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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
\n\n\n\n\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"783",leadTitle:null,fullTitle:"Pulmonary Hypertension - From Bench Research to Clinical Challenges",title:"Pulmonary Hypertension",subtitle:"From Bench Research to Clinical Challenges",reviewType:"peer-reviewed",abstract:'The textbook "Pulmonary Hypertension - From Bench Research to Clinical Challenges" addresses the following topics: structure and function of the normal pulmonary vasculature; disregulated cellular pathways seen in experimental and human pulmonary hypertension; clinical aspects of pulmonary hypertension in general; presentation of several specific forms of pulmonary hypertension, and management of pulmonary hypertension in special circumstances. \n\nThe textbook is unique in that it combines pulmonary and cardiac physiology and pathophysiology with clinical aspects of the disease. First two sections are reserved for the basic knowledge and the recent discoveries related to structure and cellular function of the pulmonary vasculature. The chapters also describe disregulated pathways known to be affected in pulmonary hypertension. A special section deals with the effects of hypoxia on the pulmonary vasculature and the myocardium. \n\nOther three sections introduce the methods of evaluating pulmonary hypertension to the reader. The chapters present several forms of pulmonary hypertension which are particularly challenging in clinical practice (such as pulmonary arterial hypertension associated with systemic sclerosis), and lastly, they address special considerations regarding management of pulmonary hypertension in certain clinical scenarios such as pulmonary hypertension in the critically ill.',isbn:null,printIsbn:"978-953-307-835-9",pdfIsbn:"978-953-51-6710-5",doi:"10.5772/1291",price:139,priceEur:155,priceUsd:179,slug:"pulmonary-hypertension-from-bench-research-to-clinical-challenges",numberOfPages:340,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"488ca2b21e4374b6337d1aacbd107c3b",bookSignature:"Roxana Sulica and Ioana Preston",publishedDate:"December 9th 2011",coverURL:"https://cdn.intechopen.com/books/images_new/783.jpg",numberOfDownloads:58650,numberOfWosCitations:13,numberOfCrossrefCitations:4,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:17,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:34,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 1st 2011",dateEndSecondStepPublish:"March 1st 2011",dateEndThirdStepPublish:"July 6th 2011",dateEndFourthStepPublish:"August 5th 2011",dateEndFifthStepPublish:"December 3rd 2011",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"74136",title:"Dr.",name:"Roxana",middleName:null,surname:"Sulica",slug:"roxana-sulica",fullName:"Roxana Sulica",profilePictureURL:"https://mts.intechopen.com/storage/users/74136/images/1910_n.jpg",biography:"Dr. Roxana Sulica is Assistant Professor of Medicine at Albert Einstein College of Medicine, Bronx, New York and is the Director of the Beth Israel Pulmonary Hypertension Program. She earned her medical degree at “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania. She has authored numerous papers in the area of pulmonary hypertension. She was a member of the Editorial Board of the journal Advances in Pulmonary Hypertension and also served as a reviewer for numerous acknowledged journals such as Chest, Critical Care Medicine, Mount Sinai Journal of Medicine, Sarcoidosis, Vasculitis and Diffuse Lung Diseases. She also received a Dean’s Award for Excellence in Medical School.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Yeshiva University",institutionURL:null,country:{name:"United States of America"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"66680",title:"Dr.",name:"Ioana",middleName:null,surname:"Preston",slug:"ioana-preston",fullName:"Ioana Preston",profilePictureURL:"https://mts.intechopen.com/storage/users/66680/images/1912_n.jpg",biography:"Dr. Ioana Preston is Assistant Professor of Medicine at Tufts University School of Medicine in Boston, Massachusetts and is the Co-Director of the Pulmonary Hypertension Center at Tufts Medical Center. She graduated from “Carol Davila” University School of Medicine and Pharmacy, Bucharest, Romania and underwent postgraduate training at Brown University in Providence, Rhode Island and at Tufts Medical Center in Boston. Dr. Preston is actively involved in preclinical and clinical research on pulmonary hypertension.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Tufts Medical Center",institutionURL:null,country:{name:"United States of America"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1047",title:"Pulmonology",slug:"pulmonology"}],chapters:[{id:"24749",title:"Pulmonary Hypertension: Endothelial Cell Function",doi:"10.5772/26198",slug:"pulmonary-hypertension-endothelial-cell-function",totalDownloads:2142,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,abstract:null,signatures:"Rajamma Mathew",downloadPdfUrl:"/chapter/pdf-download/24749",previewPdfUrl:"/chapter/pdf-preview/24749",authors:[{id:"65828",title:"Dr.",name:"Rajamma",surname:"Mathew",slug:"rajamma-mathew",fullName:"Rajamma 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Over the past few decades, studies have found that physiological data and the appeal of health benefits are insufficient to encourage people to maintain regular physical activity. Therefore, understanding the relationship between affect and exercise is a vital step toward revealing what factors lead to maintenance of or dropout from exercise programs. This chapter presents the concept of basic affect and its distinction from moods and emotions, as well as the possibility of measuring affect in the context of exercise from a dimensional perspective. In terms of the affect-exercise relationship, it will address the importance of the intensity of the exercise prescription model (self-selected or imposed) in affective responses and the use of motivational music to stimulate pleasurable sensations or distract from the discomfort that exercise can cause.
\nThe analysis of affective constructs from general and abstract aspects (such as mental health, psychological well-being, and psychological health) has provided a plethora of terms, such as humor, emotion, and affect, with similar and diverse definitions, not all of which are universally accepted [1]. To understand the meaning of affect and its application in the context of exercise, it is important to define the concepts of mood and emotion. Emotions are immediate responses to specific stimuli (often directed at a specific object), typically characterized by a short duration and high intensity. In contrast, moods are characterized as diffuse and lacking a specific target, are typically associated with downward or no-action trends, and may be less intense and longer lasting than emotions [1, 2]. In this sense, moods refer to the larger and more diffuse existential issues of life, while emotions refer to an immediate response, having a specific and relatively narrow purpose in an encounter with variable environmental stimuli [1].
\nThe term “affect” can be defined as the intrapersonal or experiential basis of all contrasting responses (positive or negative, pleasant or unpleasant), including, but not limited to, emotions and moods [2, 3]. Unlike emotions and moods, affect encompasses a more general description of the psychological response and can be considered basic and central. Therefore, the use of the word affect encompasses the notion that all emotions are affective conditions, but not all affective conditions are emotions [2, 4].
\nThe investigation of affective phenomena can be envisioned from a categorical or dimensional perspective. In the categorical view of affect, affective states are ordered into different categories, comprising states that resemble the prototypical examples, such as anger, fear, sadness, disgust, happiness, love, and pride [4]. In the dimensional perspective, affective states are systematically interrelated, and their relationships can be modeled by a stringent set of dimensions. Although both categories have advantages and limitations, the dimensional approach provides a wider perspective, corroborating the characteristics of basic affect and providing a model or “map” of the affective space that offers a broad and balanced scope for investigation of affect in exercise [2, 4]. The dimensional model of affect allows the exercise-induced affective experience to be captured and the observation of affective changes throughout the exercise context [2, 4, 5].
\nThe measurement of affect can be performed with one- or two-dimensional models [6]. Some scales are commonly used to measure affective valence and perceived activation from both models. The Feeling Scale is used to measure affective valence (\nFigure 1\n). This instrument comprises an 11-point scale, ranging from +5 (“very good”) to −5 (“very bad”) [7]. Its purpose is to quantify the exercise-related sense of pleasure and displeasure. The Felt Arousal Scale is an instrument used to measure perceived activation [8] (\nFigure 2\n); the scale comprises six levels of activation, ranging from low activation (1) to high activation (6). High perceived activation can be characterized by excitement, anxiety, or anger, whereas low activation may be described as relaxation, boredom, or tranquility.
\nFeeling scale.
Felt arousal scale.
The circumplex model measures affect from a two-dimensional model, which involves an affective valence dimension (also called pleasure-displeasure) and a perceived activation dimension (also called arousal) [6, 9]. The use of the circumplex model in exercise is intended to avoid measuring affect with terms such as anxiety, depression, and various mood descriptions and to provide a map of affect in the broad context of exercise (before, during, and after activity) [10].
\nIn the circumplex model (\nFigure 3\n), the horizontal dimension represents the affective valence (pleasure-displeasure), and the vertical dimension represents the perceived activation. Affective spaces are divided into four quadrants: quadrant 1 corresponds to a sense of high activation and displeasure (tension, nervousness, distress); quadrant 2 corresponds to a sense of high activation and pleasure (energy, excitement, vigor); quadrant 3 corresponds to a sense of low activation and displeasure (fatigue, boredom, tiredness); quadrant 4 corresponds to a sense of low activation and pleasure (tranquility, relaxation, calmness) [5, 6, 10].
\nCircumplex model of affect (adapted [
Several studies using dimensional models of affect have verified the importance of measuring affective responses in exercise, as well as the factors that may influence this relationship [11, 12, 13].
\nThe relationship between exercise and affective response is complex and multifaceted [2]. Although many studies relate exercise to affect as a single phenomenon, there is evidence that considerable complexity lies beneath this factor. This complexity is based on the nature of the affective changes and patterns in their relationship with relevant variables, such as contextual factors (exercise scenario), exercise stimulus aspects (intensity), and individual differences (physical activity level) [2, 14]. These factors may influence affective responses during exercise.
\nAffective valence, based on observations in neuroscience, has shown that negative affect is one of the first signs of conscious and significant changes in energy regulation and body balance [15, 16]. Neuroanatomical and neurophysiological studies suggest that interoceptive stimuli of afferent signals from baroreceptors, chemoreceptors, and mechanoreceptors located in the viscera and muscles are linked to affective responses [17]. This hypothesis suggests that changes in the transition between aerobic and anaerobic metabolism during exercise would be accompanied by unpleasant affective responses [17].
\nOne of the main determinants of affective responses during exercise is the intensity at which the activity is performed [18]. According to the dual model theory [2], the ventilatory threshold (VT) or lactate threshold functions as a marker of exercise intensity [19, 20, 21, 22], demonstrating that, at prescribed intensities below or around the VT, affective responses maintain a positive predominance. However, during exercise at VT, the affective valence is less pleasant and, in some cases, negative [19, 20, 22, 23]. An important aspect of intensities below or near the VT is the great variability of affective responses between individuals, in whom exercise can increase, decrease, or stabilize affective responses of pleasure. However, above VT, individual variations are smaller, and, generally, a decline in pleasure is experienced [22].
\nAccording to Dishman [24], feelings of pleasure and well-being appear to be the most compelling reasons for continued participation in an exercise program, rather than the knowledge of or belief in the health benefits of physical activity. The idea of exercise giving pleasure may indicate its usefulness to the individual, whereas discomfort indicates damage or danger [20]. The variability in affective responses may be an indication that the situation is providing substantial benefit or imminent danger. However, whenever all or most individuals respond in a similar way, with pleasure or displeasure (within a reasonable quantitative range), it can be assumed that the situation is one that has consistent (positive or negative) implications for change [20].
\nExercise intensity is an important factor in exercise prescription [12, 25]. Performing 30 minutes of moderate-intensity exercise, i.e., 64–76% of maximum heart rate (HRmax) (at least 5 days a week), or 20 minutes of vigorous intensity, i.e., 77–95% of HRmax (3 days a week), is the minimum recommendations proposed by the American College of Sports Medicine (ACSM) for health-related physiological benefits (ACSM, 2011). Studies published in recent decades have shown that exercise intensity is also one of the main influencers of affective exercise response [5, 26, 27, 28].
\nIn a study by Vandoni [25], which compared the affective responses of exercise performed at moderate and vigorous intensities, the results showed that vigorous exercise promoted lower affective responses than moderate exercise. Alves [29], when observing weight training in elderly women, found higher affective pleasure responses in exercises performed with a low one-repetition maximum (1RM) percentage (35%) in relation to higher intensities (50% and 70% 1RM). Follador [30] observed that, even in moderately active adults, high-intensity protocols promoted less pleasure responses, and protocols prescribing maximal or supramaximal intensities were the most likely to stimulate the affective response of displeasure and probably have the highest negative impact on exercise program adherence.
\nThe relevance of affective responses in the exercise program should be to prioritize the task response over the postexercise response [31]. Studies have shown that, when exercise intensity exceeds the VT, there is a decrease in affective response and this change has a greater impact on the future behavior of maintaining exercise continuity than the affective responses obtained after exercise [31, 32]. However, the difficulty and complexity of conducting medium- to long-term studies have not facilitated much investigation into adherence to exercise programs. Parfitt [28] verified the 6-month effect on physical fitness and affective responses of sedentary people after an 8-week intervention program. Three groups participated in the training: a control group, a group that exercised in PSE 13 (Borg 06-20), and group in PSE 15. Their results show that the group that performed the training at a lower intensity (PSE 13) showed more positive affective responses during the intervention, maintaining the level of physical fitness acquired during training, in relation to the control and PSE 15 groups. In the study by Perri [33], which aimed to observed the relationship between intensity, frequency, and adherence to exercise over 6 months, the results showed that exercise prescription of moderate intensity produced greater exercise adherence (66 vs. 58%) than exercise prescription of higher intensity.
\nA self-selected intensity exercise is an activity in which the participant chooses the preferred intensity [34]. For beginners, exercise at intensities above the anaerobic/VT may provide affective responses of displeasure and stimulate changes in exercise intensity toward self-selected intensities. In this sense, beginners of exercise programs seek lower perceptions of effort and greater affective pleasure responses [35].
\nMotivational aspects related to the practice of exercise have been investigated using behavioral theories. To better understand the factors leading to the permanence, or dropout, of beginners of exercise programs, the hedonic theory and the self-determination theory have been important in understanding self-selected exercise [36, 37, 38].
\nThe hedonic theory of motivation suggests that when one experiences a situation that promotes pleasure, joy, or fun, one will seek to repeat that activity. However, if the situation induces displeasure, pain, or discomfort, the chance of adherence or repetition of the activity is lower [37, 39]. The self-determination theory is a general theory of human motivation that prioritizes autonomous aspects of behavior over controlled ones. Its emphasis is on providing a sense of granted autonomy and can promote a pleasant, self-gratifying feeling and greater intrinsic motivation [36, 39, 40]. The sense of autonomy and positive feelings forms the fundamental aspects of self-selected exercise.
\nThe psychological elements of behavioral theories are linked to the physiological components of effort. Lower-intensity activities are inversely correlated with feelings of displeasure and, consequently, with adherence [34]. However, the duration of activity may also be related to displeasure, with shorter duration exercises being more conducive to adherence than very long activities [39, 41].
\nSelf-selected intensity exercise has been proposed by several authors as a strategy to improve the participation and adherence of physical activity programs by sedentary people [3, 34]. Studies have shown that insufficiently active people are able to self-select an exercise intensity according to the ACSM parameters for maintaining and/or developing cardiorespiratory fitness, associated with lower exertion perceptions and positive affective responses [27, 28, 42]. Although some studies have addressed the fact that affective responses are more dependent on exercise intensity than on how it is prescribed (imposed or self-selected exercise) [43, 44], other studies point out that, even when the exercise session is prescribed at the same intensity as the self-selected exercise session, the affective responses may be different. Hamlyn-Williams [45] observed that aerobic exercise lowers perceptual responses and affective responses are higher during self-selected intensity than during imposed intensity. Similar results were observed in the study by Da Silva [46] on resistance training, in which three of the four exercises used in the study had lower perceptual responses, and all exercises showed higher affective responses for self-selected intensity.
\nIn intervention studies, self-selected intensity has been shown to be an excellent strategy to provide similar or more pleasurable affective responses than imposed intensity exercises [47]. In the study by Freitas [27], which compared walking exercise programs at self-selected and imposed intensities (10% above VT) over 12 weeks of training, the results showed that self-selected exercise induced more pleasurable affective responses, where the percentage of HR and PSE responses were lower than in the imposed exercise regime. In addition, walking at a self-selected intensity was sufficient to promote improvement in maximal oxygen uptake at the end of training. Yang [48] concluded, from a 12-week study, that both self-selected and prescribed intensities improved the level of physical activity and positive affect and reduced physiological parameters (waist circumference, systolic and diastolic blood pressure) in retirees. However, the self-selected intensity was more favorable to the increase of positive affect than the prescribed intensity.
\nThe evolution of technology in recent decades has provided facilities and amenities that were difficult or restricted to access in the past. Music has benefited in this respect, and with the creation and evolution of smartphones, headphones, MP3 players, and the Internet, access to music content of different styles and from various countries has become easier and more commonplace, and the technology has increased our capacity to transport music [3]. Nowadays, people have become more accustomed to listening to music during their various daily activities, such as walking in the park, commuting, doing homework, exercising at the gym, and leisure times [3].
\nIn sport and exercise, music has been used for the purpose of improving performance, reducing the monotony of the activity, or as a musical background [49, 50]. Music can improve mood and emotion, reduce the perception of effort, dissociate from pain and fatigue, etc. The psychophysiological responses of music are supported by four pillars: rhythmic response, musicality, cultural impact, and association [50].
\nThe rhythmic response represents the natural response to musical rhythm, which refers to the speed of music in beats per minute. Musicality refers to related elements such as pitch and harmony. Cultural impact is the representativeness of music to society or a cultural group. Association is the extramusical reflection that music can promote. These four factors are presented in their hierarchical order, so that there is a greater importance conferred on musical rhythm and less importance on association [49, 51]. In this sense, the use of motivational music is thought to be an important strategy in exercise for promoting acute and chronic benefits and assisting in exercise adherence [49].
\nMotivational music can be defined as stimulating music with a fast musical tempo and prominent beat. Studies that have investigated the acute effects of music on exercise have demonstrated the psychological and physiological influences on different populations [52, 53]. In diabetic patients, the practice of exercise with music provided greater affective responses than exercise without music [54]. In Silva’s research [55], motivational music provided a greater shift of focus from feelings of discomfort and effort than when exercise was performed without music in overweight and obese women. Macone [56] found positive changes in young adults in tension, depression, mood, confusion, and fatigue and improved running performance with motivational music compared to no music. Finally, music performs different functions in the context of exercise, and its action on motivational and dissociative aspects can affect psychophysiological factors and promote a positive and enjoyable experience during physical activity.
\nThe definitions of the terms “affect,” “humor,” and “emotion,” from a perspective that allows us to analyze their differences, are fundamental for the evolution of understanding “affect” and its application in exercise—a fact that has enabled researchers and other professionals to focus on observing “affect” from a categorical or dimensional perspective [1, 2]. In the field of exercise science, dimensional vision has allowed the appropriation and adaptation of instruments of affect measurement to be more appropriate to the context of the area, contributing to the growth of research, the comparison between studies, and the development of the field [32].
\nThe observation of affective responses before, during, and after exercise does not replace the prescription and observation of exercise-related physiological and perceived exertion responses, but their interrelated aspects complement the importance of the psychological and physiological benefits derived from regular practice [42]. The analysis of the relationship between intensity and affective responses has challenged exercise science to investigate exercise prescription strategies that provide pleasurable sensations and achieve appropriate physiological parameters for health benefits, as well as strategies for making exercises that require a higher physiological stimulus more enjoyable [39, 55, 57].
\nPrescribing exercise at a self-selected intensity was one of the possibilities that emerged in order to make exercise practice more enjoyable for sedentary individuals and beginners [39]. Investigations in this area present important results, with several limitations, such as reaching physiological stimuli beyond the ventilatory threshold [2, 57]. The use of music reaches broader parameters in the context of affective responses, stimulating positive changes from its rhythmic and cultural elements, as well as dissociating feelings of discomfort arising from exercise [47, 58]Thus, the effects of music, according to its specificities, may provide benefits independent of the intensity or mode of prescription.
\nUsing physical exercise as a nonpharmacological tool in disease prevention and treatment is a reality that tends to increase in the coming years; thus, the importance of understanding the affect-exercise relationship and its challenges will help in adhering to and, consequently, in obtaining the physiological and the psychological benefits from regular exercise.
\nUnderstanding affect from a dimensional perspective provides a broader view of the affect-exercise relationship. Although affect is understood to be a complex phenomenon, exercise intensity seems to be one of the main determinants of its quality and quantity. Selecting an appropriate exercise prescription mode and musical stimulation can also induce a more pleasurable affective experience and assist in the consistent adherence to exercise programs.
\nMyasthenia gravis (MG) is a clinically heterogeneous, B-cell-mediated disorder affecting the neuromuscular junction (NMJ) and is mostly caused by the abnormal production of autoantibodies against the acetylcholine receptor (AChR) located in the postsynaptic membrane [1]. MG is generally considered a prototypical autoimmune disease, since the main target of the autoimmune response in the affected patients is well known. However, it is uniquely characterized by morphological and functional thymic abnormalities (hyperplasia and thymoma), which make this organ the main site of immunological alterations leading to the disease. Indeed, if the muscle is the target organ in MG patients, the thymus is now widely accepted as the main effector organ, in which B-cell expansion, anti-AChR autosensitization, and autoimmune response arise and are perpetuated [2]. The exact mechanisms triggering and sustaining autoimmunity in MG thymus are still unknown. As with many autoimmune conditions, considerable evidence indicates a multifactorial MG pathogenesis based on complex interactions among multiple genetic and environmental factors and their interplay with the immune system [3]. Among environmental factors, viruses are the main suspects to play a role in autoimmune diseases, mainly by their ability to induce persistent or aberrant Toll-like receptor (TLR)-mediated innate immune responses, which are able to promote or favor autoimmunity in genetically susceptible individuals. In our studies, we provided evidence of dysregulated Epstein-Barr virus (EBV) infection in hyperplastic and thymomatous MG thymuses in association with TLR overexpression, thus revealing EBV as a key contributing factor to intra-thymic B-cell tolerance disruption and sustained B-cell-mediated autoimmunity in MG patients [4].
MG is an autoimmune disorder of the NMJ, leading to fluctuating weakness and fatigability of skeletal muscles, exacerbated by repetitive contraction and improved on resting. Frequently, MG starts with ocular symptoms, as diplopia and ptosis, but in 80–85% of cases, ocular disease progresses to a generalized form within the first 2–5 years from onset, involving skeletal, bulbar, or respiratory muscles [5]. Respiratory failure (myasthenic crisis) occurs in 15–20% of patients and can be observed in younger and older patients [6].
MG is a heterogeneous condition whose clinical variability allows classification of patients in distinct disease subgroups, mainly based on autoantibodies, age at onset, and thymic histology [1, 7, 8]. In more than 80% of patients, the autoimmune attack is mediated by autoantibodies against AChR, less frequently (1–5%) against the muscle-specific kinase receptor (MuSK) or the low-density lipoprotein receptor-related protein 4 (LRP4), two proteins involved in AChR clustering. In addition, autoantibodies against other NMJ components, including cortactin, agrin, titin, and ryanodine receptor (RyR), have been described, especially in late-onset or thymoma-associated disease; their presence is concomitant to anti-AChR autoantibodies and indicates more severe manifestations [7]. Around 10% of generalized (non-ocular) patients results negative for anti-AChR, anti-MuSK, or anti-LRP4 antibodies. Clinically, these seronegative patients are similar to AChR-MG patients and can show thymic hyperplastic changes [9]. The triple seronegative MG subgroup may be heterogeneous, including patients with antibodies having affinities or concentrations too low to be detected with standard routine assays, or patients with antibodies against relevant antigens not identified yet. The introduction of cell-based assays (CBAs), having increased sensitivity compared to the routine assays commonly used, has significantly increasing the chance to identify autoantibodies to low-affinity clustered AChR, MuSK, and LRP4, thus improving MG diagnosis [7, 10, 11, 12].
As mentioned above, AChR-MG is associated with thymic patho-histological changes, including follicular hyperplasia and thymoma [13, 14]. Its severity is related with the loss of AChRs on NMJ, but not with the titers of circulating autoantibodies [15]. According with age at onset, AChR-MG follows a bimodal pattern, with the first peak under 50 years (early-onset MG, EOMG), and a second peak >50 years (late-onset MG, LOMG) [16, 17]. EOMG occurs most in young women and is generally associated with thymic hyperplasia. LOMG, which usually is generalized, mainly affects men, who frequently present thymic involution. Thymoma-associated MG that presents more severe symptoms can occur at any age, though it is more frequent in the elderly myasthenic patients and is frequently associated with the presence of antibodies against RyR and titin along with anti-AChR antibodies [14, 17].
MuSK-MG patients are mainly young females and typically have severe clinical symptoms [18]. An intra-thymic pathogenesis for MuSK-MG is not considered relevant, although a recent study found hyperplasia in 23% of MG patients positive for anti-MuSK antibodies by CBA [11]. LRP4-MG is less characterized but largely overlaps with AChR-MG clinical features; typical thymic histopathology has been recorded with a sparing of thymoma, at least in the European multinational cooperative study by Zisimopoulou and colleagues [12]. Most of LRP4-MG patients present ocular or generalized mild manifestations, and about 20% have only ocular weakness for more than 2 years [12, 19].
In MG, degradation of the postsynaptic membrane results in decreased AChRs and voltage-gated sodium channels, causing a significant reduction of endplate potential and raising the firing threshold, which is required to generate an action potential. Thus, during prolonged synaptic activity, as the quantal ACh content normally runs down, the summation of endplate potentials falls below the threshold, and they can no longer trigger the action potential of muscle fibers, leading to typical muscle weakness [20]. Three mechanisms of action of anti-AChR autoantibodies can explain NMJ impairment: (1) functional AChR block due to autoantibodies binding to the ACh-binding sites; (2) cross-linking and subsequent AChR internalization due to the ability of autoantibodies to target two antigen molecules (antigenic modulation); and (3) complement pathway activation, which leads to the generation of the membrane attack complex (MAC) and hence the destruction of the postsynaptic membrane. Complement activation at NMJ is thought to be the main pathogenic mechanism of anti-AChR antibodies, which are mainly of the IgG1 and IgG3 classes and therefore can bind and activate the complement system [20].
MuSK antibodies are generally IgG4, lacking complement-fixing, and are considered functionally monovalent, being unable to induce antigenic modulation. They affect MuSK ability to maintain the correct AChR cluster at the NMJ, by inhibiting the formation of MuSK-LRP4 complex and the agrin-stimulated MuSK phosphorylation [21, 22]. In addition, anti-MuSK antibodies are able to block binding of ColQ to the NMJ, compromising agrin-mediated AChR clustering [23]. Experimentally, animals receiving repeated daily injections of MuSK-positive patients’ IgG, or actively immunized with MuSK, show impaired neuromuscular transmission, with reductions in endplate AChRs [24].
Both AChR-MG and MuSK-MG fulfill Witebsky’s criteria for autoimmune diseases [25]. LRP4-MG also seems to adhere to these criteria: mice immunized with the LRP4 extracellular domain, or with IgGs purified from LRP4-immunized rabbits, present anti-LRP4 antibodies, exhibit MG-associated symptoms and their serum is able to decrease cell surface LRP4 levels [26, 27]. Anti-LRP4 autoantibodies mainly belong to the IgG1 subclass, thus they can activate the complement system; moreover, they prevent agrin-induced MuSK activation and AChR clustering [27].
Current therapeutic approaches for MG include symptomatic treatment with cholinesterase inhibitors, non-specific immunosuppression with corticosteroids and thymectomy in selected patients. Plasmapheresis or immunoglobulins are used for acute management of severe muscular weakness [8]. New biological drugs targeting molecules involved in the specific immune-pathological mechanisms, like eculizumab, which blocks the C5 terminal complement component, and efgartigimod, a functional IgG neonatal Fc receptor blocker, are promising for more specific and effective intervention to reduce corticosteroids side effects and to treat refractory patients [8].
The thymus is a primary lymphoid organ that provides a complex environment essential for T-cell differentiation and the establishment of central tolerance. It is composed of various cell types, mainly thymocytes and thymic epithelial cells (TECs), but also myoid cells, dendritic cells (DCs), macrophages, and B-cells in a limited number. By expressing tissue-specific antigens, mainly via the transcription factor autoimmune regulator (AIRE), medullary TECs play a key role in negative selection of thymocytes. Indeed, interactions between these cells and developing thymocytes lead to the elimination of autoreactive T cells, whereas the self-tolerant T cells continue their differentiation through the different thymus compartments, to be exported to the periphery [28].
Structural and functional pathological alterations of the thymus are found in approximately 80% of AChR-MG patients with generalized disease, including thymic hyperplasia (about 70% of patients) and thymoma (10–15%); the remaining patients (10–20%) present an atrophic or involuted thymus, mainly consisting of adipose tissue with residual areas of thymic parenchyma, in some cases showing hyperplastic changes (Figure 1) [13, 29, 30]. Hyperplasia is characterized by the presence of B-lymphocyte infiltrates invading the thymic medulla, or present in expanded perivascular spaces fused with the thymic medulla. B-cell infiltrates can be scattered throughout the medullary parenchyma (diffuse hyperplasia) or be organized into ectopic B-cell germinal centers (GCs) which, together with DCs and follicular helper T (Tfh) cells, form follicles (follicular hyperplasia) [30]. GCs are microarchitectures specialized to produce high-affinity antibodies against antigens, to establish the humoral immune response [31]. They are present in secondary lymphoid organs but rarely into the thymus, implying that GC development in the thymus of MG patients is a pathological event related to autoimmunity development. Ectopic GC formation is a characteristic feature of other organs target of chronic inflammation and autoimmunity, including multiple sclerosis (MS) brain and synovia of rheumatoid arthritis (RA) patients, indicating that lymphoid neogenesis plays a relevant role in the immune-pathological process of inflammatory autoimmune conditions [31, 32, 33]. In MG, GC formation is associated with the production of high endothelial venules expressing inflammatory chemokines, that abnormally recruit peripheral immune cells into the thymus, including the chemokine ligand 21 (CCL21), a key molecule that orchestrates thymic hyperplastic changes by promoting B-cell infiltration [34]. Uniquely, MG thymic GCs are surrounded by muscle-like myoid cells expressing AChR and other muscle antigens, along with plasma cells [35], thus supporting the idea that GCs may be the site of autosensitization and autoantibody production in the thymus of MG patients.
Pathological abnormalities of myasthenia gravis thymus. Immunohistochemistry stainings showing CD20-positive B-cells in ectopic germinal centers (GCs) and lymphoid infiltrates of follicular hyperplastic (MG-FH) and diffuse hypeplastic (MG-DH) thymuses. CD20-positive B-cells are also scattered throughout the residual thymic parenchima in involuted MG thymuses characterized by abundant interlobular fat (MG-INV). CD20-positive B-cells, isolated or present as aggregates, can be detected in the cytokeratin (CK)-positive tumoral tissue of MG thymomas (MG-T).
A wealth of data indicates that MG thymus contains all the elements necessary for developing and perpetuating an AChR-specific autoimmune response: TECs and muscle-like myoid cells expressing the autoantigen, professional antigen-presenting cells, AChR-specific autoreactive T cells and B-cells, and plasma cells producing autoantibodies [30]. Indeed, transplantation of MG thymic fragments to immunodeficient mice induces the formation of anti-AChR antibodies and their deposition at the skeletal muscle endplates [36].
As regard to the autoantigen presentation, TECs express major histocompatibility (MHC) class II complex and AChR subunits, including α, β, and γ subunits [37]. Thymic myoid cells express not only AChR subunits but also a functional AChR, whose fragments can be presented to T lymphocytes by cross-presentation via DCs, since myoid cells do not express MHC class II molecules [38, 39]. Cross-presentation may be favored by a persistent autoantibody and complement-mediated attack to myoid cells, which make the levels of autoantigen more available to DCs [40, 41]. Both TECs and myoid cells respond to pro-inflammatory cytokines by increasing the expression of AChR components, mainly the α subunit, which contains the main immunogenic region, thus suggesting that inflammation in the thymic microenvironment can results in enhanced autoantigen presentation and possible autosensitization against AChR [42]. Indeed, several lines of evidence indicate that MG thymus is in a state of chronic inflammation, characterized by an overexpression of pro-inflammatory cytokines and chemokines (IL-6, CCL19, CCL21, CXCL10, CXCL11, CXCL13, and RANTES) [43]. Among cytokines, type I interferons (IFNs) and IFN-induced genes are significantly up-regulated in hyperplastic MG thymuses and have been critically involved in driving thymic events that can lead to follicular hyperplastic changes, AChR overexpression and autosensitization. In particular, IFN-β was found to increase α-AChR-specific expression in TECs, along with the expression of inflammatory chemokines (e.g., CXCL13 and CCL21), and was able to recruit T and B-cells into the thymus, as well as B-cell activating factor (BAFF), which favors B-cell survival [44]. In hyperplastic MG thymus, no changes in the frequency of CD4+ and CD8+ T cells exported to the periphery was observed, but functional defects of regulatory T cells (Tregs) were demonstrated, along with resistance of conventional T cells to the Treg immunosuppressive function, thus indicating dysregulation of immunoregulatory mechanisms [45]. Altered Treg/T effector cell balance was associated with increased expression of pro-inflammatory cytokines by MG T cells, mainly IL-17, IFN-γ, IL-21, and tumor necrosis factor α (TNF-α) [45].
Thymoma is a rare thymic epithelial tumor, associated with autoimmune and paraneoplastic syndromes. The most common thymoma-associated autoimmune disorder is MG: up to 50% of thymoma cases may develop MG, whereas 10–15% of MG patients present thymoma [46]. Histologically, thymoma is a slow growing, locally invasive tumor consisting of transformed epithelial cells surrounded by maturing polyclonal T cells. The most recent World Health Organization (WHO) classification identified five types, A, AB, B1, B2, and B3, based on the nature of the cortical or medullary epithelial cells, and on the proportion of lymphocytes, with B2 and AB being the WHO types most frequently associated with MG [47, 48]. MG associated with thymoma usually has worse prognosis, showing generalized and maximum severe symptoms [48]. Alterations typical of the thymoma microenvironment may explain the development of AChR-specific autoimmunity in thymoma patients. They include: the lack of a functional medulla expressing AIRE; the reduction, or absence, of tolerogenic myoid cells; the reduced expression of HLA class II molecules; and the failure of Treg generation, which ultimately leads to autosensitization to AChR, and other locally expressed muscle antigens, and defective negative T-cell selection [14, 49, 50]. Recently, a higher proportion of GCs was abnormally found in non-neoplastic thymic tissue adjacent to thymoma in MG patients compared to thymoma patients without MG, suggesting that B-cell dysregulation characterizes not only thymic hyperplasia but also thymoma-associated MG, and that GCs may represent a risk factor for the development of MG in thymoma patients [51].
An important evidence of the central contribution of the thymus in autoimmune response development and maintenance in MG is the ability of thymectomy to improve the disease course in non-thymomatous patients over a 2-year period after the surgery, as demonstrated by the MGTX clinical trial, and its extension study [29, 52]. Thymectomy is mandatory for thymoma patients. Its efficacy as treatment option in non-thymomatous patients is plausibly due to eradication of the site of autoimmunity, as indicated by the fact that AChR antibody titers usually fall after thymectomy, and the magnitude of this fall correlates with the proportion of GC B-cells in the removed thymus [53]. However, autoantibody titers do not always fall, suggesting other possible sites of autoantibody production in some patients [54].
Innate immunity is the first line of defense against pathogen infections. Its interplay with the adaptive-humoral immune system plays a key role in central and peripheral tolerance maintenance, and strictly depends on a fine regulation of TLRs. TLRs are a family of pattern recognition receptors (PRRs) able to recognize specific conserved microbial-derived molecular structures, thus sensing danger signals. They are expressed by a variety of cell types, but mainly by innate immune cells, such as DCs and macrophages [55]. The TLR family includes at least 11 members in humans: TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10, which are located on the cell surface and recognize microbial membrane-associated molecules (e.g., LPS, lipoprotein, and peptidoglycan); TLR3, TLR7, TLR8, TLR9, and TLR11, present on the intra-cellular endosome membranes and able to distinguish bacterial or viral nucleic acids, including ssRNA, dsRNA, and unmethylated cytosine phosphate guanine (CpG)-containing DNA [55]. Upon its own specific ligand binding, TLR dimerizes, internalizes, and interacts with the intracellular adaptor myeloid differentiation primary response gene 88 (Myd88) or with the TIR domain-containing adapter-inducing IFN-β (TRIF), which activates nuclear factor κB (NFκB) and IFN response factor transcription. The TLR signaling cascade induces the expression of pro-inflammatory agents (e.g., IFN-I, IL-6, IL-12, IL-23, and TNF-α), which in turn contribute to activate immune system cells [56]. In this way, the first function of TLRs is to set up an innate immune response to protect the organism from pathogens. However, TLRs have been implicated in several autoimmune diseases, including systemic lupus erythematosus (SLE), RA, and MS, by studies performed in humans and animal models [56, 57]. Specifically, dysregulated or persistent TLR activation has been demonstrated to contribute to autoimmunity by (i) abnormal stimulation of antigen-presenting cell maturation and increased IFN-I and pro-inflammatory cytokine production; (ii) altered balance between Treg and T helper 17 (Th17) cells; (iii) induction of co-stimulatory signals for proliferation, maturation, and survival of B-cells, which compromise B-cell tolerance; and (iv) promotion of GC formation [56, 57, 58].
In hyperplastic MG thymuses, overexpression of TLR3, TLR4, TLR7, and TLR9, in association with chronic inflammation, has been demonstrated in different studies, thus supporting the existence of a critical cross talk between innate immunity and autoimmunity in the intra-thymic MG pathogenesis [59, 60, 61, 62, 63].
Our group was the first to demonstrate a marked overexpression of TLR4 in involuted and hyperplastic MG thymuses, especially in TECs [59]. Later, we revealed that TLR4 stimulation in MG TECs was able to increase the production of Th17-related cytokines and the expression of CCL17 and CCL22, two chemokines involved in peripheral immune system cell recruitment in inflamed organs, that we found to be overexpressed in MG thymuses [60]. Moreover, by generating an in vitro imaging model based on experimental autoimmune MG co-cultures of Th1/Th17 AChR-specific T cells, naïve Tregs, DCs, and TECs, we found that TLR4 stimulation increased AChR-specific T-cell activation and impaired Treg function, thus disclosing a contribution of dysregulated TLR4 signaling to the inflammatory and autoimmune process in the MG thymic milieu [60].
Cufi and colleagues showed that also TLR3 is overexpressed in MG thymuses and demonstrated that stimulation of this TLR with its ligand poly(I:C), a synthetic analog of viral dsRNA, induced a specific up-regulation of α-AChR in TECs but not of other AChR subunits or tissue-specific antigens, via IFN-β release [61]. Of interest, another study of the same group disclosed that poly(I:C) injection in wild-type mice, in combination with LPS, that stimulates TLR4 was able to increase α-AChR thymic expression and induce thymic hyperplastic changes along with production of serum anti-AChR antibodies [62]. These mice developed MG symptoms in absence of any AChR immunization, thus supporting the idea that pathogen infections could contribute to anti-AChR sensitization and autoimmunity development via persistent or abnormal TLR stimulation [62].
Along with TLR3 and TLR4, TLR7 and TLR9 have also been implicated in the intra-thymic pathological events leading to MG. Indeed, we recently revealed a significant TLR7 and TLR9 up-regulation in both involuted and hyperplastic MG thymuses compared to normal thymuses, with the two receptors being mainly expressed in B-cells, TECs, plasmacytoid DCs, and macrophages [63]. TLR7 was also enhanced in thymic myeloid DCs and its transcriptional levels positively correlated with those of IFN-β [63]. Interestingly, as described in the following paragraphs, the two receptors were markedly expressed in B-cells and plasma cells positive for EBV proteins, indicating EBV as contributing environmental factor implicated in dysregulated TLR activation in MG thymuses.
Of interest, due to the key contribution of TLRs to chronic inflammation and immune system dysregulation, their pathways are rapidly emerging as attractive targets for therapeutic strategies able to mitigate or inhibit autoimmune processes [64].
EBV is the main virus suspected to play a role in autoimmune diseases due to its unique ability to infect, activate, and immortalize B-cells, allowing them to evade immune surveillance, at the same time, promoting inflammatory state via TLR-mediated innate immune responses [65, 66].
EBV is a DNA virus of the herpes virus family transmitted through saliva exchange and infecting approximately 95% of the world’s population [65]. EBV primary infection mostly occurs during childhood and shows mild symptoms or more frequently none. However, in adolescence or adulthood, EBV causes infectious mononucleosis in 30–70% of cases, with up to 20% of B-cells being infected [67]. After resolution of primary infection, EBV persists lifelong in the host in rare circulating memory B-cells. In the latent state, it is not detectable by immune system and its genome circularizes and replicates together with the host’s chromosomal DNA, resulting in a restricted expression of a maximum of nine viral genes: the EBV nuclear antigens (EBNA1, −2, −3A, -3B, and -3C), the leader protein (LP), and the latent membrane proteins (LMP1, −2A, and -2B). Different expression patterns of EBV latent genes determine the occurrence of EBV latency types I, II, or III, each type being associated with distinct EBV-related diseases [65, 68, 69, 70]. EBV-encoded small nuclear RNA (EBER) 1 and 2 as well as EBNA1 are expressed in all the latency types [65]. EBNA2 is expressed during latency type III (known as growth program), typical of newly infected naïve B-cells, lymphoproliferative disorders, and mononucleosis [68, 69, 70, 71]. LMP1 and LMP2A, key proteins that rescue infected B-cells from apoptosis, act as functional homologs of CD40 and B-cell receptor (BCR) and are expressed during latency III and II (known as default program), with type II being observed in memory B-cells and GC cells, Hodgkin and non-Hodgkin lymphoma, and nasopharyngeal carcinoma [65, 68]. Finally, latency I (known as true latency) is characterized by EBNA1 and EBER expression only; it is typically observed in rare peripheral blood memory B-cells and is associated with Burkitt’s lymphoma [65, 68].
The exact mechanism waking up lytic EBV activities is not clear, but it seems to be the result of dynamic interactions between the host’s immune response and the infection state. When infected B-cells differentiate into plasma cells, the promoter of early lytic genes can be reactivated, driving expression of numerous proteins involved in viral activities (i.e., BSLF1, BALF2, BBLF4, and BALF5) [65]. Two genes, BZLF1 and BRLF1, which encode viral transcription factors, orchestrate the transition from viral latency to lytic infection [69]. New virions primarily infect B-cells, and the viral entry is mediated by viral gp350 protein binding to CD21 [70].
Uniquely, EBV ensures early mechanisms of immune evasion, such as the inhibition of IFN pathways, through a viral IL-10 homolog, the suppression of cytotoxic T-cell responses and the down-regulation of MHC class I and II expression. Moreover, some of the viral proteins are anti-apoptotic, including the early antigen restricted (EA/R), which is a Bcl2 viral homolog that protects infected B-cells from apoptosis and immortalize them [71]. Several mature EBV miRNAs also contribute to immune system alterations in the host by modulating expression of genes involved in immune recognition, antigen presentation and cellular migration, such as miR-BHRF1–3, which regulates IFN-inducible T-cell-attracting chemokine CXCL-11 expression, or miR-BART20-5p and miR-BART8, which affect the IFN-γ signal transduction pathway [72].
Despite it is innocuous in most cases, EBV has true pathogenic potential due to persistent latent infection with periodic reactivations. Disruption of the virus-host balance in susceptible individuals can favor autoimmunity or the abovementioned B-cell malignancies [68, 73]. Among autoimmune diseases, EBV has been associated with MS, SLE, and RA by a number of sero-epidemiological and immunological studies [65, 68, 73]. Moreover, EBV persistence and reactivation have been demonstrated in ectopic B-cell follicles detected in MS brains [74], in the Sjögren’s Syndrome salivary glands [75], and in synovia from RA patients [76], suggesting that EBV might be a common pathogenic feature of autoimmune conditions characterized by B-cell activation and lymphoid neogenesis.
Several mechanisms have been described to explain how viruses may rise an autoimmune response, including molecular mimicry and immune system general activation via TLRs. Molecular mimicry is due to T-cell Receptor (TCR) and BCR recognition flexibility, so that a microbial peptides, structurally similar to a self-peptide, may trigger the autoimmune response [77]. As regard to EBV, EBV-encoded proteins, such as BZLF1, share regions with the host transcription factors of the fos/jun family and host ankyrin proteins, which anchor the cytoskeleton and regulate host transcription factors, including NF-kB, which is critically involved in the immune response [78]. Quantitative and qualitative differences in CD4+ T-cell response to EBNA1 have been described in MS patients [79], and a small percentage of EBNA1-specific T-cell clones cross-recognize myelin-derived epitopes [80]. A further well-characterized example of molecular mimicry between EBV and host proteins is the similarity of regions of EBNA1 with ribonuclear protein Smith (Sm) antigen or the Ro self-protein in SLE [81]. There are also several examples of molecular mimicry relevant for RA, related to aminoacid motif sharing between HLA-DRB1 and EBV gp110, cytokeratin and type II collagen, and citrullinated human fibrin and a citrullinated EBNA1 form [82].
Another hypothesis of virus-induced autoimmunity is bystander activation, in which viruses act as super-antigens that promote general activation of the immune system; in this context, specialized antigen presenting cells present self-antigens, obtained by inflamed tissue destruction or by the uptake of local dying cells, to autoreactive T cells [77]. In MS, bystander activation may result in central nervous system damage by CD8+ T-cell cytotoxicity and EBER-induced IFN-α production via innate immune response, both described in post-mortem brain tissue from MS patients [74, 83]. EBV can promote inflammation in the infected organs by innate immune system activation, through release of molecules able to activate diverse TLRs and type I IFN production [66, 84]. The EBV envelope protein gp350 stimulates TLR2, whereas EBERs bind TLR3; moreover, EBV RNA and DNA can activate pathways mediated by TLR7 and TLR9 [66]. Thus, EBV ability to stimulate persistent TLR signaling may also contribute to disrupt immune system balance, favoring chronic inflammation and autoimmunity.
Evidence of chronic inflammation, GC formation, and TLR overexpression in MG thymus, along with data demonstrating a role of TLRs in inducing anti-AChR autoimmunity and MG symptoms in mice, pointed out the idea that MG pathogenesis could be associated with viral infections [43, 59, 60, 61, 62, 63].
Based on the hypothesis that active EBV infection may be a common pathogenic event of organs site of autoimmunity, in our previous studies we searched for the expression of EBV markers in the thymus of MG patients. Of interest, we provided the first demonstration of EBV presence in both hyperplastic and thymoma MG thymuses, but not in normal thymuses and non-MG thymomas, obtaining results indicative of a contribution of the virus to B-cell dysregulation, TLR overexpression and B-cell-mediated autoimmunity in MG [4, 63, 85, 86, 87].
Earlier serological studies to associate MG with EBV produced contrasting results. One of them underlined no significant difference in incidence or antibody titers to EBV, cytomegalovirus, herpes simplex type 1 and other virus, in 104 MG patients compared to age-matched healthy controls, weakening the virus hypothesis in MG pathogenesis [88]. More recently, Bhibhatbhan and colleagues reported a case of young woman with abrupt onset of both MuSK-MG and type I diabetes mellitus, following infectious mononucleosis, bringing attention back to EBV in MG [89]. Few years after, according with a possible association between MG and EBV, Csuka and collaborators discovered a strong association between EOMG and high anti-EBNA1 IgG serum concentration in EOMG patients [90]. Despite these results were conflicting, our recent pathological findings, which are deeply described below, allowed us to include MG among the autoimmune diseases critically associated with EBV.
To our knowledge, the earliest study attesting EBV presence in MG thymuses was performed by McGuire and colleagues, who found EBV DNA in thymuses of 2/4 MG patients with thymic hyperplasia, and 2/2 patients with thymoma [91]. Before that, several attempts were made for identifying or isolating viruses from homogenates or cell suspensions of MG thymuses, but without success [92, 93]. However, these initial studies used techniques, and tissue storage methods, that cannot be considered sufficiently sensitive or optimal today.
Based on data showing EBV reactivation in intra-meningeal B-cell follicles in MS patients [74], our group decided to check for signs of EBV infection in MG thymuses (n = 17), both hyperplastic (follicular and diffuse) and involuted thymuses by using a combination of techniques, including in situ hybridization (ISH) to detect EBERs, immunohistochemistry (IHC) for latent and lytic EBV antigens, real-time PCR for viral DNA (LMP1 gene), and nested PCR for viral transcripts. As controls, normal thymuses (n = 6) from adult cardiopathic donors without autoimmune diseases were analyzed [85]. Interestingly, all MG, but not normal thymuses, resulted positive for EBV latency and lytic markers, strongly indicating EBV persistence and reactivation as a common feature of MG patients’ thymuses (Figure 2). In details, by ISH, variable number of EBERs-positive cells was detected in medullary infiltrates of all the MG thymuses analyzed, particularly in GCs of hyperplastic MG thymuses. Accordingly, IHC results showed expression of EBV latency proteins EBNA2, LMP1, and LMP2A in cells scattered throughout the thymic medulla and in GCs. The early BFRF1 and BMRF1, and the late p160 and gp350/220 lytic phase EBV proteins were also found in most MG thymuses, but not in control tissues, indicating EBV reactivation. Double immunofluorescence and confocal microscopy then revealed that latently infected cells were diffuse infiltrating and GC B-cells, whereas plasma blasts, mainly located around GCs, were positive for the lytic markers [85]. By PCR approaches, latent EBNA1 and LMP2A transcripts, and the early BZLF1 lytic transcript, along with EBV DNA, were detected in MG thymuses, but not in normal thymuses, thus confirming the active EBV infection. Due to the EBV properties to activate and immortalize B-cells, our findings thus suggested a critical contribution of the virus to intra-thymic B-cell dysfunction and B-cell-mediated autoimmunity in MG patients [85].
Detection of EBV markers in follicular hyperplastic MG thymus (MG-FH), and MG thymoma (MG-T), but not in non-MG thymoma (No MG-T) and normal thymus. Representative images of immunohistochemistry and immunofluorescence stainings showing: EBER-positive cells and cells positive for latent LMP2A and lytic BMRF1 proteins in MG-FH; latent EBNA1-positive cells and CD20-positive B-cells expressing LMP1 in MG thymomas; absence of EBNA1-positive and LMP2A-positive cells in No MG-T; absence of LMP1-positive cells in normal thymuses.
In a following study, we extended the analysis of EBV to additional MG thymuses (n = 19). Real-time PCR for EBV DNA (
In contrast to our outcomes, Meyer and colleagues [94] and Kakalacheva and colleagues [95] reported absence or very low presence of EBV in MG thymuses. The first group performed ISH on formalin-fixed, paraffin-embedded MG thymic tissues (n = 44) and did not observe EBER-positive cells, likewise on cases of Hashimoto thyroiditis (n = 25), except for an isolate case in which rare EBER-positive lymphocytes were detected. Moreover, EBNA1 or BZLF1-positive cells were absent in MG thymuses or Hashimoto thyroiditis by IHC, whereas in infectious mononucleosis rare scattered positive cells were detected [94]. Kakalacheva
To better understand the EBV role in MG pathogenesis, we recently investigated the potential cross talk between TLRs and EBV in rising or sustaining self-reactivity. In details, since EBV molecules (EBERs, EBV DNA) are known to activate TLR7 and TLR9, and considering that these two receptors have super-addictive effects on EBV-induced B-cell activation and transformation process [66, 97], we analyzed their expression in EBV-positive MG and EBV-negative normal thymuses. We revealed an increased percentage of proliferating B-cells positive for EBV markers, and overexpressing TLR7 and TLR9, in EBV-positive hyperplastic MG thymuses compared to controls [63]. Our overall data thus indicated for the first time that aberrant EBV-driven TLR7 and TLR9 signaling in MG thymuses might contribute to abnormal B-cell activation and proliferation, in turn promoting or perpetuating B-cell-mediated autoimmunity in MG patients.
Since the 1980s, the involvement of EBV in thymoma, associated or not with MG, has long been investigated. However, data obtained by the different studies were contrasting: (i) McGuire et al. found EBV DNA in three thymomas, of which two were from MG patients [91]; (ii) absence of EBV in thymic epithelial tumors was reported by Inghirami
Recently, by combining ISH, IHC and molecular techniques, our group demonstrated the presence of latency EBV markers in MG-associated thymomas, but only rarely in thymomas from patients without MG [87]. Specifically, by real-time PCR we showed a significantly higher frequency of EBV DNA and EBER1 detection in MG (53.8% and 84.6%) than non-MG (21.4%) thymomas, with the higher viral load and EBER1 levels being mainly observed in B2 and B2-mixed tumors, the WHO subtypes most frequently associated with MG. These data were in contrast with data on EBV DNA from Cufi and colleagues [102], likely because of the different sensitivity of the protocol used for the viral genome detection.
We then confirmed our molecular results by ISH, which showed the presence of cells positive for EBERs in MG, but not in non-MG thymomas [87]. Latent EBNA2 and late gp350/220 lytic transcripts were undetectable in all thymomas, except one, as well as the early lytic transcript BZLF1, thus revealing that early infection and EBV reactivation are very rare event in thymomas. By IHC analysis, we confirmed EBV persistence in MG thymomas, but not in thymomas without MG, and identified the phenotype of EBV-positive cells, that were B-cells positive for the EBV latency proteins EBNA1, LMP1, and LMP2, diffused throughout the MG neoplastic tissues (Figure 2). Based on the EBV gene expression pattern, we suggested EBV latency type II in MG thymomas. Due to the absence of EBV in thymic epithelial cells, these results thus revealed an association of EBV with B-cell-mediated autoimmunity in MG associated with thymoma, rather than with thymic neoplastic transformation [87]. We also found higher TLR3 transcriptional levels in MG than non-MG thymomas. Transcriptional levels of this receptor positively correlate with EBER1 levels, supporting a possible role for EBER1 in inducing persistent TLR3 signaling pathways in thymoma from MG patients [87]. Due to the previously described role of TLR3 in triggering an anti-AChR autoimmune response [62], our findings strengthened the idea of a critical contribution of EBV to B-cell-mediated autoimmunity via TLR3 in these pathological tissues. Indeed, the activation of EBV-driven TLR3 signaling may well contribute to create an altered tumor microenvironment, which supports the recruitment of peripheral B-cells, and thus B-cell dysregulation and tolerance disruption.
EBV has been associated with several autoimmune diseases by sero-epidemiological and immunological data. Our findings revealed for the first time a contribution of EBV to the intra-thymic MG pathogenesis, thus allowing to include MG among the autoimmune conditions associated with the virus. Based on our results and literature data, we postulate that, in the context of a genetically susceptible background, EBV persistence and reactivation into the thymus may favor B-cell dysregulation, TLR over-stimulation, inflammation, and B-cell-mediated autoimmune response to AChR, which can be perpetuated in the periphery. Further advancement in the knowledge of the exact involvement of EBV and TLRs in MG pathogenesis could set the basis for novel investigations aimed at developing innovative therapeutic applications targeting EBV-positive cells, TLRs, or components of their signaling pathways to counteract autoimmunity in MG and potentially other EBV-associated autoimmune diseases.
The authors wish to thank Dr. Francesca Aloisi and Dr. Barbara Serafini of the Department of Cell Biology and Neuroscience at the Istituto Superiore di Sanità (Rome, Italy) for the key contribution to the studies on EBV in MG thymuses. The authors also thank the neurologists and biologists of the Neurology IV Unit—Neuroimmunology and Neuromuscular Disease at the Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta (Milan, Italy), for their participation in various aspects of these studies, and the Italian Association of Myasthenia Gravis (A.I.M., Associazione Italiana Miastenia e Malattie Immunodegerative—Amici del Besta Onlus) for their kind support to the research activity. The research activity was supported by the Italian Ministry of Health (GR-2013- 02358564 and annual research funding).
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Biosensors, Biomaterials and Tissue Engineering",value:9,count:1},{group:"subseries",caption:"Bioinspired Technology and Biomechanics",value:8,count:2},{group:"subseries",caption:"Bioinformatics and Medical Informatics",value:7,count:9}],publicationYearFilters:[{group:"publicationYear",caption:"2021",value:2021,count:4},{group:"publicationYear",caption:"2019",value:2019,count:5},{group:"publicationYear",caption:"2018",value:2018,count:3}],authors:{paginationCount:250,paginationItems:[{id:"274452",title:"Dr.",name:"Yousif",middleName:"Mohamed",surname:"Abdallah",slug:"yousif-abdallah",fullName:"Yousif Abdallah",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274452/images/8324_n.jpg",biography:"I certainly enjoyed my experience in Radiotherapy and Nuclear Medicine, particularly it has been in different institutions and hospitals with different Medical Cultures and allocated resources. Radiotherapy and Nuclear Medicine Technology has always been my aspiration and my life. As years passed I accumulated a tremendous amount of skills and knowledge in Radiotherapy and Nuclear Medicine, Conventional Radiology, Radiation Protection, Bioinformatics Technology, PACS, Image processing, clinically and lecturing that will enable me to provide a valuable service to the community as a Researcher and Consultant in this field. My method of translating this into day to day in clinical practice is non-exhaustible and my habit of exchanging knowledge and expertise with others in those fields is the code and secret of success.",institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"313277",title:"Dr.",name:"Bartłomiej",middleName:null,surname:"Płaczek",slug:"bartlomiej-placzek",fullName:"Bartłomiej Płaczek",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313277/images/system/313277.jpg",biography:"Bartłomiej Płaczek, MSc (2002), Ph.D. (2005), Habilitation (2016), is a professor at the University of Silesia, Institute of Computer Science, Poland, and an expert from the National Centre for Research and Development. His research interests include sensor networks, smart sensors, intelligent systems, and image processing with applications in healthcare and medicine. He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University. His research interests include computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, intelligent systems, information technology, and information systems. Prof. Sarfraz has been a keynote/invited speaker on various platforms around the globe. He has advised various students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He is a member of various professional societies and a chair and member of the International Advisory Committees and Organizing Committees of various international conferences. Prof. Sarfraz is also an editor-in-chief and editor of various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/267434/images/system/267434.jpg",biography:"Dr. Rohit Raja received Ph.D. in Computer Science and Engineering from Dr. CVRAMAN University in 2016. His main research interest includes Face recognition and Identification, Digital Image Processing, Signal Processing, and Networking. Presently he is working as Associate Professor in IT Department, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur (CG), India. He has authored several Journal and Conference Papers. He has good Academics & Research experience in various areas of CSE and IT. He has filed and successfully published 27 Patents. He has received many time invitations to be a Guest at IEEE Conferences. He has published 100 research papers in various International/National Journals (including IEEE, Springer, etc.) and Proceedings of the reputed International/ National Conferences (including Springer and IEEE). He has been nominated to the board of editors/reviewers of many peer-reviewed and refereed Journals (including IEEE, Springer).",institutionString:"Guru Ghasidas Vishwavidyalaya",institution:{name:"Guru Ghasidas Vishwavidyalaya",country:{name:"India"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:null,institution:{name:"Beijing University of Technology",country:{name:"China"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"265335",title:"Mr.",name:"Stefan",middleName:"Radnev",surname:"Stefanov",slug:"stefan-stefanov",fullName:"Stefan Stefanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/265335/images/7562_n.jpg",biography:null,institutionString:null,institution:{name:"Medical University Plovdiv",country:{name:"Bulgaria"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Igor Victorovich Lakhno was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPh.D. – 1999, Kharkiv National Medical Univesity.\nDSC – 2019, PL Shupik National Academy of Postgraduate Education \nProfessor – 2021, Department of Obstetrics and Gynecology of VN Karazin Kharkiv National University\nHead of Department – 2021, Department of Perinatology, Obstetrics and gynecology of Kharkiv Medical Academy of Postgraduate Education\nIgor Lakhno has been graduated from international training courses on reproductive medicine and family planning held at Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor in the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics, and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s been a professor in the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics, and gynecology department. He’s affiliated with Kharkiv Medical Academy of Postgraduate Education as a Head of Department from November 2021. Igor Lakhno has participated in several international projects on fetal non-invasive electrocardiography (with Dr. J. A. Behar (Technion), Prof. D. Hoyer (Jena University), and José Alejandro Díaz Méndez (National Institute of Astrophysics, Optics, and Electronics, Mexico). He’s an author of about 200 printed works and there are 31 of them in Scopus or Web of Science databases. Igor Lakhno is a member of the Editorial Board of Reproductive Health of Woman, Emergency Medicine, and Technology Transfer Innovative Solutions in Medicine (Estonia). He is a medical Editor of “Z turbotoyu pro zhinku”. Igor Lakhno is a reviewer of the Journal of Obstetrics and Gynaecology (Taylor and Francis), British Journal of Obstetrics and Gynecology (Wiley), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for a DSc degree “Pre-eclampsia: prediction, prevention, and treatment”. Three years ago Igor Lakhno has participated in a training course on innovative technologies in medical education at Lublin Medical University (Poland). Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: are obstetrics, women’s health, fetal medicine, and cardiovascular medicine. \nIgor Lakhno is a consultant at Kharkiv municipal perinatal center. He’s graduated from training courses on endoscopy in gynecology. He has 28 years of practical experience in the field.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. RELACION DE PONENCIAS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGIA. 10/2014.",institutionString:null,institution:null},{id:"243698",title:"Dr.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:null,institution:null},{id:"7227",title:"Dr.",name:"Hiroaki",middleName:null,surname:"Matsui",slug:"hiroaki-matsui",fullName:"Hiroaki Matsui",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Tokyo",country:{name:"Japan"}}},{id:"312999",title:"Dr.",name:"Bernard O.",middleName:null,surname:"Asimeng",slug:"bernard-o.-asimeng",fullName:"Bernard O. Asimeng",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Ghana",country:{name:"Ghana"}}},{id:"318905",title:"Prof.",name:"Elvis",middleName:"Kwason",surname:"Tiburu",slug:"elvis-tiburu",fullName:"Elvis Tiburu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Ghana",country:{name:"Ghana"}}},{id:"336193",title:"Dr.",name:"Abdullah",middleName:null,surname:"Alamoudi",slug:"abdullah-alamoudi",fullName:"Abdullah Alamoudi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"318657",title:"MSc.",name:"Isabell",middleName:null,surname:"Steuding",slug:"isabell-steuding",fullName:"Isabell Steuding",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"318656",title:"BSc.",name:"Peter",middleName:null,surname:"Kußmann",slug:"peter-kussmann",fullName:"Peter Kußmann",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}}]}},subseries:{item:{id:"10",type:"subseries",title:"Animal Physiology",keywords:"Physiology, Comparative, Evolution, Biomolecules, Organ, Homeostasis, Anatomy, Pathology, Medical, Cell Division, Cell Signaling, Cell Growth, Cell Metabolism, Endocrine, Neuroscience, Cardiovascular, Development, Aging, Development",scope:"Physiology, the scientific study of functions and mechanisms of living systems, is an essential area of research in its own right, but also in relation to medicine and health sciences. The scope of this topic will range from molecular, biochemical, cellular, and physiological processes in all animal species. Work pertaining to the whole organism, organ systems, individual organs and tissues, cells, and biomolecules will be included. Medical, animal, cell, and comparative physiology and allied fields such as anatomy, histology, and pathology with physiology links will be covered in this topic. 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