATD Registry (**p < 0.001, t-test).
An excellent example of the family screening possibilities opened up by a diagnosis of AATD is presented in a large family study from the Irish AATD Registry (Figure 9). In this example, the index case was diagnosed with AATD because of lung disease. Six of the nine siblings were subsequently tested revealing 3 ZZ individuals, 2 MZ individuals, and 1 MM individual.
Figure 9.
Identification of ZZ proband (red arrow) and subsequent identification of at risk relatives by family screening.
4.3. Liver assessment
A baseline liver assessment should be performed in a newly-diagnosed AATD individual to investigate the presence of liver abnormalities. The primary tools for assessment are liver function tests and abdominal ultrasound. This is a practise not routine in the specialist respiratory clinic and ignorance of AATD and the potential for liver disease can be fatal. Early recognition is important for two reasons. The first reason is to prevent, recognize, and treat early the complications of AATD-related liver disease, which can include portal hypertension, encephalopathy, and tumours [108]. The second reason is to advise the patient to avoid injurious habits, such as alcohol consumption, which can accelerate disease. Interestingly, patients who undergo liver transplantation for other causes have a higher incidence of being heterozygous for AATD than the general population [40].
4.4. Vaccination
Influenza and pneumococcal vaccinations are recommended for all individuals with AATD [4]. A 2007 study investigated the practice of vaccinations and respiratory outcomes in AATD individuals in the USA and found over 80% of AATD individuals had received adequate influenza and pneumococcal vaccinations during the influenza season [109]. However, there was no significant difference in severity or rate of exacerbations between vaccinated and unvaccinated individuals but the authors concluded that the vaccinated group may represent ‘sicker’ AATD individuals. Influenza and pneumococcal vaccinations in COPD patients are recommended in several guidelines for COPD [110, 111] and the unique susceptibility of AATD individuals provides additional motivation for vaccination, especially during influenza season.
4.5. Exacerbation management
Exposure to bacterial and viral infections can result in a respiratory exacerbation. Symptoms include increased dyspnoea, cough, and production of sputum [112]. The aggressive treatment of infections is recommended in AATD individuals as per ATS/ERS guidelines [4]. This is particularly important as frequent exacerbations have been shown to be related to worsening health-related quality of life (HRQoL). An English study investigated health status in AATD individuals over 12 months and recorded exacerbations, lung function and HRQoL. The authors concluded exacerbations occur commonly in AATD individuals and correlate to worse health status. Exacerbations were associated with a decline in the gas transfer of the lung for carbon monoxide over time (DLCO), but not FEV1 [113]. Interestingly, a study investigated exacerbation frequency in AATD individuals with COPD who were receiving augmentation therapy and found subjects with frequent exacerbations had the worst baseline HRQoL scores, as well as more physician visits and hospitalizations. Unfortunately, AATD individuals not receiving augmentation therapy were not included for comparison [114]. A recent longitudinal study undertaken in the USA, evaluated the effectiveness of a disease management and prevention programme for AATD individuals and involved 905 individuals over a 2 year period. The programme included written educational material for self-study and individualised treatment plans for exacerbations. Improved compliance was observed in the use of bronchodilators, oxygen therapy, and steroids during exacerbations. The management programme significantly reduced medical visits and showed a slower deterioration of HRQoL during exacerbations [115]. A follow-up study providing additional evidence to evaluate the long-term benefits of an AATD disease management programme would be beneficial.
4.6. Augmentation therapy
Augmentation therapy is the only specific therapy available for severe AATD, and comprises of intravenous administration of AAT derived from human plasma [116]. This treatment is available in several European countries and the USA [117]. The therapy comprises of weekly or fortnightly intravenous infusions of AAT preparations that augment the low levels of circulating AAT in severe AATD. However, its efficacy remains to be definitively proven and uncertainty persists concerning the therapy’s cost effectiveness [118]. Ongoing randomised clinical trials are being performed to definitively assess the efficacy of the treatment. Previous trials have been under-powered and have mostly demonstrated only biochemical efficacy with AAT levels restored to above the putative threshold in the blood and lung, with a failure to show clear clinical efficacy in randomised controlled trials [71, 119]. Nevertheless, there is evidence that augmentation therapy can slow lung function decline in AATD individuals, and moderately obstructed cohorts are most likely to benefit [120].
4.7. Pulmonary rehabilitation
Pulmonary rehabilitation is a tailored exercise programme aimed at restoring the best possible quality of life in patients with lung disease, particularly focused on reducing breathlessness, as well as improving independence and the physical ability to tolerate stress [121]. It is defined as a complex, multimodal treatment regimen for patients with pulmonary diseases [122]. The goal is to help patients become more physically active, to learn more about their disease, treatment options, and how to cope. Patients are encouraged to become actively involved in providing their own health care, more independent in daily activities, and less dependent on health professionals and expensive medical resources. Rather than focusing solely on reversing the disease process, rehabilitation attempts to reduce symptoms and reduce disability from the disease. In general, patients with COPD secondary to AATD tend to be younger compared to patients with usual COPD, and less comorbidity is observed. This suggests the potential for greater improvement in AATD individuals participating in rehabilitation programmes.
5. Why is testing not taking place?
The reasons for the continuing under-diagnosis of AATD are diverse and can include low medical and public awareness, the misconception that it is a rare disease, the belief that testing is complicated and expensive, and testing fatigue [123]. Current data suggests that less than 10% of individuals with severe AATD have been recognised globally [124], and increasing detection rates is the most pressing, and vexing issue for leaders in the AATD community. Unfortunately, some clinicians adopt the attitude of “what difference does a diagnosis of AATD actually make”. This is a challenge for all stakeholders and the benefits of AATD testing must be clearly stated in a simple powerful message to lung health professionals and policymakers. In particular, the potential economic benefits are not being stressed enough [125]. Early diagnosis of AATD is an example of preventative medicine. The newly-diagnosed individual and healthcare provider have the power to arrest or prevent the development of COPD through lifestyle choices, close medical observation, and focused treatment. This in turn means that the long term financial burden on the health system is reduced and by remaining healthy the individual continues to contribute to society and the exchequer. There is also the consideration of the large direct medical cost to the symptomatic AATD individual [125]. So why does testing in COPD cohorts not occur if the ATS/ERS and WHO guidelines are so clear and the benefits so convincing?
\n\t\t
\n\t\t
\n\t\t\t
Belief that AATD is a rare disorder
\n\t\t
\n\t\t
\n\t\t\t
Perception that only early-onset non-smokers are affected
\n\t\t
\n\t\t
\n\t\t\t
Therapeutic nihilism due to lack of specific treatments
\n\t\t
\n\t\t
\n\t\t\t
Fear of genetic discrimination
\n\t\t
\n\t\t
\n\t\t\t
Lack of education and awareness (in healthcare professionals & public)
\n\t\t
\n\t\t
\n\t\t\t
Testing fatigue
\n\t\t
\n\t\t
\n\t\t\t
Failure to admit lack of knowledge
\n\t\t
\n\t\t
\n\t\t\t
Reluctance to lose patients to specialist centres
\n\t\t
\n\t\t
\n\t\t\t
Lack of communication between clinicians and laboratory scientists
\n\t\t
\n\t\t
\n\t\t\t
Absence of effective national guidelines
\n\t\t
\n\t\t
\n\t\t\t
No access to testing methods
\n\t\t
\n\t\t
\n\t\t\t
Privacy concerns
\n\t\t
\n\t\t
\n\t\t\t
Perceived stigma
\n\t\t
\n\t
Table 6.
Reasons why testing for AATD is not taking place.
Many early guidelines for AATD advocated testing early-onset COPD patients and this fallacy was to the detriment of screening efforts. The age at which manifestations of airway obstruction, pulmonary emphysema, or chronic bronchitis appear in ZZ individuals is highly variable [102]. While a common feature of AATD is indeed early-onset COPD, a significant AATD cohort do not develop symptoms until much later in life, particularly if non-smokers [126, 127]. In fact, among never-smokers the risk of liver disease increases with age in ZZ individuals [127, 128]. Numerous case reports have described AATD in elderly individuals with COPD who were lifelong never smokers [129]. Taken together, it is clear that screening for AATD should be automatically performed in all COPD regardless of age or smoking history, especially as failure to do so has serious clinical repercussions for undiagnosed family members.
The fear of genetic discrimination, financial concerns, and privacy concerns are real barriers to testing for AATD in the COPD population [130]. Fears of genetic discrimination have been allayed in recent years with preventative legislation enacted in several countries, including Ireland and the US. Genetic discrimination was made illegal in Ireland from December 31st 2005 when the Irish government enacted new legislation. It became illegal to use or process the results of genetic testing for insurance, life assurance or mortgage purposes. This also applies in the case of employment, health insurance and occupational pension. What is assessed when a person is being considered for a financial product or insurance policy are the usual criteria including health history (symptom-related questions), lifestyle choices (smoking, alcohol, etc.), and the regular questions surrounding family history of particular illnesses. There are still reasons to be wary in this area. Following the advent of the Genetic Information Non-Discrimination Act (GINA) in the US in 2008, discrimination can be implicit, indirect and subtle, rather than explicit, direct and overt; and as a result can be harder to prove [131].
6. How can we increase detection of AATD?
Initiatives to increase detection rates might include automatic physician alerts suggesting AATD testing on pulmonary function test reports of patients with fixed airflow obstruction [132], better medical and patient education in the area of AATD [133], changes to national COPD guidelines, and a red flag to recommend testing for AATD on laboratory reports of patient with low AAT levels. The advent of finger-prick tests using dried blood spots (DBS) as a source of DNA has allowed home testing for AATD, with easier transportation of samples to the laboratory [94]. This method of testing eliminates the fear of needles for the individual, and is also cheaper as the test does not require a visit to a general practitioner.
\n\t\t
\n\t\t
\n\t\t\t
Improve education in undergraduate and postgraduate medical and scientific training
\n\t\t
\n\t\t
\n\t\t\t
Include primary care physicians and hepatologists in awareness efforts
\n\t\t
\n\t\t
\n\t\t\t
Educate and empower respiratory nurse specialists
\n\t\t
\n\t\t
\n\t\t\t
Public awareness campaigns
\n\t\t
\n\t\t
\n\t\t\t
Patient empowerment
\n\t\t
\n\t\t
\n\t\t\t
Update WHO and ATS/ERS guidelines for AATD
\n\t\t
\n\t\t
\n\t\t\t
Refine COPD guidelines to include automatic testing for AATD
\n\t\t
\n\t\t
\n\t\t\t
Laboratory red-flags
\n\t\t
\n\t\t
\n\t\t\t
Pulmonary function test red-flags
\n\t\t
\n\t\t
\n\t\t\t
Electronic health record prompts
\n\t\t
\n\t\t
\n\t\t\t
Embed as routine test by creating COPD care templates and physician order reminders
\n\t\t
\n\t\t
\n\t\t\t
Joint seminars between pulmonologist and laboratory scientists
\n\t\t
\n\t\t
\n\t\t\t
Presentations at national conferences
\n\t\t
\n\t\t
\n\t\t\t
Provision of free testing kits
\n\t\t
\n\t
Table 7.
Strategies to improve the detection of AATD.
An attractive strategy is the use of electronic red-flags on low AAT laboratory reports. This prompts the clinician to investigate low AAT results and reflex to phenotyping and/or genotyping. During our efforts to increase awareness at a national level in Ireland, we have advocated that hospital laboratories should include the following recommendation on AAT reports; “Serum AAT < 1.0 g/L may indicate alpha-1 antitrypsin deficiency and further investigation is recommended. Information is available from the Alpha One Foundation on www.alpha1.ie. AAT is an acute phase reactant and serum concentrations can increase significantly during trauma, acute infection or surgery.” This cost-neutral approach has been successfully implemented at 9 large hospitals in Ireland and has directly led to increased diagnosis of AATD in these centres and surrounding hinterlands. Implementation was achieved by presenting to lung specialists and laboratory scientists on site, and in the same room. This twin track approach is most effective and it is often the first time for each party to meet – those requesting the test and those performing the quantitative AAT assay. The aim is to eliminate missed diagnosis of AATD when a low AAT is reported but not acted upon. A particularly striking aspect of this strategy is that incidental findings of AATD are common, and hitherto asymptomatic cases can be detected. As AAT is an acute phase protein and a robust marker of inflammation, the test can be requested during routine blood work with the expectation that it will be dramatically increased. However, the opposite is sometimes the case. The inadvertent low finding is highlighted by the electronic red-flag and the ensuing diagnosis of AATD is the positive outcome. We are hopeful that this system will eventually be adopted on a nationwide basis and are in consultation with the government and various stakeholders to effect this change.
Figure 10.
Example of a laboratory red-flag on low AAT results from a biochemistry laboratory at a large Irish hospital.
In the era of the electronic medical record, technology can help deliver or enhance specific clinical practices, such as testing for AATD. For example, if physicians were prompted to consider this condition when they received the results of pulmonary function tests (PFT) showing fixed airflow obstruction, testing for AATD should increase. Also, if eliciting a family history of COPD or chronic liver disease prompted a physician alert on the electronic medical record to test the serum AAT level, testing could increase. For example, a small pilot study found that the frequency of AATD testing increased when a prompt to test for AATD was included on the PFT reports of patients with airflow obstruction [132]. Another similar study looked at the impact of a clinical decision support system within an electronic health record which facilitated testing for AATD [134]. The alert within the electronic health record resulted in a four-fold increase in testing for AATD.
7. Other strategies
There are a host of other strategies which could lead to increased detection of AATD. These include continuing medical education lectures, AATD teaching in medical school and clinical chemistry curricula, public awareness campaigns, lobbying of public health officials, and making available free testing kits. Moreover, the WHO and ATS/ERS guidelines need urgent updating. AATD is often relegated to a footnote in many clinical guidelines for COPD. A summary of the ATS and ERS document outlining standards for the diagnosis and treatment of patients with COPD published in 2004 mentions AATD once, stating that “patients presenting with airflow limitation at a relatively early age (4th or 5th decade) and particularly those with a family history of COPD should be tested for alpha-1 antitrypsin deficiency” [135]. Narrow definitions such as these are damaging to efforts to increase AATD detection. Another strategy to promote testing is to empower patients by providing free, high-quality, easy to understand information available, such as the information material prepared by the Alpha-1 Foundation (www.alpha-1foundation.org).
8. Conclusion
The fact that cigarette smoking is often a coincident historical finding in the assessment of COPD has probably contributed to the remarkable global under-diagnosis of AATD. For example, of the estimated 3,000 ZZ individuals on the island of Ireland, less than 10% have been diagnosed. Unfortunately for the clinician and the patient, testing for AATD is not routinely considered in the assessment of COPD. Any model for COPD diagnosis, assessment and management must include automatic testing for AATD as one of the first steps. Large variability exists in the clinical course of lung disease in AATD and therefore all COPD patients should be tested for AATD, regardless of age or smoking history. The under-diagnosis of AATD in COPD is a situation that must not be allowed to continue.
Acknowledgments
We thank all the AATD individuals attending our centre for their continued collaboration in research, awareness and detection efforts. The Irish National AATD Targeted Detection Programme is supported by funding from the Irish Government. We thank Dr. Ilaria Ferrarotti, Dr. Stefania Ottaviani, and Prof. Maurizio Luisetti from the University of Pavia for their continued assistance with rare and novel variant identification. We would like to thank John Walsh and Angela McBride of the Alpha-1 Foundation (USA) for their continued support and encouragement. Finally, we wish to thank Pat O’Brien and Emma Pentony in the Department of Chemical Pathology in Beaumont Hospital for help with sampling and turbidimetry.
\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/46784.pdf",chapterXML:"https://mts.intechopen.com/source/xml/46784.xml",downloadPdfUrl:"/chapter/pdf-download/46784",previewPdfUrl:"/chapter/pdf-preview/46784",totalDownloads:2735,totalViews:599,totalCrossrefCites:4,totalDimensionsCites:4,totalAltmetricsMentions:3,impactScore:2,impactScorePercentile:81,impactScoreQuartile:4,hasAltmetrics:1,dateSubmitted:"September 18th 2013",dateReviewed:"April 18th 2014",datePrePublished:null,datePublished:"July 16th 2014",dateFinished:"May 23rd 2014",readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/46784",risUrl:"/chapter/ris/46784",book:{id:"3833",slug:"copd-clinical-perspectives"},signatures:"Tomás P. Carroll, M. Emmet O’Brien, Laura T. Fee, Kevin Molloy, Blair\nMurray, Seshma Ramsawak, Oisín McElvaney, Catherine O’Connor\nand Noel G. McElvaney",authors:[{id:"42784",title:"Prof.",name:"Noel G.",middleName:null,surname:"McElvaney",fullName:"Noel G. McElvaney",slug:"noel-g.-mcelvaney",email:"gmcelvaney@rcsi.ie",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Royal College of Surgeons in Ireland",institutionURL:null,country:{name:"Ireland"}}},{id:"83948",title:"Dr.",name:"Tomas",middleName:"Patrick",surname:"Carroll",fullName:"Tomas Carroll",slug:"tomas-carroll",email:"tcarroll@rcsi.ie",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Royal College of Surgeons in Ireland",institutionURL:null,country:{name:"Ireland"}}},{id:"169420",title:"Dr.",name:"Emmet",middleName:null,surname:"O'Brien",fullName:"Emmet O'Brien",slug:"emmet-o'brien",email:"emmetobrien@rcsi.ie",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. What is alpha-1 antitrypsin?",level:"1"},{id:"sec_2_2",title:"2.1. Clinical manifestations & presentation of AATD",level:"2"},{id:"sec_3_2",title:"2.2. Pulmonary manifestations",level:"2"},{id:"sec_4_2",title:"2.3. Liver manifestations",level:"2"},{id:"sec_5_2",title:"2.4. Extra-pulmonary manifestations",level:"2"},{id:"sec_6_2",title:"2.5. AATD heterozygosity: A risk factor for COPD?",level:"2"},{id:"sec_7_2",title:"2.6. AATD heterozygosity: A biological perspective",level:"2"},{id:"sec_8_2",title:"2.7. When does AATD present – An Irish perspective",level:"2"},{id:"sec_9_2",title:"2.8. Who should be tested?",level:"2"},{id:"sec_11",title:"3. How do we test for AATD?",level:"1"},{id:"sec_11_2",title:"3.1. AAT quantification",level:"2"},{id:"sec_12_2",title:"3.2. AAT phenotyping",level:"2"},{id:"sec_13_2",title:"3.3. AAT genotyping and sequencing",level:"2"},{id:"sec_15",title:"4. Why should we test?",level:"1"},{id:"sec_15_2",title:"4.1. Smoking cessation and occupational exposure considerations",level:"2"},{id:"sec_16_2",title:"4.2. Family screening",level:"2"},{id:"sec_17_2",title:"4.3. Liver assessment",level:"2"},{id:"sec_18_2",title:"4.4. Vaccination",level:"2"},{id:"sec_19_2",title:"4.5. Exacerbation management",level:"2"},{id:"sec_20_2",title:"4.6. Augmentation therapy",level:"2"},{id:"sec_21_2",title:"4.7. Pulmonary rehabilitation",level:"2"},{id:"sec_23",title:"5. Why is testing not taking place?",level:"1"},{id:"sec_24",title:"6. How can we increase detection of AATD?",level:"1"},{id:"sec_25",title:"7. Other strategies",level:"1"},{id:"sec_26",title:"8. Conclusion",level:"1"},{id:"sec_27",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:"Greene CM, Miller SD, Carroll T, McLean C, O'Mahony M, Lawless MW, O'Neill SJ, Taggart CC, McElvaney NG: Alpha-1 antitrypsin deficiency: a conformational disease associated with lung and liver manifestations. J Inherit Metab Dis 2008, 31:21-34."},{id:"B2",body:'Lieberman J, Winter B, Sastre A: Alpha 1-antitrypsin Pi-types in 965 COPD patients. 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Respir Med 2009, 103:335-341.'},{id:"B125",body:'Mullins CD, Huang X, Merchant S, Stoller JK, Alpha One Foundation Research Network Registry I: The direct medical costs of alpha(1)-antitrypsin deficiency. Chest 2001, 119:745-752.'},{id:"B126",body:'Campos MA, Alazemi S, Zhang G, Salathe M, Wanner A, Sandhaus RA, Baier H: Clinical characteristics of subjects with symptoms of alpha1-antitrypsin deficiency older than 60 years. Chest 2009, 135:600-608.'},{id:"B127",body:'Tanash HA, Nilsson PM, Nilsson JA, Piitulainen E: Clinical course and prognosis of never-smokers with severe alpha-1-antitrypsin deficiency (PiZZ). Thorax 2008, 63:1091-1095.'},{id:"B128",body:'Willson AB, Seow C, Zimmerman M: Severe alpha-1 antitrypsin deficiency diagnosed in an 86-year-old man. Intern Med J 2004, 34:653-654.'},{id:"B129",body:'Jack CI, Evans CC: Three cases of alpha-1-antitrypsin deficiency in the elderly. Postgrad Med J 1991, 67:840-842.'},{id:"B130",body:'Fanos JH, Strange C: "The lion, the witch and the wardrobe": impact on sibs of individuals with AAT deficiency. Am J Med Genet A 2004, 130A:251-257.'},{id:"B131",body:'Klitzman R: Views of discrimination among individuals confronting genetic disease. J Genet Couns 2010, 19:68-83.'},{id:"B132",body:'Rahaghi F, Ortega I, Rahaghi N, Oliveira E, Ramirez J, Smolley L, Stoller JK: Physician alert suggesting alpha-1 antitrypsin deficiency testing in pulmonary function test (PFT) results. COPD 2009, 6:26-30.'},{id:"B133",body:'Fromer L: Improving diagnosis and management of alpha-1 antitrypsin deficiency in primary care: translating knowledge into action. COPD 2010, 7:192-198.'},{id:"B134",body:'Jain A, McCarthy K, Xu M, Stoller JK: Impact of a clinical decision support system in an electronic health record to enhance detection of alpha(1)-antitrypsin deficiency. 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1. Introduction
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An aortic aneurysm is defined as a permanent localized dilation of the aorta with at least a 50% increase in diameter compared with a normal aortic diameter [1]. Aortic aneurysms can be classified according to location as thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA). TAA occurs in all-age people without sexual dimorphism and is highly associated with hereditary conditions [2]. By contrast, AAA is typically associated with aging, male sex, smoking, atherosclerosis, and hypertension [3, 4, 5]. AAA is the most common form of aortic aneurysm [6], affecting 4–8% of men and 0.5–1.5% of women over the age of 60 and currently accounting for nearly 2% of all deaths in Western countries [2, 3, 7]. Aortic aneurysm is an asymptomatic condition that tends to progress over time with a high mortality rate (65–85%) if rupture occurs [8]. Unfortunately, repair through open or endovascular surgery is currently the only therapeutic option for aortic aneurysm; no drug has been approved for treatment of this devastating disease [3, 5]. One of the major barriers in the field is a lack of an animal model that fully resembles human aortic aneurysm.
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Over the last few decades, a number of rodent models of AAA and TAA have been developed and have been increasingly utilized to be used in understanding the etiology of human AAA and TAA [2, 9, 10, 11]. Aortic aneurysm animal models can be classified into three groups [2, 9, 10, 11]: (1) genetically predisposed animal models (i.e., fibrillin-1 (FBN1) mutation (Marfan syndrome) mouse model [2, 12]), (2) chemical-induced animal models (i.e., Ang II infusion hyperlipidemia mouse model [9, 13]), and (3) physical or surgical animal models (i.e., decellularized aortic xenograft rat model [10, 14]). Among them, calcium chloride adventitial application model [15, 16], porcine pancreatic elastase (PPE) model [17, 18], and Ang II infusion hyperlipidemia mouse model [13, 19, 20, 21, 22, 23] are the commonest animal models currently studied in the world.
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One of the fundamental pathological characteristics in human TAA and AAA is thoracic aortic dissection (TAD) and abdominal aortic dissection (AAD), both of which can lead to aneurysmal rupture with high mortality [1, 2, 3, 4, 5, 6, 7]. Many genetically predisposed animal models have TAD and AAD (i.e., fibrillin-1 mutation mouse model [2, 12]). Some of the chemical-induced animal models also have TAD and AAD (i.e., fibrillin-1 mutation and Ang II infusion hyperlipidemia mouse models [13, 19, 20, 21, 22, 23]). Recently, a new chemical-induced mouse model for more potently induction of TAD and AAD was developed by administration of β-aminopropionitrile monofumarate (BAPN) to mice to inhibit lysyl oxidase (LOX) and/or Ang II infusion [24, 25]. Kurihara et al. demonstrated that BAPN/Ang II induced TAD in 100% of FVB mice [24]. Ren et al. confirmed this finding and further demonstrated that BAPN/Ang II induced TAD and AAD in 75% of C57BL/6J mice, whereas BAPN alone induced TAD in 87% of C57BL/6J [25].
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Although no single animal model fully reproduces the histological characteristics and natural history of the human aortic aneurysm, each of these animal models more or less recapitulate human aortic aneurysm and have significantly contributed to the current understanding of clinical management and treatment of patients with AAA and TAA [2, 9, 10, 11]. Several clinical trials have begun enrollment to examine whether angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) are effective in the treatment of human aortic aneurysm. However, the results from these clinical trials are inconsistent and disappointing: either effective [26], no effect [27], or, even worse [28], indicating that the current understanding about the etiologies of aortic aneurysm is limited and additional unknown signaling and mechanism may underlie aortic aneurysm and account for the failure of these clinical trials.
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In sharp contrast to the well-established role of Ang II in aortic aneurysm [13, 19, 20, 21, 22, 23], little is known about the role of aldosterone (Aldo) in aortic aneurysm. Aldo is a steroid hormone primarily synthesized and released by the adrenal glands. Aldo is a downstream effect of Ang II and is well recognized for its critical role in renal sodium reabsorption and water retention and consequently extracellular volume and blood pressure [29, 30]. Accumulated data over the last decade, however, demonstrate that Aldo not only acts on the kidney but also targets many other organelles, including those in the cardiovascular system, where it is critically involved in diverse pathophysiological processes [31, 32, 33].
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Several lines of clinical study implicate Aldo signaling in aortic aneurysm. First, individual case reports demonstrated that primary hyperaldosteronism is associated with aortic dissection [34, 35, 36]. Second, a retrospective study demonstrated that aldosteronism is associated with high morbidity and mortality from the early onset of hemorrhagic stroke and ruptured intracranial aneurysms [37]. Third, a few small studies have shown an association between obesity and increased levels of Aldo [38] and increased AAA [39]. Finally, perhaps also the most compellingly, an analysis of drug modulation of AAA development through 25 years of surveillance in 1269 patients demonstrated a strong association between mineralocorticoid receptor (MR; also known as Aldo receptor) blockers and slowed AAA progression [40]. However, whether Aldo causes aortic aneurysm is unknown.
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By incidence, we discovered that administration of deoxycorticosterone acetate (DOCA) to 10-month-old C57BL/6 male mice caused substantial animal death in the presence of high salt due to aortic aneurysmal rupture. A subsequent serial of substantial studies demonstrated that activation of MR by either implantation of DOCA pellet or infusion of Aldo in 10-month-old C57BL/6 male mice was sufficient to induce AAA and TAA formation and aneurysmal rupture in the presence of high salt [41, 42, 43]. Recently, we published the detailed methodology on how to implant DOCA pellet or Aldo pumps to induce aortic aneurysm [44]. Here, we will focus on the significant novel finding of this new AAA mouse model, highlight its unique features that mimic human aortic aneurysm, and discuss its significance and potential impact on the current understanding, diagnosis, and treatment of human aortic aneurysm.
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2. Development of a new mouse model of aortic aneurysm induced by DOCA- or Aldo-salt
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2.1 Discovery of DOCA-salt mouse model of aortic aneurysm by accidence
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In an independent pilot study using 10- to 12-month-old C57BL/6 male mice to investigate DOCA-salt-induced hypertension, we unexpectedly observed that many mice died from AAA rupture. We were intrigued by this observation since it raised the possibility that activation of the MR by DOCA can cause AAA in the presence of high salt. Given that administration of DOCA and salt to mice or rats have been used extensively as an experimental model of low-renin hypertension [45], it was surprising that DOCA-salt-induced AAA has not been reported in previous studies. While the exact reasons for this discrepancy are unclear, our results suggest that the age of mice (i.e., 10-month old vs. 10-week old) may be critical for DOCA and salt to induce AAA (see below).
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2.2 Both DOCA and high salt are required to induce aortic aneurysm
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To verify our pilot studies and define whether DOCA, salt, or both is critical for DOCA-salt-induced aortic aneurysm, 10-month-old C57BL/6 male mice received DOCA alone (subcutaneous implantation of DOCA pellets; 50 mg, 21-day release; Innovative Research of America, USA), salt alone (drinking water containing 0.9% NaCl plus 0.2% KCl), DOCA and salt, or no treatment (controls). We used C57BL/6 mice because C57BL/6 mice are more susceptible to chemical (i.e., BAPN/Ang II)-induced TAD, AAD, and aneurysmal rupture than other strains of mice (i.e., FVB mice) [24, 25]. We used 10-month-old rather than 10-week-old mice because we found that DOCA- or Aldo-salt-induced aortic aneurysm were aging dependent [41, 43]. We used male mice rather than female mice because DOCA- or Aldo-salt-induced aortic aneurysm has sex difference (unpublished data). All mice were euthanized 3 weeks after treatment.
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We used three different approaches to quantify DOCA-salt-induced aortic aneurysm. First, the maximal intraluminal diameters of abdominal aortas were quantified in vivo by a high-resolution ultrasound imaging system (Vevo 2100, Visualsonics, Toronto, Canada). The results showed that both DOCA and salt but not DOCA or salt alone could potently induce abdominal aortic dilation relative to the control [41]. Second, the maximal external diameters of isolated abdominal and thoracic aortas were quantified ex vivo by Nikon SMZ800 Stereo Microscope with a digital camera and NIS-Elements software. Consistently with the ultrasound data, both DOCA and salt but not DOCA or salt alone significantly increased external diameters of abdominal and thoracic aortas relative to the control [41].
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Third, we calculated the incidence of DOCA-sat-induced AAA, TAA, and aneurysmal rupture based on the definition that AAA or TAA has at least a 50% increase in diameter compared with the normal diameter of the aorta [1]. Of the 45 mice treated with DOCA-salt, 28 mice developed AAA (62%), 22 mice developed TAA (42%), and 8 mice died of aortic aneurysmal rupture (18%). In contrast, no AAA, TAA, or aortic aneurysmal rupture was observed in control, DOCA, or salt alone. Interestingly, AAA was only found in the suprarenal abdominal aorta, which is similar to that in the Ang II AAA mouse model [13], whereas TAA was mostly associated with AAA and was mostly observed in the descending thoracic aorta, indicating that TAA is likely derived from AAA.
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2.3 Infusion of mice with Aldo can also induce aortic aneurysm in the presence of high salt
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Since DOCA is a synthetic MR agonist, we wondered whether Aldo, a physiologic ligand of MR in our body, could induce aortic aneurysm in the presence of high salt. To define the concentration of Aldo that is sufficient to induce aortic aneurysm in the presence of high salt, 10-month-old C57BL/6 male mice were infused with three different doses of Aldo (200, 500, and 700 μg/kg/day) for 4 weeks. Aldo was delivered to mice via subcutaneous implantation of osmotic minipump (Alzet model 2004; DURECT, USA) containing Aldo solubilized in 50% DMSO. All groups of mice were treated for 4 weeks.
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Infusion of mice with all three doses of Aldo was very similar to implantation of mice with DOCA pellets and markedly increased maximal intraluminal and external diameters of suprarenal abdominal aortas compared to the control mice (without treatment). Similarly, infusion of mice with all three doses of Aldo is also similar to implantation of mice with DOCA pellets and potently induced AAA (over 58%), TAA (over 42%), and aneurysmal rupture (over 25%) compared to the control mice. These data demonstrated that the infusion of mice with 200 μg/kg/day Aldo is sufficient to induce AAA in the presence of high salt.
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We measured the plasma Aldo concentrations by a commercial EIA kit (Enzo Life Science, USA) 4 weeks after Aldo and salt administration. We found that plasma Aldo concentrations were elevated in a dose-dependent manner. Of note, infusions of mice with 200 μg/kg/day Aldo resulted in plasma Aldo concentrations to ~10 nM, which could be seen in some human diseases such as congestive heart failure and primary aldosteronism [31, 46, 47]. These results indicate that the Aldo-salt AAA mouse model is a physiopathological model that mimics human diseases rather than a pharmacological model that would cause concerns due to the use of high doses of reagent.
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2.4 DOCA-salt-induced aortic aneurysm is independent of Ang II
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Although systematic plasma renin and Ang II concentrations are suppressed in animals administered with DOCA and salt [45], local aortic Ang II concentration can be increased due to activation of vascular RAAS, which was thought to be of pathophysiological relevance to the development of atherosclerosis [48]. Moreover, there is a synergistic interaction between Ang II and Aldo in VSMCs [49, 50]. Therefore, it is interesting to investigate whether DOCA-salt-induced aortic aneurysm is dependent upon Ang II. To address this important question, 10-month-old C57BL/6 male mice were treated with either an ACE inhibitor (enalapril) or an ARB (losartan) before (1 week) and after (4 weeks) DOCA-salt administration. As expected, enalapril or losartan effectively decreased blood pressure, but enalapril or losartan had little effect on the DOCA-salt-induced aortic dilation, aortic aneurysm formation, and aneurysmal rupture [41]. These results demonstrate that the DOCA-salt-induced aortic aneurysm is independent of Ang II thus provide an alternative mouse model of aortic aneurysm for investigators in the field who need an Ang II-independent mouse model to verify their key findings.
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2.5 Activation of MR is a prerequisite for DOCA- or Aldo-salt to induce aortic aneurysm
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To define the role of MR in DOCA- or Aldo-salt-induced aortic aneurysm, we treated 10-month-old C57BL/6 male mice with an MR antagonist eplerenone 1 week before and 4 weeks after Aldo-salt administration [41]. Eplerenone (Pfizer, USA) was delivered by feeding mice with custom diets (chow supplemented with eplerenone at 2.5 mg/g, Research Diets, Inc., USA). In contrast to the minimal effect of blocking Ang II with enalapril or losartan, treatment of mice with eplerenone completely abolished Aldo-salt-induced aortic dilation, AAA formation, and aortic aneurysmal rupture [41]. A similar but less potent effect on DOCA-salt-induced AAA was also found in mice treated with spironolactone [41]. These results suggest that activation of MR by DOCA or Aldo is a prerequisite for DOCA- or Aldo-salt to induce aortic aneurysm.
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2.6 DOCA-salt induces aortic aneurysm independent of increased blood pressure
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Administration of DOCA and salt to mice or rats has been used in the field to induce hypertension [45]. Hypertension is recognized as a potential risk factor for aortic aneurysm [3, 4, 5]. Thus, it is important to determine whether hypertension contributes to DOCA-salt-induced aortic aneurysm. Blood pressure was measured using a noninvasive tail-cuff system (Coda 6; Kent Scientific Corp., USA). As expected, administration of DOCA or Aldo plus salt to 10-month-old male mice increased both blood pressure and external diameters of the abdominal aorta [41, 43]. However, there was no correlation between blood pressure increase and external diameters of abdominal aorta after DOCA-salt treatment. Similarly, there was also no difference in blood pressure between the mice with aortic aneurysm and the mice without aortic aneurysm. Moreover, treatment of mice with ACE inhibitor enalapril or ARB losartan effectively decreased blood pressure, but both enalapril and losartan had little effect on DOCA-salt-induced aortic aneurysm. Thus, we concluded that DOCA-salt induces aortic aneurysm independent of increased blood pressure. This conclusion is consistent with that in the Ang II infusion AAA mouse model [19].
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2.7 Vascular pathology of DOCA- or Aldo-salt induced aortic aneurysms
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Human aortic aneurysm is characterized by elastin and collagen degradation, matrix metalloproteinase (MMP), upregulation, inflammatory cell infiltration, vascular smooth muscle cell degeneration, and oxidative stress [51]. To investigate whether DOCA- or Aldo-salt-induced aortic aneurysms have these pathologic features, paraffin-embedded aortic cross-sections were subjected to Elastic-Van Gieson staining of elastin. Interestingly, elastin degradation was only observed in AAA induced by DOCA- or Aldo-salt [41, 43]. Immunocytochemistry studies revealed that MMP2, MMP9, F4/80 (macrophages), Ly6B2 (neutrophils), caldesmon (smooth muscle cells), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL; apoptosis), and dihydroethidium (DHE; oxidative stress) were increased in aortas with AAA compared with that in control aortas [41, 43].
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In agreement with these immunocytochemical studies, we determined mRNA expression of several inflammatory genes, including vascular cell adhesion molecule 1 (Vcam-1), chemokine (C-C motif) ligand 2 (Ccl2, also known as MCP-1), tumor necrosis factor (Tnf), and Ncf1 (also known as p47phox) in both abdominal and thoracic aortas from mice-administrated DOCA-salt or control mice. We found that Vcam-1, Ccl2, Ncf1, and Tnf were all markedly upregulated in thoracic aortas from mice-administrated DOCA-salt compared to control mice. Interestingly, Vcam-1, Ccl2, and Ncf1, but not Tnf, were also significantly upregulated by DOCA-salt in abdominal aorta from mice-administrated DOCA-salt compared to control mice [41, 43].
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2.8 Unique features of the DOCA- or Aldo-salt mouse model of aortic aneurysm
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The DOCA- or Aldo-salt mouse model exhibited several unique features that may be relevant to the human aortic aneurysm. First, DOCA- or Aldo-salt-induced aortic aneurysm required to use 10-month-old mice [41, 43] rather than 10-week-old mice (mostly used by the Ang II AAA mouse model [13, 19, 20, 21, 22, 23] and other chemical-induced mouse modes [17, 18, 24, 25]). Given the fact that human AAA occurs in old peoples [2, 3, 7], the DOCA- or Aldo-salt mouse model of aortic aneurysm may more resemble human AAA than other chemical-induced aortic aneurysms in this regard. Second, DOCA- or Aldo-salt-induced aortic aneurysm used wild-type C57BL/6 mice [41, 43] rather than hyperlipidemia mice (i.e., apolipoprotein E-deficient (ApoE−/−) used by Ang II infusion mouse models [13, 19, 20, 21, 22, 23]), thus avoiding the potential confounding effects of hyperlipidemia on aortic aneurysm. Third, using Aldo, a physiological agonist of MR, rather than chemicals (i.e., calcium chloride or pancreatic elastase) to induce aortic aneurysm, highlights its potential role in the etiology of aortic aneurysm. Moreover, the plasma concentration of Aldo in mice infused with Aldo [41] could be seen in human congestive heart failure and primary aldosteronism [31, 46, 47], suggesting that the Aldo-salt AAA mouse model is a pathological model rather than a pharmacological model that would cause concerns due to the use of high doses of reagent. Finally, high salt intake was required for DOCA to induce aortic aneurysm [41], indicating that high salt intake may be a new risk factor for the development of human AAA.
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2.9 Significance and potential impact of the DOCA- or Aldo-salt mouse model of aortic aneurysm
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We described a new mouse model of aortic aneurysm induced by administration of MR agonist DOCA or Aldo plus high salt to 10-month-old male mice and provided compelling preclinical evidence that reveals a previously unrecognized, but potentially significant, role of Aldo, MR, and high salt in the pathogenesis of AAA. It is worth pointing out that this new mouse model of aortic aneurysm could be used as a platform to study intervention including medication (i.e., we have tested the effect of ACE inhibitor (enalapril), ARB (losartan), and MR antagonist (eplerenone and spironolactone) [41]). It is also worth pointing out at least three significance and potential impact of the DOCA- or Aldo-salt mouse model of aortic aneurysm on the current basic research and clinical practice on the etiology, clinic diagnosis, evaluation, and treatment of AAA.
\n
First, in agreement with the pivotal role of Aldo in cardiovascular diseases (i.e., hypertension and heart failure) [31, 32, 46], our studies highlight a potentially important but previously unrecognized role of Aldo in the etiology of human aortic aneurysm. Our studies suggest that increased plasma concentration of Aldo may be a new risk factor for human aortic aneurysm or may serve as a new plasma biomarker for evaluation of aortic aneurysm progression.
\n
Second, it is well recognized that unfavorably excessive dietary sodium intakes remain prevalent around the world and are associated with an increased risk for cardiovascular diseases including hypertension, stroke, coronary heart disease, heart failure, and renal disease [52, 53, 54]. However, it is unknown that excessive dietary sodium intake may also be detrimental to the aorta with respect to aortic aneurysm. Our finding that excessive dietary sodium intake was essential for MR agonist to induce aortic aneurysm in mice suggests that excessive dietary sodium intakes may also be implicated in the etiology of human aortic aneurysm. In agreement with our findings, it was recently reported that high salt intake was associated with an increased prevalence of AAA in older men [55]. Moreover, our findings indicate that lifestyle change such as reduction of dietary sodium intakes may be effective to prevent old people from the development and progression of aortic aneurysm.
\n
Third, given the fact that currently there is no approved drug for treatment of AAA, our studies suggest that spironolactone and eplerenone, two clinically approved drugs that have been used for the treatment of human heart failure and essential hypertension [56], may also be effective in the treatment of human aortic aneurysm. Recently, a proof-of-concept randomized controlled clinical trial has been initiated based on our findings and is currently going on in Australia, which aims to test the effect of eplerenone on the progression of AAA (https://clinicaltrials.gov/ct2/show/study/NCT02345590).
\n
\n
\n
\n
3. Conclusions
\n
\n
Subcutaneous implantation of MR agonist DOCA pellets to 10-month-old C57BL/6 male mice can potently induce aortic aneurysm formation and rupture in the presence of high salt. Both DOCA and salt, but not DOCA or salt alone, are required to induce aortic aneurysm formation and rupture in mice.
Infusion of 10-month-old C57BL/6 male mice by subcutaneous implantation of osmotic pumps to release Aldo to a pathological level can also induce aortic aneurysm formation and rupture, suggesting that increased plasma concentration of Aldo may be implicated in the etiology of human aortic aneurysm.
DOCA- or Aldo-salt-induced AAA mimics human AAA with respect to elastin degradation, MMP activation, inflammatory cell infiltration, smooth muscle cell degeneration, and oxidative stress.
Treatment of mice with ACE inhibitor enalapril or an ARB losartan has little effect on DOCA-salt-induced aortic aneurysm, suggesting that DOCA-salt-induced aortic aneurysm is independent of Ang II.
Treatment of mice with MR antagonist spironolactone and eplerenone effectively abolishes or diminishes DOCa- or Aldo-salt-induced aortic aneurysm, suggesting that activation of MR is a prerequisite for DOCA- or Aldo-salt to induce aortic aneurysm, and more importantly, spironolactone and eplerenone, two clinically approved drugs, may also be effective for the treatment of some aortic aneurysm.
There is no correlation between blood pressure and aortic dilation or AAA formation in the DOCA- or Aldo-salt mouse model of aortic aneurysm, suggesting that DOCA-salt induces AAA independent of increased blood pressure.
\n\n
\n
Acknowledgments
\n
This work was supported by the US National Institutes of Health (NIH) Grants HL125228 and HL106843 and HL142973 (to M.C.G. and Z.G.), the US Department of Veteran Affairs I01BX002141 (to Z.G.), and the Institutional Development Award (IDeA) from the US National Institute of General Medical Sciences of NIH, under grant number P30 GM127211.
\n
Conflict of interest
The authors have no potential conflicts of interest with respect to the research, authorship, and publication of this article.
\n',keywords:"aortic aneurysm, angiotensin II, aldosterone, DOCA, high salt, animal model",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/67114.pdf",chapterXML:"https://mts.intechopen.com/source/xml/67114.xml",downloadPdfUrl:"/chapter/pdf-download/67114",previewPdfUrl:"/chapter/pdf-preview/67114",totalDownloads:657,totalViews:0,totalCrossrefCites:0,dateSubmitted:"September 20th 2018",dateReviewed:"April 23rd 2019",datePrePublished:"May 17th 2019",datePublished:"September 9th 2020",dateFinished:"May 14th 2019",readingETA:"0",abstract:"The renin-angiotensin-aldosterone system (RAAS) is implicated in the etiologies of many cardiovascular diseases, including abdominal aortic aneurysm (AAA) and thoracic aortic aneurysm (TAA). In particular, the infusion of angiotensin II (Ang II) in hyperlipidemia mice to induce AAA and TAA has been extensively used in the field, suggesting a critical role of Ang II in aortic aneurysm. In contrast, whether aldosterone (Aldo), a downstream effector of Ang II, is involved in aortic aneurysm is unknown. Here, we describe a new mouse model of AAA and TAA induced by subcutaneous implantation of deoxycorticosterone acetate (DOCA) pellets or infusion of Aldo using osmotic pumps to 10-month-old C57BL/6 male mice in the presence of high salt. The DOCA- or Aldo-salt-induced aortic aneurysm is dependent upon mineralocorticoid receptor activation but independent of Ang II and hypertension and exhibits several unique features that mimic human aortic aneurysm. This review aims to discuss the common animal models of AAA, TAA, and aortic dissection currently studied in the world with the most focus on the DOCA- or Aldo-salt mouse model of aortic aneurysm.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/67114",risUrl:"/chapter/ris/67114",signatures:"Ming C. Gong, Shu Liu and Zhenheng Guo",book:{id:"8217",type:"book",title:"Aortic Aneurysm and Aortic Dissection",subtitle:null,fullTitle:"Aortic Aneurysm and Aortic Dissection",slug:"aortic-aneurysm-and-aortic-dissection",publishedDate:"September 9th 2020",bookSignature:"Jeffrey Shuhaiber",coverURL:"https://cdn.intechopen.com/books/images_new/8217.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-78923-978-2",printIsbn:"978-1-78923-977-5",pdfIsbn:"978-1-83968-395-4",isAvailableForWebshopOrdering:!0,editors:[{id:"22152",title:"Dr.",name:"Jeffrey",middleName:null,surname:"Shuhaiber",slug:"jeffrey-shuhaiber",fullName:"Jeffrey Shuhaiber"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Development of a new mouse model of aortic aneurysm induced by DOCA- or Aldo-salt",level:"1"},{id:"sec_2_2",title:"2.1 Discovery of DOCA-salt mouse model of aortic aneurysm by accidence",level:"2"},{id:"sec_3_2",title:"2.2 Both DOCA and high salt are required to induce aortic aneurysm",level:"2"},{id:"sec_4_2",title:"2.3 Infusion of mice with Aldo can also induce aortic aneurysm in the presence of high salt",level:"2"},{id:"sec_5_2",title:"2.4 DOCA-salt-induced aortic aneurysm is independent of Ang II",level:"2"},{id:"sec_6_2",title:"2.5 Activation of MR is a prerequisite for DOCA- or Aldo-salt to induce aortic aneurysm",level:"2"},{id:"sec_7_2",title:"2.6 DOCA-salt induces aortic aneurysm independent of increased blood pressure",level:"2"},{id:"sec_8_2",title:"2.7 Vascular pathology of DOCA- or Aldo-salt induced aortic aneurysms",level:"2"},{id:"sec_9_2",title:"2.8 Unique features of the DOCA- or Aldo-salt mouse model of aortic aneurysm",level:"2"},{id:"sec_10_2",title:"2.9 Significance and potential impact of the DOCA- or Aldo-salt mouse model of aortic aneurysm",level:"2"},{id:"sec_12",title:"3. Conclusions",level:"1"},{id:"sec_13",title:"Acknowledgments",level:"1"},{id:"sec_16",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'\nHiratzka LF et al. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease. A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology ,American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. Journal of the American College of Cardiology. 2010;55(14):e27-e129\n'},{id:"B2",body:'\nLindsay ME, Dietz HC. Lessons on the pathogenesis of aneurysm from heritable conditions. Nature. 2011;473(7347):308-316\n'},{id:"B3",body:'\nGolledge J et al. 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ANG II infusion promotes abdominal aortic aneurysms independent of increased blood pressure in hypercholesterolemic mice. American Journal of Physiology. Heart and Circulatory Physiology. 2009;296(5):H1660-H1665\n'},{id:"B20",body:'\nCassis LA et al. Aldosterone does not mediate angiotensin II-induced atherosclerosis and abdominal aortic aneurysms. British Journal of Pharmacology. 2005;144(3):443-448\n'},{id:"B21",body:'\nRateri DL et al. Endothelial cell-specific deficiency of Ang II type 1a receptors attenuates Ang II-induced ascending aortic aneurysms in LDL receptor−/− mice. Circulation Research. 2011;108(5):574-581\n'},{id:"B22",body:'\nZhang X et al. Transient exposure of neonatal female mice to testosterone abrogates the sexual dimorphism of abdominal aortic aneurysms. Circulation Research. 2012;110(11):e73-e85\n'},{id:"B23",body:'\nThomas M et al. Deletion of p47phox attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-deficient mice. Circulation. 2006;114(5):404-413\n'},{id:"B24",body:'\nKurihara T et al. Neutrophil-derived matrix metalloproteinase 9 triggers acute aortic dissection. Circulation. 2012;126(25):3070-3080\n'},{id:"B25",body:'\nRen W et al. beta-Aminopropionitrile monofumarate induces thoracic aortic dissection in C57BL/6 mice. Scientific Reports. 2016;6:28149\n'},{id:"B26",body:'\nKristensen KE et al. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in patients with abdominal aortic aneurysms: Nation-wide cohort study. Arteriosclerosis, Thrombosis, and Vascular Biology. 2015;35(3):733-740\n'},{id:"B27",body:'\nKiru G et al. An evaluation of the effect of an angiotensin-converting enzyme inhibitor on the growth rate of small abdominal aortic aneurysms: a randomised placebo-controlled trial (AARDVARK). Health Technology Assessment. 2016;20(59):1-180\n'},{id:"B28",body:'\nSweeting MJ et al. Use of angiotensin converting enzyme inhibitors is associated with increased growth rate of abdominal aortic aneurysms. Journal of Vascular Surgery: Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter. 2010;52(1):1-4\n'},{id:"B29",body:'\nSkott O et al. Rapid actions of aldosterone in vascular health and disease—Friend or foe? Pharmacology & Therapeutics. 2006;111(2):495-507\n'},{id:"B30",body:'\nGilbert KC, Brown NJ. Aldosterone and inflammation. Current Opinion in Endocrinology, Diabetes, and Obesity. 2010;17(3):199-204\n'},{id:"B31",body:'\nFunder JW, Reincke M. Aldosterone: A cardiovascular risk factor? Biochimica et Biophysica Acta. 2010;1802(12):1188-1192\n'},{id:"B32",body:'\nBrown NJ. Eplerenone: Cardiovascular protection. Circulation. 2003;107(19):2512-2518\n'},{id:"B33",body:'\nMcCurley A, Jaffe IZ. Mineralocorticoid receptors in vascular function and disease. Molecular and Cellular Endocrinology. 2012;350(2):256-265\n'},{id:"B34",body:'\nAhmed SH et al. Is primary hyperaldosteronism a risk factor for aortic dissection? Cardiology. 2007;108(1):48-50\n'},{id:"B35",body:'\nHirai H et al. Simultaneous surgery for chronic aortic dissection and adrenal adenoma with primary aldosteronism. General Thoracic and Cardiovascular Surgery. 2010;58(5):235-237, discussion 238\n'},{id:"B36",body:'\nPodgorski M et al. Aortic dissection—A rare complication of primary aldosteronism—A case report. Kardiologia Polska. 2011;69(2):156-158, discussion 159\n'},{id:"B37",body:'\nLitchfield WR et al. Intracranial aneurysm and hemorrhagic stroke in glucocorticoid-remediable aldosteronism. Hypertension. 1998;31(1 Pt 2):445-450\n'},{id:"B38",body:'\nFlynn C. Increased aldosterone: Mechanism of hypertension in obesity. Seminars in Nephrology. 2014;34(3):340-348\n'},{id:"B39",body:'\nCronin O, Walker PJ, Golledge J. The association of obesity with abdominal aortic aneurysm presence and growth. Atherosclerosis. 2013;226(2):321-327\n'},{id:"B40",body:'\nThompson A et al. An analysis of drug modulation of abdominal aortic aneurysm growth through 25 years of surveillance. Journal of Vascular Surgery: Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter. 2010;52(1):55-61, e2\n'},{id:"B41",body:'\nLiu S et al. Mineralocorticoid receptor agonists induce mouse aortic aneurysm formation and rupture in the presence of high salt. Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;33(7):1568-1579\n'},{id:"B42",body:'\nGolledge J. Is there a new target in the renin-angiotensin system for aortic aneurysm therapy? Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;33(7):1456-1457\n'},{id:"B43",body:'\nLutshumba J et al. Deletion of BMAL1 in smooth muscle cells protects mice from abdominal aortic aneurysms. Arteriosclerosis, Thrombosis, and Vascular Biology. 2018;38(5):1063-1075\n'},{id:"B44",body:'\nLiu S, Gong MC, Guo Z. A new mouse model for introduction of aortic aneurysm by implantation of deoxycorticosterone acetate pellets or aldosterone infusion in the presence of high salt. Methods in Molecular Biology. 2017;1614:155-163\n'},{id:"B45",body:'\nSchenk J, McNeill JH. The pathogenesis of DOCA-salt hypertension. Journal of Pharmacological and Toxicological Methods. 1992;27(3):161-170\n'},{id:"B46",body:'\nWeber KT. Aldosterone in congestive heart failure. The New England Journal of Medicine. 2001;345(23):1689-1697\n'},{id:"B47",body:'\nRousseau MF et al. Beneficial neurohormonal profile of spironolactone in severe congestive heart failure: Results from the RALES neurohormonal substudy. Journal of the American College of Cardiology. 2002;40(9):1596-1601\n'},{id:"B48",body:'\nWeiss D, Taylor WR. Deoxycorticosterone acetate salt hypertension in apolipoprotein E−/− mice results in accelerated atherosclerosis: The role of angiotensin II. Hypertension. 2008;51(2):218-224\n'},{id:"B49",body:'\nMin LJ et al. Aldosterone and angiotensin II synergistically induce mitogenic response in vascular smooth muscle cells. Circulation Research. 2005;97(5):434-442\n'},{id:"B50",body:'\nMontezano AC et al. Aldosterone and angiotensin II synergistically stimulate migration in vascular smooth muscle cells through c-Src-regulated redox-sensitive RhoA pathways. Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28(8):1511-1518\n'},{id:"B51",body:'\nCurci JA. Digging in the "soil" of the aorta to understand the growth of abdominal aortic aneurysms. Vascular. 2009;17(Suppl 1):S21-S29\n'},{id:"B52",body:'\nPowles J et al. Global, regional and national sodium intakes in 1990 and 2010: A systematic analysis of 24 h urinary sodium excretion and dietary surveys worldwide. BMJ Open. 2013;3(12):e003733\n'},{id:"B53",body:'\nWhelton PK et al. Sodium, blood pressure, and cardiovascular disease: Further evidence supporting the American Heart Association sodium reduction recommendations. Circulation. 2012;126(24):2880-2889\n'},{id:"B54",body:'\nAppel LJ et al. The importance of population-wide sodium reduction as a means to prevent cardiovascular disease and stroke: A call to action from the American Heart Association. Circulation. 2011;123(10):1138-1143\n'},{id:"B55",body:'\nGolledge J et al. Reported amount of salt added to food is associated with increased all-cause and cancer-related mortality in older men in a prospective Cohort study. The Journal of Nutrition, Health & Aging. 2015;19(8):805-811\n'},{id:"B56",body:'\nMaron BA, Leopold JA. Aldosterone receptor antagonists: Effective but often forgotten. Circulation. 2010;121(7):934-939\n'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Ming C. Gong",address:null,affiliation:'
Department of Physiology, USA
Saha Cardiovascular Research Center, University of Kentucky, USA
Department of Pharmacology and Nutritional Science, USA
Saha Cardiovascular Research Center, University of Kentucky, USA
Research and Development, Lexington Veterans Affairs Medical Center, USA
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Gulrez, Saphwan Al-Assaf and Glyn O Phillips",authors:[{id:"58120",title:"Prof.",name:"Saphwan",middleName:null,surname:"Al-Assaf",slug:"saphwan-al-assaf",fullName:"Saphwan Al-Assaf"}]},{id:"13254",doi:"10.5772/13474",title:"Insight Into Adsorption Thermodynamics",slug:"insight-into-adsorption-thermodynamics",totalDownloads:7142,totalCrossrefCites:88,totalDimensionsCites:259,abstract:null,book:{id:"25",slug:"thermodynamics",title:"Thermodynamics",fullTitle:"Thermodynamics"},signatures:"Papita Saha and Shamik Chowdhury",authors:[{id:"13943",title:"Dr.",name:"Papita",middleName:null,surname:"Saha",slug:"papita-saha",fullName:"Papita Saha"},{id:"24184",title:"Mr.",name:"Shamik",middleName:null,surname:"Chowdhury",slug:"shamik-chowdhury",fullName:"Shamik Chowdhury"}]},{id:"35261",doi:"10.5772/34233",title:"Anisotropic Mechanical Properties of ABS Parts Fabricated by Fused Deposition Modelling",slug:"anisotropic-mechanical-properties-of-abs-parts-fabricated-by-fused-deposition-modeling-",totalDownloads:7260,totalCrossrefCites:114,totalDimensionsCites:240,abstract:null,book:{id:"1982",slug:"mechanical-engineering",title:"Mechanical Engineering",fullTitle:"Mechanical Engineering"},signatures:"Constance Ziemian, Mala Sharma and Sophia Ziemian",authors:[{id:"89554",title:"Dr.",name:"Mala",middleName:null,surname:"Sharma",slug:"mala-sharma",fullName:"Mala Sharma"},{id:"98759",title:"Dr.",name:"Constance",middleName:null,surname:"Ziemian",slug:"constance-ziemian",fullName:"Constance Ziemian"},{id:"137165",title:"Ms.",name:"Sophia",middleName:null,surname:"Ziemian",slug:"sophia-ziemian",fullName:"Sophia Ziemian"}]},{id:"8446",doi:"10.5772/39538",title:"2 µm Laser Sources and Their Possible Applications",slug:"2-m-laser-sources-and-their-possible-applications",totalDownloads:12049,totalCrossrefCites:138,totalDimensionsCites:218,abstract:null,book:{id:"3161",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",title:"Frontiers in Guided Wave Optics and Optoelectronics",fullTitle:"Frontiers in Guided Wave Optics and Optoelectronics"},signatures:"Karsten Scholle, Samir Lamrini, Philipp Koopmann and Peter Fuhrberg",authors:[{id:"4951",title:"Dr.",name:"Karsten",middleName:null,surname:"Scholle",slug:"karsten-scholle",fullName:"Karsten Scholle"},{id:"133366",title:"Prof.",name:"Samir",middleName:null,surname:"Lamrini",slug:"samir-lamrini",fullName:"Samir Lamrini"},{id:"133370",title:"Prof.",name:"Philipp",middleName:null,surname:"Koopmann",slug:"philipp-koopmann",fullName:"Philipp Koopmann"},{id:"133371",title:"Mr.",name:"Peter",middleName:null,surname:"Fuhrberg",slug:"peter-fuhrberg",fullName:"Peter Fuhrberg"}]},{id:"27163",doi:"10.5772/31200",title:"Synergisms between Compost and Biochar for Sustainable Soil Amelioration",slug:"synergism-between-biochar-and-compost-for-sustainable-soil-amelioration",totalDownloads:6042,totalCrossrefCites:68,totalDimensionsCites:170,abstract:null,book:{id:"873",slug:"management-of-organic-waste",title:"Management of Organic Waste",fullTitle:"Management of Organic Waste"},signatures:"Daniel Fischer and Bruno Glaser",authors:[{id:"84418",title:"Prof.",name:"Bruno",middleName:null,surname:"Glaser",slug:"bruno-glaser",fullName:"Bruno Glaser"},{id:"96141",title:"Mr.",name:"Daniel",middleName:null,surname:"Fischer",slug:"daniel-fischer",fullName:"Daniel Fischer"}]}],mostDownloadedChaptersLast30Days:[{id:"35255",title:"Mechanical Transmissions Parameter Modelling",slug:"mechanical-transmissions-parameter-modelling",totalDownloads:7279,totalCrossrefCites:1,totalDimensionsCites:2,abstract:null,book:{id:"1982",slug:"mechanical-engineering",title:"Mechanical Engineering",fullTitle:"Mechanical Engineering"},signatures:"Isad Saric, Nedzad Repcic and Adil Muminovic",authors:[{id:"101313",title:"Prof.",name:"Isad",middleName:null,surname:"Saric",slug:"isad-saric",fullName:"Isad Saric"}]},{id:"67558",title:"Polymerase Chain Reaction (PCR): Principle and Applications",slug:"polymerase-chain-reaction-pcr-principle-and-applications",totalDownloads:10511,totalCrossrefCites:6,totalDimensionsCites:15,abstract:"The characterization of the diversity of species living within ecosystems is of major scientific interest to understand the functioning of these ecosystems. It is also becoming a societal issue since it is necessary to implement the conservation or even the restoration of biodiversity. Historically, species have been described and characterized on the basis of morphological criteria, which are closely linked by environmental conditions or which find their limits especially in groups where they are difficult to access, as is the case for many species of microorganisms. The need to understand the molecular mechanisms in species has made the PCR an indispensable tool for understanding the functioning of these biological systems. A number of markers are now available to detect nuclear DNA polymorphisms. In genetic diversity studies, the most frequently used markers are microsatellites. The study of biological complexity is a new frontier that requires high-throughput molecular technology, high speed computer memory, new approaches to data analysis, and the integration of interdisciplinary skills.",book:{id:"7728",slug:"synthetic-biology-new-interdisciplinary-science",title:"Synthetic Biology",fullTitle:"Synthetic Biology - New Interdisciplinary Science"},signatures:"Karim Kadri",authors:[{id:"290766",title:"Dr.",name:"Kadri",middleName:null,surname:"Karim",slug:"kadri-karim",fullName:"Kadri Karim"}]},{id:"62059",title:"Types of HVAC Systems",slug:"types-of-hvac-systems",totalDownloads:12245,totalCrossrefCites:8,totalDimensionsCites:14,abstract:"HVAC systems are milestones of building mechanical systems that provide thermal comfort for occupants accompanied with indoor air quality. HVAC systems can be classified into central and local systems according to multiple zones, location, and distribution. Primary HVAC equipment includes heating equipment, ventilation equipment, and cooling or air-conditioning equipment. Central HVAC systems locate away from buildings in a central equipment room and deliver the conditioned air by a delivery ductwork system. Central HVAC systems contain all-air, air-water, all-water systems. Two systems should be considered as central such as heating and cooling panels and water-source heat pumps. Local HVAC systems can be located inside a conditioned zone or adjacent to it and no requirement for ductwork. Local systems include local heating, local air-conditioning, local ventilation, and split systems.",book:{id:"6807",slug:"hvac-system",title:"HVAC System",fullTitle:"HVAC System"},signatures:"Shaimaa Seyam",authors:[{id:"247650",title:"M.Sc.",name:"Shaimaa",middleName:null,surname:"Seyam",slug:"shaimaa-seyam",fullName:"Shaimaa Seyam"},{id:"257733",title:"MSc.",name:"Shaimaa",middleName:null,surname:"Seyam",slug:"shaimaa-seyam",fullName:"Shaimaa Seyam"},{id:"395618",title:"Dr.",name:"Shaimaa",middleName:null,surname:"Seyam",slug:"shaimaa-seyam",fullName:"Shaimaa Seyam"}]},{id:"70315",title:"Some Basic and Key Issues of Switched-Reluctance Machine Systems",slug:"some-basic-and-key-issues-of-switched-reluctance-machine-systems",totalDownloads:1238,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"Although switched-reluctance machine (SRM) possesses many structural advantages and application potential, it is rather difficult to successfully control with high performance being comparable to other machines. Many critical affairs must be properly treated to obtain the improved operating characteristics. This chapter presents the basic and key technologies of switched-reluctance machine in motor and generator operations. The contents in this chapter include: (1) structures and governing equations of SRM; (2) some commonly used SRM converters; (3) estimation of key parameters and performance evaluation of SRM drive; (4) commutation scheme, current control scheme, and speed control scheme of SRM drive; (5) some commonly used front-end converters and their operation controls for SRM drive; (6) reversible and regenerative braking operation controls for SRM drive; (7) some tuning issues for SRM drive; (8) operation control and some tuning issues of switched-reluctance generators; and (9) experimental application exploration for SRM systems—(a) wind generator and microgrid and (b) EV SRM drive.",book:{id:"8899",slug:"modelling-and-control-of-switched-reluctance-machines",title:"Modelling and Control of Switched Reluctance Machines",fullTitle:"Modelling and Control of Switched Reluctance Machines"},signatures:"Chang-Ming Liaw, Min-Ze Lu, Ping-Hong Jhou and Kuan-Yu Chou",authors:[{id:"37616",title:"Prof.",name:"Chang-Ming",middleName:null,surname:"Liaw",slug:"chang-ming-liaw",fullName:"Chang-Ming Liaw"},{id:"306461",title:"Mr.",name:"Min-Ze",middleName:null,surname:"Lu",slug:"min-ze-lu",fullName:"Min-Ze Lu"},{id:"306463",title:"Mr.",name:"Ping-Hong",middleName:null,surname:"Jhou",slug:"ping-hong-jhou",fullName:"Ping-Hong Jhou"},{id:"306464",title:"Mr.",name:"Kuan-Yu",middleName:null,surname:"Chou",slug:"kuan-yu-chou",fullName:"Kuan-Yu Chou"}]},{id:"70874",title:"Social, Economic, and Environmental Impacts of Renewable Energy Resources",slug:"social-economic-and-environmental-impacts-of-renewable-energy-resources",totalDownloads:4854,totalCrossrefCites:27,totalDimensionsCites:51,abstract:"Conventional energy source based on coal, gas, and oil are very much helpful for the improvement in the economy of a country, but on the other hand, some bad impacts of these resources in the environment have bound us to use these resources within some limit and turned our thinking toward the renewable energy resources. The social, environmental, and economical problems can be omitted by use of renewable energy sources, because these resources are considered as environment-friendly, having no or little emission of exhaust and poisonous gases like carbon dioxide, carbon monooxide, sulfur dioxide, etc. Renewable energy is going to be an important source for power generation in near future, because we can use these resources again and again to produce useful energy. Wind power generation is considered as having lowest water consumption, lowest relative greenhouse gas emission, and most favorable social impacts. It is considered as one of the most sustainable renewable energy sources, followed by hydropower, photovoltaic, and then geothermal. As these resources are considered as clean energy resources, they can be helpful for the mitigation of greenhouse effect and global warming effect. Local employment, better health, job opportunities, job creation, consumer choice, improvement of life standard, social bonds creation, income development, demographic impacts, social bonds creation, and community development can be achieved by the proper usage of renewable energy system. Along with the outstanding advantages of these resources, some shortcomings also exist such as the variation of output due to seasonal change, which is the common thing for wind and hydroelectric power plant; hence, special design and consideration are required, which are fulfilled by the hardware and software due to the improvement in computer technology.",book:{id:"7636",slug:"wind-solar-hybrid-renewable-energy-system",title:"Wind Solar Hybrid Renewable Energy System",fullTitle:"Wind Solar Hybrid Renewable Energy System"},signatures:"Mahesh Kumar",authors:[{id:"309842",title:"Mr.",name:"Kamlesh",middleName:null,surname:"Kumar",slug:"kamlesh-kumar",fullName:"Kamlesh Kumar"}]}],onlineFirstChaptersFilter:{topicId:"11",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82477",title:"Biochar Synergistic New Ammonia Capture of CO2 and High-Value Utilization of Intermediate Products",slug:"biochar-synergistic-new-ammonia-capture-of-co2-and-high-value-utilization-of-intermediate-products",totalDownloads:0,totalDimensionsCites:null,doi:"10.5772/intechopen.105405",abstract:"In the face of global warming and the urgent need for CO2 reduction, carbon capture, utilization, and storage, technology plays an important role. Based on the traditional liquid-phase and solid-phase CO2 capture technologies, the liquid-phase ammonia and biochar CO2 capture technologies are reviewed with emphasis. A multiphase carbon capture technology that uses biochar to enhance the mass transfer-crystallization process of the new ammonia CO2 capture technology is proposed. High CO2 capture efficiency, limited ammonia escape, and low system energy consumption can be achieved through the orderly construction of three-dimensional graded pore channels and the directional functionalization of biochar. The intermediate products of CO2 captured by the ammonia process and the special agricultural waste rice husk components were considered. The use of rice husk-based biochar for CO2 capture by synergistic new ammonia method and the process regulation of intermediate products to prepare nano-silica to achieve high-value utilization of interstitial products of carbon capture. This technology may be important to promote the development of CO2 capture technology and CO2 reduction.",book:{id:"11537",title:"Biochar - Productive Technologies, Properties and Application",coverURL:"https://cdn.intechopen.com/books/images_new/11537.jpg"},signatures:"Yu Zhang, Yalong Zhang, Dongdong Feng, Jiabo Wu, Jianmin Gao, Qian Du and Yudong Huang"},{id:"82414",title:"Use of Induction Generators in Small Hydro Power Generation System Feeding Isolated Load in Remote Mountainous Regions of Himalayas",slug:"use-of-induction-generators-in-small-hydro-power-generation-system-feeding-isolated-load-in-remote-m",totalDownloads:1,totalDimensionsCites:0,doi:"10.5772/intechopen.105650",abstract:"Providing reliable and clean power from conventional grid in remote mountainous regions is always a challenging task due to tough geographical and climatic conditions. Renewable energy sources-based power plants such as small hydro power plants play a significant role in meeting the power requirements in these remote locations in mountainous regions. Synchronous generators are the most commonly used generators in small hydro power plants. However, with the advancement in controller technology for voltage and frequency control, induction generators are nowadays preferred in renewable energy conversion systems. Self-excited induction generators (SEIG) in small hydro power plants feeding isolated domestic loads are more suitable due to their inherent advantages as compared to conventional synchronous generators. This chapter deals with the usefulness of electronic load controller used in voltage and frequency control of self-excited induction generator used in small hydro power plant feeding isolated load in remote mountainous regions of Himalayas.",book:{id:"11534",title:"Renewable Energy - Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/11534.jpg"},signatures:"Umesh C. Rathore and Sanjeev Singh"},{id:"80334",title:"Zero Emission Hydrogen Fuelled Fuel Cell Vehicle and Advanced Strategy on Internal Combustion Engine: A Review",slug:"zero-emission-hydrogen-fuelled-fuel-cell-vehicle-and-advanced-strategy-on-internal-combustion-engine",totalDownloads:2,totalDimensionsCites:0,doi:"10.5772/intechopen.102057",abstract:"Global energy consumption has gradually increased as a result of population growth, industrialization, economic development, and rising living standards. Furthermore, as global warming and pollution worsen, the development of renewable energy sources is becoming more essential. Hydrogen is one of the most promising clean and sustainable energy carriers because it emits only water as a byproduct without carbon emission and has the highest energy efficiency. Hydrogen can be produced from a variety of raw resources, including water and biomass. Water electrolysis is one of many hydrogen production technologies that is highly recommended due to its eco-friendliness, high hydrogen generation rate, and high purity. However, in terms of long-term viability and environmental effect, Polymer Electrolyte Membrane water electrolysis has been identified as a potential approach for producing high-purity, high-efficiency hydrogen from renewable energy sources. Furthermore, the hydrogen (H2) and oxygen (O2) produced are directly employed in fuel cells and other industrial uses. As a result, an attempt has been made in this work to investigate hydrogen synthesis and utilization in fuel cell vehicles. Low-temperature combustion technology has recently been applied in engine technology to reduce smoke and NOx emissions at the same time. The advantages and limitations of homogeneous charge compression ignition, partially premixed charge compression ignition, premixed charge compression ignition, and reactivity regulated compression ignition are described separately in low-temperature combustion strategy.",book:{id:"11164",title:"Diesel Engines and Biodiesel Engines Technologies",coverURL:"https://cdn.intechopen.com/books/images_new/11164.jpg"},signatures:"Babu Dharmalingam, Ramakrishna Reddy Ramireddy, Santhoshkumar Annamalai, Malinee Sriariyanun, Deepakkumar Rajagopal and Venkata Ramana Katla"},{id:"82360",title:"Development and Usage of Electronic Teaching Technologies for the Economic Training of Students in a Technical University",slug:"development-and-usage-of-electronic-teaching-technologies-for-the-economic-training-of-students-in-a",totalDownloads:2,totalDimensionsCites:0,doi:"10.5772/intechopen.105610",abstract:"In this chapter, the experience of the Department of Economic Theory in the development and use of electronic technologies in teaching economic theory for students of technical directions is described. The necessity of electronic testing in the context of the concept of practice-oriented teaching has been substantiated. The stages of development and structure of electronic testing are presented. The process of forming the base of test tasks is described. The structure of the software is stated. The experience of approbation and application of testing technology is presented. The influence of electronic testing technology on teaching methods is shown. The issues of electronic support of business games are considered. Electronic technologies are considered as a necessary and essential element in the organization and implementation of business games developed at the department. An assessment of the impact of electronic testing and electronic support of business games on the quality of the educational process is given.",book:{id:"11170",title:"Quality Control",coverURL:"https://cdn.intechopen.com/books/images_new/11170.jpg"},signatures:"Valeryi Semenov"},{id:"82348",title:"Biochar Development as a Catalyst and Its Application",slug:"biochar-development-as-a-catalyst-and-its-application",totalDownloads:1,totalDimensionsCites:0,doi:"10.5772/intechopen.105439",abstract:"Biochar is a carbon-rich pyrogenic material that is made from carbon-neutral sources (i.e., biomass). It offers key strategies for carbon capture and storage (CCS) as well as being an environmentally friendly means of soil amendment. The recent recognition of biochar as a versatile media for catalytic applications has prompted preliminary research into biochar’s catalytic capacity and mechanistic practices via various routes. This chapter provides a review of biochar production technologies, biochar’s catalyst development, and its application in various catalytic processes as well as descriptions of the benefits and drawbacks of the various applications currently available. The characteristics of biochar-based catalysts, challenges of effective application of this catalyst system, emerging application, prospects, and future work consideration for effective utilization of biochar-based catalysts were presented.",book:{id:"11537",title:"Biochar - Productive Technologies, Properties and Application",coverURL:"https://cdn.intechopen.com/books/images_new/11537.jpg"},signatures:"Stephen Okiemute Akpasi, Ifeanyi Michael Smarte Anekwe, Jeremiah Adedeji and Sammy Lewis Kiambi"},{id:"82437",title:"Water Availability for the Environmental Flow in Two Rivers of Mexico under Climate Change",slug:"water-availability-for-the-environmental-flow-in-two-rivers-of-mexico-under-climate-change",totalDownloads:4,totalDimensionsCites:0,doi:"10.5772/intechopen.104881",abstract:"Adaptation to climate change requires, among others, the modification of river flow regimes to account for the change in household, agricultural, industry, and energy water consumption as well as their short/medium/long-term socioeconomic impact. In this study, the comparative analysis of the variation of the precipitation in relation to the availability of water in the Yautepec and Cuautla rivers in Morelos, Mexico, for the previous period and subsequent period is carried out, to determine the change in the availability of water in the ecosystem. In winter (February), an increase in rainfall on the Yautepec and Cuautla River was observed, where annual seasonal agriculture and Pine and Oyamel forest are the characteristic vegetation. In autumn (October), a decrease in precipitation takes place. The flows in some regions do not coincide with the increase in the percentage of precipitation (Oaxtepec and Las Estacas Stations) and point out the synergistic effect of the human use of the water resource and the effects of climate change. On Ticumán Station, the depletion of the flow only can be associated with the use of the resource by human influence. The modifications caused by alteration of a river’s flow regime and climatic change must be studied through comparative multidisciplinary studies that give to decision-makers the design of environmental flows.",book:{id:"11532",title:"River Basin Management - Under a Changing Climate",coverURL:"https://cdn.intechopen.com/books/images_new/11532.jpg"},signatures:"Rebeca González-Villela, Alfonso Banderas Tarabay and Marco Mijangos Carro"}],onlineFirstChaptersTotal:266},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:318,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:106,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:15,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. 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Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. 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Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. 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He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. Dr. Ekinci serves as the Editor in Chief of four international books and is involved in the Editorial Board of several international journals.",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null},{id:"17",title:"Metabolism",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",isOpenForSubmission:!0,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. 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Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. 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She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. 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She is now a lecturer at the University of Witwatersrand, South Africa, and a principal researcher at the Health Economics and Epidemiology Research Office (HE2RO), South Africa. Dr. Moolla holds a Ph.D. in Psychology with her research being focused on mental health and resilience. In her professional work capacity, her research has further expanded into the fields of early childhood development, mental health, the HIV and TB care cascades, as well as COVID. She is also a UNESCO-trained International Bioethics Facilitator.",institutionString:"University of the Witwatersrand",institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419588",title:"Ph.D.",name:"Sergio",middleName:"Alexandre",surname:"Gehrke",slug:"sergio-gehrke",fullName:"Sergio Gehrke",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038WgMKQA0/Profile_Picture_2022-06-02T11:44:20.jpg",biography:"Dr. Sergio Alexandre Gehrke is a doctorate holder in two fields. The first is a Ph.D. in Cellular and Molecular Biology from the Pontificia Catholic University, Porto Alegre, Brazil, in 2010 and the other is an International Ph.D. in Bioengineering from the Universidad Miguel Hernandez, Elche/Alicante, Spain, obtained in 2020. In 2018, he completed a postdoctoral fellowship in Materials Engineering in the NUCLEMAT of the Pontificia Catholic University, Porto Alegre, Brazil. He is currently the Director of the Postgraduate Program in Implantology of the Bioface/UCAM/PgO (Montevideo, Uruguay), Director of the Cathedra of Biotechnology of the Catholic University of Murcia (Murcia, Spain), an Extraordinary Full Professor of the Catholic University of Murcia (Murcia, Spain) as well as the Director of the private center of research Biotecnos – Technology and Science (Montevideo, Uruguay). Applied biomaterials, cellular and molecular biology, and dental implants are among his research interests. He has published several original papers in renowned journals. In addition, he is also a Collaborating Professor in several Postgraduate programs at different universities all over the world.",institutionString:null,institution:{name:"Universidad Católica San Antonio de Murcia",country:{name:"Spain"}}},{id:"342152",title:"Dr.",name:"Santo",middleName:null,surname:"Grace Umesh",slug:"santo-grace-umesh",fullName:"Santo Grace Umesh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/342152/images/16311_n.jpg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"333647",title:"Dr.",name:"Shreya",middleName:null,surname:"Kishore",slug:"shreya-kishore",fullName:"Shreya Kishore",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333647/images/14701_n.jpg",biography:"Dr. Shreya Kishore completed her Bachelor in Dental Surgery in Chettinad Dental College and Research Institute, Chennai, and her Master of Dental Surgery (Orthodontics) in Saveetha Dental College, Chennai. She is also Invisalign certified. She’s working as a Senior Lecturer in the Department of Orthodontics, SRM Dental College since November 2019. She is actively involved in teaching orthodontics to the undergraduates and the postgraduates. Her clinical research topics include new orthodontic brackets, fixed appliances and TADs. She’s published 4 articles in well renowned indexed journals and has a published patency of her own. Her private practice is currently limited to orthodontics and works as a consultant in various clinics.",institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"323731",title:"Prof.",name:"Deepak M.",middleName:"Macchindra",surname:"Vikhe",slug:"deepak-m.-vikhe",fullName:"Deepak M. Vikhe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/323731/images/13613_n.jpg",biography:"Dr Deepak M.Vikhe .\n\n\t\n\tDr Deepak M.Vikhe , completed his Masters & PhD in Prosthodontics from Rural Dental College, Loni securing third rank in the Pravara Institute of Medical Sciences Deemed University. He was awarded Dr.G.C.DAS Memorial Award for Research on Implants at 39th IPS conference Dubai (U A E).He has two patents under his name. He has received Dr.Saraswati medal award for best research for implant study in 2017.He has received Fully funded scholarship to Spain ,university of Santiago de Compostela. He has completed fellowship in Implantlogy from Noble Biocare. \nHe has attended various conferences and CDE programmes and has national publications to his credit. His field of interest is in Implant supported prosthesis. Presently he is working as a associate professor in the Dept of Prosthodontics, Rural Dental College, Loni and maintains a successful private practice specialising in Implantology at Rahata.\n\nEmail: drdeepak_mvikhe@yahoo.com..................",institutionString:null,institution:{name:"Pravara Institute of Medical Sciences",country:{name:"India"}}},{id:"204110",title:"Dr.",name:"Ahmed A.",middleName:null,surname:"Madfa",slug:"ahmed-a.-madfa",fullName:"Ahmed A. Madfa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204110/images/system/204110.jpg",biography:"Dr. Madfa is currently Associate Professor of Endodontics at Thamar University and a visiting lecturer at Sana'a University and University of Sciences and Technology. He has more than 6 years of experience in teaching. His research interests include root canal morphology, functionally graded concept, dental biomaterials, epidemiology and dental education, biomimetic restoration, finite element analysis and endodontic regeneration. Dr. Madfa has numerous international publications, full articles, two patents, a book and a book chapter. Furthermore, he won 14 international scientific awards. Furthermore, he is involved in many academic activities ranging from editorial board member, reviewer for many international journals and postgraduate students' supervisor. Besides, I deliver many courses and training workshops at various scientific events. Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Univeristy of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:null},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:null},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. Her knowledge of English is at an advanced level.",institutionString:null,institution:null},{id:"332914",title:"Dr.",name:"Muhammad Saad",middleName:null,surname:"Shaikh",slug:"muhammad-saad-shaikh",fullName:"Muhammad Saad Shaikh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jinnah Sindh Medical University",country:{name:"Pakistan"}}},{id:"315775",title:"Dr.",name:"Feng",middleName:null,surname:"Luo",slug:"feng-luo",fullName:"Feng Luo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sichuan University",country:{name:"China"}}},{id:"423519",title:"Dr.",name:"Sizakele",middleName:null,surname:"Ngwenya",slug:"sizakele-ngwenya",fullName:"Sizakele Ngwenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419270",title:"Dr.",name:"Ann",middleName:null,surname:"Chianchitlert",slug:"ann-chianchitlert",fullName:"Ann Chianchitlert",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419271",title:"Dr.",name:"Diane",middleName:null,surname:"Selvido",slug:"diane-selvido",fullName:"Diane Selvido",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419272",title:"Dr.",name:"Irin",middleName:null,surname:"Sirisoontorn",slug:"irin-sirisoontorn",fullName:"Irin Sirisoontorn",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"355660",title:"Dr.",name:"Anitha",middleName:null,surname:"Mani",slug:"anitha-mani",fullName:"Anitha Mani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"355612",title:"Dr.",name:"Janani",middleName:null,surname:"Karthikeyan",slug:"janani-karthikeyan",fullName:"Janani Karthikeyan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"334400",title:"Dr.",name:"Suvetha",middleName:null,surname:"Siva",slug:"suvetha-siva",fullName:"Suvetha Siva",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}}]}},subseries:{item:{id:"1",type:"subseries",title:"Oral Health",keywords:"Oral health, Dental care, Diagnosis, Diagnostic imaging, Early diagnosis, Oral cancer, Conservative treatment, Epidemiology, Comprehensive dental care, Complementary therapies, Holistic health",scope:"
\r\n This topic aims to provide a comprehensive overview of the latest trends in Oral Health based on recent scientific evidence. Subjects will include an overview of oral diseases and infections, systemic diseases affecting the oral cavity, prevention, diagnosis, treatment, epidemiology, as well as current clinical recommendations for the management of oral, dental, and periodontal diseases.
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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",keywords:"Phenolic Compounds, Essential Oils, Modification of Biomolecules, Glycobiology, Combinatorial Chemistry, Therapeutic peptides, Enzyme Inhibitors"},{id:"17",title:"Metabolism",scope:"Metabolism is frequently defined in biochemistry textbooks as the overall process that allows living systems to acquire and use the free energy they need for their vital functions or the chemical processes that occur within a living organism to maintain life. Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. Thus all studies on metabolism will be considered for publication.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",keywords:"Biomolecules Metabolism, Energy Metabolism, Metabolic Pathways, Key Metabolic Enzymes, Metabolic Adaptation"},{id:"18",title:"Proteomics",scope:"With the recognition that the human genome cannot provide answers to the etiology of a disorder, changes in the proteins expressed by a genome became a focus in research. Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. The Proteomics topic aims to attract contributions on all aspects of MS-based proteomics that, by pushing the boundaries of MS capabilities, may address biological problems that have not been resolved yet.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",keywords:"Mono- and Two-Dimensional Gel Electrophoresis (1-and 2-DE), Liquid Chromatography (LC), Mass Spectrometry/Tandem Mass Spectrometry (MS; MS/MS), Proteins"}],annualVolumeBook:{},thematicCollection:[],selectedSeries:{title:"Biochemistry",id:"11"},selectedSubseries:null},seriesLanding:{item:null},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"profile.detail",path:"/profiles/104778",hash:"",query:{},params:{id:"104778"},fullPath:"/profiles/104778",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()