Summary of Autoimmune liver disease
\r\n\t
",isbn:"978-1-80356-951-2",printIsbn:"978-1-80356-950-5",pdfIsbn:"978-1-80356-952-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"bb6fc82b35ad2c63618a9bc15aeb61ce",bookSignature:"Dr. Kim Ho Yeap and Dr. Magdalene Goh Wan Ching",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11948.jpg",keywords:"MOSFET, CMOS, OFET, JFET, FinFET, Integrated Circuit (IC), Oxidation, Metallization, Semiconductor, Silicon (Si), Gallium Arsenide (GaAs), Silicon Carbide (SiC)",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 7th 2022",dateEndSecondStepPublish:"June 16th 2022",dateEndThirdStepPublish:"August 15th 2022",dateEndFourthStepPublish:"November 3rd 2022",dateEndFifthStepPublish:"January 2nd 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"9 days",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"A researcher in the fields of microelectronics and electromagnetics. Member of IEEE, IET, IEM.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"24699",title:"Dr.",name:"Kim Ho",middleName:null,surname:"Yeap",slug:"kim-ho-yeap",fullName:"Kim Ho Yeap",profilePictureURL:"https://mts.intechopen.com/storage/users/24699/images/system/24699.jpg",biography:"Kim Ho Yeap is an Associate Professor at Universiti Tunku Abdul Rahman, Malaysia. He is an IEEE senior member, a Professional Engineer registered with the Board of Engineers, Malaysia,a Chartered Engineer registered with the UK Engineering Council, and an ASEAN Chartered Professional Engineer (ACPE). He received his BEng (Hons) Electrical and Electronics Engineering from Universiti Teknologi Petronas in 2004, his MSc in microelectronics from Universiti Kebangsaan Malaysia in 2005, and his PhD from Universiti Tunku Abdul Rahman in 2011. In 2008 and 2015, respectively, Dr. Yeap underwent research attachment at the University of Oxford (UK) and Nippon Institute of Technology (Japan). Dr. Yeap is the external examiner and external course assessor of Wawasan Open University. He is also the Editor in Chief of the i-manager’s Journal on Digital Signal Processing. He has also been a guest editor for the Journal of Applied Environmental and Biological Sciences and Journal of Fundamental and Applied Sciences. Dr. Yeap has been given the university teaching excellence award, and 22 research grants. He has published more than 100 research articles (including refereed journal papers, conference proceedings, books, and book chapters). Prior to joining the academic industry, Dr. Yeap worked in Intel corporation in the pre-silicon validation group. He was awarded 4 Kudos awards by Intel for his contributions in the design and verification of the microchip’s design for testability (DFT) features.",institutionString:"Universiti Tunku Abdul Rahman",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"Universiti Tunku Abdul Rahman",institutionURL:null,country:{name:"Malaysia"}}}],coeditorOne:{id:"454196",title:"Dr.",name:"Magdalene",middleName:null,surname:"Goh Wan Ching",slug:"magdalene-goh-wan-ching",fullName:"Magdalene Goh Wan Ching",profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:"Dr Magdalene Goh Wan Ching\r\nDesignation: Senior lecturer\r\nQualifications: Diploma in Electrical & Electronics Engineering (Inti College), BEng in Electrical\r\nEngineering & Electronics (University of Liverpool, UK), PhD in Solid State\r\nDevice Physics & RF Transistors Design (University of Liverpool, UK)\r\n\r\nProfessional Body\r\nMemberships:\r\n\r\nInaugural Senior Member, International Engineering & Technology Institute\r\n(IETI), Hong Kong\r\n\r\nBiodata: Dr. Magdalene Goh obtained her Diploma in Electrical & Electronics Engineering\r\nfrom Inti College before leaving for the UK to pursue her BEng in Electrical\r\nEngineering & Electronics and later on, her PhD. Prior to joining the academia,\r\nshe has worked for a few years in the industry in the areas of semiconductor\r\nprocess technology, silicon wafer characterizations, mask layout design,\r\nanalogue circuits design and design for testability (DFT). While in the academic,\r\nshe had served as a judge for Innovate Malaysia undergraduate final year\r\nprojects competition from 2012 - 2015. She had served as an external examiner\r\nfor a PhD candidate from VIT University, India in 2013, and an external examiner\r\nfor SEGi College Penang from 2014 – 2018. She has been actively involved with\r\nthe Penang Science Cluster in their radio telescope team since 2014, where she\r\nworks with a team of volunteers (from both academia and the industry in\r\nPenang) to create curricula in radio astronomy, for the purpose of introducing the\r\nconcepts of radio astronomy and radio telescopes to both school pupils and\r\ncollege students. She has been a member of the Astronomical Society of\r\nPenang since 2016.\r\n\r\nCourse Development\r\nExperience:\r\n\r\nSince joining WOU, Dr. Goh has developed eight courses, namely Control\r\nSystems, Microprocessors, Digital Communications, Microelectronics, VLSI\r\nDesign, Process Control & Instrumentation, Power Electronics & Drives and\r\nElectrical Power & Drives.\r\n\r\nResearch Interest: Dr. Goh’s research interests are in the areas of semiconductor physics and\r\nelectromagnetics. She also has strong interest in the field of astronomy and is\r\nworking with a group of volunteers to promote astronomy education in the\r\nsecondary schools in Penang. She had also worked with some interns on the\r\nradio telescope project at the Penang Science Cluster.\r\n\r\nResearch Projects and\r\nConsultancy Work:\r\nSelected Publications: Design of Radio Frequency Metal-Insulator-Metal (MIM) Capacitors. \r\n\r\nExperimental Investigation on Thermoelectric Generator for Battery - Charger\r\nBased Oven.\r\nAnalyzing the Physics of Radio Telescopes and Radio Astronomy (book\r\nchapters).\r\n\r\nConferences,\r\nSeminars and\r\nWorkshops:\r\n\r\nDr. Goh was appointed as one of the Technical Committee Member for the\r\nVirtual Conference on Electronics and Communication: Loading Intelligence on\r\nFuture Electronics (October 2020).\r\n\r\nHonorary\r\nAppointments and\r\nAwards:\r\n\r\nDr. Goh is a reviewer of the following journals:-\r\n1. Microwave and Optical Technology Letters.\r\n2. Journal of Electrical Engineering.\r\n3. Journal on Digital Signal Processing.\r\n\r\nOfficial\r\n\r\nDr. Magdalene Goh Wan Ching\r\nSenior Lecturer & Programme Coordinator of Bachelor of Technology in\r\n\r\nCorrespondence\r\nAddress:\r\n\r\nElectronics,\r\nSchool of Science & Technology\r\nWawasan Open University\r\n54, Jalan Sultan Ahmad Shah,\r\n10050 Penang\r\n\r\nEmail Address: magdalenegoh@wou.edu.my\r\nPersonal Homepage\r\n(optional):\r\n\r\nBTEL facebook page:\r\nhttps://www.facebook.com/groups/238200129533176/",institutionString:"Technology Wawasan Open University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"11",title:"Engineering",slug:"engineering"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"444312",firstName:"Sara",lastName:"Tikel",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/444312/images/20015_n.jpg",email:"sara.t@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"10198",title:"Response Surface Methodology in Engineering Science",subtitle:null,isOpenForSubmission:!1,hash:"1942bec30d40572f519327ca7a6d7aae",slug:"response-surface-methodology-in-engineering-science",bookSignature:"Palanikumar Kayaroganam",coverURL:"https://cdn.intechopen.com/books/images_new/10198.jpg",editedByType:"Edited by",editors:[{id:"321730",title:"Prof.",name:"Palanikumar",surname:"Kayaroganam",slug:"palanikumar-kayaroganam",fullName:"Palanikumar Kayaroganam"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. 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It is characterised by the immune mediated injury to the hepatocytes and bile ducts. Hepatocyte injury is the predominant features in autoimmune hepatitis and biliary injury is the hallmark of primary biliary cirrhosis (Intrahepatic bile duct injury), primary sclerosing cholangitis or Immunoglobulin (Ig) G4 mediated cholangitis (both intra and extra-hepatic bile duct injury). Overlap or variant syndrome indicates the presence of simultaneous injury to both hepatocytes and cholangiocytes during the course of the disease. Imbalance in effector and regulatory arm of adaptive immune cells had been described as the immunopathogenesis of AILD. Antigenic causative factors are still poorly understood across AILD but genetic, environmental factors and microbiota play a major role in disease pathology.
The aim of the chapter is to describe in depth of each disease entity in regard to their immuno-pathogenesis, diagnosis, investigations and management strategies including standardised care as well as future novel therapies.
Long term global immunosuppressive therapy in AIH with multiple side effects and lack of definitive treatment to tackle the underlying immunopathology in PBC and PSC are major challenging aspects in AILD. Thorough understanding of causative antigens, immuno-pathogenesis, OMIC profiles (genomic, metabolomics, proteomic and microbiomic) of AILD patients will direct clinicians for stratification and individualized personal care. Novel new immunological based cell and cytokines therapies are urgently warranted in defined unique group of AILD patients.
The diagnosis and management of AILD can be constantly challenging due to the presence of overlap features at diagnosis or gradual evolution in phenotype of diseases from one spectrum (typical AIH) to others (overlap of AIH/PBC and AIH/PSC) during the disease process. Therefore, the continuous assessment of the disease presentations are essential in follow up of patients with AILD.
An autoimmune liver disease (AILD) is an umbrella term for diseases caused by immune mediated reaction to either hepatocytes or bile ducts. Regulatory T cells (Treg) play an important and essential role in the maintenance of homeostasis and prevention of autoimmune responses [1]. Autoimmune hepatitis (AIH) is caused by an immune mediated injury of the hepatocytes and characterised by presence of lobular and interface hepatitis on liver histology, presence of hypergammaglobulinaemia and high titre of antinuclear antibodies (ANA) in the serum with transaminitis on liver biochemistry. The main aim of treatment is to suppress the immune system globally and the first line therapies used are prednisolone and azathioprine. Second line therapies such as tacrolimus and mycophenolate mofetil are also used in AIH patients. Two commonly used biologics in difficult-to-treat AIH patients are anti- tumour necrosis factor (anti-TNF) for example Infliximab and anti-CD20 monoclonal antibody therapy as in Rituximab. New novel antigen-specific autologous regulatory T cells therapy development is also in progress for future treatment of autoimmune hepatitis.
Primary biliary cirrhosis (PBC) is an injury to the intra-hepatic biliary ducts and tends of present in 4th to 6th decade of life. The main therapy is ursodeoxycholic acid (UDCA) but new therapies for PBC such as Obeticholic acid have been emerged recently. Patients with PBC tend to suffer with significant itch and management of itch can be challenging at times. There are therapies available for itch from the spectrum to cholestyramine to immunoglobulins infusion treatment.
Primary sclerosing cholangitis (PSC) is an immune mediated injury, mainly to biliary system either intrahepatic or extrahepatic or both. PSC is common in young, male patient and commonly associated with inflammatory bowel disease (IBD), especially ulcerative colitis. There is a significant risk of developing cancer such as cholangiocarcinoma or gall bladder cancer or bowel cancer in these groups of patients and hence surveillance is important. There are no targeted treatments available for PSC and liver transplantation is necessary in end stage PSC.
Detailed summary of three autoimmune liver disease (autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis) are documented in table 1.
Summary of Autoimmune liver disease
ANA: Anti-nuclear antibodies, ASMA: anti smooth muscle antibodies, LKM: Liver- kidney-microsomal antibodies, g G: Immunoglobulin G, Ig M: Immunoglobulin M, Anti-gp 210: Antibodies against the nuclear pore membrane glycoprotein (anti-gp210), Anti-Sp 100: Antibodies against the nuclear protein Sp100, ULN: Upper limit of normal, UDCA: Ursodeoxycholic acid
Adapted from 1) Trivedi, P.J. and G.M. Hirschfield, Review article: overlap syndromes and autoimmune liver
Autoimmune hepatitis (AIH) is an immune mediated, chronic inflammatory disease of unknown aetiology, mainly affecting the hepatocytes. It was first defined in 1950 by Waldenström when he described a chronic hepatitis in young woman which eventually lead to liver cirrhosis [2]. It is characterised by the morphological changes of interface hepatitis on liver biopsy, hypergammaglobulinaemia and the presence of high circulating ANA in the serum [3, 4]. It is more common in women (around 75%) and can affect at any age from young to elderly. It is also associated with other autoimmune conditions such as hypothyroidism, ulcerative colitis, type 1 diabetes mellitus, rheumatoid arthritis, coeliac disease or skin disorders such as vitiligo. Therefore, obtaining a detailed history especially family history of autoimmune conditions are important in the assessment of patients with potential AIH diagnosis.
There is limited evidence regarding the incidence and prevalence of AIH. From the data so far, it has been estimated that the prevalence of AIH is around 5 to 20 cases per 100,000 among the Caucasian population in Western Europe [5]. AIH accounts for up to 20% of chronic hepatitis among the Caucasian population of North America and Western Europe [5]. AIH prevalence and clinical expression appear to vary according to ethnicity. Previous studies showed that black patients tend to have more aggressive disease [6] whereas Hispanic populations had a higher prevalence of cirrhosis [7]. Asian patients develop the disease later in life and have a poorer survival [7] and Alaskan native patients presented more frequently with acute AIH [8].
Clinically, there are three forms of AIH. Type 1 AIH is common in adults and characterised by the presence of ANA and/or anti smooth muscle antibodies (ASMA) with raised Immunoglobulin-G (Ig G). Type 2 is seen mostly in children and characterised by the presence of anti-liver-kidney-microsomal (LKM) antibodies directed against cytochrome P450 (CYP-2D6) [9, 10] and with lower frequency against UDP-glucuronosyltransferases (UGT) [2, 11]. Antibodies against soluble liver or liver-pancreas (SLP) antigens are common in type 3 AIH. Around 19% of patients can present with seronegative disease at the time of diagnosis [12].
The exact aetiopathogenesis of AIH is still unknown. It is a complex process interlinking environmental and genetic factors in a susceptible host. The most common environmental trigger thought to cause AIH is viral infection. Drug induced AIH is a recognised entity and the commonly associated drugs are anti-TNF treatment such as Adalimumab, antibiotics such as minocycline or nitrofurantion or statins such as rosuvastatin [13-15]. Both T cells and B cells play an important role in the adaptive immune response to both self and non-self-antigen. T cells, both CD4 and CD8 T cells, play a major role in the immnuopathogenesis with effector responses mediated by Natural Killer (NK) cells and macrophages [16]. Regulatory T cells (Treg) play an essential role in the homeostasis and prevention of autoimmune conditions [1]. They are classified as CD4+ CD25high CD127Low and represent the 2 % of the CD3 subset [17]. Foxp3 (forkhead box P3) is a transcription factor which controls the phenotype, development and function of Treg [18]. Commitment to Treg lineage primary occurs in the thymus as a result of presenting self- antigens by medullary thymic epithelium. In AIH, the number of Tregs is normal but their function is impaired [19]. Reduction in frequency of Treg has also been reported [17, 20].
Type 1 AIH is associated with human leukocyte antigen (HLA) DR3 (HLA-DRB1*0301) and DR4 (HLA-DRB1*0401) in white North Europe and North American patients [21, 22]. It has been suggested the presence of DR3 is associated with poorer response to treatment and hence requires liver transplantation (LT) [21, 22]. On the other hand, patients with DR4 are usually older and more responsive to treatment with steroid [21]. A recent geno-wide association study of type 1 AIH in Netherlands showed that type 1 AIH is associated with the rs3184504*A allele in the SH2B3 gene [22]. These single nucleotide polymorphisms (SNP) represent the first genetic AIH locus outside the Major Histocompatibility Complex (MHC) region [22]. It encodes a missense variant in exon 3 of the Scr homology 2 adaptor protein 3 (SH2B3) genes located in the 12q24 region [22]. SH2B3 is a negative regulator of T-cell activation, tumour necrosis factor, and Janus kinase 2 and 3 signalling, and plays an essential role in normal haematopoiesis [22]. Capcase recruitment domain family member 10 (CARD 10) gene with allele rs6000782 has been shown to be associated with type 1 AIH [22]. CARD 10 is a scaffold protein and induces pro-inflammatory nuclear factor kB activation and it is widely expressed in a variety of non-haematopoietic tissue including hepatocytes [22].
Proposed pathway of pathogenesis in AIH has been shown in Figure 1.
Most patients present with nonspecific symptoms such as fatigue, arthralgia and anorexia at the time of presentation. About 25% of patient present asymptomatically [23] and the majority of patients present late with symptoms of portal hypertension and decompensated cirrhosis. Recent systematic review mentioned that around 25 % of elderly patients (age 60 to 65) were more likely to present asymptomatically, they are more likely to be HLA-DR4 positive and cirrhotic at initial presentation [24]. They are less likely to be HLA-DR3-positive and to relapse after treatment withdrawal after complete remission [24]. AIH can also present during pregnancy or postpartum period. Physical examination can either be normal, or show hepatomegaly, splenomegaly or signs of chronic liver disease. In some patients, AIH present as acute severe hepatitis and rarely, they progress to fulminant form and require liver transplantation [2].
Blood tests can show signs of hepatitis with raised alanine transaminase (ALT, U/L) (usually less than 500 U/L), aspartate transaminase (AST, U/L) and occasionally bilirubin (umol/L). Typical immunology profile in AIH patients are raised Ig G with positive ANA, ASMA (in type 1 AIH) and LKM (in type 2 AIH). Patients with acute presentation of AIH should be monitored for synthetic function such as international normalised ratio (INR) and albumin as well as mental status or sign of hepatic encephalopathy since some patients can progress to acute liver failure rapidly and will need liver transplantation. Viral hepatitis, toxins, drugs should be excluded in patient presenting with acute or chronic form of hepatitis. Men with AIH appear to have a higher relapse rate and younger age of disease onset [25, 26]. Cirrhosis at presentation [27, 28] and presence of SLA antibodies are poor predictive outcomes in type 1 AIH patients [29, 30].
Liver biopsy is recommended at the time of presentation to establish the diagnosis as well as to guide the treatment, however in patients presenting with acute hepatitis who has suspicious diagnosis of AIH, the treatment should not be delayed [31]. The histological hallmarks of AIH is a lymphoplasmacytic peri-portal infiltrate invading the limiting plate, also called piecemeal necrosis or “interface hepatitis” and eventually lead to lobular hepatitis (Figure 2) [13]. Patients with chronic AIH usually have plasma cell- rich mononuclear infiltrate involving portal and peri-portal regions [16] which subsequently lead to peri-portal fibrosis. Up to 30% of patients with AIH had histological features of cirrhosis at the time of presentation [2]. In 17% of patients with peri-portal hepatitis whereas 82% of patients who had bridging fibrosis, cirrhosis develops within 5 years [2].
The diagnosis of AIH is based on multiple investigations and diagnostic criteria was proposed by the international AIH group in 1993 and subsequently updated in 1999 (Table 2) [13, 32, 33]. In 2008, the groups established the simplified scoring system which is more user friendly in day to day clinical care[13] (Table 3). The scoring is based on combination of the serum immunoglobulins titres (ANA, SMA or LKM), serum liver enzymes and liver histology features with absence of viral hepatitis.
Histology findings of autoimmune hepatitis
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\t+2 | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t |
• <1.5 • 1.5-3.0 • >3.0 | \n\t+2 0 -2 | \n
\n\t\t | \n\t\n |
• >2.0 • 1.5-2.0 • 1.0-1.5 • <1.0 | \n+3 +2 +1 0 | \n
\n\t\t | \n\t\n |
• >1:80 • 1:80 • 1:40 • <1:40 | \n+3 +2 +1 0 | \n
\n\t\t | \n\t\n |
• Positive • Negative | \n\t-4 +1 | \n
\n\t\t | \n\t\n |
• <25g/day • >60g/day | \n+2 -2 | \n
\n\t\t | \n\t\n |
• Interface hepatitis • Lymphoplasmacytic infiltrate • Rosette formation • None of the above • Biliary changes • Other changes | \n\t+3 +1 +1 -5 -3 -2 +2 | \n
\n\t\t | \n\t\n |
\n\t\t | \n\t-4 | \n
\n\t\t | \n\t\n |
• Positive • Negative | \n\t-3 +3 | \n
Definite AIH Probable AIH | \n\t>15 10-15 | \n
Revised International Autoimmune Hepatitis Group Scoring System for the Diagnosis of Autoimmune Hepatitis (AIH) (Adapted from Alvarez et al [21] and Chandok et al [22])
ALP: alkaline phosphatase, AST: Aspartate transaminase, Ig: Immunoglobulin, ANA: Antinuclear antibodies, SMA: Smooth muscle antibodies, LKM: Liver kidney microsomal antibodies, AMA: Anti-mitochondrial antibod
\n\t\t\t | \n\t\t\n\t\t\t | \n\t\t\n\t\t\t | \n\t
ANA or SMA | \n\t\t≥ 1;40 | \n\t\t1 | \n\t
\n\t\t | ≥ 1:80 | \n\t\t2 | \n\t
Or LKM 1 | \n\t\t≥ 1:40 | \n\t\t2 | \n\t
Or SLA | \n\t\tPositive | \n\t\t1 | \n\t
Ig G | \n\t\t>upper limit of normal | \n1 | \n
\n\t | >1.1x upper limit of normal | \n2 | \n
Liver histology | \n\tCompatible with AIH | \n\t1 | \n
\n\t | Typical of AIH | \n\t2 | \n
Absence of viral hepatitis | \n\tYes | \n\t2 | \n
Simplified scoring system for autoimmune hepatitis
ANA: anti-nuclear antibodies; SMA: anti-smooth-muscle antibodies; LKM1: liver/ kidney microsomal antibody type 1; SLA: anti-soluble liver antigen.
Definite AIH: A cumulative score ≥7
Probable AIH: A cumulative score =6
Liver histology typical of AIH: interface hepatitis, emperipolesis, hepatic rosette formation
Liver histology compatible with AIH: chronic hepatitis with lymphocytic infiltration, without typical features.
The main aim for treatment of AIH is to suppress the ongoing inflammation and the first line therapies used are steroids (either prednisolone or budesonide) with or without azathioprine (AZA). Steroid side effects such as cosmetic changes, osteopenia, hirsutism, steroid induced diabetes are seen in about 44% of patients within 12 months of treatment and 80% within 24 months of treatment [2]. Budesonide is a preferred choice of treatment for patients who do not tolerate prednisolone due to side effects and in patients with diabetes mellitus. It is a synthetic steroid with high first-pass metabolism in the liver, which is in principle capable of limiting systemic side effects compared to conventional steroids [2]. Due to those side effects mentioned above, the adherence to medication can be an issue and hence, compliance needs to be monitored throughout the treatment period. Patients who need long term steroid therapy (> 3 months) should be started on calcium and vitamin D3 supplements to prevent osteoporosis.
The combination regimen of prednisone and azathioprine is associated with a lower occurrence of corticosteroid-related side effects than the higher dose prednisone regimen (10% versus 44%), and it is the preferred treatment in patients with AIH. AZA side effects include abdominal discomforts, pancreatitis, nausea, cholestatic hepatitis, rashes and leukopenia and they can be seen in 15% of patients who received 50mg of AZA [2]. Azathioprine metabolite and Thiopurine S-Methyl Transferase (TPMT) levels will guide the optimal dose for individual patients. Some patients who cannot tolerate AZA benefit from Mercaptourine. The metabolism of AZA has been demonstrated in Figure 3.
Azathioprine metabolism
Around 90% of adult patients respond to therapy within first 2 weeks with improvement in serum immunoglobulins and liver enzymes levels [31]. Treatment should be continued until normalisation of serum immunological and, biological parameters as well as improvement in liver histology. Relapsed AIH is characterized by an increase in the serum aminotransferase levels to at least threefold normal and it occurs in 50% to 86% of patients who previously had complete remission of their disease and usually happens during the first 6 months after the termination of therapy [13, 31]. In patients who has sub-optimal response to initial therapy or relapsed AIH should be considered for more potent treatments such as tacrolimus or mycophenolate mofetil.
Alternative therapies include tacrolimus, mycophenolate mofetil (MMF), cyclosporine, methotrexate, cyclophosphamide, ursodeoxycholic acid (UDCA), infliximab and rituximab [14]. Although there are some encouraging results with each of the medications, the treatment has not been implemented into standard management due to lack of randomised control data. Most of the evidence is based on from small, retrospective, single centre case series [34]. Therefore, these treatments should be only commenced in the specialised centre with presence of experienced hepatologists.
Patients with acute, severe AIH who are untreated have poorer short and long term survival compared to treated AIH patients [48-50]. For patients with the severe acute phenotype of AIH, failure to respond to treatment within the first 7–14 days after presentation is associated with a mortality of almost 50% [51]. For patients with established cirrhosis at presentation, treatment can induce remission and improve long-term outcome, with 10-year life expectancies of greater than 90% [52, 53]. Patient with cirrhosis due to AIH usually develop hepatocellular carcinoma at a mean of 9 to 10 years according to previous published case series and hence, routine surveillance with 6 monthly ultrasound scan and alpha feto protein (AFP) is recommended for these cohort of patients [54, 55]. Autoimmune hepatitis is an acceptable reason for liver transplantation, with frequency of survival exceeding 75% at 5 and 10 years after transplant [56, 57]. In summary, the overall prognosis of AIH is good for patient who are treated and responded to immunosuppressive therapy. Therefore, compliance is important which can be achieved by supporting patient and education to the patient. It is also crucial to recognise and treat the patients who are not responsive to standard immunosuppressive therapies with more novel treatments. It is essential to have smooth handover and transition between paediatric and adult hepatology team which will help young patients with AIH to continue with their treatment and follow up.
Primary biliary cirrhosis (PBC) is an autoimmune condition and causes a chronic and progressive destruction of intrahepatic bile ducts resulting in chronic cholestasis, portal inflammation, fibrosis and then gradually lead to cirrhosis and liver failure [58]. The disease is predominantly seen in women than men with a ratio of 10:1 [60] and had a prevalence of 1 in 1000 women over the age of 40 [59].
The highest prevalence and incidence rates have been reported in Great Britain, Scandinavia and the northern Midwest region of the USA [5, 61]. It has been suggested that the incidence of PBC is rising and in the United Kingdom (UK), the incidence rate rose from 2.05 cases per 100,000 populations per year in Sheffield from 1980 to 1999 [5, 62] and from 1.1 to 3.2 cases per 100,000 population per year in Newcastle- Upon- Tyne from 1976 to 1994 [63, 64].
Both genetic and environmental factors such as chemical substances, bacterial and viruses play an important role in the pathogenesis of PBC. In general, data indicate that 1 to 6% of PBC cases have at least one other family member presenting with the disease [60]. The concordance rate observed among monozygotic twins for PBC is 63%, among the highest reported in autoimmune diseases [60]. Prior to the advent of genome-wide association studies, only class II HLA loci (HLA-DRB1*08, *11, and *13) had been reproducibly shown to associate with disease [59]. With the application of genome-wide technology, HLA was confirmed as the strongest association and many other risk loci have been identified, with equivalent effect size to HLA, including IL12A, IL12RB2, STAT4, IRF5-TNPO3, 17q12.21, MMEL1, SPIB, and CTLA-4 [59]. These collectively support an important role for innate and adaptive immunity in development of disease [59].
There is an increased auto reactive CD4 pyruvate dehydrogenase complex (PDC)-E2 specific T cells in liver and regional lymph nodes in patients with PBC and CD8 PDC-E2 T cells infiltrates in the liver suggesting that anti-mitochondrial response is either directed to the aetiology or associated with other environmental or genetic trigger [65].
The majority of patients are asymptomatic at the time of diagnosis. With progression of the disease, patients usually develop fatigue and pruritus. Fatigue is the most common symptom and is present in up to 78% of patients with PBC [65]. Fatigue is not associated with disease severity or disease duration or histological findings and it is difficult to manage in most patients. Pruritus is a more specific symptom of PBC than fatigue and formerly occurred in 20%-70% of patients with PBC [65]. It can be local or diffuse, usually worse at night and tend to be in the palms and soles of the feet. Pruritus is often exacerbated by contact with wool, other fabrics, heat, or during pregnancy [65]. Sicca syndrome, hypothyroidism, vitamin D deficiency, osteopenia and hypercholesterolemia are commonly seen in patients with PBC and should be investigated and managed appropriately.
Individuals with abnormal cholestatic liver function tests such as raised alkaline phosphatase (ALP), gamma glutamyl transferase (GGT) and elevated conjugated bilirubin should be investigated for underlying PBC [66]. Immunologically, the majority of patients (around 95%) have positive anti-mitochondrial antibodies (AMA) in their serum and raised levels of immunoglobulins-M (Ig M) [67].
AMA reactivity is classically studied by immunofluorescence and considered positive at a titre of ≥1:40 [66]. The targets of the disease-specific ant mitochondrial response are all members of a family of enzymes, the 2-oxo-acid dehydrogenase complexes and include PDC-E2, branched chain 2-oxo-acid dehydrogenase complex, and 2-oxo-glutaric acid dehydrogenase complex [65]. These enzymes catalyse the oxidative decarboxylation of keto acid substrates and are located in the inner mitochondrial membrane [65].
Patient who had raised ALP and high titre of AMA (tire of ≥ 1:40) or AMA type 2 (M2) can be diagnosed with PBC without liver biopsy as per EASL (European Association for the Study of the Liver) guideline [66]. Positive ANA titres are also found in 30–50% of individuals with PBC (more commonly in the few who are AMA negative), but in this setting ANA reactivity is, in contrast to AIH, often antigen specific (anti gp-210 and anti sp-100) [12, 68].
\n\t\t\t | \n\t\t\n\t\t\t | \n\t
1 (Portal tract Inflammation) | \n\t\tPortal tract inflammation from mainly lymphoplasmacytic infiltrates with or without florid bile duct lesions resulting in septal and interlobular bile ducts. | \n\t
2 (Peri-portal fibrosis) | \n\t\tGradual increase of peri-portal lesions extending into the hepatic parenchyma- referred as interface hepatitis. | \n\t
3 (Bridging fibrosis) | \n\t\tDistortion of the hepatic architecture with numerous fibrous septa. Ductopenia (defined as loss of >50% of interlobular bile ducts) becomes more frequent at this stage. | \n
4 (Cirrhosis) | \n\tCirrhosis with the existence of regenerative nodules. | \n
Liver histology stages seen in primary biliary cirrhosis
The stages of PBC are shown in Figure 4.
Liver biopsy is rarely needed in the diagnosis of PBC. However, in patients with overlap of AIH/PBC might need liver biopsy to access the degree of the liver injury. In PBC, liver histology is divided into 4 stages (Table 4, Figure 4). Nowadays, the degree of fibrosis can be determined by performing non-invasive procedure such as transient elastography or Fibroscan. Magnetic resonance cholangio-pancreatography (MRCP) and Endoscopic retrograde cholangio-pancreatography (ERCP) are sometimes required to exclude other biliary pathology or PSC.
Histology finding of Primary biliary cirrhosis (PBC)
Ursodeoxycholic acid (UDCA) is the only approved treatment for patients with PBC and shown to be associated with improvement in liver biochemistries, delayed histologic progression of disease, and delayed development of oesophageal varices and prolong transplant free survival [67, 69]. UDCA at a dose of 13-15 mg/kg is proven benefit. Various risk scores have been validated to access the response of UDCA in patients with PBC and these are Barcelona, Paris I and II, Rotterdam and Toronto criteria (table 5) [127-131].
\n\t\t\t | \n\t\t\n\t\t\t | \n\t
Barcelona | \n\t\tDecrease of serum ALP > 40% or ALP normalisation (after 1 year) | \n
Paris I | \n\tALP ≤ 3 x ULN, AST ≤ 2 x ULN and serum albumin ≤ 1mg/dl (after 1 year) | \n
Paris II | \n\tALP and AST < 1.5 x ULN, serum bilirubin <1mg/dl (after 1 year) | \n
Rotterdam | \n\tNormalisation of abnormal serum bilirubin and/or serum albumin (after 1 year) | \n
Toronto | \n\tALP < 1.67 x ULN (after 2 years) | \n
Assessment of response to UDCA in patients with PBC
ALP: alkaline phosphatase, AST: Aspartate transaminase, ULN: upper limit of normal
Ursodeoxycholic acid is a hydrophilic bile acid and normally present in about 3% of bile in humans [70]. In patient with cholestasis, there is a decrease in endogenous production of bile acids as well as reduction in the absorption of UDCA [70]. After oral administration of UDCA, it is absorbed in small intestine and colon and transported to liver via portal tract. The absorption of UDCA is increased after meal consumption due to alkaline pH status. Administration of 13-15 mg/kg of UDCA in PBC patients causes enrichment of 40 to 50 % in primary bile acids [70].
Other drugs have been tested, but none have been found as single agents to be of benefit. These include chlorambucil, penicillamine, cyclosporine, corticosteroids, azathioprine, mycophenolate mofetil, thalidomide, methotrexate, malotilate, and colchicine [65].
Fatigue can be difficult to manage and other underlying conditions such as anaemia, thyroid disorder should be investigated and ruled out. There is no proposed treatment for fatigue and it can sometime persist even after Liver transplantation. A study by Jones et al showed that Modafinil at a dose of 100 to 200 mg/day was associated with a significant improvement in fatigue and improved day time somnolence [71].
There are few effective treatments available for pruritus in PBC patients. Cholestyramine is a non-absorbable resin and it is the first line therapy in the management of pruritus. The recommended dose of cholestyramine is 4 g per dose to a maximum of 16 g/day given 2-4 hours before or after UDCA [65]. In general, cholestyramine is well tolerated, although some patients report bloating, constipation, and diarrhoea [65].
Rifampicin is a P450 enzyme inducer and used in treatment of pruritus for PBC patients. The recommended dose is 150 mg once daily or twice daily based on the level of bilirubin. Side effects of rifampicin remain a serious concern because cases of hepatitis and hepatic failure, haemolysis and renal impairment and therefore, patient should be closely monitored during the treatment [65]. It should not be used together with serotonin reuptake inhibitor (SSRI) in patient with severe depression since it decrease the effect of SSRI[65].
Opioid antagonist, Naltrexone 50 mg daily, has been shown to be effective in treatment of pruritus in PBC patients. Other agents are SSRI (sertraline), Etarnacept (TNF-alpha inhibitor), Amitriptyline, Anti histamine. Some patient with difficult to treat pruritus can be managed with plasmapheresis.
Several pilot studies and randomized controlled trials have evaluated various agents in PBC. Trials with mesenchymal stem cells, Rituximab, Ustekinumab, Moexipril which is an angiotensin-converting enzyme (ACE) inhibitor and Abatacept treatments in PBC is currently ongoing (www.clinicaltrials.gov).
There is a suggestion that beta retrovirus might be involved in the pathogenesis of PBC and hence, a randomised controlled trial with lamivudine and zidovudine was studied in PBC patients [72]. There is a good biochemical response seen in patient taking lamivudine and zidovudine but complete biochemical normalisation was not observed [72]. The study did not showed any correlation with virus and biochemical response and as a result, treatment is not recommended in PBC [72].
Recently, fibrates have been thought to be beneficial in PBC since it has anti-inflammatory effect via peroxisome proliferator activated receptor alpha (PPAR-a) [67]. Fenofibrate is a fibric acid and thought to modulate immune response and the cell proliferation and pilot study which treated 20 patients with fenofibrate and UDCA showed significant improvement in liver biochemistry (ALP and ALT) and Ig M although albumin and bilirubin remained unchanged [73]. Larger studies are needed in future. Similar findings were seen in study with bezafibrate.
Obeticholic acid (OCA) is a farnesoid X receptor (FXR) agonist [74]. FXR is expressed in liver, intestine, adrenal glands and kidneys and has an important role in the enterohepatic circulation of bile acids [74, 75]. FXR reduces bile acid synthesis by acting on the enzyme cholesterol 7a hydroxylase and also by down-regulating the expression of the sodium/taurocholate co-transporting peptide, a bile acid uptake protein[75]. Preliminary studies of OCA in patients with PBC have demonstrated marked biochemical improvement when administered in combination with UDCA and alone [74]. Pruritus is the most common side effects and seen at high dose. Currently, there is a phase 3 trial ongoing for OCA treatment in PBC patients.
There are many criteria used to assess biochemical response to UDCA (Table 5). The 1-year biochemical response to UDCA provides significant prognostic information even in the early stage of PBC [70]. Early-stage patients who show ALP and AST ⩽1.5× upper limit of normal (ULN), and normal bilirubin level after 1 year of treatment appear to be at very low or no risk of liver failure or progression to cirrhosis. In those patients, they had a 10-year transplant-free survival rate of 90% compared to 51% for those who did not (
Primary sclerosing cholangitis (PSC) is a rare autoimmune liver disease and primary affects larger bile ducts. It is caused by chronic inflammation which then leads to fibrotic strictures and dilatation of hepatic biliary system and leading to chronic cholestasis. Chronic cholestasis can subsequently lead to liver cirrhosis with portal hypertension and liver failure [78]. PSC can affect any part of the biliary system including the gallbladder [78].
It is more common in male with median age of around 40 and affects mostly Northern European descendants [79]. The most important underlying risk factor associated with PSC is inflammatory bowel disease and PSC is seen in 75 % of cases of patients with IBD [79]. Around 60 to 80% of patients with PSC have underlying ulcerative colitis, mainly on the right side of the colon and 4% of patients with UC have co-existing PSC [80].
A recent study in UK showed the incidence of PSC to be 0.41 cases per 100,000 populations [81], although the true incidence may be underestimated since it is a relatively rare diseases and needs expertise and invasive procedures to make the diagnosis [79].
The exact mechanism of pathogenesis in PSC is unknown but thought to be multifactorial. It has thought that PSC occurs in individuals with genetic predisposition triggers various environmental stimuli [80]. Patient who has first degree relative with PSC have 9 to 39 fold increased risk of developing PSC and the most associated HLA are HLA DRB1 and DRQ1 [80]. Gut and liver axis theory had been proposed in the pathogenesis of PSC [82]. Manipulation of the intestinal micro flora changes the immune and metabolic pathway [83]. There has been hypothesized that translocation of microbial flora across the inflamed, permeable gut via the portal system to liver and biliary system activate the immune system and cause inflammation of the biliary tree [84-86]. Homing of mucosal lymphocytes which possess (C-C motif chemokine receptor-9) CCR9 and alpha4beta7 in the liver leads to biliary damage in PSC [87, 88]. Recently mucosa associated innate T cells and innate lymphoid cells has been proposed in the pathogenesis of PSC [89]. Although the putative gut-derived trigger(s) of hepatobiliary pathobiology in PSC has not been determined, microbial metabolites or products (i.e., pathogen-associated molecular patterns, PAMPs) such as lipopolysaccharide (i.e., endotoxin, LPS) and peptidoglycan (i.e., a bacterial cell wall polymer, PG) have been proposed as likely candidates [90].
About 15-40% of patients are asymptomatic during the early stage of the clinical course and at later stage, the most common symptoms are jaundice, pruritus, fatigue and abdominal pain [79]. Any patient who has underlying IBD and abnormal liver blood tests especially raised ALP should be investigated for PSC. In 95 % of cases, ALP rose 3-10 times the upper limit of normal and other liver enzymes ALT and AST were 2-3 times above the normal limit [79]. Bilirubin tends to be within normal range in about 60% of patients. In 69-95% of patients with PSC, 50 to 80% of patients with UC and 10-20% of patients with Crohn’s colitis have positive perinuclear antineutrophil autoantibodies (pANCA) [79].
Mayo risk score is used in PSC and the score is calculated using age, bilirubin, albumin, liver transaminase, AST and varcieal bleed and it is used to estimate survival of patient with PSC for up to 4 years [132]. The Mayo Risk Score= (0.0295 * (age in years)) + (0.5373 * (total bilirubin in mg/dL)) - (0.8389 * (serum albumin in g/dL)) + (0.5380 * (AST in IU/L) + (1.2426 * (points for variceal bleeding; 0= No, 1=Yes)). The score of less than or equal to zero is regarded as low risk, between 0 and 2 as intermediate and above 2 as high risk groups.
The diagnosis is best confirmed by MRCP, which is a non-invasive and first line investigation for the diagnosis of PSC. ERCP is used mainly for therapeutic purposes such as stenting, balloon dilatation and biliary brushing in patient with PSC. Contrast cholangiography, which reveals characteristic features of diffuse, multifocal strictures and focal dilation of the bile ducts, leading to a beaded appearance [79]. Liver biopsy is rarely necessary due to good diagnostic yield with MRCP or ERCP investigations except in suspicion of small duct PSC or overlap with AIH. Periductal concentric (“onion-skin”) fibrosis is a classic histopathologic finding of PSC, but this observation is infrequent in PSC [91] (Figure 5).
Histology findings in Primary Sclerosing Cholangitis (PSC)
In addition to biliary cirrhosis, complications of PSC include dominant strictures of the bile ducts, cholangitis, cholangiocarcinoma, colon dysplasia and cancer in patients with IBD, gallbladder polyps, gallbladder cancer, and hepatic osteodystrophy [79]. Cholangitis occurs in 10 to 15 % of patients with PSC [80]. The cumulative lifetime risk for cholangiocarcinoma in PSC is estimated at 7 to 15% [67]. About half of those cholangiocarcinomas are diagnosed within one year of PSC diagnosis and the rate of cancer development is 0.5 to 1.5% per year subsequently after the first year[67]. Suspected dominant stricture should be investigated by Endoscopic ultrasound scan (EUS) and biopsy along with Positron Emission Tomography (PET) scan.
Immunoglobulin G4 (Ig-G4) associated cholangitis is similar to PSC and is characterized by the presence of biliary strictures, lymphoplasmacytic infiltration and elevated Ig G4 serum levels [92]. Ig G4 elevation is seen in 12% of PSC patients [92]. The biliary features are similar on the cholangiogram in these two conditions and hence, it is important to check Ig G4 level and review the anatomy of pancreas on imaging. Tissue from liver biopsy can be stained using monoclonal anti-human IgG4 antibody. It is important to differentiate between the two because Ig G4 associated cholangitis or pancreatitis responsive to steroids unlike PSC.
To date, there are no effective therapies for patients with PSC and the only treatment for end stage PSC is liver transplantation. Timing for liver transplantation is challenging in PSC as these patients sometimes do not fulfil MELD criteria MELD criteria but they can deteriorate rapidly thus early referral to experience centres is essential. UDCA has been used in cholestatic patients with PSC although the data suggested that the medication has not improved overall survival. Studies utilizing doses between 10–15 mg/kg/day were associated with biochemical and histologic improvement [93, 94]. Two previous studies looking at high dose UDCA at a dose of 17-23 mg/kg/day [95] and 28-30 mg/kg/day [96, 97] showed that there were no difference in mortality or LT but increased in adverse events. A recent meta-analysis found no difference in fatigue, mortality, histologic progression or development of cholangiocarcinoma for standard or high dose UDCA [92, 98] and therefore, high dose UDCA is not used in routine clinical practice.
Antibiotics are used in patients with biliary sepsis in the background of PSC and some clinicians used rotating antibiotics in patients with resistant bacteremia. Published data looking into vancomycin or metronidazole treatment suggests that both are efficient in treatment of infection but vancomycin achieved improvement in ALT more than metronidazole with less side effects [99]. A recent randomised pilot study of vancomycin or metronidazole treatment in PSC patients showed that both antibiotics are effective although only vancomycin group reached the primary end point of reduction in ALP at 12 weeks [99].
There are many ongoing clinical trials in PSC such as obeticholic acid, mitomycin, thalidomide, LUM001: an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTi), GS-6624: a Monoclonal Antibody against Lysyl Oxidase like 2 (LOXL2), Xifaxan, Cladribine and the combination of UDCA and all trans-retinoid acid (ATRA) (www.clnicaltrial.gov). There are ongoing phase 1 and 2 trials on anti-fibrotic therapies in PSC.
The term ‘overlap syndrome’ described co-existence of AIH with features of PBC or PSC [12]. The diagnosis can be challenging and there is no single test available to diagnose. Therefore, it is important to revisit clinical history or repeat investigation if there is in doubt with the diagnosis. The diagnosis can be made with combination of tests such as blood biochemistry, immunology with addition of radiology and tissue biopsy. It is assumed that overlap syndrome can be found in 5-20% of cases [12].
AIH/PBC should be considered in patients with mixed pattern of cholestastic and hepatitis features or anyone with suboptimal response to immunosuppressions. It has been reported that AIH/PC occurs in 8% of patients with either AIH or PBC. Some PBC patients express negative AMA with positive ANA serology or SMA serology and hence, diagnosis based on immunology alone can be tricky. In general, IgG elevation is common in AIH and IgM is manly observed in PBC. Treatment should be targeted both AIH and PBC in these patients.
In adults with both AIH and IBD, cholangiographic changes suggestive of PSC are present in up to 44% patients and may affect therapy and prognosis [13]. Those who develop AIH during childhood or Autoimmune sclerosing cholangitis are most common to develop into AIH/PSC overlap. MRCP and repeat liver biopsy is recommended. Treatment should be directed towards PSC and immunosuppression should be slowly weaned off unless they are indicated for inflammatory bowel disease.
Liver transplantation (LT) is the treatment for patients with end stage AIH, PBC or PSC disease. The common indications are decompensated liver cirrhosis as indicated by the presence of refractory or resistant ascites, hepatic encephalopathy or uncontrolled variceal bleeding. Hepatocellular carcinoma, hepatopulmonary syndrome and portopulmonary hypertension are the other indications for LT. Model for End Stage Liver Disease (MELD) score is calculated by using renal function (Creatinine), International Normalised ratio (INR) and Bilirubin. MELD score= [0.957x Loge (creatinine in mg/dL) + 0.378x Loge (bilirubin in mg/dL) + 1.120x Loge (INR) + 0.643) [133]. Patients with MELD score of above 16 with other indication is considered for liver transplant assessment. MELD score was initially developed to predict survival in patients undergoing Trans jugular Porto systemic shunt [100, 101]. In 2002, UNOS (the United Network of Organ Sharing) adapted a new approach to allocate organ giving priority to the sickest patient and the assessment is based on MELD score [102]. Implementation of MELD in 2002 led to an immediate reduction in LT waiting list registrations for the first time in history of LT (12% decrease in 2002) [103] as well as reduction in mortality on the waiting list [104].
Since 1996, listing for transplantation in the United Kingdom was based on the following principles: selecting patients if the expected survival without transplantation was 1 year or less or liver disease that was associated with an unacceptable quality of life and expecting that patients would have an at least 50% survival at 5 years with acceptable quality of life [105]. Serum sodium was associated with a higher risk of mortality independent of the MELD score in patients listed for orthotropic liver transplantation [106]. In United Kingdom, UKLED score (United Kingdom End Stage Liver Disease has been used since 2008 and it is calculated from patient’s INR, serum creatinine, serum bilirubin and serum sodium) has been used in assessment of liver transplantation. UKELD score of 49 is the baseline entry criteria for LT assessment. Patients with UKELD score of 49 have 9% one year mortality and score above 60 has mortality of 50% [105].
LT is required in about 10% of patients with AIH and in Europe; 4-6 % of LT are for the indication of AIH [2, 7]. Long-term survival is excellent in AIH patients with 5 year survival being up to 92 % [2]. Recurrence of AIH can occur post LT and the rate of recurrence is between 8-12 % at year 1 and higher after 5 years follow up with the rate of around 36-65% [107]. The treatment should be either increase with the ongoing immunosuppressive therapies or change to alternative therapies such as addition of MMF, replacement of tacrolimus with cyclosporine or the replacement of calcineurin inhibitor (CNI) with sirolimus [108].
In patients with PBC, LT is indicated for decompensated liver cirrhosis, hepatocellular carcinoma and intractable pruritus with unacceptable quality of life. Patient should be referred for LT assessment when the bilirubin reaches around 100 umol/L with MELD >12 and Mayo risk score of 7-8 [134]. PBC can recur in post LT and the median time is 3 to 5.5 years although it can happen within the first year of transplantation [108]. PBC recurs in 15 to 30% of patients after LT and most of the patients do not lose their graft [67]. The treatment of recurrence PBC is UDCA, which causes improvement with ALP and ALT but not the patient or graft survival [109].
In addition to above mentioned indication for LT, some patients with PSC will need LT due to intractable pruritus, recurrent cholangitis in the presence of dominant bile duct strictures that cannot be managed endoscopically and the presence of limited stage cholangiocarcinoma [108]. 5 year survival post LT is around 80%[92]. Recurrence of PSC have been documented among LT recipients and its prevalence ranges from 15 to 30% and the median time for recurrence is between 3 and 5 years post LT [108] and can be associated with poor survival and graft loss [67].
De novo autoimmune hepatitis (d-AIH) in LT patients whom were transplanted for other reasons than AIH was documented in late 1990 [110]. De novo autoimmune hepatitis occurs in 1-7 % of patients 0.1-9 years after transplantation, especially in children [135]. Risk factors for de novo-AIH had been associated with older age donor, female donor, acute cellular rejection and the use of tacrolimus [111, 112]. The disease is usually characterized by features of acute hepatitis in otherwise stable transplant recipients. The characteristic feature is a marked hypergammaglobulinaemia with positive ANA. Antibodies against glutathione S-transferase T1 (GSTT1) has been reported in patients with de novo immune hepatitis following liver transplantation, thus suggesting that immune system recognizes the Glutathione S-transferase theta-1 (GSTT1) protein as a non-self-antigen, and mount an allo-reactive immune response and molecular mimicries that override self-tolerance[113]. Antibodies against cytokeratin 8/18 in patient with de novo autoimmune hepatitis after living-donor liver transplantation had also been reported thus the changes in cytokeratin 8/18 in hepatocytes might be one of the sources of pathogenesis of de novo autoimmune hepatitis after liver transplantation[114]. A histologic pattern of centri-lobular injury including increased necroinflammatory activity and increased plasma cell infiltration correlates with measurements of autoimmunity in de novo AIH recipients [115]. Treatment with increased dose of steroids or Azathioprine results in an improved outcome. However, maintenance therapy is usually required [116]. Standard liver tests do not reflect the extent of these changes, so protocol liver biopsies may be required to detect these changes [117].
Pregnancy constitutes a major challenge to the maternal immune system. AIH tends to improve after the second trimester of pregnancy, allowing a decrease in immunosuppressive therapy. It is due to a variety of immunological alterations that are induced by pregnancy in order to protect the semi-allogeneic fetus from rejection. Immuno-regulation induced by pregnancy polarizes the immune system to T-Helper (TH)-2 predominant phenotype. The increase of circulating inhibitors of pro-inflammatory cytokines occurring in pregnancy could act as a potent anti-inflammatory agent in AIH. T regulatory (Treg) cells are a recently discovered subset of T-lymphocytes with potent suppressive activity and pivotal roles in curtailing destructive immune responses and preventing autoimmune disease[118]. Systemic expansion of the maternal T suppressor or CD4+CD25+ regulatory T cell pool during pregnancy suppress an aggressive allogeneic response directed against the fetus[119].
Premature birth is the greatest risk and fetal mortality is reported to be around 21%, perinatal mortality is 4% and maternal mortality is 3% [14]. Poor disease control in the year prior to pregnancy and the absence of drug therapy are associated with poor outcomes [120]. Adverse pregnancy outcomes were highly associated with the presence of antibodies against soluble liver antigen/liver-pancreas (SLA/LP) and Ro/SSA [121] Preconception advice and discussion is important and should be emphasised. More than half of the women reduced or stopped the immune suppression during pregnancy or breastfeeding. AZA is a Food and Drug Administration (FDA) category D drug and safety in pregnancy has not been well established in human studies [14] however, current pharmacological treatment including azathioprine appears to be safe during pregnancy and lactation. There are no reported increased in congenital malformations with AZA and it is safe to use in mother who plan to breast-feed the baby. AIH commonly exacerbates following delivery [122, 123] and therefore, vigilance is required during the postpartum period. Patients with AIH need to be monitored carefully during pregnancy and for several months post partum [124]. Women with advance cirrhosis and portal hypertension have an increased risk of variceal bleed during the pregnancy and therefore, eradication of varices either with banding or pharmaco-therapy are recommended prior to conception. Pregnant women with cirrhosis and portal hypertension should undergo upper GI endoscopy during the second trimester and careful discussion with obstetric team and fetal medicine team is required for the safety of mother and the baby.
There are limited data for pregnancy and PBC. It has been noted that early diagnosis of PBC and early used of UDCA have a favourable outcomes on the pregnancy [125]. PSC rarely occur in female but the condition does not seem to reduce fertility in both men and women according to case series [126].
AILD is a spectrum of autoimmune condition mainly affecting liver (in the case of AIH) and biliary system (in PBC and PSC). The diagnosis is guided by clinical, biochemical and immunological parameters, although liver biopsy is still useful especially in patients with AIH to diagnose as well as for the assessment and monitoring of the disease status. In AIH, the aim of the treatment is to suppress the immune system with long term immunosuppressive medications such as azathioprine. There are new therapies emerging on the horizon. In PBC, women are more affected and the current treatment used is UDCA although there are many trials running ongoing in the treatment of PBC and it is an exciting era. For PSC, the definitive treatment is liver transplantation and more research is needed to understand that pathogenesis and treatment in this field of subject.
The histology slides were kindly provided by Professor Stefan Hubscher, Liver Histology Department, University Hospital Birmingham NHS Trust, Birmingham, UK. N.N.T is funded by National Institute for Health Research (NIHR) and Y.H. O is funded by Medical research council (MRC).
Aging is an inevitable physiological condition that comes with organ and tissue function impairment. It is the most significant risk factor for developing chronic diseases, including cancer, cardiovascular disease, metabolic dysfunction, osteoarthritis, and osteoporosis. Osteoporosis originated from the Greek word for porous bones, is one of the most common metabolic diseases. Associated with advancing chronological age, it affects more than 200 million patients worldwide and increases morbidity, mortality, and creates a significant burden of economic expenditures [1, 2]. Given that the population segment with the most rapid growth is the elderly in many countries, osteoporosis could present a global challenge impacting affected individuals’ health quality and life span. Characteristics of aging bone are low bone mineral density and deterioration of bone architecture, producing weakened bone prone to fractures. Thus, osteoporosis presents severe global health concerns, disposing to over 9 million fractures every year [3]. Senescent cells play a crucial role in aging bone; therefore, it is essential to understand the cellular and molecular mechanisms to develop treatments to prevent age-related diseases and maximize a healthy life span. This chapter provides a comprehensive treatise of senescence in bone and emerging therapeutic approaches to treatment.
The skeletal system is one of the most complex structures in mammals and is essential for storing and maintaining the homeostasis of the body’s minerals. Composed of various bones, cartilages, ligaments, tendons, and other tissues, it provides the framework for the body, supports locomotion, and protects vital organs such as the brain and bone marrow. It is commonly thought that the metabolic functions are carried out primarily by trabecular bone and the mechanical functions mainly by cortical bone. Bone, specifically, is a complex tissue that exhibits four types of cells: osteoclasts, bone lining cells, osteocytes, and osteoblasts. In addition, it houses bone marrow and serves as the main reservoir for the body’s calcium and phosphate.
Bone is a highly dynamic tissue that adapts to change and is constantly shifting throughout life. The most rapid rate of bone modeling occurs during childhood and adolescence, where bones are architecturally modified to support skeletal functions. Moreover, human skeletal tissue is in a constant state of remodeling throughout life [4]. A retained net bone mass is needed for homeostasis.
Discovered more than five decades ago by Hayflick and Moorhead [5], cellular senescence has played a significant role in our understanding and advancement in science. By definition, cellular senescence is a permanent state of cell cycle arrest characterized by specific phenotypic changes [6]. Characteristics include distinct cellular morphological alterations, gene expression, chromatin structure, cell signaling, and the senescence-associated secretory phenotype (SASP). Cellular senescence is found in bone and promotes age-related diseases such as osteoporosis [7]. In addition, senescent cells damage bone remodeling by impairing bone formation and osteoblast progenitor cell function, thus promoting osteoclastogenesis [8]. This is triggered by various stressors, including oxidative stress, genomic instability, and telomere shortening (replicative senescence). Telomeres protect chromatins and help maintain replication and genome stability.
The various physiological and pathological processes such as remodeling, aging, and injury can cause cells to become senescent. With aging, more cells become senescent and accumulate in tissues, including bones. A prominent characteristic of cell senescence is the SASPs, which are proinflammatory proteins that are primary contributors to their disease-inducing properties. Cyclin-dependent kinase inhibitors (CDKis) such as p16, p21, p27, the release of cytokines, chemokines, and soluble factors, causes this impaired microenvironment known as SASP. The SASP increases proinflammatory factors and upregulates NF-κB, contributing to aging bone disease [9].
As a hallmark of aging, it is essential to understand cellular senescence to effectively identify novel drugs to treat osteoporosis. Moreover, targeting cellular senescence has emerged as a therapeutic target for preventing or treating age-related diseases. Clearing these cells in mouse models has delayed tissue and organ dysfunctions [10]. In addition, senescence has been shown to have antiproliferative effects, a fundamental key to identifying novel drugs to treat osteoporosis.
Bone loss is a part of the natural aging process in both men and women [11]. Developmental, genetic, and lifestyle factors (lack of physical activity, injuries, medication use, smoking, poor diet) contribute to bone fragility in older people. The skeletal system goes through progressive bone loss, where changes in bone quality and quantity will occur. An accumulation of weakened skeletal bone may result in osteoporosis. Advancing chronological age is one of the significant risk factors for osteoporosis [12]. Characteristics of aging bone include low bone mineral density and weakened bone architecture, significantly increasing the risk of fractures for affected individuals (Figure 1).
Pathogenesis of osteoporosis. Aging and various environmental exposures can induce DNA damage and instability, oxidative stress, telomere attrition, dysfunction at the molecular level, and cell cycle arrest and senescence at the cellular level. These will break the remodeling process of bone formation and resorption, decrease bone mineral density, and progress to osteoporosis.
Throughout life, old bone is replaced by new bone, a process termed bone remodeling. This continuous cycle is necessary for fracture healing and adaptation to mechanical strains such as exercise. Bone regeneration occurs within bone cavities to target and replaces bone with accumulated microfracture fatigue.
On a cellular level, the well-balanced actions of three main specialized cell types, osteoclasts, osteoblasts, and osteocytes, regulate bone homeostasis [4]. Osteoclasts resorb damaged bone, and osteoblasts subsequently refill the resorbed area with an equal amount of new bone matrix. Osteocytes are mechanosensory cells that act as the central coordinators of this balanced process in transmitting signals needed to sustain mechanical loads [13, 14]. Disruption among the actions of this repertoire can turn to bone pathological conditions such as osteoporosis and rheumatoid arthritis. On a subcellular level, the bone matrix is changed by rearrangement of trabecular struts, changes in calcium deposition, subperiosteal expansion, and enlargement of the medullary cavity. Unrepaired micro-damaged bone reduces bone health, resulting in the mechanical failure of the tissue (fracture). The remodeling process is the same in cortical and trabecular bone.
Under normal physiological conditions, the amount of bone resorbed and replaced is equal, maintaining the bone mass. This process relies on having an adequate supply of osteoblasts, which comes from the generation of stimulatory signals for osteoblast formation produced by osteoclasts and osteocytes released during resorption [15]. Osteocytes regulate this fundamental bone regeneration process by sending signals to osteoclasts and osteoblasts to control their actions [16]. Furthermore, there is an association between lower osteocyte density in human central cancellous bone and increased surface remodeling [17], an independent contributor to bone fragility [18]. Therefore, a primary strategy in finding therapeutic targets to treat osteoporosis involves targeting osteoclasts [19].
Several molecular mechanisms concur to regulate osteoblast/osteoclast/osteocyte activity. The main one involves the receptor activator of nuclear factor-kappa-Β ligand (RANKL) of tumor necrosis factor (TNF) superfamily ligand 11 (TNFSF11) [20]. This cytokine is expressed on the surface of osteoblasts and osteocytes. On the membrane of osteoclast precursors and mature osteoclasts, RANKL binds to its receptor RANK, a ligand-receptor binding process termed the critical paracrine system, regulating osteoclast function. This process can be inhibited by osteoprotegerin (OPG), a decoy of RANKL produced by osteoblasts and osteocytes.
Moreover, osteocytes regulate bone formation by secreting modulators of the wingless-type mouse mammary tumor virus [MMTV] integration site members (Wnt) signaling pathways. These include activators nitric oxide and ATP, inhibitors sclerostin SOST, as well as dickkopf-related protein 1 (DKK1)). Wnts modulate cell proliferation, differentiation, and stem cell remodeling [21]. Previous studies have found that the activation of Wnts impacts osteoblasts and osteoblast lineages by increasing quantities and enhancing the functionality of osteoblasts [22]. Recently, studies were done in vivo to test whether the Fzd-Lrp receptor with Wnt mimetics can activate Wnt/β-catenin signaling and promote rapid bone growth [23]. It was found that within 2 weeks after treatment with selected Wnt mimetics, bone mineral density and vertebral cortical and trabecular bone growth increased significantly [23]. This could provide a therapeutic therapy used to target bone diseases such as osteoporosis.
However, with aging, the bone remodeling process is affected. Osteoporosis occurs when bone metabolism is perturbed. In addition, chronic diseases such as estrogen deficiency, malignant disease, and chronic inflammation also cause the uncoupling of osteoclasts and osteoblasts [24, 25]. As a result, less new bone is formed relative to the resorption of old bone, ending in a net bone loss. The cortical and trabecular thinning thereby leads to an overall bone loss and fragility. Thus, bone remodeling causes a drastic loss of bone mass and strength over prolonged periods, eventually osteoporosis.
The process of senescence in bone begins after peak bone mass is reached. This is generally during the third decade of life but varies between sexes. Estrogens and androgens are hormones that play crucial roles in skeletal homeostasis during growth and adulthood.
Estrogen is the primary hormonal regulator of bone metabolism, inhibiting osteoblast and osteocyte apoptosis [26, 27]. Therefore, a decrease in androgen and estrogen levels negatively affects bone remodeling by causing the uncoupling of osteoclasts and osteoblasts [28]. Hormonal withdrawal also contributes to mineral disturbances with calcium absorption [29].
The association between a decline of estrogen levels in postmenopausal women and the onset of osteoporosis was first noted by Fuller Albright in 1940. Since then, estrogen deficiency has become the primary cause of bone loss in older women [11]. An accelerated decrease occurs in the perimenopausal period when there is rapid bone remodeling. As a result, women experience the loss of whole trabecular components and combined with a negative remodeling balance, the bone loses mass and strength. In addition, estrogen levels affect T cells by increasing tumor necrosis factor secretion, promoting RANKL-induced osteoclastogenesis [30]. In men, a loss of both estrogens and androgens is associated with a loss of bone mass and the development of osteoporosis [31]. Small increases in estrogen levels can improve bone health without some of the adverse effects of conventional-dose estrogen therapy [32]. Sex steroids can regulate osteoclastogenesis and the survival of osteoclasts [33].
Cellular senescence has been identified as a response to multiple stressors. Common denominators of aging include telomere attrition, genotoxic agents, oxidative stress, chromosome instability, and oncogene activation. Skeletal involution results from the accumulation of poor nutrition, immobility, and the effects of treatments, all of which often come with old age. Mediated with bone remodeling, the progressive and cumulative pathologies of these factors contribute to the pathogenesis of osteoporosis.
Bone homeostasis is a balanced equilibrium between osteoblast and osteoclast activities. In senescent cell microenvironments, osteocytes control myeloid lineage cells [34]. Therefore, the SASP can be the cause of some of the severe effects of senescent cells. With aging, more osteocytes become senescent that acquire a new phenotype. As a result, they secrete various factors, including proinflammatory cytokines, growth modulators, which collectively comprise the SASP. Regulated at epigenetic, transcriptional, and posttranscriptional levels, SASP plays a critical role in contributing to various outputs of senescence [35]. For example, SASP factors mediate developmental senescence, wound healing, and tissue plasticity. In addition, the SASPs secrete signals that are communicated and amplified by neighboring myeloid lineage cells (such as B cells, osteoblasts, and T cells), resulting in the overproduction of proinflammatory cytokines. As a result, it contributes to chronic inflammation and creates a toxic local microenvironment that contributes to age-related bone loss.
DNA damage is considered to be the root of aging-associated multimorbidity [36]. It is caused by exposure to harmful exogenous factors (such as chemical compounds in the environment, chemotherapy, and UV radiation from the sun) and endogenous factors (such as reactive oxygen species and metabolic by-products). Consequences of accumulated DNA damage happen on the cellular and molecular levels. With aging, there are impaired cell and organ functions, inflammation, and cancer [36]. On the cellular level, DNA damage induces permanent cell-cycle arrest. It molecularly triggers genome instability with chromosome aberrations and mutations. Irreparable DNA damage accumulation in tissues and organs leads to cellular senescence, one of the main driving forces of aging [37].
Telomere dysfunction is induced in response to DNA damage. About half of the DNA damage foci in senescent cells localize to telomeres. Accumulated and progressive telomere shortening is a senescence biomarker and drives the aging process, a concept first discovered in the late 1980s [38]. Telomeres are short DNA sequences found at the ends of eukaryotic chromosomes that determine cellular life span [39]. Telomeric TTAGGG repeats and compound proteins make up the ends of chromosomes or the cap. The cap protects the telomere ends from appearing as double-break strands and prevents chromosome fusion and genome degradation.
During each cell replication, DNA polymerase cannot fully replicate chromosome ends, resulting in a loss of DNA. Accumulation of DNA damage at telomeres causes uncapping. With each cell division, telomeres shorten in length, and cell proliferation is restricted [40], a phenomenon termed replicative senescence [41]. To counteract telomere shortening, a specialized ribonucleoprotein enzyme called telomerase synthesizes new telomeric DNA [42].
The result of telomere shortening is telomeric DNA loop destabilization and telomere uncapping, which produces telomere dysfunction-induced foci (TIFs). This further activates the DNA damage repair (DDR), which recognizes double-strand breaks and activates the p53/p21 and p16 pathways [43]. These factors result in the pre-senescent cells withdrawing from the cell cycle and becoming senescent, which increases with age [44]. Furthermore, through inflammatory cytokines and impaired growth signaling, DDR results in replicative senescence [43].
Oxidative stress is a potential cause of results from various diseases and an important mechanism in bone degradation. Aging causes an increase in reactive oxygen species (ROS), which results in an imbalance of ROS and antioxidant defenses. Increased reactive oxygen species influence numerous cellular processes, including the timing of death by apoptosis, and have been linked to aging and the development of age-related diseases. It can damage DNA and contribute to aging. It has been found that oxidative stress increases with age in the bone of female or male C57BL/6 mice [33]. Oxidative stress alters the bone remodeling process by disrupting osteoclast and osteoblast activity. This can result in low bone mineral density, the characteristics of osteoporosis.
DNA damage is also responsible for oncogene-induced senescence (OIS). Oncogenic stress is commonly known as a critical mechanism of cancer. Oncogene activation is genetic stress and phenotypic changes that induce senescence. With activated oncogenes, there are high levels of replication. Pathways such as the ataxia telangiectasia and Rad3-related (ATR), ataxia–telangiectasia mutated (ATM), and p53 converge with the cyclin-dependent kinase inhibitors p16, p21, and p27 and hyperphosphorylation of the retinoblastoma protein, thereby triggering withdrawal from the cell cycle [45].
Glucocorticoids are drugs used to suppress allergic, autoimmune, and inflammatory diseases. However, prolonged use of glucocorticoids can result in complications such as glucocorticoid-induced osteoporosis (GIO). Glucocorticoids cause senescence in various cell lines and have been found to stimulate the p21 gene expression. During the initial treatment, this drug increases bone resorption with an enhancement of osteoclast maturation and differentiation. However, long-term use inhibits osteoclastogenesis by promoting apoptosis of osteoblasts and osteocytes [46, 47]. Dexamethasone, a type of glucocorticoid, was found to promote cell senescence and activate parts of SASP through inhibition of osteoblast function [48]. This resulted in decreased bone formation and increased bone resorption. Other effects include suppressing insulin-like growth factor 1, which promotes bone formation and further causes collagen degradation and osteoblast apoptosis [48].
Chronic inflammatory diseases are associated with bone loss, which increases bone resorption and decreases bone formation, resulting in a bone deficit [24, 49].
The summary of the pathological factors that induce cellular senescence is provided in Table 1.
Pathological factors | Causes | Mechanisms |
---|---|---|
SASP | Aging | Chronic inflammation |
DNA damage | Aging, environmental factors | Cellular senescence |
Telomere dysfunction | DNA damage | Telomere uncapping, activates the p53/p21 and p16 pathways |
Oxidative stress / ROS | Aging | imbalance of ROS and antioxidant defenses |
Oncogene stress | DNA damage (i.e. cancer) | oncogene-induced senescence. Inhibits, osteoclastogenesis |
Glucocorticoid | Glucocorticoid drugs | stimulate the p21 gene expression, Osteoblast apoptosis |
Chronic-inflammation | Chronic-inflammatory diseases (i.e. arthritis | Increase osteoclast function, decrease osteoblast function |
Summarized mechanisms of bone senescence.
Both nonpharmacological (lifestyle factors, supplements) and pharmacological (antiresorptive and anabolic) treatments exist. The chapter also highlights the ongoing advancements of senescence research on aging-bone diseases (Figure 2).
Treatments of osteoporosis. Antiresorptive and anabolic and senolytic treatments of osteoporosis. These treatments target different pathways. Anabolic treatment options include teriparatide (A), strontium ranelate (B), and romosozumab (C). The antiresorptive treatment includes bisphosphonates (D), calcitonin (E), denosumab (F), cathepsin K inhibitors (G), and SERMs (H). With particular regard, senolytic drugs treatment includes Fisetin, Dasatinib, quercetin, and D + Q.
Optimizing lifestyle factors by diet and physical exercise is beneficial to bone health. Physical exercise and an active lifestyle have a significant impact on bone health. During the muscular activity, the mechanical forces produced are sensed by osteocytes and promote bone growth. In response to exercise, skeletal muscle also secretes myokines, which are molecules that directly affect bone metabolisms, such as irisin, myostatin, and insulin-like growth factor-1 [50]. Exercise also restores body coordination and balance, decreasing the risk of falls, especially among older people. On the other hand, limited physical movement and muscle atrophy with old age result in osteoporosis [51].
In addition, an increase in nutrient intake, specifically vitamin D, protein, calcium, and vitamin K2, will slow osteoporotic regression. Vitamin D has a critical role in regulating calcium homeostasis and bone metabolism. In addition, calcium and vitamin D can suppress serum levels of parathyroid hormones and stimulate bone growth, making them have an antiresorptive effect. The daily calcium intake recommendation is between 800 and 1200 mg, and vitamin D intake is 800 IU per day for men and women over 50 [52].
Vitamin D insufficiency and low serum calcium levels are widespread in elderly people, contributing to lower BMD and increased bone fragility [53]. Dietary sources are the preferred option, but supplementation is beneficial, especially in elderly people. With daily calcium and vitamin D supplements, fracture risk drops significantly, making them essential in aging-bone disease treatments [54]. In most clinical studies testing the efficacy of antiresorptive and anabolic therapies, calcium and vitamin D have been used. When given together, they have been found to have been effective in preventing fractures [53, 55]. However, in most clinical cases, calcium supplementation is subsidiary to bisphosphonates or anti-RANKL drugs [56].
Nutraceuticals are substances including isolated nutrients, dietary supplements, herbal products, and medical foods. For example, higher intakes of antioxidants, phytoestrogens (plant compounds that function like estrogen agonist-antagonists), and other minerals such as phosphorus can be markers for a healthy lifestyle [57, 58]. Phosphorus is another critical factor in preventing aging-bone diseases such as osteoporosis. It is an essential nutrient for bone formation, but too much of it harms bone health [58].
Physical exercise and muscle fitness have a dramatic impact on bone health. Muscle secretes a set of molecules, known as myokines, directly affecting bone metabolisms, such as irisin, myostatin, and insulin-like growth factor-1. During activity that produces mechanical force, osteocytes sense this and convert it into bone deposition. On the contrary, disuse or muscle atrophy results in osteoporosis.
The search for armamentariums targeting metabolic bone diseases is increasing. Currently, various antiresorptive and anabolic therapies are available as treatments for osteoporosis [23]. Antiresorptive therapies are the most common pharmacological tools to prevent osteoporosis progression. These drugs inhibit osteoclast proliferation and the recruitment and differentiation of its precursors [54]. It is suggested for early menopausal women or patients with moderate osteoporosis. Anabolic therapies are another option for treatment that targets osteoblasts to stimulate bone mineralization.
In comparison to antiresorptive medications, anabolic agents reduce fracture risk more efficiently. Thus, these should be considered first-line therapy for patients at very high risk or with a history of vertebral fracture [59]. In addition, pharmaceutical medications seek to improve bone fidelity and architectural foundation for long-term skeletal health. Therefore, the search for armamentariums targeting skeletal diseases is increasing. Currently, various antiresorptive and anabolic therapies are available as treatments for osteoporosis [23].
Bone homeostasis is a balanced equilibrium between osteoblast and osteoclast activities. In senescent cell microenvironments, osteocytes control myeloid lineage cells [34]. With aging, more osteocytes become senescent that produces SASP signals. These signals are communicated and amplified by neighboring myeloid lineage cells (such as B cells, osteoblasts, and T cells), resulting in the overproduction of proinflammatory cytokines. As a result, a toxic local microenvironment is created that contributes to age-related bone loss.
The antioxidant NAC, coupled with estrogens or androgens in male and female mice, prevents a gonadectomy-induced increase in oxidative stress, bone loss, osteoblast, and osteocyte apoptosis. So, sex steroids can regulate osteoclastogenesis and the survival of osteoclasts via antioxidant actions [33].
Antiresorptive therapy is the most common pharmacological tool to prevent osteoporosis progression. These drugs inhibit osteoclasts’ proliferation and the recruitment and differentiation of their precursors [54].
Bisphosphonates (BPs) are the primary therapeutic options used to inhibit osteoclast-mediated bone resorption. These nitrogen-containing drugs have a strong affinity for bone apatite in vitro and in vivo. BPs bind to hydroxyapatite crystals on bone surfaces and inhibit the mevalonate pathway in osteoclasts, increasing apoptosis. This preferentially occurs in sites with accelerated skeletal turnover rates. BPs have been shown to increase bone mineral density (BMD), reduce bone turnover markers, and reduce the risk of osteoporotic fractures. Some drug options include alendronate, risedronate, and zoledronic acid. Currently, they are the most common and effective drugs used for osteoporosis, Paget’s disease, and inflammation-related bone loss [60].
Denosumab, an anti-RANKL antibody, is a fully human monoclonal antibody to the RANKL, which blocks its binding to RANK. The prevention of RANKL and its receptor RANK interaction thereby inhibits osteoclast differentiation [61]. Presently, denosumab is the only FDA-approved monoclonal antibody to treat osteoporosis. These antiresorptive agents have been most influential in decreasing the risk of vertebral fractures by more than 50%, nonvertebral fractures by 20–25%, and hip fractures by 40–50% [62].
Selective Estrogen Receptor Modulators (SERMs) are an alternative for estrogen and are used primarily in postmenopausal women of younger age. SERMs rely on their tissue-selective estrogen receptor agonist or antagonist activity and their interaction with the estrogen receptor. They interact with the RANKL/RANK/OPG system and downmodulate osteoclast function [63]. This process allows for the treatment of vasomotor systems and the prevention of osteoporosis [64]. Various SERMs, including raloxifene, which represents dual agonistic and antagonistic properties in estrogenic pathways, have decreased bone fragility. In postmenopausal women with low BMD, raloxifene has been shown to reduce vertebral fracture risk by 30–50% [63]. In particular, this drug is recommended for patients with a family history of breast cancer, as it has also significantly demonstrated reduced risks of breast cancer in women [29].
Calcitonin receptors are found on osteoclasts and osteoblasts and serve as regulators of osteoclast function and maturation. Calcitonin is a naturally occurring peptide hormone that binds to specific receptors primarily on the surface of osteoclasts to inhibit bone resorption activity strongly. It has been used to treat osteoporosis for many years, especially for patients with acute osteoporotic fractures and postmenopausal women [65].
Cathepsin K (CatK) is one of the most potent proteases in the lysosomal cysteine proteases family. CatK’s primary function is to mediate bone resorption, making it a strategic target for osteoporosis treatments. The only CatK inhibitor candidate, Odanacatib (ODN), was developed by Merck & Co. Phase III clinical trials; it showed high therapeutic efficacy in patients with postmenopausal osteoporosis but was terminated due to the cardio-cerebrovascular adverse effects. As of now, there is no available drug approved by the FDA that targets cathepsin k but is an ongoing direction for osteoporosis treatment [66].
PTHrP is required for normal bone development. Teriparatide is a bioactive form of the parathyroid hormone of recombinant human PTH 1–34 fragment rhPTH(1–34) [67]. It is the first and only available therapeutic agent that activates and stimulates osteoblasts. In contrast with antiresorptive therapy, teriparatide increases bone formation by inhibiting sclerostin production in osteocytes and increases bone resorption by stimulating RANKL production by osteoblasts and osteocytes. In addition, PTH inhibits p16Ink4a and thereby downregulates senescence [68]. Intermittent administration of PTH increases osteoblast amounts and activities, thereby improving skeletal architecture at both trabecular and cortical bone sites [69].
Furthermore, this drug provides some remediation of the architectural defects in the osteoporotic skeleton [70]. Daily injections of teriparatide in patients with severe osteoporosis can reduce hip fractures by 56% [71]. Abaloparatide, a 34 amino acid synthetic analog of parathyroid hormone-related protein analog drug, is an FDA-approved drug to treat postmenopausal osteoporosis.
Wnt signaling pathways modulate cell proliferation, differentiation, and stem cell remodeling [21]. Activation of Wnts impacts bone remodeling by increasing quantities and enhancing the functionality of osteoblasts. The discovery of this pathway has opened the way to new anabolic treatments. For example, sclerostin is a protein secreted primarily by osteocytes and protects against the excessive bone formation. Anti-sclerostin antibodies stimulate osteoprotegerin production, leading to decreased bone resorption and uncoupling of osteoclast and osteoblast activity [4]. In addition, romosozumab, an anti-sclerostin monoclonal antibody that binds sclerostin, has favorable dual effects on bone by increasing bone formation and reducing bone resorption [72]. In studies done with postmenopausal women prone to osteoporosis, a dose of 210 mg romosozumab monthly amounts resulted in significantly increased BMD and was more effective than daily teriparatide or weekly alendronate doses [73]. Thus, it is considered another emerging therapeutic for skeletal aging.
Strontium ranelate is a relatively novel drug currently approved in Europe for the treatment of postmenopausal osteoporosis. It has dual effects of inhibiting bone resorption and promoting bone formation [74, 75]. It can stimulate the differentiation of pre-osteoblasts into osteoblasts and promotes osteoblast release of OPG. This can act as a decoy receptor for RANKL and thereby interfere with osteoclast differentiation. In every gram of bone, strontium is naturally occurring in trace amounts at around 100 μg. In other words, the therapeutic strategy with strontium ranelate is producing more strontium available to incorporate into bone [76]. In other words, the therapeutic approach with strontium ranelate is producing more strontium available to incorporate into bone [76].
Dual acting treatments that can coordinately stimulate osteoblasts and inhibit osteoclasts have significantly improved bone quality compared with monotherapy [77]. For example, a combination of teriparatide and denosumab generated more significant increases in BMD and bone strength than independent use of either drug [77]. In addition, the combination of Wnt mimetics and current clinical treatments has been found to improve bone mass and strength [23]. Thus, compared with monotherapy, sequential therapy can improve bone health and serve as an emerging option for treatment. Compared with monotherapy, dual-acting treatments that can coordinately stimulate osteoblasts and inhibit osteoclasts have significantly improved bone quality [67]. For example, the combination of Wnt mimetics and current clinical treatments has been found to improve bone mass and strength [23]. Thus, in comparison to monotherapy, sequential therapy has the potential to improve bone health significantly.
Interest in targeting senescence to halt or prevent age-related diseases, also known as senotherapy, has grown. Senolytic drugs are SASP modulators that eliminate cell senescence. More cells become senescent with advancing age and accumulate in tissues, suggesting that targeting the senescent cells is a promising treatment. Hence, several studies have explored senescent cells and their role in aging-bone diseases. The first thorough evidence showing senescence in mammalian bone cells was found in 2016 [78]. Osteocytes have the vital role of orchestrating bone remodeling, and osteocytes with senescence attributes contribute to osteoporosis [78]. To build off of this, another study found that genetically eliminating senescent cells and their SASP could prevent age-related osteoporosis [79]. In addition, the elimination of p16Inka-senescent cells improved bone quality. To build on this finding, researchers performed another study and found that genetically eliminating senescent cells and their SASP could prevent age-related osteoporosis [79]. Also, the elimination of p16Inka-senescent cells improved bone quality [10]. In mice, senolytic intervention improved bone mass, strength, and microarchitecture [7]. Novel drugs that use this strategy include Dasatinib (D), Quercetin (Q), D + Q [80], and Fisetin [81]. Senolytic drugs have shown a positive impact on bone metabolism by preventing bone loss and increasing health span.
The cellular morphological changes that come with aging dramatically affect bone health and increase the risk of developing age-related bone diseases. The sequelae of osteoporosis include decreased bone mass and increased pronation to fractures, a significant concern for the aging population. Recent literature is addressing utilizing new pharmaceutical targets to reverse or treat the adverse effects of aging. For example, cell senescence in bone paves the way for developing new therapeutic targets. With improved knowledge of the pathophysiology of osteoporosis and new targets, potential new treatments are being investigated. The use of pharmaceuticals and nonpharmaceuticals appears promising in preventing or treating aging bone diseases, including osteoporosis.
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Moreover, the life of old structures has to be extended. This includes the replacement of expensive periodic in-service inspections with cost-efficient structural health monitoring (SHM) with permanently installed sensors. Mooring chains for floating offshore installations, typically designed for a 25-year service life, are loaded in fatigue in a seawater environment. There is no industry consensus on failure mechanisms or even defect initiation that mooring chains may incur. Moorings are safety-critical areas, which by their nature are hazardous to inspect. Close visual inspection in the turret is usually too hazardous for divers, yet is not possible with remotely operated vehicles (ROVs), because of limited access. Conventional non-destructive techniques (NDTs) are used to carry out inspections of mooring chains in the turret of floating production storage and offloading (FPSO) units. Although successful at detecting and assessing the fatigue cracks, the hazardous nature of the operation calls for remote techniques that can be applied continuously to identify damage initiation and progress. Appropriate replacement plans must enhance current strategies by implementing real-time data retrofit.",book:{id:"5874",slug:"structural-health-monitoring-measurement-methods-and-practical-applications",title:"Structural Health Monitoring",fullTitle:"Structural Health Monitoring - Measurement Methods and Practical Applications"},signatures:"Ángela Angulo, Graham Edwards, Slim Soua and Tat-Hean Gan",authors:[{id:"78586",title:"Prof.",name:"Tat Hean",middleName:null,surname:"Gan",slug:"tat-hean-gan",fullName:"Tat Hean Gan"},{id:"178330",title:"Dr.",name:"Slim",middleName:null,surname:"Soua",slug:"slim-soua",fullName:"Slim Soua"},{id:"185485",title:"Ms.",name:"Ángela",middleName:null,surname:"Angulo",slug:"angela-angulo",fullName:"Ángela Angulo"},{id:"205582",title:"Mr.",name:"Graham",middleName:null,surname:"Edwards",slug:"graham-edwards",fullName:"Graham Edwards"}]},{id:"75395",doi:"10.5772/intechopen.96070",title:"Biomedical Applications with Using Embedded Systems",slug:"biomedical-applications-with-using-embedded-systems",totalDownloads:713,totalCrossrefCites:4,totalDimensionsCites:4,abstract:"Besides the use of embedded systems in the field of electrical and electronics engineering, industrial, telecommunication, military, and many other commercial applications, and the other applications in the field of medical and biomedical are becoming increasingly common. Embedded system applications are increasing not only with designs on devices or with clothing, factories, medical and military equipments, portable devices, but also with applications such as ‘mobile worlds’ and ‘e-worlds’, Artificial Intelligence and IoT (Internet of things) with the possibility to make all kinds of software on them. In recent years, with the rise of infectious diseases such as the Covid 19 virus, there is a growing need for telemedicine applications such as diagnosis, prognosis and patient management. Embedded system technologies have occupied an important area in biomedical technology. Especially, to develop tools for the purposes of increasing the safety of healthcare workers in the event of epidemic infectious diseases in processes such as pandemics. For this purpose, monitoring of patients discharged from hospitals at home or non-intensive care beds during quarantine, or isolated in their homes, outpatient, and mildly ill, remotely, instantly, safely and quickly, are becoming increasingly important. In this section, we will give an overview of the embedded system structure and applications.",book:{id:"9973",slug:"data-acquisition-recent-advances-and-applications-in-biomedical-engineering",title:"Data Acquisition",fullTitle:"Data Acquisition - Recent Advances and Applications in Biomedical Engineering"},signatures:"Gulcicek Dere",authors:[{id:"318714",title:"Ph.D. Student",name:"Gulcicek",middleName:null,surname:"Dere",slug:"gulcicek-dere",fullName:"Gulcicek Dere"}]},{id:"63107",doi:"10.5772/intechopen.80312",title:"Application of Genomic Data for PCR Screening of Bet v 1 Conserved Sequence in Clinically Relevant Plant Species",slug:"application-of-genomic-data-for-pcr-screening-of-bet-v-1-conserved-sequence-in-clinically-relevant-p",totalDownloads:867,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"Bet v 1 is a highly immunogenic protein, which is the main cause of sensitivity to birch pollen and is described as the main birch allergen. Despite the structural similarity, Bet v 1 homologs show different properties and immunoreactivity. Here, the bioinformatic algorithms were applied for known Bet v 1 homologous nucleic acids sequences to find homology and conserved regions. Genomic sequences of PR proteins of two different fruit species, which allergens belong to PR proteins of the same type as Bet v 1, were selected to design degenerate primers. Subsequently, screening of the presence of Bet v 1 conserved genomic sequence was performed in 45 clinically relevant plant species.",book:{id:"8646",slug:"systems-biology",title:"Systems Biology",fullTitle:"Systems Biology"},signatures:"Jana Žiarovská and Lucia Zeleňáková",authors:[{id:"94292",title:"Dr.",name:"Lucia",middleName:null,surname:"Zeleňáková",slug:"lucia-zelenakova",fullName:"Lucia Zeleňáková"},{id:"257512",title:"Dr.",name:"Jana",middleName:null,surname:"Žiarovská",slug:"jana-ziarovska",fullName:"Jana Žiarovská"}]},{id:"73234",doi:"10.5772/intechopen.93565",title:"Control of a Prosthetic Arm Using fNIRS, a Neural-Machine Interface",slug:"control-of-a-prosthetic-arm-using-fnirs-a-neural-machine-interface",totalDownloads:623,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"Development in the field of bio-mechatronics has provided diverse ways to mimic and improve the function of human limbs. Without an elbow joint, the hand remains stiff because all the muscles tension passes through this joint. Advanced myoelectric prosthetic devices are limited due to the lack of appropriate signal sources on residual amputee muscles and insufficient real-time control. Neural-machine interfaces (NMI) are representing a recent approach to develop effective applications. In this research study, an NMI is designed that presents real-time signal processing for command generation. The human brain hemodynamic responses are, therefore, translated into control commands for people suffering from transhumeral amputation. A novel and first of its kind scheme is proposed which utilizes functional near-infrared spectroscopy (fNIRS) to generate the control commands for a three-degree-of-freedom (DOF) prosthetic arm. The time window for fNIRS signals was set to 1 second. The average accuracy was found to be 82% which is a state-of-the-art result for such a technique. The accuracy ranged from 65 to 85% subject-wise. The data were trained and tested on both artificial neural network (ANN) and linear discriminant analysis (LDA). Eight out of 10 motions were correctly predicted in real time by both classifiers.",book:{id:"9973",slug:"data-acquisition-recent-advances-and-applications-in-biomedical-engineering",title:"Data Acquisition",fullTitle:"Data Acquisition - Recent Advances and Applications in Biomedical Engineering"},signatures:"Usama Ali Syed, Zareena Kausar and Neelum Yousaf Sattar",authors:[{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed"},{id:"328508",title:"Ms.",name:"Neelum",middleName:null,surname:"Yousaf Sattar",slug:"neelum-yousaf-sattar",fullName:"Neelum Yousaf Sattar"},{id:"328509",title:"Dr.",name:"Zareena",middleName:null,surname:"Kausar",slug:"zareena-kausar",fullName:"Zareena Kausar"}]},{id:"55663",doi:"10.5772/intechopen.68385",title:"Structural Damage Detection Based on Improved Multi-Particle Swarm Co-Evolution Optimization Algorithm",slug:"structural-damage-detection-based-on-improved-multi-particle-swarm-co-evolution-optimization-algorit",totalDownloads:1020,totalCrossrefCites:0,totalDimensionsCites:2,abstract:"This chapter presents an improved multi-particle swarm co-evolution optimization algorithm (IMPSCO) to detect structural damage. Firstly, IMPSCO is integrated with Newmark’s algorithm for damage detection and system identification, which just need few sensors. In addition, for reducing the searching parameters, a two-stage damage detection method based on modal strain energy and IMPSCO is presented. In order to validate the proposed method, a seven-story steel frame experiment in laboratory conditions is performed and a comparison is made between the proposed approach and genetic algorithm (GA). The results show that: (1) the proposed methods can not only effectively locate damage location but also accurately quantify the damage severity. Besides, it has excellent noise-tolerance and adaptability; (2) for integrating IMPSCO and Newmark’s algorithm, it implements only by using any kinds of structural time-series responses and the excitation force; (3) compared with genetic algorithm, IMPSCO is more efficient and robust for damage detection with a better noise-tolerance.",book:{id:"5874",slug:"structural-health-monitoring-measurement-methods-and-practical-applications",title:"Structural Health Monitoring",fullTitle:"Structural Health Monitoring - Measurement Methods and Practical Applications"},signatures:"Shaofei Jiang and Shenglan Ma",authors:[{id:"199255",title:"Prof.",name:"Shaofei",middleName:null,surname:"Jiang",slug:"shaofei-jiang",fullName:"Shaofei Jiang"},{id:"205301",title:"Dr.",name:"Shenglan",middleName:null,surname:"Ma",slug:"shenglan-ma",fullName:"Shenglan Ma"}]}],mostDownloadedChaptersLast30Days:[{id:"75395",title:"Biomedical Applications with Using Embedded Systems",slug:"biomedical-applications-with-using-embedded-systems",totalDownloads:713,totalCrossrefCites:4,totalDimensionsCites:4,abstract:"Besides the use of embedded systems in the field of electrical and electronics engineering, industrial, telecommunication, military, and many other commercial applications, and the other applications in the field of medical and biomedical are becoming increasingly common. Embedded system applications are increasing not only with designs on devices or with clothing, factories, medical and military equipments, portable devices, but also with applications such as ‘mobile worlds’ and ‘e-worlds’, Artificial Intelligence and IoT (Internet of things) with the possibility to make all kinds of software on them. In recent years, with the rise of infectious diseases such as the Covid 19 virus, there is a growing need for telemedicine applications such as diagnosis, prognosis and patient management. Embedded system technologies have occupied an important area in biomedical technology. Especially, to develop tools for the purposes of increasing the safety of healthcare workers in the event of epidemic infectious diseases in processes such as pandemics. For this purpose, monitoring of patients discharged from hospitals at home or non-intensive care beds during quarantine, or isolated in their homes, outpatient, and mildly ill, remotely, instantly, safely and quickly, are becoming increasingly important. In this section, we will give an overview of the embedded system structure and applications.",book:{id:"9973",slug:"data-acquisition-recent-advances-and-applications-in-biomedical-engineering",title:"Data Acquisition",fullTitle:"Data Acquisition - Recent Advances and Applications in Biomedical Engineering"},signatures:"Gulcicek Dere",authors:[{id:"318714",title:"Ph.D. Student",name:"Gulcicek",middleName:null,surname:"Dere",slug:"gulcicek-dere",fullName:"Gulcicek Dere"}]},{id:"63667",title:"Lentiviral Vectors Come of Age? Hurdles and Challenges in Scaling Up Manufacture",slug:"lentiviral-vectors-come-of-age-hurdles-and-challenges-in-scaling-up-manufacture",totalDownloads:1295,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"The pharmaceutical industry has been attracted to the gene therapy field and is starting to support clinical trials, establishing collaborative strategies to develop commercial products which in many cases are based on lentiviral vectors. The predictable widespread use of lentiviral vectors in next-generation gene therapy scenarios aimed at dealing with not only rare diseases raises important challenges and hurdles regarding their manufacture. The author reflects on this in the chapter on the state of the art in the manufacture of lentiviral vectors, addressing some current manufacturing processes, their achievements, and the uncertainties in ensuring a validated process capable of releasing consistent vector quality that meets global health authorities’ requirements. In summary, the proposal looks at the goals and challenges that must be addressed in manufacturing lentiviral vectors, in order to satisfy supply in the commercial stage, before we reach the next stage in gene therapy.",book:{id:"8646",slug:"systems-biology",title:"Systems Biology",fullTitle:"Systems Biology"},signatures:"Juan C. Ramirez",authors:[{id:"242227",title:"Ph.D.",name:"Juan C",middleName:null,surname:"Ramirez",slug:"juan-c-ramirez",fullName:"Juan C Ramirez"}]},{id:"73234",title:"Control of a Prosthetic Arm Using fNIRS, a Neural-Machine Interface",slug:"control-of-a-prosthetic-arm-using-fnirs-a-neural-machine-interface",totalDownloads:623,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"Development in the field of bio-mechatronics has provided diverse ways to mimic and improve the function of human limbs. Without an elbow joint, the hand remains stiff because all the muscles tension passes through this joint. Advanced myoelectric prosthetic devices are limited due to the lack of appropriate signal sources on residual amputee muscles and insufficient real-time control. Neural-machine interfaces (NMI) are representing a recent approach to develop effective applications. In this research study, an NMI is designed that presents real-time signal processing for command generation. The human brain hemodynamic responses are, therefore, translated into control commands for people suffering from transhumeral amputation. A novel and first of its kind scheme is proposed which utilizes functional near-infrared spectroscopy (fNIRS) to generate the control commands for a three-degree-of-freedom (DOF) prosthetic arm. The time window for fNIRS signals was set to 1 second. The average accuracy was found to be 82% which is a state-of-the-art result for such a technique. The accuracy ranged from 65 to 85% subject-wise. The data were trained and tested on both artificial neural network (ANN) and linear discriminant analysis (LDA). Eight out of 10 motions were correctly predicted in real time by both classifiers.",book:{id:"9973",slug:"data-acquisition-recent-advances-and-applications-in-biomedical-engineering",title:"Data Acquisition",fullTitle:"Data Acquisition - Recent Advances and Applications in Biomedical Engineering"},signatures:"Usama Ali Syed, Zareena Kausar and Neelum Yousaf Sattar",authors:[{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed"},{id:"328508",title:"Ms.",name:"Neelum",middleName:null,surname:"Yousaf Sattar",slug:"neelum-yousaf-sattar",fullName:"Neelum Yousaf Sattar"},{id:"328509",title:"Dr.",name:"Zareena",middleName:null,surname:"Kausar",slug:"zareena-kausar",fullName:"Zareena Kausar"}]},{id:"72580",title:"Acoustic Monitoring of Joint Health",slug:"acoustic-monitoring-of-joint-health",totalDownloads:552,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"The joints of the human body, especially the knees, are continually exposed to varying loads as a person goes about their day. These loads may contribute to damage to tissues including cartilage and the development of degenerative medical conditions such as osteoarthritis (OA). The most commonly used method currently for classifying the severity of knee OA is the Kellgren and Lawrence system, whereby a grade (a KL score) from 0 to 4 is determined based on the radiographic evidence. However, radiography cannot directly depict cartilage damage, and there is low inter-observer precision with this method. As such, there has been a significant activity to find non-invasive and radiation-free methods to quantify OA, in order to facilitate the diagnosis and the appropriate course of medical action and to validate the development of therapies in a research or clinical setting. A number of different teams have noted that variation in knee joint sounds during different loading conditions may be indicative of structural changes within the knee potentially linked to OA. Here we will review the use of acoustic methods, such as acoustic Emission (AE) and vibroarthrography (VAG), developed for the monitoring of knee OA, with a focus on the issues surrounding data collection and analysis.",book:{id:"9973",slug:"data-acquisition-recent-advances-and-applications-in-biomedical-engineering",title:"Data Acquisition",fullTitle:"Data Acquisition - Recent Advances and Applications in Biomedical Engineering"},signatures:"Lucy Spain and David Cheneler",authors:[{id:"319073",title:"Dr.",name:"David",middleName:null,surname:"Cheneler",slug:"david-cheneler",fullName:"David Cheneler"},{id:"319195",title:"Dr.",name:"Lucy",middleName:null,surname:"Spain",slug:"lucy-spain",fullName:"Lucy Spain"}]},{id:"55607",title:"A New Method of SHM for Steel Wire Rope and its Apparatus",slug:"a-new-method-of-shm-for-steel-wire-rope-and-its-apparatus",totalDownloads:1506,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Steel wire ropes often operate in a high‐speed swing status in practical engineering, and the reliable structural health monitoring (SHM) for them directly relates to human lives; however, they are usually beyond the capability of present portable magnet magnetic flux leakage (MFL) sensors based on yoke magnetic method due to its strong magnetic force and large weight. Unlike the yoke method, a new method of SHM for steel wire rope is proposed by theoretical analyses and also verified by finite element method (FEM) and experiments, which features much weaker magnetic interaction force and similar magnetization capability compared to the traditional yoke method. Meanwhile, the relevant detection apparatus or sensor is designed by simulation optimization. Furthermore, experimental comparisons between the new and yoke sensors for steel wire rope inspection are also conducted, which successfully confirm the characterization of smaller magnetic interaction force, less wear, and damage in contrast with traditional technologies. Finally, methods for SHM of steel wire rope and apparatus are discussed, which demonstrate the good practicability for SHM of steel wire rope under poor working conditions.",book:{id:"5874",slug:"structural-health-monitoring-measurement-methods-and-practical-applications",title:"Structural Health Monitoring",fullTitle:"Structural Health Monitoring - Measurement Methods and Practical Applications"},signatures:"Shiwei Liu, Yanhua Sun and Wenjia Ma",authors:[{id:"178404",title:"Associate Prof.",name:"Yanhua",middleName:null,surname:"Sun",slug:"yanhua-sun",fullName:"Yanhua Sun"},{id:"200684",title:"Dr.",name:"Shiwei",middleName:null,surname:"Liu",slug:"shiwei-liu",fullName:"Shiwei Liu"},{id:"200685",title:"MSc.",name:"Wenjia",middleName:null,surname:"Ma",slug:"wenjia-ma",fullName:"Wenjia Ma"}]}],onlineFirstChaptersFilter:{topicId:"1345",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},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:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:103,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:31,numberOfPublishedChapters:314,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:11,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:105,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:16,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:4,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:14,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403",scope:"Artificial Intelligence (AI) is a rapidly developing multidisciplinary research area that aims to solve increasingly complex problems. In today's highly integrated world, AI promises to become a robust and powerful means for obtaining solutions to previously unsolvable problems. This Series is intended for researchers and students alike interested in this fascinating field and its many applications.",coverUrl:"https://cdn.intechopen.com/series/covers/14.jpg",latestPublicationDate:"June 11th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:9,editor:{id:"218714",title:"Prof.",name:"Andries",middleName:null,surname:"Engelbrecht",slug:"andries-engelbrecht",fullName:"Andries Engelbrecht",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNR8QAO/Profile_Picture_1622640468300",biography:"Andries Engelbrecht received the Masters and PhD degrees in Computer Science from the University of Stellenbosch, South Africa, in 1994 and 1999 respectively. He is currently appointed as the Voigt Chair in Data Science in the Department of Industrial Engineering, with a joint appointment as Professor in the Computer Science Division, Stellenbosch University. Prior to his appointment at Stellenbosch University, he has been at the University of Pretoria, Department of Computer Science (1998-2018), where he was appointed as South Africa Research Chair in Artifical Intelligence (2007-2018), the head of the Department of Computer Science (2008-2017), and Director of the Institute for Big Data and Data Science (2017-2018). In addition to a number of research articles, he has written two books, Computational Intelligence: An Introduction and Fundamentals of Computational Swarm Intelligence.",institutionString:null,institution:{name:"Stellenbosch University",institutionURL:null,country:{name:"South Africa"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:6,paginationItems:[{id:"22",title:"Applied Intelligence",coverUrl:"https://cdn.intechopen.com/series_topics/covers/22.jpg",isOpenForSubmission:!0,editor:{id:"27170",title:"Prof.",name:"Carlos",middleName:"M.",surname:"Travieso-Gonzalez",slug:"carlos-travieso-gonzalez",fullName:"Carlos Travieso-Gonzalez",profilePictureURL:"https://mts.intechopen.com/storage/users/27170/images/system/27170.jpeg",biography:"Carlos M. Travieso-González received his MSc degree in Telecommunication Engineering at Polytechnic University of Catalonia (UPC), Spain in 1997, and his Ph.D. degree in 2002 at the University of Las Palmas de Gran Canaria (ULPGC-Spain). He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. He won the “Catedra Telefonica” Awards in Modality of Knowledge Transfer, 2017, 2018, and 2019 editions, and awards in Modality of COVID Research in 2020.\n\nPublic References:\nResearcher ID http://www.researcherid.com/rid/N-5967-2014\nORCID https://orcid.org/0000-0002-4621-2768 \nScopus Author ID https://www.scopus.com/authid/detail.uri?authorId=6602376272\nScholar Google https://scholar.google.es/citations?user=G1ks9nIAAAAJ&hl=en \nResearchGate https://www.researchgate.net/profile/Carlos_Travieso",institutionString:null,institution:{name:"University of Las Palmas de Gran Canaria",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"23",title:"Computational Neuroscience",coverUrl:"https://cdn.intechopen.com/series_topics/covers/23.jpg",isOpenForSubmission:!0,editor:{id:"14004",title:"Dr.",name:"Magnus",middleName:null,surname:"Johnsson",slug:"magnus-johnsson",fullName:"Magnus Johnsson",profilePictureURL:"https://mts.intechopen.com/storage/users/14004/images/system/14004.png",biography:"Dr Magnus Johnsson is a cross-disciplinary scientist, lecturer, scientific editor and AI/machine learning consultant from Sweden. \n\nHe is currently at Malmö University in Sweden, but also held positions at Lund University in Sweden and at Moscow Engineering Physics Institute. \nHe holds editorial positions at several international scientific journals and has served as a scientific editor for books and special journal issues. \nHis research interests are wide and include, but are not limited to, autonomous systems, computer modeling, artificial neural networks, artificial intelligence, cognitive neuroscience, cognitive robotics, cognitive architectures, cognitive aids and the philosophy of mind. \n\nDr. Johnsson has experience from working in the industry and he has a keen interest in the application of neural networks and artificial intelligence to fields like industry, finance, and medicine. \n\nWeb page: www.magnusjohnsson.se",institutionString:null,institution:{name:"Malmö University",institutionURL:null,country:{name:"Sweden"}}},editorTwo:null,editorThree:null},{id:"24",title:"Computer Vision",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",isOpenForSubmission:!0,editor:{id:"294154",title:"Prof.",name:"George",middleName:null,surname:"Papakostas",slug:"george-papakostas",fullName:"George Papakostas",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hYaGbQAK/Profile_Picture_1624519712088",biography:"George A. Papakostas has received a diploma in Electrical and Computer Engineering in 1999 and the M.Sc. and Ph.D. degrees in Electrical and Computer Engineering in 2002 and 2007, respectively, from the Democritus University of Thrace (DUTH), Greece. Dr. Papakostas serves as a Tenured Full Professor at the Department of Computer Science, International Hellenic University, Greece. Dr. Papakostas has 10 years of experience in large-scale systems design as a senior software engineer and technical manager, and 20 years of research experience in the field of Artificial Intelligence. Currently, he is the Head of the “Visual Computing” division of HUman-MAchines INteraction Laboratory (HUMAIN-Lab) and the Director of the MPhil program “Advanced Technologies in Informatics and Computers” hosted by the Department of Computer Science, International Hellenic University. He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. Dr Ventura also holds the positions of Affiliated Professor at Virginia Commonwealth University (Richmond, USA) and Distinguished Adjunct Professor at King Abdulaziz University (Jeddah, Saudi Arabia). Additionally, he is deputy director of the Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI) and heads the Knowledge Discovery and Intelligent Systems Research Laboratory. He has published more than ten books and over 300 articles in journals and scientific conferences. Currently, his work has received over 18,000 citations according to Google Scholar, including more than 2200 citations in 2020. In the last five years, he has published more than 60 papers in international journals indexed in the JCR (around 70% of them belonging to first quartile journals) and he has edited some Springer books “Supervised Descriptive Pattern Mining” (2018), “Multiple Instance Learning - Foundations and Algorithms” (2016), and “Pattern Mining with Evolutionary Algorithms” (2016). He has also been involved in more than 20 research projects supported by the Spanish and Andalusian governments and the European Union. He currently belongs to the editorial board of PeerJ Computer Science, Information Fusion and Engineering Applications of Artificial Intelligence journals, being also associate editor of Applied Computational Intelligence and Soft Computing and IEEE Transactions on Cybernetics. Finally, he is editor-in-chief of Progress in Artificial Intelligence. He is a Senior Member of the IEEE Computer, the IEEE Computational Intelligence, and the IEEE Systems, Man, and Cybernetics Societies, and the Association of Computing Machinery (ACM). Finally, his main research interests include data science, computational intelligence, and their applications.",institutionString:null,institution:{name:"University of Córdoba",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"26",title:"Machine Learning and Data Mining",coverUrl:"https://cdn.intechopen.com/series_topics/covers/26.jpg",isOpenForSubmission:!0,editor:{id:"24555",title:"Dr.",name:"Marco Antonio",middleName:null,surname:"Aceves Fernandez",slug:"marco-antonio-aceves-fernandez",fullName:"Marco Antonio Aceves Fernandez",profilePictureURL:"https://mts.intechopen.com/storage/users/24555/images/system/24555.jpg",biography:"Dr. Marco Antonio Aceves Fernandez obtained his B.Sc. (Eng.) in Telematics from the Universidad de Colima, Mexico. He obtained both his M.Sc. and Ph.D. from the University of Liverpool, England, in the field of Intelligent Systems. He is a full professor at the Universidad Autonoma de Queretaro, Mexico, and a member of the National System of Researchers (SNI) since 2009. Dr. Aceves Fernandez has published more than 80 research papers as well as a number of book chapters and congress papers. He has contributed in more than 20 funded research projects, both academic and industrial, in the area of artificial intelligence, ranging from environmental, biomedical, automotive, aviation, consumer, and robotics to other applications. He is also a honorary president at the National Association of Embedded Systems (AMESE), a senior member of the IEEE, and a board member of many institutions. His research interests include intelligent and embedded systems.",institutionString:"Universidad Autonoma de Queretaro",institution:{name:"Autonomous University of Queretaro",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null},{id:"27",title:"Multi-Agent Systems",coverUrl:"https://cdn.intechopen.com/series_topics/covers/27.jpg",isOpenForSubmission:!0,editor:{id:"148497",title:"Dr.",name:"Mehmet",middleName:"Emin",surname:"Aydin",slug:"mehmet-aydin",fullName:"Mehmet Aydin",profilePictureURL:"https://mts.intechopen.com/storage/users/148497/images/system/148497.jpg",biography:"Dr. Mehmet Emin Aydin is a Senior Lecturer with the Department of Computer Science and Creative Technology, the University of the West of England, Bristol, UK. His research interests include swarm intelligence, parallel and distributed metaheuristics, machine learning, intelligent agents and multi-agent systems, resource planning, scheduling and optimization, combinatorial optimization. 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He is the author of several scientific articles, book chapters, and books.",institutionString:"University of Hassan II Casablanca",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"7",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"University of Hassan II Casablanca",institutionURL:null,country:{name:"Morocco"}}},equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"7060",title:"Gingival Disease",subtitle:"A Professional Approach for Treatment and Prevention",coverURL:"https://cdn.intechopen.com/books/images_new/7060.jpg",slug:"gingival-disease-a-professional-approach-for-treatment-and-prevention",publishedDate:"October 23rd 2019",editedByType:"Edited by",bookSignature:"Alaa Eddin Omar Al Ostwani",hash:"b81d39988cba3a3cf746c1616912cf41",volumeInSeries:4,fullTitle:"Gingival Disease - A Professional Approach for Treatment and Prevention",editors:[{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"7572",title:"Trauma in Dentistry",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7572.jpg",slug:"trauma-in-dentistry",publishedDate:"July 3rd 2019",editedByType:"Edited by",bookSignature:"Serdar Gözler",hash:"7cb94732cfb315f8d1e70ebf500eb8a9",volumeInSeries:3,fullTitle:"Trauma in Dentistry",editors:[{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",institutionURL:null,country:{name:"Turkey"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"7139",title:"Current Approaches in Orthodontics",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7139.jpg",slug:"current-approaches-in-orthodontics",publishedDate:"April 10th 2019",editedByType:"Edited by",bookSignature:"Belma Işık Aslan and Fatma Deniz Uzuner",hash:"2c77384eeb748cf05a898d65b9dcb48a",volumeInSeries:2,fullTitle:"Current Approaches in Orthodontics",editors:[{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"6668",title:"Dental Caries",subtitle:"Diagnosis, Prevention and Management",coverURL:"https://cdn.intechopen.com/books/images_new/6668.jpg",slug:"dental-caries-diagnosis-prevention-and-management",publishedDate:"September 19th 2018",editedByType:"Edited by",bookSignature:"Zühre Akarslan",hash:"b0f7667770a391f772726c3013c1b9ba",volumeInSeries:1,fullTitle:"Dental Caries - Diagnosis, Prevention and Management",editors:[{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",institutionString:"Gazi University",institution:{name:"Gazi University",institutionURL:null,country:{name:"Turkey"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Prosthodontics and Implant Dentistry",value:2,count:2},{group:"subseries",caption:"Oral Health",value:1,count:6}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:2},{group:"publicationYear",caption:"2020",value:2020,count:2},{group:"publicationYear",caption:"2019",value:2019,count:3},{group:"publicationYear",caption:"2018",value:2018,count:1}],authors:{paginationCount:250,paginationItems:[{id:"274452",title:"Dr.",name:"Yousif",middleName:"Mohamed",surname:"Abdallah",slug:"yousif-abdallah",fullName:"Yousif Abdallah",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274452/images/8324_n.jpg",biography:"I certainly enjoyed my experience in Radiotherapy and Nuclear Medicine, particularly it has been in different institutions and hospitals with different Medical Cultures and allocated resources. Radiotherapy and Nuclear Medicine Technology has always been my aspiration and my life. As years passed I accumulated a tremendous amount of skills and knowledge in Radiotherapy and Nuclear Medicine, Conventional Radiology, Radiation Protection, Bioinformatics Technology, PACS, Image processing, clinically and lecturing that will enable me to provide a valuable service to the community as a Researcher and Consultant in this field. My method of translating this into day to day in clinical practice is non-exhaustible and my habit of exchanging knowledge and expertise with others in those fields is the code and secret of success.",institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"313277",title:"Dr.",name:"Bartłomiej",middleName:null,surname:"Płaczek",slug:"bartlomiej-placzek",fullName:"Bartłomiej Płaczek",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313277/images/system/313277.jpg",biography:"Bartłomiej Płaczek, MSc (2002), Ph.D. (2005), Habilitation (2016), is a professor at the University of Silesia, Institute of Computer Science, Poland, and an expert from the National Centre for Research and Development. His research interests include sensor networks, smart sensors, intelligent systems, and image processing with applications in healthcare and medicine. He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University. His research interests include computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, intelligent systems, information technology, and information systems. Prof. Sarfraz has been a keynote/invited speaker on various platforms around the globe. He has advised various students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He is a member of various professional societies and a chair and member of the International Advisory Committees and Organizing Committees of various international conferences. Prof. Sarfraz is also an editor-in-chief and editor of various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/267434/images/system/267434.jpg",biography:"Dr. Rohit Raja received Ph.D. in Computer Science and Engineering from Dr. CVRAMAN University in 2016. His main research interest includes Face recognition and Identification, Digital Image Processing, Signal Processing, and Networking. Presently he is working as Associate Professor in IT Department, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur (CG), India. He has authored several Journal and Conference Papers. He has good Academics & Research experience in various areas of CSE and IT. He has filed and successfully published 27 Patents. He has received many time invitations to be a Guest at IEEE Conferences. He has published 100 research papers in various International/National Journals (including IEEE, Springer, etc.) and Proceedings of the reputed International/ National Conferences (including Springer and IEEE). He has been nominated to the board of editors/reviewers of many peer-reviewed and refereed Journals (including IEEE, Springer).",institutionString:"Guru Ghasidas Vishwavidyalaya",institution:{name:"Guru Ghasidas Vishwavidyalaya",country:{name:"India"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:null},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:null,institution:{name:"Beijing University of Technology",country:{name:"China"}}},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Lakhno Igor Victorovich was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPhD – 1999, Kharkiv National Medical Univesity.\nDSc – 2019, PL Shupik National Academy of Postgraduate Education \nLakhno Igor has been graduated from an international training courses on reproductive medicine and family planning held in Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor of the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s a professor of the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education . He’s an author of about 200 printed works and there are 17 of them in Scopus or Web of Science databases. Lakhno Igor is a rewiever of Journal of Obstetrics and Gynaecology (Taylor and Francis), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for DSc degree \\'Pre-eclampsia: prediction, prevention and treatment”. Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: obstetrics, women’s health, fetal medicine, cardiovascular medicine.",institutionString:"V.N. Karazin Kharkiv National University",institution:{name:"Kharkiv Medical Academy of Postgraduate Education",country:{name:"Ukraine"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"243698",title:"M.D.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:"Shanxi Eye Hospital",institution:{name:"Shanxi Eye Hospital",country:{name:"China"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. RELACION DE PONENCIAS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGIA. 10/2014.",institutionString:null,institution:null},{id:"265335",title:"Mr.",name:"Stefan",middleName:"Radnev",surname:"Stefanov",slug:"stefan-stefanov",fullName:"Stefan Stefanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/265335/images/7562_n.jpg",biography:null,institutionString:null,institution:null},{id:"7227",title:"Dr.",name:"Hiroaki",middleName:null,surname:"Matsui",slug:"hiroaki-matsui",fullName:"Hiroaki Matsui",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Tokyo",country:{name:"Japan"}}},{id:"318905",title:"Prof.",name:"Elvis",middleName:"Kwason",surname:"Tiburu",slug:"elvis-tiburu",fullName:"Elvis Tiburu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Ghana",country:{name:"Ghana"}}},{id:"336193",title:"Dr.",name:"Abdullah",middleName:null,surname:"Alamoudi",slug:"abdullah-alamoudi",fullName:"Abdullah Alamoudi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"318657",title:"MSc.",name:"Isabell",middleName:null,surname:"Steuding",slug:"isabell-steuding",fullName:"Isabell Steuding",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"318656",title:"BSc.",name:"Peter",middleName:null,surname:"Kußmann",slug:"peter-kussmann",fullName:"Peter Kußmann",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"338222",title:"Mrs.",name:"María José",middleName:null,surname:"Lucía Mudas",slug:"maria-jose-lucia-mudas",fullName:"María José Lucía Mudas",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Carlos III University of Madrid",country:{name:"Spain"}}}]}},subseries:{item:{id:"7",type:"subseries",title:"Bioinformatics and Medical Informatics",keywords:"Biomedical Data, Drug Discovery, Clinical Diagnostics, Decoding Human Genome, AI in Personalized Medicine, Disease-prevention Strategies, Big Data Analysis in Medicine",scope:"Bioinformatics aims to help understand the functioning of the mechanisms of living organisms through the construction and use of quantitative tools. 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The considerable development of technology, including the computing power of computers, is also conducive to the development of bioinformatics, including personalized medicine. In an era of rapidly growing data volumes and ever lower costs of generating, storing and computing data, personalized medicine holds great promises. Modern computational methods used as bioinformatics tools can integrate multi-scale, multi-modal and longitudinal patient data to create even more effective and safer therapy and disease prevention methods. 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living organisms through the construction and use of quantitative tools. The applications of this research cover many related fields, such as biotechnology and medicine, where, for example, Bioinformatics contributes to faster drug design, DNA analysis in forensics, and DNA sequence analysis in the field of personalized medicine. Personalized medicine is a type of medical care in which treatment is customized individually for each patient. Personalized medicine enables more effective therapy, reduces the costs of therapy and clinical trials, and also minimizes the risk of side effects. Nevertheless, advances in personalized medicine would not have been possible without bioinformatics, which can analyze the human genome and other vast amounts of biomedical data, especially in genetics. The rapid growth of information technology enabled the development of new tools to decode human genomes, large-scale studies of genetic variations and medical informatics. The considerable development of technology, including the computing power of computers, is also conducive to the development of bioinformatics, including personalized medicine. In an era of rapidly growing data volumes and ever lower costs of generating, storing and computing data, personalized medicine holds great promises. Modern computational methods used as bioinformatics tools can integrate multi-scale, multi-modal and longitudinal patient data to create even more effective and safer therapy and disease prevention methods. Main aspects of the topic are: Applying bioinformatics in drug discovery and development; Bioinformatics in clinical diagnostics (genetic variants that act as markers for a condition or a disease); Blockchain and Artificial Intelligence/Machine Learning in personalized medicine; Customize disease-prevention strategies in personalized medicine; Big data analysis in personalized medicine; Translating stratification algorithms into clinical practice of personalized medicine.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",keywords:"Biomedical Data, Drug Discovery, Clinical Diagnostics, Decoding Human Genome, AI in Personalized Medicine, Disease-prevention Strategies, Big Data Analysis in Medicine"},{id:"8",title:"Bioinspired Technology and Biomechanics",scope:'Bioinspired technologies take advantage of understanding the actual biological system to provide solutions to problems in several areas. Recently, bioinspired systems have been successfully employing biomechanics to develop and improve assistive technology and rehabilitation devices. The research topic "Bioinspired Technology and Biomechanics" welcomes studies reporting recent advances in bioinspired technologies that contribute to individuals\' health, inclusion, and rehabilitation. 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Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering"}],annualVolumeBook:{},thematicCollection:[],selectedSeries:{title:"Biomedical Engineering",id:"7"},selectedSubseries:null},seriesLanding:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"June 24th, 2022",hasOnlineFirst:!0,numberOfOpenTopics:4,numberOfPublishedChapters:314,numberOfPublishedBooks:31,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. 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We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics include, but are not limited to: Advanced techniques of cellular and molecular biology (Molecular methodologies, imaging techniques, and bioinformatics); Biological activities at the molecular level; Biological processes of cell functions, cell division, senescence, maintenance, and cell death; Biomolecules interactions; Cancer; Cell biology; Chemical biology; Computational biology; Cytochemistry; Developmental biology; Disease mechanisms and therapeutics; DNA, and RNA metabolism; Gene functions, genetics, and genomics; Genetics; Immunology; Medical microbiology; Molecular biology; Molecular genetics; Molecular processes of cell and organelle dynamics; Neuroscience; Protein biosynthesis, degradation, and functions; Regulation of molecular interactions in a cell; Signalling networks and system biology; Structural biology; Virology and microbiology.",annualVolume:11410,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"79367",title:"Dr.",name:"Ana Isabel",middleName:null,surname:"Flores",fullName:"Ana Isabel Flores",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRpIOQA0/Profile_Picture_1632418099564",institutionString:null,institution:{name:"Hospital Universitario 12 De Octubre",institutionURL:null,country:{name:"Spain"}}},{id:"328234",title:"Ph.D.",name:"Christian",middleName:null,surname:"Palavecino",fullName:"Christian Palavecino",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000030DhEhQAK/Profile_Picture_1628835318625",institutionString:null,institution:{name:"Central University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"186585",title:"Dr.",name:"Francisco Javier",middleName:null,surname:"Martin-Romero",fullName:"Francisco Javier Martin-Romero",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSB3HQAW/Profile_Picture_1631258137641",institutionString:null,institution:{name:"University of Extremadura",institutionURL:null,country:{name:"Spain"}}}]},{id:"15",title:"Chemical Biology",keywords:"Phenolic Compounds, Essential Oils, Modification of Biomolecules, Glycobiology, Combinatorial Chemistry, Therapeutic peptides, Enzyme Inhibitors",scope:"Chemical biology spans the fields of chemistry and biology involving the application of biological and chemical molecules and techniques. In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. 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Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. The Proteomics topic aims to attract contributions on all aspects of MS-based proteomics that, by pushing the boundaries of MS capabilities, may address biological problems that have not been resolved yet.",annualVolume:11414,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null,editorialBoard:[{id:"72288",title:"Dr.",name:"Arli Aditya",middleName:null,surname:"Parikesit",fullName:"Arli Aditya Parikesit",profilePictureURL:"https://mts.intechopen.com/storage/users/72288/images/system/72288.jpg",institutionString:null,institution:{name:"Indonesia International Institute for Life Sciences",institutionURL:null,country:{name:"Indonesia"}}},{id:"40928",title:"Dr.",name:"Cesar",middleName:null,surname:"Lopez-Camarillo",fullName:"Cesar Lopez-Camarillo",profilePictureURL:"https://mts.intechopen.com/storage/users/40928/images/3884_n.png",institutionString:null,institution:{name:"Universidad Autónoma de la Ciudad de México",institutionURL:null,country:{name:"Mexico"}}},{id:"81926",title:"Dr.",name:"Shymaa",middleName:null,surname:"Enany",fullName:"Shymaa Enany",profilePictureURL:"https://mts.intechopen.com/storage/users/81926/images/system/81926.png",institutionString:"Suez Canal University",institution:{name:"Suez Canal University",institutionURL:null,country:{name:"Egypt"}}}]}]}},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"profile.detail",path:"/profiles/245456",hash:"",query:{},params:{id:"245456"},fullPath:"/profiles/245456",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()