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IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
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\\n\\nLaunching 2021
\\n\\nArtificial Intelligence, ISSN 2633-1403
\\n\\nVeterinary Medicine and Science, ISSN 2632-0517
\\n\\nBiochemistry, ISSN 2632-0983
\\n\\nBiomedical Engineering, ISSN 2631-5343
\\n\\nInfectious Diseases, ISSN 2631-6188
\\n\\nPhysiology (Coming Soon)
\\n\\nDentistry (Coming Soon)
\\n\\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\\n\\nNote: Edited in October 2021
\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/132"}},components:[{type:"htmlEditorComponent",content:'With the desire to make book publishing more relevant for the digital age and offer innovative Open Access publishing options, we are thrilled to announce the launch of our new publishing format: IntechOpen Book Series.
\n\nDesigned to cover fast-moving research fields in rapidly expanding areas, our Book Series feature a Topic structure allowing us to present the most relevant sub-disciplines. Book Series are headed by Series Editors, and a team of Topic Editors supported by international Editorial Board members. Topics are always open for submissions, with an Annual Volume published each calendar year.
\n\nAfter a robust peer-review process, accepted works are published quickly, thanks to Online First, ensuring research is made available to the scientific community without delay.
\n\nOur innovative Book Series format brings you:
\n\nIntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\n\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
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\n\nBiomedical Engineering, ISSN 2631-5343
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\n\nDentistry (Coming Soon)
\n\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\n\nNote: Edited in October 2021
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Dr. Bahm is a member of the Belgian (BHG) and German (DGH) Association of Hand Surgeons, a Member of the German Plastic Surgeons Association (DGPRÄC), Member of the german “Nerv Club” and “Narakas club” for brachial plexus surgery.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"78207",title:"Prof.",name:"Jörg",middleName:null,surname:"Bahm",slug:"jorg-bahm",fullName:"Jörg Bahm",profilePictureURL:"https://mts.intechopen.com/storage/users/78207/images/system/78207.jpg",biography:"Jörg Bahm obtained an MD in 1987 and a Ph.D. from Université libre de Bruxelles (ULB), Brussels, Belgium in 2011. As a general, plastic, and hand surgeon, Dr. Bahm worked for five years at University Hospital Aachen, Germany. Since 1994, he has focused on brachial plexus surgery. He has been a chief surgeon in the Reconstructive Microsurgery Unit of the Franziskushospital, Aachen, Germany since 2000. In 2020, this unit was transferred into the Aachen University Hospital as the Division for Plexus Surgery within the Department for Plastic, Hand and Burn Surgery. \nSince 2003, Dr. Bahm has been a consultant for peripheral nerves in the Orthopaedic Department, Erasme University Hospital, Brussels, Belgium. He is an active member of the German (DGH) and Belgian (BHG) Hand Surgery Society and of the German Plastic Surgery Society (DGPRÄC). He is a member of the Narakas club for brachial plexus surgery and editor of the online Journal of Brachial Plexus and Peripheral Nerve Injury. He has written more than 50 scientific papers and presented at more than 200 congresses.\nDr. Bahm was president of the BHG in 2012 and 2013 and congress president of the FESSH Hand Surgery congress 2012 in Antwerp, Belgium.\nHis specific interests are peripheral nerve surgery and microsurgical reconstruction of the upper limb.",institutionString:"RWTH University Hospital",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Universitätsklinikum Aachen",institutionURL:null,country:{name:"Germany"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1148",title:"Neurosurgery",slug:"neurosurgery"}],chapters:[{id:"79635",title:"Introductory Chapter: Treatment of Brachial Plexus Lesions - A New Transdisciplinary Approach",slug:"introductory-chapter-treatment-of-brachial-plexus-lesions-a-new-transdisciplinary-approach",totalDownloads:62,totalCrossrefCites:0,authors:[{id:"78207",title:"Prof.",name:"Jörg",surname:"Bahm",slug:"jorg-bahm",fullName:"Jörg Bahm"}]},{id:"77532",title:"Nerve Transfers for Restoring Elbow Flexion in Brachial Plexus Palsy",slug:"nerve-transfers-for-restoring-elbow-flexion-in-brachial-plexus-palsy",totalDownloads:172,totalCrossrefCites:0,authors:[{id:"356223",title:"Emeritus Prof.",name:"Teodor",surname:"Stamate",slug:"teodor-stamate",fullName:"Teodor Stamate"},{id:"422017",title:"Dr.",name:"Dan Cristian",surname:"Moraru",slug:"dan-cristian-moraru",fullName:"Dan Cristian Moraru"}]},{id:"77904",title:"Nerve Transfers to Recover External Rotation of the Shoulder after Brachial Plexus Injuries in Adults",slug:"nerve-transfers-to-recover-external-rotation-of-the-shoulder-after-brachial-plexus-injuries-in-adult",totalDownloads:121,totalCrossrefCites:0,authors:[{id:"40328",title:"Dr.",name:"Jean-Noel",surname:"Goubier",slug:"jean-noel-goubier",fullName:"Jean-Noel Goubier"},{id:"414005",title:"Dr.",name:"Frédéric",surname:"Teboul",slug:"frederic-teboul",fullName:"Frédéric Teboul"},{id:"414006",title:"Dr.",name:"Camille",surname:"Echalier",slug:"camille-echalier",fullName:"Camille Echalier"},{id:"414628",title:"Dr.",name:"Elodie",surname:"Dubois",slug:"elodie-dubois",fullName:"Elodie Dubois"}]},{id:"78166",title:"Derotational Osteotomies for The Late Treatment of Brachial Plexus Injury",slug:"derotational-osteotomies-for-the-late-treatment-of-brachial-plexus-injury",totalDownloads:110,totalCrossrefCites:0,authors:[{id:"356769",title:"Associate Prof.",name:"Ahmet Emrah",surname:"Açan",slug:"ahmet-emrah-acan",fullName:"Ahmet Emrah Açan"},{id:"426178",title:"Dr.",name:"Ertuğrul",surname:"Şahin",slug:"ertugrul-sahin",fullName:"Ertuğrul Şahin"}]},{id:"78304",title:"The Role of Functional Electrical Stimulation in Brachial Plexus Injury Repair",slug:"the-role-of-functional-electrical-stimulation-in-brachial-plexus-injury-repair",totalDownloads:395,totalCrossrefCites:0,authors:[{id:"314534",title:"Dr.",name:"Lin",surname:"Yang",slug:"lin-yang",fullName:"Lin Yang"},{id:"414339",title:"Ms.",name:"Jia",surname:"He",slug:"jia-he",fullName:"Jia He"},{id:"414341",title:"MSc.",name:"YaXuan",surname:"Li",slug:"yaxuan-li",fullName:"YaXuan Li"},{id:"414342",title:"Ms.",name:"MengNan",surname:"Jiang",slug:"mengnan-jiang",fullName:"MengNan Jiang"},{id:"421931",title:"BSc.",name:"Qianling",surname:"Zhang",slug:"qianling-zhang",fullName:"Qianling Zhang"}]},{id:"77527",title:"Outcome Measures in OBPP",slug:"outcome-measures-in-obpp",totalDownloads:174,totalCrossrefCites:0,authors:[{id:"414275",title:"Dr.",name:"Aleksandra",surname:"McGrath",slug:"aleksandra-mcgrath",fullName:"Aleksandra McGrath"},{id:"414279",title:"Dr.",name:"Alice",surname:"Chu",slug:"alice-chu",fullName:"Alice Chu"},{id:"418526",title:"B.Sc.",name:"Nivetha",surname:"Srinivasan",slug:"nivetha-srinivasan",fullName:"Nivetha Srinivasan"},{id:"418527",title:"B.Sc.",name:"Jasmine",surname:"Mahajan",slug:"jasmine-mahajan",fullName:"Jasmine Mahajan"},{id:"418529",title:"B.Sc.",name:"Shivani",surname:"Gupta",slug:"shivani-gupta",fullName:"Shivani Gupta"},{id:"422006",title:"B.Sc.",name:"Amy",surname:"Song",slug:"amy-song",fullName:"Amy Song"}]},{id:"77632",title:"Factors of Cortical Plasticity in Brachial Plexus Injury",slug:"factors-of-cortical-plasticity-in-brachial-plexus-injury",totalDownloads:114,totalCrossrefCites:0,authors:[{id:"355641",title:"Associate Prof.",name:"Nora F.",surname:"Dengler",slug:"nora-f.-dengler",fullName:"Nora F. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"57959",title:"Pemphigus: Subtypes, Clinical Features, Diagnosis, and Treatment",doi:"10.5772/intechopen.71712",slug:"pemphigus-subtypes-clinical-features-diagnosis-and-treatment",body:'Pemphigus is a distinct organ-specific autoimmune blistering disorder involving skin and mucous membranes associated with autoantibodies directed against desmosomes-intercellular adhesive molecule complex localized on the keratinocyte cell surface [1, 2, 3, 4].
Pemphigus has three major variants, which are classified depending on the basis of the clinical, histological features, immunofluorescence staining pattern and autoantibody profile of the disease including
The term “pemphigus” origins from the Greek word “pemphix”, which has a meaning of “blister” [1]. It is a chronic potentially life-threating bullous disorder if not treated on time [4, 7, 8]. The phenotypes of pemphigus represent a complex spectrum with multiple genetic and environmental factors playing a role in disease pathogenesis [9, 10].
Together with clinical manifestations, the histopathological and immunopathological data support the diagnosis of the disease. The best site for the cutaneous biopsy for the appropriate histopathological examination is a fresh (< 24 h) small vesicle or 1/3 of the peripheral portion of the blister including the perilesional normal appearing skin. For direct immunofluorescence microscopic (DIF) examination, a perilesional normal appearing skin area up to 1 cm from a fresh vesicle should be taken and should be transformed in saline or in a cylinder of liquid nitrogen in a period lesser than 36 h [11, 12, 13].
As though some pemphigus variants, particularly PV and PNP, are potentially life-threatening diseases, early diagnosis is necessary and early onset of immunosuppressive treatment should be promptly initiated [14]. Moreover, some variants of pemphigus may indicate the presence of an underlying malignancy [15].
In this chapter, after the classification of pemphigus, firstly, pathogenetic properties and mechanism of acantholysis are discussed. After then, the review of pemphigus including the epidemiology, clinical features, histopathological and immunopathological findings, target antigens, and comorbidities of each pemphigus variant is discussed briefly.
Pemphigus is classified into two major types according to the level of intraepidermal separation by the most authors: PV and PF [2, 16, 17]. In the last decades, rarer and newer variants of pemphigus have taken part in classification [1, 4, 6], which is described in the following sections.
The evidence outlines that pemphigus is mediated by pathogenic circulating anti-Desmoglein 1/3 (Dsg) antibodies, which mediate blister formation [1, 2, 3, 4, 5, 6, 16, 17, 18, 19, 20, 21]. Previously, it was accepted that the presence of anti-Dsg antibodies alone is sufficient for the development of pemphigus [22]. According to the compensation hypothesis, the development of pemphigus is based on the normal epidermal distribution of Dsg1 and 3 molecules and Dsg1 and 3 antibody profiles [2, 16]. However, several reports have been reported pointing the discrepancy between clinical phenotype and autoantibody profile that contradicts with this theory [22, 23, 24, 25, 26].
While the production of pathogenic autoantibodies (Abs) is the key for the development of the disease, today it is obvious that many immunological steps are also required prior to the antibody induction [3, 22, 27]. Recent studies investigating the role of lymphocytes have demonstrated the role of T cells and B cells in mouse models of pemphigus and patients, revealing insights into the mechanisms of autoimmunity [28].
Today, it is obvious that some HLA class II alleles are involved in the activation of Dsg3-specific CD4+ T cells, which drives the pathogenetic pathways. The epidermal loss of adhesion is induced by pathogenic IgG Abs, which are produced by B cells. HLA-DRB1*04:02 is highly prevalent in PV, which provides the recognition of Dsg3 by CD4+ T cells. T cell-dependent B cell activation is critical for the induction of pathogenic IgG Abs [28, 29, 30, 31].
Recent studies have also emphasized the important role of T regulatory (reg) cells in the development of pemphigus, and it has been concluded that a balance between self-reactive lymphocytes and T reg cells may be a key element in determining whether individuals produce pathogenic Abs and develop pemphigus or not [9, 32, 33].
PV is the most commonly seen and representative clinical form of pemphigus with an incidence of 0.1–0.5/100.000 population [1, 2, 7, 13]. The average age at onset is usually at fourth and fifth decades, but may occur in the elderly or children. The incidence rate is higher among patients with Jewish and Mediterranean ancestry [1, 2, 5, 7, 13]. Various environmental factors such as drugs (captopril, penicillamine), infections (herpes simplex virus, Epstein–Barr virus, etc.), pesticides, ultraviolet radiation (UVR), ionizan radiation, thermal burns, stress and food containing an allium, phenol, thiol, or urushiol have been reported to trigger PV [10, 13, 34].
Patients with PV may present with only mucosal involvement and some with both mucosal and skin involvement [2, 4, 5]. In majority of the patients, oral mucosa is the site of onset, while cutaneous involvement usually occurs subsequently. It is most commonly characterized by painful erosions, erosions with whitish exudate and erythematous patches usually localized on gingiva and buccal mucosa [1, 2, 4, 5, 13] (Figures 1 and 2). The other mucosal areas, nasal cavity, larynx (epiglottis, vocal cords), oropharynx, esophagus, vagina, vulva, penis, and anus may also be affected [1, 13]. Epistaxis and hoarseness are present owing to the involvement of the nose, pharynx, and larynx [1, 13, 35, 36, 37]. Genital mucosa is one of the frequent sites involved in PV after the oral mucosa [37].
The eroded lesions are seen on the palate, right and left sides of the lower lip.
The erosions with whitish exudates are seen on the left posterior side of the buccal mucosa.
Cutaneous involvement usually follows mucosal lesions by 3 or 4 months [1, 4, 5]. The skin lesions cause burning and painful sensation. Cutaneous lesions are characterized by flaccid bullae evolving into painful extensive erosive areas (Figure 3). These blisters appear on the normal or erythematous skin, which are fragile, break rapidly, and it is hard to find an unruptured bullae. The Nikolsky sign is present. The bullae in PV can be localized or generalized, and any area of the skin may be involved. The most frequent areas affected are: face, axilla, and scalp, and this may be due to the fact that Dsg3 has its highest expression in these areas [1, 2]. Umbilicus and/or nail involvement are the other sites that may be affected [2, 4, 5, 13, 38, 39, 40]. The presence of the nail lesions may be the sign of relapse or recurrence of the disease [40]. Apart from these, cases of PV with the involvement of only cutaneous lesions have also been reported [41, 42, 43].
The extensive erosions localized on the back of the patient.
Intraepidermal suprabasal acantholysis and infiltration with predominantly neutrophils and eosinophils are observed (tombstone pattern) [2, 5, 13].
DIF examination shows lace-like IgG deposition with or without C3 on the surface of the keratinocytes in the mid-lower or entire epidermis [2, 5, 12, 13, 16]. Indirect immunofluorescence (IIF) examination, using a substrate of normal human skin or monkey esophagus, shows circulating antiepithelial IgG and lace-like deposition [2, 4, 5, 12]. Enzyme-linked immunosorbent assay (ELISA) is also available in detecting antigens of PV and serves as a tool for assessing the disease severity [44, 45]. Target antigens identified in PV are Dsg1 (with a molecular weight (MW) of 165 kD) and Dsg3 (MW-130 kD) [2, 3, 4, 5, 9]. Desmocollin (Dcs) is another antigen that is thought to be responsible in some pemphigus patients [46, 47].
Myasthenia gravis (MG) and abnormalities of thymus including benign or malignant thymoma and thymic hyperplasia have been reported to be associated with PV [2, 5, 48, 49]. Thymic abnormalities may precede or follow the onset of pemphigus. The other common disorders that have been reported to be associated with PV are systemic lupus erythematosus (SLE), bullous pemphigoid (BP), and PF [48].
Pemphigus vegetans (P veg) is accepted as the rarest variety of PV comprising of only 1–2% of all pemphigus patients. P veg has been reported to occur in all age groups, affecting primarily middle-aged females (sex ratio: F/M = 14/3) [50].
P veg is characterized by vegetative lesions preferentially affecting intertriginous (axillary, inframammarial areas) and periorificial regions [2, 5, 50, 51, 52]. The initial course of the disease is similar to PV. In the later stages, tumid vegetating, hypertrophic and verrucous lesions occur specifically between skin folds [5, 50, 53]. Two subtypes of P veg are recognized. The first one is Neumann P veg, which usually begins like PV with easily rupturing vesicles and bullae that evolve to form hypertrophic granulating erosions and then vegetating exuding masses. The second type is Hallopeau P veg, which is initially characterized by pustular lesions that break and gradually evolve into vegetating erosions [5, 50]. Mucosal involvement may not always be seen. Involvement of the vermillion border of the lips is the clinical hallmark of oral involvement [54]. Nail involvement is rarely described [50]. In P veg, the course of the disease is long, with remission and recurrence periods. Hallopeau P veg has a relatively benign course, while the Neumann type is often refractory to therapy. One of the frequent complications is the development of secondary bacterial infections, and also malnutrition and cachexia may coexist to the condition [5, 50].
Suprabasal acantholysis is present in the earlier stages of P veg similar to PV. In the following periods, irregular epidermal hyperplasia, papillomatosis, microabscess composed of eosinophils and neutrophils are also seen [2, 5, 50].
DIF and IIF examination results are indistinguishable from the findings of PV. As P veg is a subtype of PV, it is expected to react with the same antigens, Dsg1 and Dsg3 [2, 5, 50]. The presence of auto-Abs targeting additional desmosomal proteins including Dsc1, Dsc2, Dsc3 and periplakin have also been reported [51, 55].
PF (foliaceus originates from the Latin word folium with a meaning of “leaf”) is the superficial form of pemphigus [1, 2, 4, 5]. PF has a universal occurrence and occurs sporadically, while the endemic form of PF, called as fogo selvagem (FS) or wild fire (WF), is predominantly seen in the rural and tropical regions of Brazil [5, 7, 16, 58, 59]. Another variant of PF, a localized form, is called as pemphigus erythematosus (PE) [16, 59]. Sporadic form of PF is most common in Europe and USA [16].The average age of PF ranges between 40 and 60 years, while FS is very often in children, adolescents and young adults. It is usually seen equally in both females and males with a female preponderancy [59, 60]. FS occurs in genetically related family members. It has been reported that black fly (Simulium nigrimanum) bites were more frequent in patients with FS than in control patients [61, 62]. The authors suggested this vector or other infectious agents carry a molecule-triggering anti-Dsg1 response through antigen mimicry or cross-reactivity [58, 61].
PF is considered as a more benign form of the disease generally presenting with only cutaneous involvement [2, 5, 16, 59]. However, transition from PV to PF or vice versa may be observed [63, 64, 65]. More rarely, transition to BP has been reported [65]. The primary clinical feature of PF is fragile, superficial bullae evolving rapidly to erosive lesions. Nikolsky sign is positive. PF usually begins on the trunk, but may also be localized on the face and scalp. Sometimes yellowish crusted and scaly erythematous plaques on face and trunk predominate the clinical findings resembling the clinical picture of seborrheic dermatitis [2, 5, 16, 59, 66]. In FS, the disease usually begins on the head, neck, and seborrheic regions of the skin. The oral mucosa, palms of the hands, and plant of the feet are usually spared [59, 66]. In both PF and FS, lesions may become confluent and can transform to exfoliative erythroderma [67]. These patients should be hospitalized due to the risk of metabolic instability and mortality [1, 16, 59]. Pain and/or burning sensation may be noted. Unlike PV, there is no oral or other mucosal involvement [2, 5, 16, 59]. Mildest form of PF may be misdiagnosed for years [61].
Histological separation is more superficial than PV and exists along the granular layer. Eosinophilic spongiosis may also be seen in very early forms of PF [2, 5, 16, 59].
PE, also known as Senear-Usher syndrome, is a localized form of PF [2, 5, 16, 59]. It affects most frequently elderly population. Clinical and immunological features of PE resemble both PF and cutaneous lupus erythematosus (LE) [16, 75]. Clinically erythematous plaques, scaly to crusted lesions, occur across the malar areas of the face in a butterfly distribution mimicking the clinical appearance of LE [16]. The lesions are usually induced by UVR [75]. In 80% of the patients, antinuclear antibodies (ANA) without the presence of anti-ds-DNA antibodies may be detected [1, 2, 5, 16, 59]. DIF examination of the lesions may show both intercellular (IC) deposition IgG/C3 and granular deposition of IgG and C3 at the dermoepidermal junction (lupus band test) [5, 16, 59, 75].
PNP is a rare disease that manifests with clinically distinct painful mucosal erosions and polymorphic cutaneous lesions [1, 4, 15, 76]. The incidence of PNP is thought to be less common than PV or PF. PNP presents most often in older patients aged between 45 and 70 years [77, 78]. In almost all cases, PNP is associated with neoplasms mostly with lymphoproliferative diseases [4, 15, 66, 76, 77, 78].
The onset of the lesions usually presents with initially limited cheilitis and/or ulcerative stomatitis, which then progresses to severe, intractable, hemorrhagical stomatitis with persistent painful mucosal ulcerations in the oropharynx and esophagus [4, 5, 15, 16, 77]. Oral lesions usually extend to the vermillion border of the lips [15, 77]. Eye involvement especially includes conjunctival erosions and occurs in 70% of patients [79, 80, 81, 82]. Cutaneous lesions are usually seen after the onset of mucosal involvement with a duration of days to months [77, 83, 84]. Cutaneous lesions are widespread and are usually polymorphic including lichenoid lesions, erythema multiforme-like lesions, vesiculobullous and erosive lesions. The palmar involvement is usually observed [4]. Lichen planus-like lesions localized on skin, nails and/or mucosa resemble lichen planus, target-like lesions resemble erythema multiforme, and bullous lesions and erosive lesions resemble PV and bullous pemphigoid [4, 15, 66, 76, 77, 83, 84, 85, 86, 87]. Cutaneous lesions mimicking graft versus host disease or Stevens-Johnson syndrome may also be observed [86, 87].
As though most of the patients with PNP are associated with malignancies, the prognosis of PNP is severe with a high mortality rate [15, 77, 83, 84, 88, 89]. Internal organ involvement including lungs (Bronchiolitis obliterans), thyroid, kidney and gastrointestinal system has been documented [15, 88, 89]. Most authors have reported that the term “paraneoplastic pemphigus” is too restrictive to describe the developing multiorgan syndrome involvement and have suggested a new nomenclature named as paraneoplastic autoimmune multiorgan syndrome (PAMS) [15, 88].
Several biopsies are often required to achieve the diagnosis [77, 81]. The histopathological features of PNP reveal variability according to the type of the morphology of the cutaneous lesion [15, 77, 84, 90]. Intraepidermal suprabasal acantholysis (resembling PV), keratinocyte necrosis and vacuolar interface changes (resembling erythema multiforme/lichen planus) may be observed [77, 90].
DIF examination is characterized by the deposition of immunoreactants (IgG deposits with or without compleman) in IC region of epidermis and deposition of IgG/IgM and/or C3 along the basal zone membrane (BZM) [15, 17, 77, 84]. IIF using rat bladder epithelium as substrate shows an IC pattern that appears to be highly specific but less sensitive for PNP/PAMPS (including monkey esophagus (86% sensitivity) and murine tongue (100% sensitivity). A variety of antigens including Dsg1, Dsg3, envoplakin, periplakin, bullous pemphigoid antigen1 (BPAG1), plectin, desmoplakin 1, and desmoplakin 2 can be detected by immunoprecipitation [15, 17, 77, 84].
PNP usually precedes the diagnosis of the underlying malignancy. In 1/3 of the cases, the underlying malignancy has not been diagnosed at the time of diagnosis. Therefore, when a diagnosis of PNP is made, a comprehensive workup for an underlying malignancy is mandatory [4, 15, 76, 77]. Hematological malignancies are associated with 84% of the patients of PNP. The most common reported hematological malignancies are non-Hodgkin lymphoma (38.6%), chronic lymphocytic leukemia (18.4%), Castleman disease (18.4%), and thymoma (5.5%) [15, 48, 77, 84].
PH is a rare and distinct entity of pemhigus [6, 11]. It has been first described in patients who had clinical features that resemble dermatitis herpetiformis, but showed the features of pemphigus histopathologically and immunologically [6, 11, 91, 92]. It usually accounts 6–7% of cases and affects females and males equally [11, 92].
Patients usually have erythematous, gyrate, annular and polycyclic lesions with clusters of pustules, vesicles, in herpetiform pattern. The clinical presentation of PH may be atypical and may mimic various other bullous diseases [6, 92]. Pruritus is usually present [6, 11, 92, 93]. Mucous involvement is not a usual finding [6, 11]. PH usually has a good psis, although some cases may progress into classic pemphigus [11, 94].
The histopathological examination shows eosinophilic or neutrophilic spongiosis and microabscesses (neutrophils and/or eosinophils) in the mid or subcorneal epidermis mostly without acantholysis. Acantholysis may be seen in the later stages of the disease process and may be minimal [6, 11, 92, 93].
DIF examination shows IC deposits of IgG and C3 in epidermis, while IIF examination shows circulating IgG auto-Abs. The target antigen is usually Dsg 1 (or less frequently Dsg3) [6, 11, 95]. Recent studies have demonstrated DSc1, Dsc3 and unknown protein 178-kDa protein [11, 92, 96] by immunoblotting.
IGAP is a rare entity of pemphigus [6, 11]. It has two clinical types: intraepidermal neutrophilic type (IEN) and subcorneal pustular dermatosis (SPD) [6, 11, 66]. It is usually observed in the middle-aged or the elderly with an average age at 48 years, but also has been reported in childhood [6, 11]. There is a slight predominance of females [6].
Patients with both types of IGAP present with flaccid vesicles or pustules on either erythematous or normal skin mostly localized on axillary and groin areas, but trunk, proximal extremities and abdominal regions are also involved. The pustules tend to coalesce to form annular or circinate pattern. SPD is clinically indistinguishable from the disease subcorneal pustular dermatosis. In IEN type, pustules coalesce to form a sunflower-like configuration [2, 6, 11, 102, 103]. Pruritus is severe and affects patients’ daily activities. Mucosal involvement is rare [2, 6, 11].
There is slight acantholysis and neutrophilic infiltration in epidermis. In SPD type, neutrophilic infiltration is localized subcorneally in the upper epidermis, while in IEN type in lower epidermis or entire epidermis [5, 6, 11].
In DIF examination, deposition of IgA in IC space of epidermis is detected. IgG and/or C3 is sometimes deposited but is weaker than IgA. In the SPD type, deposition is limited to upper epidermis, while in IEN type, it is deposited in lower epidermis or in whole epidermis [6, 11]. Using healthy human skin and monkey esophagus, circulating IgA auto-Abs have been demonstrated in 50% of the patients [5, 11]. The antigens in IGAP are Dsg1, Dsg3, Dsc1, and Dsc3 [3, 4]
In SPD type, the most frequently reported association is monoclonal IgA gammopathy [11, 48, 103].
Pemphigus, especially some types, is a life-threatening disease and has a mortality risk. Therefore, the diagnosis should be made as soon as possible, and the treatment should be started. Today, a better understanding of the role of immunological dysregulation in the pathogenesis will also cause offering newly targeted therapeutical agents in the treatment of pemphigus.
Abs | Antibodies |
ACE | Angiotensin-converting enzyme |
ANA | Antinuclear antibody |
Anti-ds DNA | Double-stranded DNA antibody |
BO | Bronchiolitis obliterans |
BZM | Bazal zone membrane |
C3 | Compleman 3 |
DIF | Direct immunofluorescence |
Dsc | Desmocollin |
Dsg | Desmoglein |
ELISA | Enzyme-linked immunosorbent assay |
FS | FogoSelvagem |
HLA | Human leucocyte antigen |
IC | Intercellular |
IEN | Intraepidermal neutrophilic type |
Ig | Immunoglobulin |
IGAP | IgA Pemphigus |
IIF | Indirect immunofluorescence |
MG | Myasthenia gravis |
MW | Molecular weight |
P veg | Pemphigus vegetans |
PAMPS | Paraneoplastic autoimmune multi-organ syndrome |
PE | Pemphigus erythematosus |
PF | Pemphigus foliaceus |
PH | Pemphigus herpetiformis |
PNP | Paraneoplastic pemphigus |
PV | Pemphigus vulgaris |
Reg | Regulatory |
SLE | Systemic lupus erythematosus |
UVR | Ultraviolet radiation |
WF | Wild fire |
Alzheimer’s disease (AD) is a form of dementia, currently affecting over 55 million people worldwide. This alarming situation is projected to the elevation of 88 million people by 2050 [1, 2]. It is a complex mechanism of neurodegenerative disorder clinically categorized by advanced and continuing deterioration in intellectual capability of the brain and biochemical change due to the presence of neurotic threads, specific areas of the brain function damage subsequently synaptic signal loss. This consequence occurs due to the accumulation of specific protein amyloid-β to the external neurons and modification of the specific tau protein by hyper phosphorylation and ultimately neurofibrillary twists (NFTs) are formed in the neuron cell of the brain. This mechanism is responsible to intellectual deficit, remembrance loss, and then neuron expiry [3, 4]. AD is one of the pathetic disease eases due to the presence of disability in the oldest people and it was found that the prevalence of AD is less than 1% in the people who are underneath 60 years of age, but this prevalence is increasing to 40% among people who are older than 85 [5]. The most important thing is that, there is no specific drug for the treatment of AD to date [4]. The alarming disease burden is concerned in the world, because the projected global population of older adults (defined as those aged >60 year) in the year of 2050 will be 2 billion (approximately 21% of the world’s population) out of them 392 million will be over 80 years of old [6]. Presently preventive measures are getting more attention than pharmacological interventions after unsuccessful clinical trials of some promising drugs designed for targeting Aβ and tau proteins. Though, there is no specific treatment of the AD but world scientists are trying to control the gradual growth of AD by multidomain non pharmaceutical intervention such as exercise or diet, and intellectual or physical activity that can prevent cognitive decline at-risk of the oldest population [7]. There is no available information about together-intervention of exercise with diet pattern and social inclusion to ameliorate the prevalence of AD. This is a very important and socially demanding strategy of mass elder people rather than pharmacological intervention.
Two most important determinants in or out of the neuron cells in the brain that are involved in the mechanism of dementia progression, i.e., the β-amyloid peptide and tau proteins. The pathophysiological change of AD is normally carried out by measuring the deposition of β-amyloid peptide, a 39–43 amino acid chain that is produced in the brain and organized a flame-shaped neurofibrillary tangles of tau protein in the affected region of the brain [3]. In patient of AD, one of the determinant (β-amyloid peptide) in the brain is found abnormal due to the genetic mutations in the gene of precursor protein of β-amyloid peptide and Presenilins (PS1 and PS2) which lead to anomalous Aβ accumulation outside the neuron in the brain [4]. Another important determinant tau protein treats the microtubule gathering and maintenance due to the hyperphosphorylation of tau protein and is the cause of AD pathology, The actually mechanism of abnormal microtubule gathering is hyper phosphorylation of tau protein because the modified tau protein can accelerate the formation of neurofibrillary tangles (NFTs), that is associated with loss of remembrance and wisdom hearts [8]. The microtubule disassembly (neurofibrillary tangles; NFTs) may likewise found in other distinctive neurodegenerative diseases, have some distinguishing morphological change rather than AD and this is due to a distinctive conformation of tau isoforms that could easily differentiate from AD [9]. On the other hand, the degree of dementia was observed to be weakly correlated with the amounts and distribution of Aβ deposition within the brain [10]. In particular, the increased deposition of Aβ peptide outside the neuron cell can cause abnormal synaptic signal transduction, intellectual linkage, mitochondrial energy transduction, apoptosis of neuronal cell and, ultimately remembrance forfeiture, the hallmark of AD [11, 12]. Even though some neurotoxicity occurs in the neuronal cell, the mechanism of neurotoxicity caused by Aβ is not fully discovered. Although some studies showed that the abnormal accumulation of Aβ peptide in the brain causes induction of oxidative stress and neuroinflammation, the most important cause of neurotoxicity [13]. Early detection of the determinants is one the most important parameters for the management of AD. But the aforementioned two determinants are very difficult to early determination. Thus defective metabolism of glucose in the brain may be one of the earliest hallmarks of AD. The detection of brain glucose hypometabolism is measured by the determination of fluoro-2-deoxy-D-glucose positron emission tomography imaging system. This technique has been suggested as an effective early diagnostic tool for AD. Several studies showed the sensitivity and effectiveness of the brain glucose hypometabolism technique (about 90%) for the early diagnosis of AD [14]. Moreover, amino acids may be another hallmark of AD. For instance, abnormal elevation of homocysteine (Hcy) in the AD population. Studies showed that hyperhomocysteinemia is accompanied with amplified intellectual deterioration in healthy older adults with a higher risk of perceptive deficiency [15]. Another study found that abnormal plasma homocysteine and distressed homocysteine amino acid metabolism are risk factors for intellectual concept [5]. Several potential mechanisms have been studied on the harmful effects of homocysteine amino acid in the brain including oxidative deterioration [16], cerebrovascular impairment [17], DNA destruction [18], and activation of N-methyl-D-aspartate receptors [19]. In the Figure 1, we summarized the various modifiable risk determinants that are responsible for AD pathology.
Various modifiable risk determinants in AD pathology [
The Aβ peptide (approximate size ~4 kDa) is resulting by cleavage of the larger β-amyloid precursor protein (AβPP). β- and γ-secretase are the two membrane-bound endoprotease activities sequentially cleaved the AβPP to produce (Figure 2) the most abundant fragment Aβ40 (~80 to 90%) and Aβ42 (~5 to 10%). The somewhat extensive forms of Aβ, predominantly Aβ42, is the principal culprit for the deposition in the brain [20]. The enzyme, β-Secretase is a protease which have two major homologous (>65%) forms, one is β-site Amyloid Precursor Protein Cleaving Enzyme (BACE1) and the other is BACE2. The most important Enzyme BACE1 is mainly accountable for β-amyloid peptide production higher in the brain than BACE2 which is mostly present in the peripheral tissues. Animal studies stated that the protease BACE1 is the foremost β-secretase action in the brain, however, some residual motion might be attributable by the BACE2. Besides the brain, The BACE1 are also found in another cell type such as pancreatic β-cells where they are highly expressed in mRNA levels, however, this pancreatic isoform of BACE1 is distinctive from the brain and may not cleave AβPP. It was found that BACE1 action upsurges with oldness and is highly found (two to five-fold) in irregular AD [21, 22]. It is important that the lack of protease activity of BACE1 is related to prevent β-amyloid peptide synthesis [23]. Recent studies also observed that in a suitable situation cathepsin B or cathepsin D may help to serve such kind of enzyme like β-secretase enzymes. The two enzymes, β- and γ-secretase were considered to be the leading goals for the advance of anti-AD medications [24]. For example, alterations in γ-secretase activity by the change of allosteric γ-secretase controlling representatives may prevent the production of β-amyloid peptide [25]. Study showed a reduction in BACE1 expression that is related to glucose metabolism via regulation of insulin mRNA expression. In vivo experiments stated that reduction of BACE1 expression may lower plasma insulin concentrations and body weight through the controlling of regular glucose acceptance and insulin sensitivity [26].
Amyloidogenic pathway involved for development of AD [
Another relationship of AD has also been exposed to be concomitant with inflammation, glucose metabolism and hormonal balance. For instance, the inflammatory markers have been isolated in the cerebrospinal fluid (CSF) and abnormal amyloid formation found in the brain of AD that is much related to high expression of inflammatory molecules interleukin-6 (IL-6). This relationship is not only found in the brain but also in the other fluid such as the lumbar and ventricular region in patients with AD. Another relationship was found that circulating IL-6 is highly expressed before symptomatic sign of dementia and this increased IL-6 is related with low male hormone like testosterone in older men with type-II diabetes Mellitus (T2DM) and AD [27, 28, 29]. It was found that male hormone secretion is hampered by inflammatory molecules IL-6 and this is much related to inflammation and oxidative stress, hormonal imbalance and T2DM with AD pathology [30, 31]. Figure 2 summarized the amyloidogenic pathway involved for development of AD [32, 33, 34, 35].
The prevention of AD means the degradation of β-amyloid peptides by enzymes such as Aβ degrading enzyme Neprilysin (NEP) and insulin degrading enzyme (IDE). There are many enzymes, the aforementioned two important enzymes are metalloprotease which are responsible for most of the Aβ degradation [36, 37]. The membrane bound Neprilysin is actually type II metalloprotease which degrades the extracellular variety of peptides but the IDE enzyme can degrade both intra- and extracellular [38]. Though the affinity of IDE enzyme to the insulin is (twenty times higher) higher than Aβ but it hydrolyzes slowly. It is important that the insulin may be responsible for cleavage of β-amyloid peptides, this is the basic mechanism among type II diabetes, hyperinsulinemia, and AD [39, 40]. Most of the Aβ degradation occurs by the influence of NEP, like lysosomal degradation of cathepsin B [41]. Another study stated that other enzymes such as Endothelin Converting Enzyme (ECE), Angiotensin-Converting Enzyme (ACE), and Matrix Metalloproteinase-9 (MMP-9) may also have Aβ degrading properties [42]. Though the substantial degradation of β-amyloid peptides occurs in the brain, their undegraded portion is transported through the blood brain barrier (BBB) into the circulation by specific mechanisms. The soluble part of β-amyloid peptide is switched through the BBB into the abluminal site of the brain by the low-density lipoprotein receptor-related protein (LRP) and into the luminal side of the blood by the receptor for advanced glycation end products (RAGE) [43, 44]. Disturbing this mechanism may cause an increase of Aβ level which may be attached with other widespread co-morbid vascular irregularities in the brain function of AD. This change may exaggerate the development of amyloid pathology [45]. Figure 3 summarized the detailed preventive mechanism of AD by Aβ degradation pathway. The frequency of AD is found meaningfully higher in women than to men (almost two-thirds) indicating a strong association of sex hormones with the AD [46]. Study observed that testosterone levels are inversely associated with the plasma levels of β-amyloid peptides in elderly men population [47]. Testosterone may provide different neuroprotective effects including enlightening intellectual presentation and synaptic signal transduction by increasing relaxation, modulation synapse density level on the brain hippocampal dendritic spines [48, 49]. This hormone is also important for maintaining hippocampal function in elderly population [50], increasing blood supply to the cerebral and increasing glucose metabolism in the responsive brain regions as well as reduced the aggregation of β-amyloid peptides and neurotoxicity. Testosterone may reducing the tau protein hyperphosphorylation and in vivo experiment showed that the reduction of testosterone is directly associated with reduce intellectual performance, and it could be revised by testosterone supplementation [51, 52]. Women are more prone to AD than men because testosterone is basically a male hormone and most abundant testosterone is converted into estrogen and other adrenal hormones in women. The study showed that women are more prone to AD symptoms due to lack of testosterone [53]. Previous animal study indicated that testosterone (in male) and estrogen (in female) could modulate the invention of β-amyloid peptides by the disturbing of BACE1 action [54, 55]. The hormone like testosterone is an effective modulator of endogenous β-amyloid peptides degrading enzymes such as NEP. Animal study observed that neuronal expression of NEP is enhanced by the action of testosterone which in turn reduces the β-amyloid peptide level and ultimately reduces the symptoms of AD [56]. The increase of β-amyloid peptides degrading enzymes positively influence on the level of toxicity or fibrillization of amylin [57, 58]. Testosterone may regulate the enzymes NEP and IDE and improve the AD conditions [53]. Another protein, the APOE ε4 allele is very related to the AD, promoting β-amyloid peptides clearance, and it was found that the isoform ApoE ε2 and ApoE ε3 are very efficient than the ApoE ε4 protein. The modification among the isoform may influence the ability of ApoE to promote β-amyloid peptides degradation, and the modification of ApoE is subjected by its lipid carrier molecule ABCA1, whereby higher modification may increases the clearance of β-amyloid peptides [59, 60]. The insulin impairment and the brain function are associated with AD [53]. Brain insulin is very special and mostly originated from endogenous production which is not influenced by the plasma insulin [61]. The mechanism of insulin action in the brain describes the signal transduction via signal cascade pathway. In which first insulin binds to the insulin receptors and then phosphorylation occurs on multiple substrates such as insulin receptor substrate-1 and insulin receptor substrate-II. This phosphorylated substrate activates the downstream signaling pathways and activates the phosphatidylinositol 3-kinase, which is an important modulator for synaptic malleability, education, and remembrance. The activation of phosphatidylinositol 3-kinase subsequently activates Akt which phosphorylates enzymes related to glucose metabolism such as glycogen synthase kinase (GSK) 3β. Then GSK3β regulates tau protein phosphorylation in AD, and thereby leading to neurofibrillary tangle formation [62, 63]. In vitro and in vivo studies demonstrated that impairment of insulin signaling pathway is associated with the AD pathology [64, 65, 66]. There is a strong linkage among the hormone testosterone, insulin and glucose metabolism through glucose transporter and insulin receptor protein [67]. Studies have shown that testosterone influence the glucose uptake and transporter via activation of liver kinase B1/AMP-activated protein kinase signaling pathway in fat cell, where AMPK plays an important role for decreasing mTOR signaling activity and promotes lysosomal degradation of β-amyloid peptides in AD. However, this mechanism can also lead to β-amyloid peptides generation and tau phosphorylation [68, 69]. Several studies have shown that both precursor protein (APP) and β-amyloid peptides co-localize in mitochondria, suggesting the possibility of mitochondrial function is associated with APP biology [70]. Ketone bodies may block the mitochondrial amyloid entry and improve understanding capability [71]. This ability would predictably ameliorate Aβ-mediated suppression of respiratory chain function and perhaps could rescue the bioenergetics hypo metabolism that is observed in AD brains [72]. Alternatively, improving mitochondrial performance outright could reduce the production of Aβ and increase the production of soluble APPα [73].
Preventive mechanism of AD by Aβ degradation pathway.
Dietary patterns which are rich in antioxidant and anti-inflammatory properties, may involve the establishment of auspicious attitudes in the treatment of intellectual deterioration or suspending the development of dementia in the brain [74]. The bio ingredient of diet can change the epigenetic by regulating deoxyribonucleic acid (DNA) modification such as methylation, acetylation, histone protein modifications, and changes of gene expression in the ribonucleic acid (RNA) level. The epigenetic modification may influence the expression of particular genes and subsequently particular marker molecules that are responsible for epigenetic alterations [75]. Lipidation of several molecules are important for brain function, one of them are polyunsaturated fatty acids (PUFAs) [76]. The PUFA are the important component of neuronal cell membranes, which is responsible for membrane fluidity. The crossing of molecules through the membrane allows them for cell signaling and neuronal protection [77]. The essential PUFAs play not only neuroprotection but also involve development and brain functions. They also have antioxidant, anti-excitotoxic, and anti-inflammatory activities in the brain. Imbalance of PUFA has been found in neuropsychiatric health including dementia. The beneficial effects of long-chain omega-3 PUFAs have been observed in populations where long-chain omega-3 PUFAs effectively reduce the risk of cerebral damage in individuals without dementia. This is supported by other studies in such a way that omega-3 fatty acid may effectively reduce the initial stages of intellectual deterioration [78]. Another dietary bioactive compound, curcumin (turmeric powder), plays an important role against β-amyloid peptides deposition in the AD because they have potent antioxidant, anti-inflammatory, and neuroprotective function [79]. The bioactive compound, curcumin, regulates the genetic control by down regulation of several gene expression such as class I HDACs (HDAC1, HDAC3, and HDAC8) and enhances the acetylation of histone H4 levels. The curcumin regulates not only gene expression but also can inhibit certain epigenetic enzymes [80]. Other dietary bioactive compounds, flavonoids have potent antioxidant properties, can modulate epigenetic control by the down regulation of pro-inflammatory and inflammatory cytokines and prevent neural impairment in AD [81, 82]. Thus, flavonoids could be a promising therapeutic intervention against neurodegenerative disease. In vivo and in vitro studies showed that the bioactive compound quercetin may regulates cytokines via activation of several downstream molecules such as nuclear factor (Nrf2), Paraoxonase-2, c-Jun N-terminal kinase (c-JNK), Protein kinase C (PKC), Mitogen-activated protein kinase (MAPK) signaling cascades, and PI3K/Akt pathways [83]. Dietary source of component such as cocoa and seed coat of the black soybean, rich source of plant flavonoids and anthocyanin respectively, have been shown neuroprotective action against intellectual deterioration, oxidative stress, neurodegeneration, and memory impairment in a mouse model of AD via the PI3K/Akt/Nrf2/HO-1 pathways [84, 85]. The dietary patterns of coffee and tea that contain bioactive caffeine have been shown to reverse intellectual impairment and reduce the β-amyloid peptides aggregation in the brain in mice model of AD. This reduction occurs due to the stimulation of protein kinase A activity by the caffeine and increases the phospho-CREB levels, subsequently reducing the phospho-JNK and phosphor-ERK expression in the brain. Thus, the high level of blood caffeine may inhibit the progression to dementia [86, 87]. Dietary pattern of grapes and red wine that contains resveratrol, a polyphenol of potent antioxidant and anti-inflammatory actions [88]. The reactive oxygen species (ROS) induced oxidative stress is protected by the resveratrol by the activation of sirtuin 1 (SIRT1) [89]. Resveratrol also activates a transcriptional coactivator of energy metabolism and several studies have shown that resveratrol supplementation with vitamin D could prevent intellectual impairment in vivo through Amyloidogenic pathways [90, 91]. Another study stated that resveratrol may ameliorate the hippocampal neurodegeneration and memory performance [92]. Insufficient dietary minerals may adversely affect the critical cellular processes associated with intellectual impairment and dementia. Thus, dietary patterns of sufficient minerals may have a protective role against many metabolic diseases including intellectual deterioration [93, 94]. Compelling evidence shows that magnesium deficiency may impair memory and contributes to AD pathology [95]. Magnesium sufficient dietary patterns may modify AβPP processing and stimulate the α-secretase cleavage pathway, thereby protecting the cognitive dysfunction [96].
Dietary patterns of vitamin rich food might be useful in maintaining intellectual function and delaying the progression of AD. Studies have stated that vitamin rich dietary patterns such as folic acid and vitamin B12 can significantly improve intellectual functions [97]. In AD, oxidative stress and mitochondrial dysfunction can be prevented by vitamins, because vitamin can modulate the oxidative stress markers and misfolded proteins [98, 99]. Clinical studies suggested that ketogenic therapies may be beneficial for AD patients. It was found that plasma ketone levels were increased by the medium chain triglyceride and ketone ester supplementations and improved the intellectual function in AD patients [100]. Another source of fuel for the brain is ketone bodies (KB), which may provide energy for the brain and also increase mitochondrial efficiency and cognitive function. The two forms of KB are very important for these mechanisms in the brain; beta-hydroxybutyrate (b-HB) and acetoacetate. Evidence suggests that brain ketone body utilization is not problematic in AD like glucose, making it an alternative energy source of brain function [101]. Figure 4 summarized the dietary management of AD.
Mechanism of how dietary patterns are involved for the treatment of AD.
In the brain of an AD patient, there are several mechanisms for the changes of β-amyloid peptides synthesis and degradation and tau protein modification. Physical activity may change many signaling molecules both at the mRNA and protein level that may induce the anatomical changes of the brain, chemical and electrophysiological change of the nerve, subsequently enhance the plasticity of neurons of the brain and improve the brain function. Multiple paths of physical exercise and dietary pattern are likely enabled to adjust the level of β-amyloid peptides and tau protein directly or indirectly. Both physical activity and habituated dietary healthy food are effective interventions in such a way that can limit the prevalence of neurodegenerative diseases through the minimization of mitochondrial dysfunction in bioenergetics processes [102, 103]. Physical exercise play an important role on neuroplasticity of the brain and cellular energy homeostasis well as improve the cognitive functions by controlling the activation of several signaling molecules such as PGC-1α and a nicotinamide adenosine dinucleotide (NAD)-dependent deacetylase, SIRT1 [104, 105]. There is a loss of muscle mass and muscle activity with elderly people. Thus, regular exercise and a healthy dietary pattern reduces the development of aging-related muscle deterioration and promotes muscle activity with the older people [106]. Few have shown the that efficacy of exercise with men and women in AD people, even though differences were found in men and women cognitive improvement with exercise. Study showed that exercise can modulate insulin action and as well as blood glucose [107]. In vivo and clinical study have shown the benefit of exercise and dietary pattern as a non-pharmlogical option in reducing the β-amyloid peptides aggregation and tau protein phosphorylation in the aging brain. This mechanism happens less in women rather than men due to the change of hormone level [108]. In vivo study stated that exercise and healthy dietary patterns can reduce cortical BACE1 expression and activity by modulating the MAPK signaling in the cortex in AD patients [109].
Interestingly, animal and human studies have shown that exercise and specific dietary patterns may increase testosterone production but it is depending on the intensity of exercise and exercise-induced testosterone sustained for a long time in the body. It was found that high intensity of exercise can increase testosterone levels in T2DM patients, which is important for the reduction of risk factors of AD [110].
The most important neurotrophins, BDNF (brain-derived neurotrophic factor) is responsible for neurogenesis and synaptogenesis. Not only can the central nervous system (CNS) produce the BDNF but also skeletal muscle through the exercise. The underlying molecular mechanisms of exercise to produce testosterone may be mediated by BDNF production in the brain. Physical exercise may increase testosterone. Thus, exercise and dietary patterns may increase BDNF levels as a stimulus for the induction of neurogenesis to improve synaptic plasticity [111, 112]. Together physical exercise and dietary patterns not only increase the BDNF but also increase the insulin like growth factor-I (IGF-I). The mechanism of exercise and dietary pattern have been shown to enhance IGF-1 expression in the brain [113]. Moreover, exercise may release several factors like BDNF and IGF-1 into the circulation by testosterone activation. Neurocognitive damage is lifelong incidence with cellular dysfunction. For instance, impairment of BDNF production may influence the synaptic plasticity and neurogenesis in the aging adult brain [114, 115]. Exercise as well as dietary patterns such as low-calorie intake is another important intervention for enlightening metabolic health. The molecular mechanism of low-calorie intake (LCI) is effective against ROS induced-oxidative stress, in which the LCI can reduce β-amyloid peptides aggregation and γ-secretase and plays a preventive role in AD pathology [116, 117]. It was found that the mechanism of low-calorie intake exerts its action by inhibiting nutrient-sensing and inflammatory pathways, thus physical activity and dietary pattern may also be effective methods for the preventive measures of AD [118]. The cellular energy homeostasis is mediated by AMPK in mitochondria, adipose tissue, skeletal muscle, and liver. This mechanism is activated by LKB1 and in response to metabolic stresses, exercise, sex hormones, and insulin sensitizing agents such as Metformin. Thus, the physical exercise and healthy dietary pattern plays a key role in AD patients [119, 120, 121]. Oxidative stress and inflammation are the hallmarks of dementia. Individuals’ cognitive abilities are related to both non-modifiable factors and modifiable risk factors such as exercise and dietary status. Low calorie diet may be effective against cognitive decline and the high calorie is vice versa [122]. Additionally, some dietary patterns that contain bioactive compounds may increase signaling molecules and neuronal hormones that are responsible for cognitive improvement. Diet therapy such as vitamin rich food may affect the bodies’ central metabolism as well as brain function, and the production of neurotransmitters for modulation of mood in AD [123, 124]. Conversely, it was found that lack of basic B complex (folic acid, B6, and B12) in the dietary pattern is also proposed to impact on the rate of brain atrophy associated with mild cognitive impairment (MCI) [125]. Strength exercise and other dietary patterns such as intake of seafood and other sources of long-chain omega-3 polyunsaturated fats (LC-n3-FA) may have long-term beneficial effects on cognitive function [126, 127]. Thus, exercise and dietary patterns may balance several factors such as LC-n3-FA act via BDNF, and insulin-like growth factor-1 (IGF-1) can alter the expression of a number of protein pathways in neuronal function, plasticity, and neurogenesis [128]. Figure 5 summarized the exercise and dietary management of AD.
Mechanism of exercise mediated management of AD.
Social inclusion is multidimensional including social and cultural connection with family, friends, work, personal interests and local community, deal with personal crisis etc., and operates at various social levels. In AD, the deterioration of brain activity begins in the hippocampus areas primarily associated with memory and emotion. The deterioration then spreads to other regions, resulting in reduced neuronal processing, eventually associated with episodic memory, emotion and mood, sensation, self-awareness, attention, memory retrieval and theory of mind which is adversely affected in the early stages of AD. Thus, it could be suggested that the brain regions affected by AD may share something in common, including their role of regulating emotion, memory and awareness and social inclusion can significantly affect in a broad range of measures, including a reduction of cognitive decline, reduction in perceived stress, increase in quality of life, as well as increases in functional connectivity, percent volume brain change and cerebral blood flow in areas of the cortex [129, 130, 131]. For the treatment of AD, Social inclusion is potentially beneficial in improving the cognitive function of older adults with mild to moderate dementia and improving their quality of life. Thus, it is recognized as a priority field of AD research, as pharmacologic treatments have not demonstrated effective outcomes [132]. Social inclusion may promote communication and enhance social interaction skills that are important for potentially beneficial cognitive functions and domains of memory and recall of older adults with dementia. These non-pharmacological interventions aim to reduce the behavioral symptoms of the AD. For instance, music therapy involves listening to music and singing songs, can modulate the factors involved in cognition and conduct, divert the attention of older adults to provoke emotional responses and modulate them, draw on different cognitive functions, and evoke movement patterns. Another study has indicated that singing traditional songs, which emerged from the life experiences of people living with dementia, activates their implicit memory with a priming effect [133]. Traditional opera can potentially be an effective therapy for improving the cognitive function of older adults with dementia, reducing their behavioral and psychiatric symptoms and enhancing their quality of life [134]. Moreover, it helps improve their memory as well as the coherence and expressiveness of their speech [135]. About ninety percent people with dementia showed behavioral and psychological symptoms and can cause serious complications but reduction of this complication by use of single antipsychotic medications is very difficult. Several studies showed that consideration of both the physical and the social inclusion can promote self-determination and opportunities for meaning and purpose of persons with dementia [136]. Recent studies concluded that the level of evidence is considered insufficient to support the use of single non pharmacological interventions in prevention efforts of AD; however, mega study reported that around one third of ADs cases worldwide might be attributable to potentially modifiable risk factors such as smoking, physical inactivity, and midlife obesity [137].
Single nonpharmacological interventions for the treatment of pathophysiological hallmarks of AD was not sufficient. It should include a new approach of three effector modulations such as exercise–eating pattern and social (EES) activities for the treatment of AD. However, when considering the single modulator exercise, adapting the physical environment is necessary but not sufficient. To effectively address AD, the exercise and eating pattern must also be incorporated into the intervention. Also, when considering social inclusion related to initiatives aimed at decreasing AD, providing initial training is necessary, ongoing training and support to mindfulness, meditation in the form of effective enabling and reinforcing factors must also be included. Finally, development of individualized approaches that promote self-control exercise, eating patterns and social inclusion of persons with dementia. This new approach EES should also be included with other interventions aimed at decreasing AD. Though it is very important that the combination of EES and other interventions would be supportive by the success of interventions. It is our hope that this new approach EES also provides direction for future research and initiatives aimed at successful and sustainable nonpharmacological management of AD.
I am particularly grateful Jashore University of Science and Technology for the logistic support of this review article.
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\\n"}]'},components:[{type:"htmlEditorComponent",content:'Copyright is the term used to describe the rights related to the publication and distribution of original Works. Most importantly from a publisher's perspective, copyright governs how Authors, publishers and the general public can use, publish, and distribute publications.
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On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. 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This chapter documents some of the studies on antibiotic usage in poultry farming; with specific focus on some selected bacterial species, their economic importance to poultry farming and reports of resistances of isolated species from poultry settings (farms and poultry products) to essential antibiotics.",book:{id:"6978",slug:"antimicrobial-resistance-a-global-threat",title:"Antimicrobial Resistance",fullTitle:"Antimicrobial Resistance - A Global Threat"},signatures:"Christian Agyare, Vivian Etsiapa Boamah, Crystal Ngofi Zumbi and\nFrank Boateng Osei",authors:[{id:"182058",title:"Dr.",name:"Christian",middleName:null,surname:"Agyare",slug:"christian-agyare",fullName:"Christian Agyare"},{id:"261271",title:"MSc.",name:"Crystal Ngofi",middleName:null,surname:"Zumbi",slug:"crystal-ngofi-zumbi",fullName:"Crystal Ngofi Zumbi"},{id:"261272",title:"MSc.",name:"Frank Boateng",middleName:null,surname:"Osei",slug:"frank-boateng-osei",fullName:"Frank Boateng Osei"},{id:"261273",title:"Dr.",name:"Vivian Etsiapa",middleName:null,surname:"Boamah",slug:"vivian-etsiapa-boamah",fullName:"Vivian Etsiapa Boamah"}]},{id:"39599",doi:"10.5772/50046",title:"Encapsulation Technology to Protect Probiotic Bacteria",slug:"encapsulation-technology-to-protect-probiotic-bacteria",totalDownloads:12448,totalCrossrefCites:45,totalDimensionsCites:87,abstract:null,book:{id:"3145",slug:"probiotics",title:"Probiotics",fullTitle:"Probiotics"},signatures:"María Chávarri, Izaskun Marañón and María Carmen Villarán",authors:[{id:"150285",title:"Dr.",name:"María",middleName:null,surname:"Chávarri Hueda",slug:"maria-chavarri-hueda",fullName:"María Chávarri Hueda"},{id:"151613",title:"MSc.",name:"Izaskun",middleName:null,surname:"Marañon",slug:"izaskun-maranon",fullName:"Izaskun Marañon"},{id:"151621",title:"Dr.",name:"Mª Carmen",middleName:null,surname:"Villarán",slug:"ma-carmen-villaran",fullName:"Mª Carmen Villarán"}]},{id:"39607",doi:"10.5772/50121",title:"Recent Application of Probiotics in Food and Agricultural Science",slug:"recent-application-of-probiotics-in-food-and-agricultural-science",totalDownloads:10168,totalCrossrefCites:32,totalDimensionsCites:77,abstract:null,book:{id:"3145",slug:"probiotics",title:"Probiotics",fullTitle:"Probiotics"},signatures:"Danfeng Song, Salam Ibrahim and Saeed Hayek",authors:[{id:"107905",title:"Prof.",name:"Salam",middleName:null,surname:"Ibrahim",slug:"salam-ibrahim",fullName:"Salam Ibrahim"},{id:"150202",title:"Dr.",name:"Danfeng",middleName:null,surname:"Song",slug:"danfeng-song",fullName:"Danfeng Song"},{id:"151025",title:"MSc.",name:"Saeed",middleName:null,surname:"Hayek",slug:"saeed-hayek",fullName:"Saeed Hayek"}]},{id:"49246",doi:"10.5772/61300",title:"Chitosan as a Biomaterial — Structure, Properties, and Electrospun Nanofibers",slug:"chitosan-as-a-biomaterial-structure-properties-and-electrospun-nanofibers",totalDownloads:4720,totalCrossrefCites:27,totalDimensionsCites:63,abstract:"Chitosan is a polysaccharide derived from chitin; chitin is the second most abundant polysaccharide in the world, after cellulose. Chitosan is biocompatible, biodegradable and non-toxic, so that it can be usedin medicalapplications such as antimicrobial and wound healing biomaterials. It also used as chelating agent due to its ability to bind with cholesterol, fats, proteins and metal ions.",book:{id:"4648",slug:"concepts-compounds-and-the-alternatives-of-antibacterials",title:"Concepts, Compounds and the Alternatives of Antibacterials",fullTitle:"Concepts, Compounds and the Alternatives of Antibacterials"},signatures:"H. M. Ibrahim and E.M.R. El- Zairy",authors:[{id:"90645",title:"Dr.",name:"Hassan",middleName:null,surname:"Ibrahim",slug:"hassan-ibrahim",fullName:"Hassan Ibrahim"},{id:"175694",title:"Dr.",name:"Enas",middleName:null,surname:"El- Zairy",slug:"enas-el-zairy",fullName:"Enas El- Zairy"}]},{id:"51065",doi:"10.5772/63499",title:"Role of the Biofilms in Wastewater Treatment",slug:"role-of-the-biofilms-in-wastewater-treatment",totalDownloads:6849,totalCrossrefCites:28,totalDimensionsCites:61,abstract:"Biological wastewater treatment systems play an important role in improving water quality and human health. This chapter thus briefly discusses different biological methods, specially biofilm technologies, the development of biofilms on different filter media, factors affecting their development as well as their structure and function. It also tackles various conventional and modern molecular techniques for detailed exploration of the composition, diversity and dynamics of biofilms. These data are crucial to improve the performance, robustness and stability of biofilm-based wastewater treatment technologies.",book:{id:"5197",slug:"microbial-biofilms-importance-and-applications",title:"Microbial Biofilms",fullTitle:"Microbial Biofilms - Importance and Applications"},signatures:"Shama Sehar and Iffat Naz",authors:[{id:"180364",title:"Dr.",name:"Iffat",middleName:null,surname:"Naz",slug:"iffat-naz",fullName:"Iffat Naz"},{id:"183345",title:"Dr.",name:"Shama",middleName:null,surname:"Sehar",slug:"shama-sehar",fullName:"Shama Sehar"}]}],mostDownloadedChaptersLast30Days:[{id:"65613",title:"The Methods for Detection of Biofilm and Screening Antibiofilm Activity of Agents",slug:"the-methods-for-detection-of-biofilm-and-screening-antibiofilm-activity-of-agents",totalDownloads:9257,totalCrossrefCites:15,totalDimensionsCites:26,abstract:"Biofilm producer microorganisms cause nosocomial and recurrent infections. Biofilm that is a sticky exopolysaccharide is the main virulence factor causing biofilm-related infections. Biofilm formation begins with attachment of bacteria to biotic surface such as host cell or abiotic surface such as prosthetic devices. After attachment, aggregation of bacteria is started by cell-cell adhesion. Aggregation continues with the maturation of biofilm. Dispersion is started by certain conditions such as phenol-soluble modulins (PSMs). By this way, sessile bacteria turn back into planktonic form. Bacteria embedded in biofilm (sessile form) are more resistant to antimicrobials than planktonic bacteria. So it is hard to treat biofilm-embedded bacteria than planktonic forms. For this reason, it is important to detect biofilm. There are a few biofilm detection and biofilm production methods on prosthetics, methods for screening antibacterial effect of agents against biofilm-embedded microorganism and antibiofilm effect of agents against biofilm production and mature biofilm. The aim of this chapter is to overview direct and indirect methods such as microscopy, fluorescent in situ hybridization, and Congo red agar, tube method, microtiter plate assay, checkerboard assay, plate counting, polymerase chain reaction, mass spectrometry, MALDI-TOF, and biological assays used by antibiofilm researches.",book:{id:"8427",slug:"antimicrobials-antibiotic-resistance-antibiofilm-strategies-and-activity-methods",title:"Antimicrobials, Antibiotic Resistance, Antibiofilm Strategies and Activity Methods",fullTitle:"Antimicrobials, Antibiotic Resistance, Antibiofilm Strategies and Activity Methods"},signatures:"Sahra Kırmusaoğlu",authors:[{id:"179460",title:"Associate Prof.",name:"Sahra",middleName:null,surname:"Kırmusaoğlu",slug:"sahra-kirmusaoglu",fullName:"Sahra Kırmusaoğlu"}]},{id:"62553",title:"Antibiotic Use in Poultry Production and Its Effects on Bacterial Resistance",slug:"antibiotic-use-in-poultry-production-and-its-effects-on-bacterial-resistance",totalDownloads:7313,totalCrossrefCites:42,totalDimensionsCites:89,abstract:"A surge in the development and spread of antibiotic resistance has become a major cause for concern. Over the past few decades, no major new types of antibiotics have been produced and almost all known antibiotics are increasingly losing their activity against pathogenic microorganisms. The levels of multi-drug resistant bacteria have also increased. It is known that worldwide, more than 60% of all antibiotics that are produced find their use in animal production for both therapeutic and non-therapeutic purposes. The use of antimicrobial agents in animal husbandry has been linked to the development and spread of resistant bacteria. Poultry products are among the highest consumed products worldwide but a lot of essential antibiotics are employed during poultry production in several countries; threatening the safety of such products (through antimicrobial residues) and the increased possibility of development and spread of microbial resistance in poultry settings. This chapter documents some of the studies on antibiotic usage in poultry farming; with specific focus on some selected bacterial species, their economic importance to poultry farming and reports of resistances of isolated species from poultry settings (farms and poultry products) to essential antibiotics.",book:{id:"6978",slug:"antimicrobial-resistance-a-global-threat",title:"Antimicrobial Resistance",fullTitle:"Antimicrobial Resistance - A Global Threat"},signatures:"Christian Agyare, Vivian Etsiapa Boamah, Crystal Ngofi Zumbi and\nFrank Boateng Osei",authors:[{id:"182058",title:"Dr.",name:"Christian",middleName:null,surname:"Agyare",slug:"christian-agyare",fullName:"Christian Agyare"},{id:"261271",title:"MSc.",name:"Crystal Ngofi",middleName:null,surname:"Zumbi",slug:"crystal-ngofi-zumbi",fullName:"Crystal Ngofi Zumbi"},{id:"261272",title:"MSc.",name:"Frank Boateng",middleName:null,surname:"Osei",slug:"frank-boateng-osei",fullName:"Frank Boateng Osei"},{id:"261273",title:"Dr.",name:"Vivian Etsiapa",middleName:null,surname:"Boamah",slug:"vivian-etsiapa-boamah",fullName:"Vivian Etsiapa Boamah"}]},{id:"65914",title:"Introductory Chapter: The Action Mechanisms of Antibiotics and Antibiotic Resistance",slug:"introductory-chapter-the-action-mechanisms-of-antibiotics-and-antibiotic-resistance",totalDownloads:4414,totalCrossrefCites:6,totalDimensionsCites:10,abstract:null,book:{id:"8427",slug:"antimicrobials-antibiotic-resistance-antibiofilm-strategies-and-activity-methods",title:"Antimicrobials, Antibiotic Resistance, Antibiofilm Strategies and Activity Methods",fullTitle:"Antimicrobials, Antibiotic Resistance, Antibiofilm Strategies and Activity Methods"},signatures:"Sahra Kırmusaoğlu, Nesrin Gareayaghi and Bekir S. Kocazeybek",authors:[{id:"179460",title:"Associate Prof.",name:"Sahra",middleName:null,surname:"Kırmusaoğlu",slug:"sahra-kirmusaoglu",fullName:"Sahra Kırmusaoğlu"},{id:"248288",title:"Prof.",name:"Bekir",middleName:null,surname:"Kocazeybek",slug:"bekir-kocazeybek",fullName:"Bekir Kocazeybek"},{id:"406463",title:"Dr.",name:"Nesrin",middleName:null,surname:"Gareayaghi",slug:"nesrin-gareayaghi",fullName:"Nesrin Gareayaghi"}]},{id:"50992",title:"Probiotics: A Comprehensive Review of Their Classification, Mode of Action and Role in Human Nutrition",slug:"probiotics-a-comprehensive-review-of-their-classification-mode-of-action-and-role-in-human-nutrition",totalDownloads:5418,totalCrossrefCites:16,totalDimensionsCites:28,abstract:"Probiotics are live microorganisms that live in gastrointestinal (GI) tract and are beneficial for their hosts and prevent certain diseases. In this chapter, after a complete introduction to probiotics, definition, mechanism of action, and their classification, currently used organisms will be discussed in detail. Moreover, different kinds of nutritional synthetic products of probiotics along with their safety and drug interaction will be noticed. This chapter mentions all clinical trial studies that have been done to evaluate probiotic efficacy with a focus on gastrointestinal diseases.",book:{id:"5193",slug:"probiotics-and-prebiotics-in-human-nutrition-and-health",title:"Probiotics and Prebiotics in Human Nutrition and Health",fullTitle:"Probiotics and Prebiotics in Human Nutrition and Health"},signatures:"Amirreza Khalighi, Reza Behdani and Shabnam Kouhestani",authors:[{id:"179560",title:"Dr.",name:"Amirreza",middleName:null,surname:"Khalighi",slug:"amirreza-khalighi",fullName:"Amirreza Khalighi"},{id:"185238",title:"Dr.",name:"Reza",middleName:null,surname:"Behdani",slug:"reza-behdani",fullName:"Reza Behdani"},{id:"185239",title:"Dr.",name:"Shabnam",middleName:null,surname:"Kouhestani",slug:"shabnam-kouhestani",fullName:"Shabnam Kouhestani"}]},{id:"56849",title:"Physiology and Pathology of Innate Immune Response Against Pathogens",slug:"physiology-and-pathology-of-innate-immune-response-against-pathogens",totalDownloads:6205,totalCrossrefCites:21,totalDimensionsCites:28,abstract:"Pathogen infections are recognized by the immune system, which consists of two types of responses: an innate immune response and an antigen-specific adaptive immune response. The innate response is characterized by being the first line of defense that occurs rapidly in which leukocytes such as neutrophils, monocytes, macrophages, eosinophils, mast cells, dendritic cells, etc., are involved. These cells recognize the pathogen-associated molecular patterns (PAMPs), which have been evolutionarily conserved by the diversity of microorganisms that infect humans. Recognition of these pathogen-associated molecular patterns occurs through pattern recognition receptors such as Toll-like receptors and some other intracellular receptors such as nucleotide oligomerization domain (NOD), with the aim of amplifying the inflammation and activating the adaptive cellular immune response, through the antigenic presentation. In the present chapter, we will review the importance of the main components involved in the innate immune response, such as different cell types, inflammatory response, soluble immune mediators and effector mechanisms exerted by the immune response against bacteria, viruses, fungi, and parasites; all with the purpose of eliminating them and eradicating the infection of the host.",book:{id:"5975",slug:"physiology-and-pathology-of-immunology",title:"Physiology and Pathology of Immunology",fullTitle:"Physiology and Pathology of Immunology"},signatures:"José Luis Muñoz Carrillo, Flor Pamela Castro García, Oscar\nGutiérrez Coronado, María Alejandra Moreno García and Juan\nFrancisco Contreras Cordero",authors:[{id:"214236",title:"Dr.",name:"Jose Luis",middleName:null,surname:"Muñoz-Carrillo",slug:"jose-luis-munoz-carrillo",fullName:"Jose Luis Muñoz-Carrillo"},{id:"216080",title:"Dr.",name:"Alejandra",middleName:null,surname:"Moreno-García",slug:"alejandra-moreno-garcia",fullName:"Alejandra Moreno-García"},{id:"216081",title:"Dr.",name:"Oscar",middleName:null,surname:"Gutiérrez-Coronado",slug:"oscar-gutierrez-coronado",fullName:"Oscar Gutiérrez-Coronado"},{id:"216082",title:"Dr.",name:"Pamela",middleName:null,surname:"Castro-García",slug:"pamela-castro-garcia",fullName:"Pamela Castro-García"},{id:"220717",title:"Dr.",name:"Juan Francisco",middleName:null,surname:"Contreras Cordero",slug:"juan-francisco-contreras-cordero",fullName:"Juan Francisco Contreras Cordero"}]}],onlineFirstChaptersFilter:{topicId:"13",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82972",title:"Actinomycosis: Diagnosis, Clinical Features and Treatment",slug:"actinomycosis-diagnosis-clinical-features-and-treatment",totalDownloads:0,totalDimensionsCites:0,doi:"10.5772/intechopen.104698",abstract:"Actinomycosis is a filamentous bacterium that forms part of the normal human flora of the gastrointestinal, oropharynx and female genitalia. This indolent infection is characterized by abscess formation, widespread granulomatous disease, fibrosis, cavitary lung lesions and mass-like consolidations, simulating an active malignancy or systemic inflammatory diseases. It is subacute, chronic and variable presentation may delay diagnosis due to its capability to simulate other conditions. An accurate diagnostic timeline is relevant. Early diagnosis of pulmonary actinomycosis decreases the risk of indolent complications. Proper treatment reduces the need for invasive surgical methods. Actinomycosis can virtually involve any organ system, the infection spread without respecting anatomical variables as metastatic disease does, making malignancy an important part of the differential diagnosis. As it is normal gastrointestinal florae, it is difficult to cultivate, and share similar morphology to other organisms such as Nocardia and fungus. It is often difficult to be identified as the culprit of disease. Its true imitator capability makes this infectious agent a remarkable organism within the spectra of localized and disseminated disease. In this chapter, we will discuss different peculiarities of actinomycosis as an infectious agent, most common presentation in different organ systems, and challenging scenarios.",book:{id:"10893",title:"Actinobacteria",coverURL:"https://cdn.intechopen.com/books/images_new/10893.jpg"},signatures:"Onix J. Cantres-Fonseca, Vanessa Vando-Rivera, Vanessa Fonseca-Ferrer, Christian Castillo Latorre and Francisco J. Del Olmo-Arroyo"},{id:"82412",title:"Potential of Native Microalgae from the Peruvian Amazon on the Removal of Pollutants",slug:"potential-of-native-microalgae-from-the-peruvian-amazon-on-the-removal-of-pollutants",totalDownloads:2,totalDimensionsCites:0,doi:"10.5772/intechopen.105686",abstract:"Environmental pollution is a severe and common problem in all the countries worldwide. Various physicochemical technologies and organisms (e.g., plants, microorganisms, etc.) are used to address these environmental issues, but low-cost, practical, efficient, and effective approaches have not been available yet. Microalgae offer an attractive, novel, and little-explored bioremediation alternative because these photosynthetic organisms can eliminate pathogenic microorganisms and remove heavy metals and toxic organic compounds through processes still under study. Our research team has conducted some experiments to determine the bioremediation potential of native microalgae on some pollutant sources (i.e., leachate and wastewater) and its ability to remove hazardous chemical compounds. Therefore, in this chapter, we provide the results of our research and updated information about this exciting topic. Experiments were conducted under controlled culture conditions using several native microalgae species, variable time periods, different pollutant sources, and hazardous chemicals such as ethidium bromide. The results indicated that native microalgae can remove pollutants (i.e., phosphorus, ammonia, etc.) of wastewater, leachate, and some hazardous chemical compounds such as ethidium bromide. In conclusion, native microalgae have an excellent potential for removing several pollutants and, consequently, could be used to develop bioremediation technologies based on native microalgae from the Peruvian Amazon.",book:{id:"11366",title:"Microalgae",coverURL:"https://cdn.intechopen.com/books/images_new/11366.jpg"},signatures:"Marianela Cobos, Segundo L. Estela, Carlos G. Castro, Miguel A. Grandez, Alvaro B. Tresierra, Corayma L. Cabezudo, Santiago Galindo, Sheyla L. Pérez, Angélica V. Rios, Jhon A. Vargas, Roger Ruiz, Pedro M. Adrianzén, Jorge L. Marapara and Juan C. Castro"},{id:"81859",title:"Respiratory Syncytial Virus",slug:"respiratory-syncytial-virus",totalDownloads:5,totalDimensionsCites:0,doi:"10.5772/intechopen.104771",abstract:"Respiratory Syncytial Virus (RSV)-driven bronchiolitis is one of the most common causes of pediatric hospitalization. Every year, we face 33.1 million episodes of RSV-driven lower respiratory tract infection without any available vaccine or cost-effective therapeutics since the discovery of RSV eighty years before. RSV is an enveloped RNA virus belonging to the pneumoviridae family of viruses. This chapter aims to elucidate the structure and functions of the RSV genome and proteins and the mechanism of RSV infection in host cells from entry to budding, which will provide current insight into the RSV-host relationship. In addition, this book chapter summarizes the recent research outcomes regarding the structure of RSV and the functions of all viral proteins along with the RSV life cycle and cell-to-cell spread.",book:{id:"11369",title:"RNA Viruses Infection",coverURL:"https://cdn.intechopen.com/books/images_new/11369.jpg"},signatures:"Sattya Narayan Talukdar and Masfique Mehedi"},{id:"82148",title:"Mosquito Population Modification for Malaria Control",slug:"mosquito-population-modification-for-malaria-control",totalDownloads:11,totalDimensionsCites:0,doi:"10.5772/intechopen.104907",abstract:"Malaria is a mosquito-borne disease that kills millions of people every year. Existing control tools have been insufficient to eliminate the disease in many endemic regions and additional approaches are needed. Novel vector-control strategies using genetic engineering to create malaria-resistant mosquitoes (population modification) can potentially contribute a new set of tools for mosquito control. Here we review the current mosquito control strategies and the development of transgenic mosquitoes expressing anti-parasite effector genes, highlighting the recent improvements in mosquito genome editing with CRISPR-Cas9 as an efficient and adaptable tool for gene-drive systems to effectively spread these genes into mosquito populations.",book:{id:"11379",title:"Mosquito Research - Recent Advances in Pathogen Interactions, Immunity, and Vector Control Strategies",coverURL:"https://cdn.intechopen.com/books/images_new/11379.jpg"},signatures:"Rebeca Carballar-Lejarazú, Taylor Tushar, Thai Binh Pham and Anthony James"},{id:"81934",title:"Lactobacillus Use for Plant Fermentation: New Ways for Plant-Based Product Valorization",slug:"lactobacillus-use-for-plant-fermentation-new-ways-for-plant-based-product-valorization",totalDownloads:15,totalDimensionsCites:0,doi:"10.5772/intechopen.104958",abstract:"Today, plant production is increasing, but most industrial processes generate a lot of waste and by-products for which, in the current context, it is a priority to recycle or valorize them. One of the cheapest valorization routes is fermentation, in particular lactic fermentation by Lactobacillus species, which produces lactic acid and other molecules of industrial interest such as bioactive compounds such as anthocyanin, organic acid, peptides, or phenol, which are widely found in the plant matrix, mainly in cereals, grass, fruits, and vegetables. Bioactive compounds may exert beneficial health effects, such as antioxidant, anti-inflammatory, antimicrobial, or prebiotic activities. In addition, lactic acid fermentation can improve existing products and lead to new applications in food, livestock feeding and biotechnology, such as the production of lactic acid, protein, or silage. This chapter reviews the use of Lactobacillus strains in the fermentation process of many plant bioresources or by-products through their different bioactivities, active molecules, and applications.",book:{id:"11372",title:"Lactobacillus - A Multifunctional Genus",coverURL:"https://cdn.intechopen.com/books/images_new/11372.jpg"},signatures:"Morgan Le Rouzic, Pauline Bruniaux, Cyril Raveschot, François Krier, Vincent Phalip, Rozenn Ravallec, Benoit Cudennec and François Coutte"},{id:"82672",title:"Removal of Microcystins from Drinking Water by Electrocoagulation: Upscaling, Challenges, and Prospects",slug:"removal-of-microcystins-from-drinking-water-by-electrocoagulation-upscaling-challenges-and-prospects",totalDownloads:5,totalDimensionsCites:0,doi:"10.5772/intechopen.105751",abstract:"Microcystins (MCs) belong to a family of stable monocyclic heptapeptide compounds responsible for hazardous toxins in drinking water. Although several methods have been applied to remove MCs from drinking water (e.g., activated carbon filtration, ion exchange resins, high-pressure membranes, and electrochemistry), upscaling laboratory experiments to benefit municipal water treatment is still a major challenge. This chapter is a follow-up study designed to test three electrocoagulation (EC) techniques for decomposing MC by UV-ozone purification (laboratory), electrocoagulation (field unit), and coupled UV-ozone-electrocoagulation (municipal treatment). The chemistry and efficiency of the treatments were first examined followed by comparison with activated carbon filtration. Electrocoagulation outperformed activated carbon filtration by nearly 40%. When the laboratory treatments were evaluated at the municipal scale, effectiveness of the technique deteriorated by 10–20% because of UV pulse dissipation, vapor-ion plasma under-functioning, and limitations of polymer fiber filters. We confirmed previously published studies that pollutant coagulation and MC decomposition are affected by physicochemical factors such as radiation pulse density, electrical polarity, pH, and temperature dynamics. The results have relevant applications in wastewater treatment and chemical recycling.",book:{id:"11800",title:"Cyanobacteria - Recent Advances and New Perspectives",coverURL:"https://cdn.intechopen.com/books/images_new/11800.jpg"},signatures:"Stephen Opoku-Duah, Dennis Johnson, Dan Blair and Jeff Dimick"}],onlineFirstChaptersTotal:101},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:18,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:139,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:122,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:21,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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