Summary of types of hypersensitivity.
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Abdurakhmonov",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11724.jpg",keywords:"Full Genome Sequencing, Mutations and Genetic Variations, Whole-Virus Inactivated and Live-Attenuated, Recombinant Protein-Based, WHO-Protocols, Preclinical and Clinical Trials, New Strain Protection, Availability and Usage, Side Effects, Novel Designs, Country Experiences, Booster-Dose Injection",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 17th 2022",dateEndSecondStepPublish:"May 24th 2022",dateEndThirdStepPublish:"July 23rd 2022",dateEndFourthStepPublish:"October 11th 2022",dateEndFifthStepPublish:"December 10th 2022",remainingDaysToSecondStep:"5 days",secondStepPassed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"A leading biotechnologist, coordinating biotechnology science including COVID-19 vaccine development, laboratory studies, and clinical trials and production in Uzbekistan. Prof. Abdurakhmonov founded (2012) the Center of Genomics and Bioinformatics of Uzbekistan. He received a BS in Biotechnology from the National University, an MS in Plant Breeding from Texas A&M University, USA, a Ph.D. in Molecular Genetics, a Doctor of Science in Genetics, and a full professorship in Molecular Genetics.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"213344",title:"Prof.",name:"Ibrokhim Y.",middleName:null,surname:"Abdurakhmonov",slug:"ibrokhim-y.-abdurakhmonov",fullName:"Ibrokhim Y. Abdurakhmonov",profilePictureURL:"https://mts.intechopen.com/storage/users/213344/images/system/213344.jpg",biography:"Ibrokhim Y. Abdurakhmonov received his B.S. (1997) in biotechnology from the National University, M.S. in plant breeding\n(2001) from Texas A&M University of USA, Ph.D. (2002) in molecular genetics, Doctor of Science (2009) in genetics, and full professorship (2011) in molecular genetics and molecular biotechnology from Academy of Sciences of Uzbekistan. He founded (2012)\nthe Center of Genomics and Bioinformatics of Uzbekistan. He\nreceived the 2010 TWAS prize, and “ICAC Cotton Researcher of the Year 2013” for\nhis outstanding contribution to cotton genomics and biotechnology. He was elected\nas The World Academy of Sciences (TWAS) Fellow (2014) and as a member (2017)\nof the Academy of Sciences of Uzbekistan. He was appointed (2017) as a Minister\nof Innovative Development of Uzbekistan.",institutionString:"Academy of Sciences of Uzbekistan",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"12",totalChapterViews:"0",totalEditedBooks:"12",institution:null}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"252211",firstName:"Sara",lastName:"Debeuc",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/252211/images/7239_n.png",email:"sara.d@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. 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Abdurakhmonov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"47895",title:"Panoramic Radiography — Diagnosis of Relevant Structures That Might Compromise Oral and General Health of the Patient",doi:"10.5772/59260",slug:"panoramic-radiography-diagnosis-of-relevant-structures-that-might-compromise-oral-and-general-health",body:'The chapter provides information about panoramic radiography, showing the principal indications, advantages and disadvantages of this examination. Moreover, focus is given to some anatomical variations that can be detected on panoramic radiographs such as bifid mandibular canal, retromolar canal, and alterations such as calcified stylohyoid complex, arterial calcifications, phleboliths, sialolithiasis and tonsilloliths. Such structures/alterations are not reasons for indication of panoramic radiography, but they are radiographic findings, being important their identification, indication of more accurate examinations, and even referring to other professionals. Therefore, a literature review was conducted, citing relevant anatomy textbooks and scientific papers, and it was illustrated with panoramic radiographs showing these described structures/alterations.
Panoramic radiography is a radiologic technique that provides an overview of the jaws and surrounding structures. It is frequently indicated when professionals want to evaluate some structures such as unerupted third molars, orthodontic treatment, tooth development, developmental abnormalities, trauma, large lesions, and others [1, 2]. The panoramic radiograph allows the dental professional to view a large area of the maxilla and mandible on a single film [2].
The panoramic radiography is frequently used as initial diagnostic image of some alterations and based on it, the professional will verify the need of other more detailed and more accurate examinations [1].
If you have a full-mouth series, the panoramic radiography shows no more or little useful information for a patient receiving general dental care [1].
Some contraindications of panoramic radiographs are clinical situations that require detail and definition, such as carious lesions, visualization of alveolar crests, level of root canal filling [3], periodontal disease or periapical lesions [2].
In dental clinical practice, panoramic radiography is one of the most indicated radiographic examinations by dentists because it provides a general overview of dentomaxilomandibular structures and it is not so costly for patients.
Panoramic radiography has many advantages including short time for the procedure, greater patient acceptance and cooperation, overall coverage of the dental arches and associated structures (more anatomic structures can be viewed on a panoramic film than on a complete intraoral radiograph series), simplicity, low patient radiation dose [2, 4]. The dose to the patient is approximately ten times less than full-mouth survey using the long cone and E+ film and it is four times less than four bitewings using the long round cone and E+ film [4].
The panoramic radiograph is less confusing to the patient than a series of small separate intraoral radiographs, making it easier for the dentist to explain the diagnosis and treatment plan to the patient [5].
The panoramic radiograph is an excellent imaging modality in patients with trismus or trauma, because such patients cannot open their mouths and this is not needed to take a panoramic film [4]. It is an excellent projection of diverse structures on a single film, which no other imaging system can achieve. Individual structures may be imaged by other methods, once pathologic conditions have been detected using the panoramic radiography [3, 4].
Nevertheless, this radiographic examination presents a lack of details and resolution of some structures due to overlapping of anatomical structures in the image, mild distortion and magnification [1, 3]. Objects of interest that are located outside the focal trough (it is the area of the dental anatomy that is reproduced distinctly on the panoramic radiograph) [5] are not seen [2], and artifacts are commom and may easily be misterpreted [5].
These features limit the indications of panoramic radiographs in cases where details and accurate measurements are needed [1, 3].
The term "normal" in Anatomy refers to the shape and position most frequently found in individuals, that is, the typical shape. Anatomical variation is the deviation from the normal that does not bring any noticeable functional disorder [6].
Not very unusual, the bifid mandibular canals are observed on panoramic radiographs (Figure 1).
Digital panoramic radiography with a bifid mandibular canal image on the left side.
There are different frequencies and shapes in the literature.
Only 4 panoramic radiographs (0.08%) from 5,000 were highly suggestive of bifurcation [7]. Seven cases (0.35%) from 2,012 radiographs presented a suggestive image of a double mandibular canal [8]. From 700 panoramic radiographs evaluation, 3 cases (0.43%) showed bifid mandibular canal [9]. Duplication or division of the mandibular canal was found in 33 individuals (0.9%) from the 3,612 evaluated panoramic radiographs [10]. It is important to observe the presence of bifid mandibular canals to prevent potential complications during surgical dental procedures. A total of 6,000 panoramic radiographs were studied, and there were 57 bifid mandibular canals (0.95%) [11].
Three main patterns of duplication were found radiographically [10]. The first variety (Type 1) consisted of two canals originating from one foramen. The second variety of duplication or division (Type 2) was produced by a short upper canal extending to the second molar or third molar teeth. Type 3 was seen as two mandibular canals of equal dimensions apparently arising from separate foramina in the mandibular ramus and joining together to form one canal in the molar region of the body of the mandible. Other variations (Type 4) included duplication or division of the canal, apparent partial or complete absence of the canal or lack of symmetry.
The most common supplemental mandibular canals are duplicate canals commencing from a single mandibular foramen and the least common arising from two distinctly separate foramina [10]. A different classification was used by reference [9], which verified that type III (the canal is located close to the lower border of the mandible) is the most common, followed by the type II (the canal is noted between the apices of the first and second molars and the lower border of the mandible) and the type I (the canal is in close contact with the apices of the first and the second molars).
No great difference in frequency between males and females was found by reference [10] and there was no statistical significance between sex and types of the mandibular canal in the study of reference [9]. Women presented more bifid mandibular canals than men (63.5% vs. 36.5%) [8].
When bifid mandibular canals were evaluated by cone beam computed tomography (CBCT), a higher frequency was found. An incidence of 15.6% from 301 mandible sides was observed by [12] and, in a recent study an incidence of 10.2% was found in CBCT of 1933 patients [13]. However, different results were found by reference [8]. In their study, computed axial tomography was used in 3 of the 7 cases with apparent double inferior alveolar nerve images on panoramic radiographs. The existence of a bifid canal could only be confirmed in 2 of these patients. The authors suggested that the true incidence of bifid mandibular canals might be lower than reported by other studies. The possible causes underlying a false double-canal radiograph may include the imprint of the mylohyoid nerve on the internal mandibular surface where it separates from the inferior alveolar nerve and travels to the floor of the mouth [8, 14, 15]. Another explanation could be the radiologic osteocondensation image produced by the insertion of the mylohyoid muscle into the internal mandibular surface, with a distribution parallel to the dental canal [8, 16].
Bifurcation of the mandibular nerve may be a cause of inadequate anesthesia in a small percentage of cases [7, 8]. One of the seven patients who presented bifid mandibular canals on panoramic radiographs commented that her dentist had experienced problems in performing inferior alveolar nerve block in the past. Another patient had no such problems, and the remaining five patients had either never undergone anesthesia or remembered no associated problems [8]. This problem is usually resolved by performing inferior alveolar nerve anesthesia at a somewhat higher level (the so-called “Gow-Gates” technique) [8, 17]. Other possible complications can occur during surgery of the lower third molar, in orthognathic or reconstructive mandibular surgery, and in the placement of dental implants [8, 18], because of possible damage to an unidentified second mandibular canal [8].
Another anatomical variation that can be observed on panoramic radiographs is the retromolar canal, and it can be considered a type of mandibular canal division.
Retromolar canal has been observed in dry mandibles, cadaveric dissections, panoramic radiographs and cone beam computed tomography. Variability in the prevalence of the retromolar canal is also verified in different studies, 1.7% [19], 12.19% [20], 12.9% [21], 14.08% [22], 17% [23], 18% [24], 21.9% [25], 25% [26], 26.58% [27] (studies with dry mandibles); 5.8% [28], 16.8% [29] (studies with panoramic radiography); 16% [30], 75.4% in individuals assessed by tomography exams, 72% in cadavers [31], 52.5% [13], 75.4% [32] (studies with computed tomography).
In the retromolar canals there were found striated muscle fibers, myelinated nerve fibers and blood vessels [26]. In the retromolar canal an artery was found, being the branch of the inferior alveolar artery, and the existing nerve derived from the inferior alveolar nerve and went to the third-molar region, the retromolar triangle mucosa, the buccal mucosa, the vestibular gingiva of the premolar region and inferior molars [33]. Accessory canals in the retromolar region are functionally important in providing the neural and/or vascular components of the mandible [34]. Figure 2 shows one retromolar canal bilaterally.
Digital panoramic radiography presenting a retromolar canal image on both sides.
Therefore, the content of the mandibular retromolar canal, usually of nerve fibers and/or blood vessels, is very important for surgical and anesthetic procedures involving the retromolar area. The confirmation of retromolar foramen and canal locations prior to surgical procedures, such as extraction of an impacted molar and bone harvesting as a donor site for bone graft surgery [35]. Complications such as traumatic neuroma, paraesthesia, and bleeding could arise because of failure to recognize the presence of mandibular canal variation [36, 37].
Studies have demonstrated the advantage of computed tomography over panoramic radiography in identification of anatomical variations [30, 36, 38].
It is clinically significant to accurately localize a bifid mandibular canal before dentoalveolar surgery especially when their presence is suspected by panoramic radiography [39]. Therefore, when professionals have suspicious of accessory mandibular canals on panoramic radiography, computed tomography should be done to confirm them and avoid complications.
Due to the broad coverage of panoramic radiographs, sometimes we can visualize some structures that affect more than the patient\'s oral health, but also general health. Many changes are asymptomatic and can be identified casually, as when the panoramic radiography is required for dental evaluation.
Among them, there are the calcified stylohyoid complex, arterial calcifications and other soft tissue calcifications.
The styloid process is a cylindrical bone originated on the temporal bone [40-44] in front of the stylomastoid foramen [41-43], being located between the internal and external carotid arteries and laterally to the tonsillar fossa [43, 45, 46].
According to reference [47], elongated styloid process defines a styloid process that is longer than normal and thus associated with calcification of the process and its ligament, but some authors preferred the term calcified stylohyoid complex to describe the elongated process with advanced calcification [47].
The stylohyoid ligament is attached to the lesser horn of the hyoid bone [43, 48] and the calcification of the stylohyoid complex includes the stylohyoid ligament which connects the styloid process to the lesser horn of the hyoid bone [43].
The etiology of elongated styloid process is unknown [40, 43-45, 49, 50]. It was suggested that calcified styloihyoid complex could be resulted from local chronic irritations, history of trauma, endocrine disorders in female at menopause, persistence of mesenchymal elements, bone tissue growth and mechanical stress or trauma during stylohyoid ligament development [40, 43, 45, 46, 49], although no significant difference between females at menopause or not were showed [43]. A case report of twins suggested a possibility that calcified stylohyoid complex might be originated from genetic factors [44].
Only one report commented about the positive correlation that was found between the length of the styloid process and serum calcium concentration, heel bone density and body height and weight [47]. Previous studies reported difference in age for calcified stylohyoid ligament [51], i.e., the length increased with the age [41-43, 52], and its occurrence is rare in children [46]. Thus, dentists should pay attention not only for pathosis of the teeth and jaws, but also for information on general health conditions [47].
The measurements of the calcified stylohyoid complex on the panoramic radiography consist on the distance from the point where the styloid process left the tympanic plate to the tip of the process, involving mineralized parts of the ligament [42, 47, 50].
The literature reports that calcified styloid process is considered normal when it does not extend below the mandibular foramen. It is considered elongated when it extends below the mandibular foramen [51]. Finally, calcification of the stylohyoid ligament occurs when the calcification extends below the mandibular foramen and does not appear to be continuous with the base of the skull [51]. Figure 3 presents a panoramic radiography showing a calcified stylohyoid complex on both sides.
Digital panoramic radiography with a calcified stylohyoid complex on both sides. On the right side we can observe the stylohyoid ligament calcification near the hyoid bone. On the left side a fragmented stylohyoid ligament calcification can be seen.
Cervicalpharyngeal pain is classified into 3 entities: Eagle syndrome, stylohyoid syndrome and pseudostylohyoid syndrome [46]. Eagle’s syndrome comprises elongated styloid process when it causes clinical symptoms, including dysphagia, foreign body sensation [45, 46, 48, 50, 53, 54], odynophagia, hypersalivation, and more rarely, temporary voice changes [53]. Eagle syndrome needs a history of trauma or neck surgery and painful symptoms on clinical palpation of the elongation or ossification of the stylohyoid process complex [46]. It may also cause stroke when compresses carotid arteries [40].
Stylohyoid syndrome does not comprise a history of trauma or surgery [46], and it occurs due to the compression of the internal and external carotid arteries and vascular structures [43, 53], resulting in a persistent pain to the carotid region, as headache, chronic neck pain, pain upon head movement and pain radiating to the eye [53]. It also shows radiographic elongation or ossification of the stylohyoid process complex [46] and it affects patients older than 40 years [46, 48]. This condition is more prevalent than Eagle syndrome [48].
In pseudostylohyoid syndrome there is no evidence of any elongation or ossification, but the patient describes the symptoms [46].
In Eagle syndrome, the styloid process is longer than 25mm [46]; from 25mm to 30mm it is considered elongated [42], although it varies in length in different people and even on the two sides of the same person [41, 42]. There is a significant prevalence for men concerning the styloid process length [42, 47]. However, there was no difference between sexes on the pattern distribution of calcified stylohyoid complex [43, 47, 51, 52]. The calcified stylohyoid complex bilaterally is prevalent [1, 41-43, 49, 52].
Radiographic imaging may include panoramic radiography, lateral cephalometry, Towne projection film, or computed tomogragphy (CT) scan [42, 43, 45, 46, 48, 53].
Calcified stylohyoid complex is usually visualized on panoramic radiography [1, 40, 51] as an incidental finding [49], as a long, thin, radiopaque process that is thicker at its base, posteriorly to the external acoustic meatus, with a trajectory downward and forward [1, 46]. A thicker calcified stylohyoid complex is uncommon. Figure 4 presents a very thick calcified stylohyoid complex.
Digital panoramic radiography shows a thick calcified stylohyoid complex on the right side.
Panoramic radiography is the best imaging modality to visualize the styloid process bilaterally [42, 45] in patients with or without symptoms, and helps avoid misinterpretation of symptoms as tonsillar pain or dental pain, pharyngeal or muscular origin [42]. Panoramic radiography may be the first choice as imaging modality, because of its availability, low cost, diagnostic performance, and less patient dose compared to other imaging methods [43]. Nevertheless, panoramic radiography is not appropriate for measuring the length, and to show direction and anatomical variation of calcified stylohyoid complex compared to the multislice computed tomography [40, 46, 48, 54] and cone beam computed tomography do [43].
Data from clinical history, physical and radiographic examination must be considered when diagnosing Eagle’s syndrome [46, 47, 54]. In the physical examination the calcified stylohyoid complex can be palpated on the tonsillar fossa as a hard and pointed structure [45, 49, 54].
The differentiation diagnosis of styloid ligament calcification may include calcified carotid artery atheromas, pheboliths and lymph node calcification [47] and for symptomatic elongated styloid process may comprise temporomandibular joint disorder, glossopharyngeal and trigeminal neuralgias, temporal arteritis, migraine, myofacial pain, atypical odontalgia, sialadenitis, sialolithiasis, cervical arthritis and tumors [46, 49], pain secondary to unerupted or impacted third molars, histaminic headache [46].
Most patients with calcified stylohyoid complex are asymptomatic [1, 44, 52] and no treatment is required [1]. The first choice of treatment is the use of analgesics and anti-inflammatory medications [46, 49]. However, for severe symptomatic patients with Eagle’s syndrome the surgical excision of the stylohyoid complex is recommended [1, 44, 46, 54]. Regardless the cervicalpharyngeal pain it is important for the dentist who is involved in the diagnosis and treatment of these syndromes to identify on the panoramic radiography the calcified stylohyoid complex and to refer the patient to a specialized team.
The common carotid artery originates from the aorta artery and in the height of the upper edge of the thyroid cartilage branches into two terminal branches: internal and external carotid artery. The identification of the point of bifurcation is often located 3 cm below the lower edge of the mandible [55].
It is considered a dystrophic calcification where there are deposited calcium salts in chronically inflamed or necrotic tissues. The presence of an atheromatous plaque in the extracranial carotid vascular path is the main cause for vasculocerebral embolism and obstructive diseases [1].
Carotid artery atherosclerotic plaques develop when fatty substances, cholesterol, platelets, cellular waste products, and calcium are deposited in the lining of the artery [56]. Some risk factors for atherosclerosis are: diabetes mellitus, obesity, hypertension, smoking, inadequate diet, chronic kidney disease and menopause among others [57].
Panoramic radiographs, obtained during professional dental examinations, are a potential method for early detection of Calcified Carotid Artery Atheroma (CCAA) [58]. Patients found to have carotid calcification on panoramic radiographs should be referred for cerebrovascular and cardiovascular evaluation and aggressive management of vascular risk factors [59]. Patients who have risk factors and CCAA on panoramic radiographs have a higher chance of suffering a vascular event compared with patients without image CCAA on panoramic radiographs, indicating that the incidental finding of calcifications on a panoramic dental radiograph is a powerful marker for future adverse, nonfatal, vascular events, with cardiovascular events being more common than cerebrovascular events [56].
The prevalence of CCAA in HIV+patients was assessed by reference [60] through review of medical records and on panoramic radiography and the authors concluded that infection and the treatment used to treat HIV infection can influence the identification of CCAA. Thus, a careful examination of panoramic radiographs in these patients is recommended and the need for further studies related to the subject is reinforced.
Authors [61] observed hypertension as the major risk factor associated with carotid artery calcification followed by diabetes mellitus and hyperlipidemia in the Thai population. A standard panoramic dental radiography detected the presence of calcified cervical carotid artery disease in approximately 31% of postmenopausal women with no history of transient ischemic attack or stroke. It was demonstrated that hypertension was a significant risk factor for the development of atheromas [62]. Other authors [63] observed that patients who had evidence of calcified carotid plaque on panoramic radiographs had lower incidence of diabetes mellitus and hyperlipidemia but were more likely to have stroke, compared with patients with negative panoramic radiography for calcification.
The utility of observing calcification will obviously depend on the prevalence and amount of calcium within these lesions, which varies according to each patient [64].
A high interobserver agreement (92.4%) on the detection of carotid artery calcification (CAC) on panoramic radiographs of male patients above 50 years old was observed by reference [65]. No significant difference in the prevalence CCA in HIV+patients using conventional and digital panoramic radiograph was found [60]. Authors [66] emphasized that digital panoramic radiograph allow low intensity calcifications to be visualized due to the possibility of changing the contrast, density and expansion.
Radiographically, calcified carotid atheroma is initially developed at the bifurcation of arteries, soft tissues of the neck, and adjacent to the greater horn of the hyoid bone and the cervical vertebrae C3 and C4 or the intervertebral space between them. They are radiopaque, usually multiple and irregularly shaped, with a vertical distribution and they have an internally heterogeneous radiopacity [1]. The shape varies from circular to mostly linear with irregular margins and appears punctate containing areas of radiolucencies [67]. Figures 5 and 6 present panoramic radiographs with images suggesting the presence of atheromas.
Digital panoramic radiography with images suggesting the presence of atheroma on both sides.
Digital panoramic radiography with image suggesting the presence of atheroma on left side.
Panoramic radiographs of a 67-year-old white woman were evaluated, and observed the presence of multiple, irregular, nonhomogenous radiopacities lying overboth the right and the left carotid bifurcations [64]. The calcifications were located inferior to the angle of the mandible and the tip of the hyoid bone, and to the top tip of the thyroid cartilage and the C3, C4 and C5 vertebrae [64]. Other authors [61] evaluated panoramic radiographs in 1370 patients and reported the presence of calcified carotid artery as irregular, heterogenous, vertcolinear or circular radiopaque lower to the neck at the level of the C3 and C4 intervertebral junction in the Thai population. The carotid artery calcifications were located within the soft tissues of the neck, approximately 2 centimeters inferior and posterior to the angle of the mandible, at about the level of the lower margin of the third cervical vertebra [62].
The differential diagnosis of CCAA image can be performed with several nearby anatomical structures such as the hyoid bone, styloid process, especially the thyroid cartilage and triticeous cartilage.
The triticeous cartilage often occurs in each lateral thyrohyoid ligament forming the edges of the thyrohyoid membrane [68].
The calcified triticeous cartilage can be confused with an atheromatous plaque but the shape, outline and location help in discriminating the triticeous cartilage from calcification in the carotid arteries [1, 67].
Triticeous cartilages and calcified carotid atheromas are located in a similar region on panoramic radiographs; the shape and outline help in differentiating these 2 calcifications in the neck. Triticeous cartilage is specifically located between the greater horn of the hyoid and superior horn of the thyroid cartilage, and the shape is mostly well-defined oval, with a smooth, well-defined corticated border [67]. Figure 7 shows a panoramic radiography with triticeous cartilages on both sides.
Digital panoramic radiography with image suggesting triticeous cartilage on both sides (between the greater horn of the hyoid and superior horn of the thyroid cartilage).
Authors [57] emphasized that although the panoramic radiography is not the test of choice, it is possible to identify atheroma in the carotid artery and therefore the dentist may instruct the patient to seek medical advice as soon as possible.
In order to confirm the presence of CACs, advanced imaging techniques such as duplex ultrasound, magnetic resonance imaging, and angiography should be performed [61].
The reliability of digital panoramic radiographs in detecting atheroma in the carotid artery was assessed [69] and the authors compared with ultrasound examinations. The results showed that digital panoramic radiography has a high level of agreement with ultrasonography with 76% of sensitivity and 98.66% of specificity. The authors concluded that the panoramic radiograph should not be routinely used in the detection of calcified carotid atheromatous plaques although when detected on a routine dental examination it is very useful.
The image of CCAA on panoramic radiograph was confirmed utilizing duplex ultra-sonography, which revealed carotid artery stenosis (CAS) [64]. The authors suggested that calcifications seen lying over the carotid bifurcation on panoramic radiographs should prompt further evaluation for CAS.
The dystrophic calcification of the tunica intima resulting in CCAA can be distinguished radiographically from another calcified form of arteriosclerosis, medial artery arteriosclerosis (MAA) or Mönckeberg\'s medial calcific sclerosis. The calcification in MAA is generalized because it affects the tunica media of medium and smaller muscular arteries. Calcifications are typically diffuse, multiple, and circumferential along the wall of the arterial vessel. MAA may be an indicator of peripheral artery disease, including diabetes mellitus or chronic kidney disease. MAA is generally observed in the limbs and rarely reported in the head and neck [70]. MAA can be identified on the panoramic radiography when the facial artery is affected. According to reference [71], the panoramic radiography can be the first auxiliary in diagnosis for detecting facial artery calcification in patients in hemodialysis. The authors suggested that more studies should be performed, in order to determine the incidence of that alteration in those patients.
Radiographically, the calcium deposited in the arterial wall outlines the artery contour, being identified as a pair of parallel, thin radiopaque lines, or with circular aspect, depending on the evaluated view [1].
Sialolithiasis is the most common disease of the salivary glands [72-74] characterized by obstruction of salivary secretion by a calculus, associated with swelling, pain [72, 75, 76] and infection of the affected gland [75]. More than 80% of the salivary gland calculi occurs in the submandibular gland [1, 72, 74-78] and 5%-20% in the parotid gland [72, 75-78] and rarely in the sublingual gland and the minor salivary glands (1% to 2%) [72, 75-77]. It is common in adults (1.2% of the population), with a male predominance [1, 72, 74, 76, 77], although previous investigators cited that sialolithisis occurs more frequently in white woman [73]. Children are rarely involved and sialolithiasis is more frequently in the third to the sixth decades of life [72, 74-77].
Patients with sialolithiasis may complain of moderate to intense pain when it involves the duct of a major salivary gland, particularly at mealtimes, when salivary flow is stimulated [1, 73], associated with enlargement of the gland [73].
Sialoliths are stones found within the ducts of salivary glands [1] and may be single or multiple [72, 76]. Single sialolith is more common seen [1, 79]. Figure 8 shows a panoramic radiography with a single sialolith on the right side in the submandibular gland. They measure from 1 mm to less than 1 cm [72, 74, 75]. Giant sialoliths are rare, bigger than 3.5 cm and also occur in male patients and are commonly located in the submandibular gland [74].
Digital panoramic radiography with image suggesting a single sialolith in the right submandibular gland.
According to reference [74], several factors seem to be involved in the development of salivary calculi in the submandibular gland tissues such as: the submandibular excretory duct is wider in diameter and longer than the Stensen’s duct; the secretion against gravity [74, 77]; the secretion is more alkaline compared with pH of the parotid saliva; the submandibular saliva contains a higher quantity of mucin proteins, while parotid saliva is entirely serous; then its saliva presents high calcium and phosphate content [73, 74, 77].
Initial events that contribute for the formation of a nidus that later will be the site for the precipitation of mineral salts contained in the salivary secretion include infection, inflammation, physical trauma, salivary stagnation, introduction of foreign bodies and the presence of desquamated ephitelial cells [73, 74].
The likely mechanism of sialolith formation in the sublingual gland is mechanical trauma with mucus extravasation, which serves as a nidus for stone formation [77]. In summary, the formation of a sialolith requires salivary stagnation, a nidus and a precipitation of salivary salts [75].
Depending on the sialolith size and calcification degree, it can be visible in conventional radiographs. In panoramic radiography, the calcification image may appear superimposed on the mandible; therefore, it may be mistaken by an intrabone lesion [73]. Plain film radiography demonstrates dystrophic calcifications and the possible involvement of adjcent osseous structures [1].
Panoramic radiography usually shows sialoliths in the submandibular gland if they are located in the posterior duct [1]. If calculi can not be visualized in conventional radiographs, other imaging examinations may be necessary [73]. Sialography is used to evaluate obstructive and inflammatory conditions of the ductal system. If the patient is allergic to the iodine contrast agent used in sialography, the alternative imaging examination is ultrasonography or scintilography [1].
Computed tomography or magnetic resonance imaging are appropriate if the sialography suggests the presence of a space-occupying mass [1]. According to previous investigation, panoramic radiography and CT scan estimation appeared to be somewhat closer to the surgical specimen size [75].
Sialoliths in the sublingual gland are usually round or oval shaped. However, stones in Wharton’s duct may be elongated. Parotid stones are usually smaller and more often multiple [77]. A single mass of calcification of the parotid gland with a calcification of part of its duct can be seen in the Figure 9.
Digital panoramic radiography showing a image suggesting a calcification in the right parotid gland and in its duct.
Giant sublingual sialolith was previous described as a large single calcified mass in sublingual area on panoramic radiography. Giant sublingual sialolith has already been associated with dysphagia as well as eating and speaking difficulty [76]
Sialolith is usually homogeneously radiopaque, although it can show evidence of multiple layers of calcification if large [1, 79]. Salivary stones are usually shaped by the duct and then they are elongated [77, 79]. Sialoliths are more likely localized in the Wharton’s duct (submandibular gland) than in the Stensen’s duct (parotid gland) [79]. Figure 10 shows calcifications in the submandibular and parotid glands.
Digital panoramic radiography with image suggesting calcifications in the right submandibular and parotid glands.
A previous report described 3 cases with multiple microliths in their parotid parenchyma in Sjögren’s syndrome showing panoramic radiography with many spots-like calcifications observed around the gonial angle and in the posterior part of the ramus [78]. According to previous publication, parotid calculi are frequently seen about halfway up on the ramus and may be multiple [80] as cited above. We can observe a panoramic radiography with multiple microliths in the parotid gland on both sides in the Figure 11.
Digital panoramic radiography with image suggesting multiple microliths in the parotid gland on both sides.
Although this report is about panoramic radiography, previous investigations comment about cone beam computed tomography (CBCT) and reported that for visualization of the delicate structures of the parotid and submandibular salivary glands and for identification of sialoliths and single ductal strictures, CBCT sialography may be better than plain film sialography [81]. CBCT is the preferable imaging modality for salivary calculus diagnosis considering its high diagnostic-information-to-radiation-dose ratio [82] and to show the shapes of stones more clearly [75].
Vascular malformation with phleboliths must be included in the differential diagnosis of salivary gland obstruction and magnetic resonance imaging may be able to distinguish between them, but sialography is the most effective diagnostic modality to this differentiation [79].
According to [72], sialolithiasis treatment depends on the localization of the salivary calculus [72, 73]. The sialolith should be removed via a transoral sialolithotomy avoing sialadenectomy. Intraglandular sialoliths necessitate sialadenectomy [73, 75]. Solitary sialoliths usually do not recur [72].
Phleboliths are idiopathic calcification (or calcinosis) that results from deposition of calcium in the normal tissue. This calcification results from deposition of calcium in the normal tissue, despite normal serum levels of calcium and phosphate [1]. Phleboliths are calcified thrombi found within vascular channels, often in the presence of hemangiomas or vascular malformations. They may originate from injury to a vessel wall or result from stagnation of the flow of blood [83, 84]. A case of intramuscular hemangioma was related by reference [85], where it was observed the large number of phleboliths of the tongue due to the long-term presence of hemangioma and stagnant blood flow. The authors [86], when reporting an intramuscular hemangioma also suggested that the cause of the large number of phleboliths is the long-term presence of hemangioma and stagnant blood.
The presence of vascular anomalies in the head and neck has a great importance for the professionals working in this area, since any procedure performed in this region without the due caution may trigger the onset of an emergency, as bleeding, which can lead to the patient’s death. Therefore, there is a need to conduct a thorough diagnosis in order to help in the discovery of the existence of these defects, so that such situations are avoided [87]. Those authors reviewed the charts of 108 patients with vascular anomalies and observed in 31% of the cases that the changes were in the region of the mouth and tongue, being the period of childhood and adolescence the most affected (64%).
Clinically, the vascular changes may have a swollen soft tissue, which is throbbing and with its modified coloration and some noises when auscultating [1].
A case of a patient with multiple swellings on the surface and in the mouth with a purplish coloration in intraoral examination was reported by reference [88]. Radiographic examination showed small phleboliths in the left submandibular region, and ultrasound also showed calcifications. Histological examination showed that the characteristics are originated from venous malformation. Three cases of hemangioma of the head and neck varying like the clinical characteristics presented were presented by reference [89], however some commonalities between them could be noticed as swelling, absence of pulse or noise, and two cases showed discoloration.
Phleboliths calcification starts in the center of the thrombus and consists of apatite crystals of calcium phosphate and carbonate [1]. Initially, calcification of the thrombus occurs, forming the core of the phlebolith. The fibrinous component then undergoes secondary calcification and becomes attached. Repetition of this process causes enlargement of the phlebolith [86].
Radiographically, the phlebolith features radiopaque, rounded or oval image measuring more than 6mm in diameter and uniform periphery. Internally, it can present a homogeneous radiopacity, but it commonly presents a laminated appearance with a target aspect [1]. A patient with an oral mixed mucosal and submucosal venous malformation with multiple phleboliths, which the panoramic radiograph revealed multiple round-to-oval radiopaque bodies located in the soft tissues of the left retromolar trigone. Those structures had a laminated pattern and were interpreted as phleboliths [90].
A patient presented a small mass that contained calcification in the anterior part of the masseter muscle and the plain radiograph showed a round, uniformly radiopaque lesion [91]. The same was observed by other authors [92], who reported about a patient with a masseteric intramuscular hemangioma, which other than a mild facial asymmetry, was subjectively asymptomatic. This diagnosis could not be reached without computed tomography (CT) scan that identified the presence of the calcified body confirmed by the panoramic radiograph. The patient did not exhibit the lamellated feature of a phlebolith. MRI with contrast was ordered for further evaluation and diagnosis that clearly visualized an enhanced vascular lesion within the left masseter muscle, and confirmed the presence and location of the phlebolith. However, phleboliths are not easily recognized in magnetic resonance image (MRI) film because of their very low signal intensity. They are best identified on plain radiograph and CT scan. Authors [93] observed in occlusal radiograph of a patient with vascular malformation, two oval radiopaque images, diagnosed after microscopic examination as being phlebolith.
Studies about hemangiomas and venous malformations associating imaging methods have been reported in literature aiming to improve the diagnosis of these changes and the presence of phleboliths. CT was used in 3 cases that revealed phleboliths so no other imaging was considered to be necessary [89]. Phlebolith was observed on radiography and ultrasonography of paranasal sinus [88]. Plain x-rays may also help with the diagnosis because of the typical appearance of the calcified bodies and computed tomography, magnetic ressonance, and ultrasonography are more useful for making an accurate diagnosis [91]. A case of intramuscular hemangioma and another one of vascular malformation presenting phleboliths by the use of sialography and occlusal radiographs was presented by reference [84]. Occlusal radiography and Doppler ultrasonography also were used in a case of vascular malformation [93].
The radiographic image of phlebolith can be similar to a sialolith [1]. Phleboliths are usually multiple, with oval shape, randomly located and lamellated [92]. Figure 12 shows a panoramic radiography with multiple phleboliths on the right side.
Panoramic radiography with image suggesting multiple phleboliths on the right side.
The sialoliths are frequently elliptically or elongated shaped due to the anatomic contour of the salivary duct [90, 92]. According to reference [90], sialography usually reveals a filling defect at the site of the salivary calculus, whereas phleboliths appear to be external to the duct system [90]. A case of recurrent episodes of pain and swelling in the right submandibular region was reported by reference [79]. Radiopaque images were identified in occlusal and panoramic radiographs, being diagnosed as sialoliths. The sialendoscopy was indicated and no intraductal stones were detected. A vascular network of capillaries was detected in all the ductal lumen altering the sialolithiasis diagnostic to a vascular malformation with phleboliths. The authors concluded that the vascular malformation obstructing the duct of the salivary gland is overlooked by physicians, and that phleboliths may be confounded with sialoliths.
Tonsilloliths are calcifications within a tonsillar crypt, which involve primarily the palatine tonsil caused by dystrophic calcification as a result of chronic inflammation [94]. Small concretions are not uncommon findings especially in the aged population [95], however large tonsillar concretions occur with a much lower incidence [95-98].
The prevalence of tonsilloliths (measuring above 2 mm) in 1524 patients attending the oral and maxillofacial radiology clinic of The University of Iowa was observed to be 8.14% by reference [99]. The age range of subjects was 9.2–87 years (mean 52.6 years), the average size of tonsillolith was 4mm (range: 3–11 mm), with no sex predilection.
The large tonsilloliths occur in males and females equally [98, 100], and on the fifth decade of life [100]. Tonsilloliths in children are rare and they are more common in young adults with long stories of recurrent tonsillar inflammation [98, 100].
The exact etiology and pathogenesis is unknown. Repeated episodes of inflammation may produce fibrosis at the openings of the tonsillar crypts. Bacterial and epithelial debris then accumulates within these crypts and contributes to the formation of retention cysts. Calcification occurs subsequent to the deposition of inorganic salts and the enlargement of the formed concretion takes place gradually. The tonsilloliths derive their phosphate and carbonate of lime and magnesia from saliva secreted by salivary glands [94-98, 101]. The mineral content of tonsilloliths can be composed by phosphorus, calcium, carbonate or magnesium [95].
On the panoramic radiography, tonsilloliths commonly appear as multiple, small, and ill-defined radiopacities [99]. On the other hand, other authors [94] described tonsilloliths as usually being single and unilateral, but occasionally they may be multiple or bilateral. Tonsilloliths should be the first differential diagnosis when multiple opaque lesions with ill-defined borders, which are superimposed on the palatal uvula and the ramus are detected on the panoramic radiography [94]. The radiographic appearance of tonsilloliths was predominantly multiple and well defined (62.90%) and the single, well-defined tonsillolith in a similar location constituted 28.23% in the study of reference [99]. The authors verified that the majority of the cases were located in the lower one third of the mandibular ramus (93.55%). Figures 13 and 14 shows panoramic radiographs with multiple tonsilloliths in the lower one third of the mandibular ramus on both sides.
Digital panoramic radiography with image suggesting multiple tonsilloliths in the lower one third of the mandibular ramus on both sides.
Digital panoramic radiography with image suggesting multiple tonsilloliths in the lower one third of the mandibular ramus on both sides.
Calcifications in the carotid arterial, lymph nodes, salivary gland and stylohyoid ligament are some of the differential diagnosis that might be considered [101].
On the clinical examination, it should be considered malignancy or calcified granulomatous disease such as tertiary syphilis, tuberculosis and deep fungal infection as differential diagnosis [98].
When no predisposing causes can be discovered (like chronic obstructive sialolithiasis of the salivary glands, past medical history of kidney stone), the medical history represents the most important element to recognise the tendency of some patients to develop calcifications, as in the case reported [96]. The observations in the study of [99] do not support any correlations between tonsilloliths and calcifications in other body organs, tissues, or ducts.
Patients with tonsilloliths may be asymptomatic probably when the calcifications have small size [101], and their lesions discovered incidentally on panoramic radiographs or they can present pain or soreness, dysphagia, halitosis, otalgia, infection, a foreign body-like sensation, irritable cough, difficulty in swallowing, bad/altered taste [94-96, 98-100].
Incidental findings of large tonsilloliths are reported using panoramic radiography [96, 98, 100]. The panoramic radiography helps to observe the location of opacities, but considering its two-dimensional limitations, a computed tomography or cone beam computed tomography scan is necessary to accurately position the calcifications [96, 100].
Treatment is usually removal of concretions by curettage and larger lesions may require local excision [96, 98, 99]. If there is evidence of chronic tonsillitis, tonsillectomy offers definitive therapy; however it is advisable to postpone tonsillectomy until all acute symptoms have subsided [98].
The diagnosis of tonsillar calculi, exploring their etiology, evaluating them for removal, and not dismissing them as clinically insignificant it is important because of the significant morbidity via chronic infection, pain, and/or swallowing abnormalities, with the potential of further pulmonary complications [95].
Panoramic radiograph is a radiological technique that provides an overview of the jaws and adjacent structures. Asymptomatic patients may show anatomical variations or alterations that may be randomly displayed on panoramic radiographs. These alterations may contribute to clinical complications and damage the patient’s oral and general health. Therefore, it is of utmost importance that dentists be able to recognize the evidence of these variations and alterations on panoramic radiographs and request additional examinations that provide a more accurate diagnosis. Thus, we conclude that the panoramic radiograph, within its limitations, contributes effectively to the initial diagnosis of anatomic variations and alterations, and the dental professional can identify the risks and refer their patients to a specialist.
Reactive Oxygen Species (ROS) are by-products of chemical reactions that involve a one-electron reduction of oxygen, leading to the production of a diatomic oxygen radical known as superoxide. Superoxide serves as a precursor for multiple ROS generation. The oxygen anion can be produced mainly by enzymatical or non-enzymatical means. Enzymes such as Phagocytic Nicotinamide Adenine Dinucleotide Phosphate Oxidase (NADPH Oxidase), cytochrome P450–dependent oxygenase, and the proteolytic conversion of cytosolic Xanthine dehydrogenase can produce singlet-oxygen molecules [1, 2]. The enzymatic generation of superoxide is the main generator of superoxide, especially NADPH oxidase. However, non-enzymatic generation can also cause a significant increase in reactive species. This occurs mostly in the mitochondria during ATP synthesis. The electron transport chain (ETC) has been reported to consist of centers that can leak electrons to oxygen, thereby causing a reduction of the oxygen [1]. Additionally, reduced coenzymes and prosthetic groups such as flavins and metal ions can directly transfer an electron to oxygen. The produced singlet-oxygen undergoes dismutation, catalyzed by the enzyme superoxide dismutase, to produce hydrogen peroxide, a more stable and less reactive molecule. The increased availability of ROS can lead to an imbalance between oxidants and antioxidants, resulting in a state that is known as oxidative stress [2]. During this state, the various deleterious effects of ROS such as disruption of cellular homeostasis, structures and function are manifested in the cell. Therefore, ROS overproduction has a pathological role in the development of various conditions and diseases, including inflammation and autoimmune disease.
Inflammation is a none-specific immune response of cells or tissues to a stimulus such as a pathogen, cell damage, or toxicity that plays an important role in host defense. This response involves the signaling molecules, immune cells and blood vessels. The process is marked by the proliferation of inflammatory cells like monocytes, neutrophils, and lymphocytes. These cells release various molecules such as ROS, pro-inflammatory cytokines and various enzymes that have the ability to induce oxidative stress in the target tissues [3]. Therefore, inflammation and oxidative stress can co-occur, and one process can induce the other and vice versa.
Inflammatory responses can be complex as they involve multiple interactions of many cells and mediators. There are four major patterns of inflammatory response that are also common mechanisms of diseases. These patterns depend on the type of hypersensitivity. Two or more types of hypersensitivity can occur at once in a patient.
Type 1: This type of hypersensitivity is mediated by immunoglobulin (Ig) E that is found on the surface of mast cells. The interaction between this antibody and a respective antigen causes the release of inflammation mediators such as serotonin and histamine, among others. The release of these molecules causes diminished blood pressure due to vasodilation, increased vascular endothelium permeability, and bronchoconstriction [4]. Interestingly, increased activation of mast cells can cause a systemic response that causes anaphylactic shock. Mediators that are released by mast cells can also recruit inflammatory cells such as eosinophils and increase the production of PAF, leukotrienes, prostaglandins and cytokines like TNF-α, IL-1, IL-3 and IL-5 [5]. This results in a sustained inflammatory response and reduces transient respiratory efficiency.
Type 2: This type of hypersensitivity is triggered by the binding of antibodies, IgG and IgM to the cellular antigens, causing tissue destruction. The binding of antibodies results in lysis of the cell via the in-situ fixation complement. Ig M is an effective inducer of this process [5]. Fixation of complement is an important cause of cell injury, and it can cause opsonization as well as being an active recruiter of inflammatory cells.
Type 3: This is heavily marked by serum sickness due to increased circulating immunocomplexes. The deposition of these immunocomplexes can lead to injury at the site of deposition (usually vascular beds). This is because the complexes are efficient activators of the classical pathway of the complement cascade [6]. The properties of the complexes determine which vascular bed they are deposited in. This deposition is precise and distinct in pathophysiology of different diseases such chronic autoimmune diseases such as systemic lupus erythematosus [5, 6]. Certain inflammatory responses have a confection of features of type 2 and type 3 hypersensitivity.
Type 4: This type of hypersensitivity usually takes longer to occur after antigen exposure and is also referred to as delayed-type hypersensitivity. It is typified by antigen-specific T cells activation after 24–48 hours of exposure to antigen. The antigens modify cellular proteins and these proteins are targeted by T cells. CD8+ T cells interact with the antigen presented by MHC-I and become activated [7]. This causes the T cell to kill all the cells that are presenting that antigen. Antigen-presenting cells also display antigens via the MHC-II that activates CD4+ T cells and causes the release of cytokines [5]. Activation of the two T cell activation leads to an increase in antigen-specific response, leading to hypersensitivity reaction over time. In some events, an immediate inflammatory response is initiated due to a positive response. The positive response occurs when the T cells are pre-primed as a result of prior ongoing exposure to the pathogenic antigen [6]. During this event, the interaction between the T cells and macrophages causes the release of TNF- and IFN, which are responsible for the inflammatory response. Other types of hypersensitivity responses that are triggered by cellular components of the immune system can also be referred to as type 4 even without being antigen specific (Table 1).
Type | Mediator | Components | Antigen & Antibody | Principle | Phenotype | Time/Period | Example |
---|---|---|---|---|---|---|---|
1 | IgE | Mast cells, Basophils, Histamine | Antigen: exogenous, free in circulation Antibody: fixed on mast and basophil cells | Destruction of cells via antibody mediated degranulation of granulocytes. | Weal and Flare | Early ≤3 hours | Asthma, Bee sting, Rhinitis |
2 | IgG/IgM | Neutrophils, Complement system components | Antigen: endogenous or exogenous, fixed on cells Antibody: Free in circulation | Annihilation of normal tissue cells via antibody mediated pathway. | Lysis and Necrosis | Intermediated 5–8 hour | Rhesus hemolytic disease, autoantigen-induced cell damage, Drug-induced anemia |
3 | IgG/IgM | Compliment system components, Phagocytes, Killer cells | Antigen: free in circulation, with exogenous or endogenous origin Antibody: free in circulation | Antigen–antibody complex mediated cell death | Erythema and Edema | Early - Intermediate depending on stimulant 2–8 hours | SLE, Lung arthritis, glomerulonephritis, vasculitis |
4 | CD4+ Th cells, CD8+ Tc cells | Antigen presenting cells (APC), Macrophages, Cytokines | Antigen: from exogenous or endogenous sources, soluble or fixed on cell. Antibody: none | T lymphocytes mediated cell damage | Erythema and Induration | Delayed ≥ 24 hrs from stimulation | Granuloma formation, Diabetes Mellitus, |
Summary of types of hypersensitivity.
Inflammation is triggered to eliminate harmful agents so as to minimize the effects of the injuries. However, minimal inflammation (acute inflammation) usually does not inhibit these effects and prolonged inflammation (chronic inflammation) is associated with multiple diseases and conditions [3]. Acute inflammation is known to be part of the innate immune response as it is the initial response to a stimulus. In this phase of inflammation, platelets and granulocytic cells like basophils, eosinophils and mast cells are activated. These cells migrate from the blood vessels to the site of injury and release molecules that initiate, stimulate and attenuate inflammation for a short period [8]. For this to occur, the blood vessel becomes more permeable, consequently leading to the escape of proteins, outflow of fluids known as exudate and migration of other blood cells from the vessels to the site of inflammation, causing a swelling known as edema on the site. Neutrophils are the primary cells during this phase and they tend to engulf the foreign materials and organisms together with other debris. As neutrophils are short-lived cells, they are replaced by monocytes that differentiate into macrophages [8]. The acute phase usually resolves after hours or days, or even within a week. The persistent presence of monocytic cells due to ongoing and long-term response to stimuli leads to the development of chronic inflammation.
During chronic inflammation, there is a continuous accumulation of macrophages and lymphocytes at the site of inflammation due a persistent stimulus from the immune system [9]. The prolonged inflammatory response that might last for a week, months and in some cases a lifetime, will eventually lead to tissue injury. This can be induced by viral or certain bacterial infection and in some individuals, genetic polymorphism of inflammation mediators and cell receptors can also induce and favor extensive chronic inflammation [10]. In addition to the accumulation of macrophages, chronic inflammation is also marked by the proliferation of fibroblasts and small blood vessels. In rare cases when the inflammatory response encounters an agent that is difficult to eliminate, the response proceeds to granulomatous inflammation.
Granulomatous inflammation is a specific type of chronic inflammation that is marked by the presence of crystalline materials embedded into the tissues. Macrophages are the predominant effectors and they are recruited by T cells. Th1 cells have been reported to be the major mediators of granulomatous inflammation reactions [11]. Following the activation of Th1 cells by the antigens presented on MHC-II on the macrophages, Th1 secretes IFN-γ and other cytokines. These molecules then transform macrophages into activated tissue macrophages. Although the activated macrophages have increased capacity to eliminate foreign pathogens, they have a tendency to fuse and form multinucleated giant cells which forms concentric nodules that are known as granulomas [12]. Central necrosis can develop in these granulomas. This phenomenon has have been observed in infections caused by
Although inflammation is an essential process to the host defense, it can easily induce excessive tissue damage, resulting in acute or chronic tissue damage, organ or system dysfunction with fatal outcomes. Studies have shown increasing evidence of the involvement of chronic inflammation in autoimmune diseases, including but not limited to rheumatoid arthritis (RA), inflammatory bowel disease (IBD) systemic lupus erythematosus (SLE), gout, and diabetes [14]. This happens when inflammatory activity causes the production of autoimmune molecules and reactive species that sensitizes the immune system to a non-pathogenic component of the body.
Autoimmune diseases are chronic conditions that result from the loss of immune tolerance to self-antigens, causing the immune system to attack the organisms’ healthy cells, tissues, and/or organs. Autoreactive T cells and autoantibodies are identified as the major attackers of self-antigen [15]. The differentiation and activation of these key attackers are still not fully elaborated. These disorders can be classified into two major groups, organ-specific autoimmune diseases and multiple organs or systemic autoimmune diseases. Different types of autoimmune diseases have been found to share common phenotypic features, from clinical signs and symptoms to genetic factors and pathophysiology mechanisms [16, 17, 18]. However, it is likely that some inducing factors may differ as different autoimmune diseases target different cells, organs and systems. Additionally, environmental factors also play a role in the onset of these diseases.
Factors that are common in different autoimmune diseases include but is not limited to the following features.
Pathology: The phenotypic manifestation of autoimmune varies, depending on the affected or target cell or system. However, the major pathogenic role is contributed by the phagocytic T cells and B cells. Other predominant cells include macrophages, neutrophils, and CD8+ T cells. Other cells that also contribute to the pathogenesis of autoimmune diseases are T helper cells, especially Th1, Th9 and Th17 [19]. The array of complex biological functions displayed by these cells such as cytokine production, antigen presentation, exosome release, the release of neutrophil extracellular traps (NETs), ROS, Arginase 1 and programmed death-ligand 1 have been implicated in the induction of autoreactive T cells and B cells as well as tissue damage and inflammation [20]. Abnormalities in the function of cells that participate in the classic immune response such as higher expression of IL-6, interferon-α, APRIL and BAFF can cause the dysregulation of adaptive immune cells [21]. These cells then go on to cause cell death either directly or indirectly by releasing cytokines, ROS, RNS and prostaglandins. Interestingly, specialized pro-inflammatory neutrophils with enhanced NETs and inflammatory cytokine production capacity have been found in the peripheral blood of patients suffering from different autoimmune diseases [15]. These cells have a low density due to altered buoyancy properties.
Peripheral tissues contain activated regulatory T cells that control inflammation and autoimmunity responses by eliminating malfunctioning neutrophils, lymphocytes and macrophages. Cells such as CD25+ and CD4+ T cells can secrete anti-inflammatory cytokines that can reduce Th1, Th9 and Th17 activity, thereby preventing autoimmune disease development [22]. However, their function can be inhibited by environmental agents such as pathogenic toxins or smoking.
Risk factors
Gender: Statistically women are more susceptible to autoimmune diseases than men. With nearly 5% of the total global population suffering from these diseases, 80% of the reported cases are women [23]. Pathophysiology in the progression of autoimmune diseases in women tends to be different from men and can cause polyautoimmunity. Factors that contribute to this are differences in hormonal orientation and genetic factors [24]. High levels of estrogen, progesterone and prolactin have been implicated in the development of autoimmune diseases.
Age: Diseases like systemic lupus erythematosus (SLE) and type1 diabetes mellitus tend to have a high severity when the onset is early [25]. However, other autoimmune diseases are not influenced by the time of onset, e.g. rheumatoid arthritis and Sjogren’s syndrome.
Environmental agents: One of the most crucial environmental autoimmunity triggers is infectious agents. Viruses like the Epstein–Barr virus and cytomegalovirus have been implicated in multiple autoimmune inductions [26]. However certain viruses like the hepatitis B virus have the putative ability to protect against autoimmune disease development.
Genetics: The genetic risk factors of autoimmune diseases can be divided into two groups, the common factors and the specific factors. Autoimmune phenotype is determined by a combination of common and disease-specific alleles interacting with environmental and epigenetic factors [27]. Autoimmune phenotypes have also been confirmed to be the outcomes of nonspecific diseases genes [28]. Additionally, genetic ancestry can also influence the heterogeneity and variation of the clinical manifestation disease [29]. Certain population subgroups and races have been associated with having a relatively high frequency of autoimmune diseases risk alleles. However, genetic risk factors only confer a small risk and can only explain a limited proportion of heritability in relation to autoimmune diseases [30]. Investigated population and additive and non-additive factors should be considered when assessing heritability in autoimmunity.
Other autoimmune conditions: People with a history of autoimmunity or who have an existing autoimmune infection are at higher risks of developing another autoimmune disease [31]. Diverse manifestation of disease phenotype originating from the same gene causes a condition known as polyautoimmunity [17]. The coexistence of more than two autoimmune diseases in a patient leads to a syndrome known as multiple autoimmune syndromes (MAS). MAS is known to favor the pathogenesis of other autoimmune diseases. Dermatological autoimmune disease is present in most MAS. Aside the existence of other autoimmune conditions, the development of MAS is associated with genetic, immunologic, infectious, and psychological factors.
Subphenotype: Signs and symptoms of autoimmunity are shared across a wide range of autoimmune diseases. Symptoms such as fatigue, dizziness, arthritis, alopecia, and Raynaud’s phenomenon and high levels of cytokines are common in most autoimmune diseases [32]. However, these diseases can have a heterogeneous spectrum if the disease course is dependent on the patient. Additionally, the disease phases differ from one patient to another and even within the same patient [33]. This can increase the challenge in acquiring a better understanding of autoimmune diseases because although subphenotypes are similar, they can change depending on the diseases activity and duration [34].
Recurrence risk: Complex diseases such as autoimmune diseases tend to cause phenotype clusters in the family of the infected individual. This aggregation usually occurs in a higher frequency than what is observed in the general population [29]. The presence of different autoimmune diseases in the members of the nuclear family is known as familial autoimmunity. When a specific autoimmune disease occurs in the family, it is known as familial autoimmune diseases [18]. Familial autoimmunity is common than a familial autoimmune disease (Figure 1).
Development of autoimmune disease. Following the generation and maturation of immune cells in the bone marrow and thymus, the cells undergo a series of processes to produce immuno tolerant cells. A small number of T and B cells evade this process and form autoreactive T and B cells. However these cells are harmless until acted upon by genetic or environmental factors autoantibody can trigger autoimmunity for long term.
Production of ROS in phagocytic cells during the oxidative burst is essential to the elimination of pathogens during an immune response. However, it is also connected with the promotion of inflammation and tissue damage. Interestingly, recent studies have demonstrated that phagocyte derived ROS plays a role in the regulation of inflammation as well as providing protection against autoimmunity. This is mainly because chronic inflammation in multiple pathologic conditions has been associated with ROS deficiency.
The activation of the oxidative burst is highly marked by increased uptake of oxygen in the neutrophils. The consumed oxygen is primarily converted to singlet-oxygen molecules. This leads to an increase of the membrane-permeable hydrogen peroxide due to elevated dismutation activity within the phagocytes. This initiates the generation of various radical and non-radical ROS molecules via the activity of myeloperoxidase. In the events of oxidative burst, the NADPH oxidase complexes serve as one of the major generators of ROS but the localization and timing of the products depend on the stimulus [35]. Despite the localization and efficiency of ROS production, a high concentration of the molecules has been reported to cause the inactivation of proteins and enzymes via the adduct formation due to lipid peroxidation products [36]. Among the enzymes that are inactivated by this mechanism is NOX2, a potent producer of superoxide molecules. To counter this inhibition, phagocytic cells recruit cytochrome-b558 from the lysosomal pool via the soluble NSF attachment receptor 23 (SNARE) [37]. This enables the continuous production of ROS even after the inactivation of NOX2. This mechanism ensures the efficient eradication of pathogens and has been reported to potentially play a vital role in the regulation of autoimmunity [38]. The failure to move the NOX2 to the endosomes due to decreased Ncf4 expression in phagocytic cells can cause autoimmune responses but without the elimination of pathogenic molecules. Notably, increased activity of NOX2 is known to cause the destruction of membranes because of lipid peroxidation and this results in the leakage of the endosome contents such as antigens [39]. This process allows the presentation as well as cross-presentation of antigens to MHC-I. ROS production is therefore essential for the eradication of intracellular pathogens [39, 40].
Some evidence of the role of ROS in the maturation of dendritic cells and the increased expression of MHC-II molecules has been proposed, however, this is met with conflicting research results that NOX2-ROS production does not play a role in the maturation, differentiation and production of cytokines. This is despite its important role in the elimination of intracellular foreign stimuli. Nevertheless, ROS enables regulated presentation of antigen by MHC-II via the oxidation of cathepsin cysteinyl thiols which prevents excessive protein degradation in early phagosomes. Intracellular foreign pathogen infections such as bacterial and fungal infections have been reported to be persistent in conditions where NOX2 activity is lacking [41]. NOX2 is also involved in backup mechanisms of pathogen capturing such as the formation of neutrophil extracellular traps (NETs) [42]. NETs are mainly composed of chromatin coated in antimicrobial peptides and proteases. During NETs formation, ROS are required for the release of elastase while myeloperoxidase participates in the formation of azurophilic neutrophils granules that facilitate histone degradation in the nucleus [42].
Oxidative damage caused by ROS can generate deleterious byproducts consisting mainly of proteins and lipids that are modified into peroxides. These molecules play important roles in the pathogenesis of several diseases. These molecules have also been implicated in the pathophysiology of cell death and tissue damage. Some of these have the ability to cause immunogenic reactions by inducing pathogenic antibody release in diseases such as systemic lupus erythematous, alcoholic liver disease, diabetes mellitus, inflammation, degenerative diseases, and rheumatoid arthritis. Aldehydic by-products that form adducts with proteins make up two-thirds of molecules that have been implicated in these conditions.
Stress-induced by ROS or any other factor compromises the antioxidant activity within a cell can lead leading to an imbalance in the pro-oxidant/antioxidant balance. The prevalence of this phenomenon has been shown to increase lipid peroxidation. Lipid peroxidation is the degeneration of polyunsaturated fatty acids by free radical activity. The process involves three steps: initiation, propagation and termination. In the first step, a reactive radical extracts a hydrogen molecule from the methylene group. This leaves an unpaired electron on the carbon that combines with molecular oxygen in the propagation phase which then forms reactive peroxyl radicals that react with other lipids thereby forming hydroperoxides. Notably, peroxyl can produce fatty acid radicals and this can cause a chain reaction that causes lipid peroxide toxicity. Lipid peroxidation can also be induced by incidences of exacerbated conjugated dienes, 4-hydroxyl-2-nonenal modified proteins, malondialdehyde modified proteins and 4-hydroxynonenal among other molecules. Products of lipid peroxidation such as 4-hydroxy-2-alkenals can form the an adduct with the amino groups of proteins, leading to ROS induced protein modification. Modified proteins that gain the function of an aldehyde are highly immunogenic. ROS-induced lipid peroxidation and protein modification are likely to co-occur, and the two processes can mutually induce each other. Some products of these processes can avidly react with antioxidants including glutathione and cofactors of ketoglutarate dehydrogenase causing further damage to the antioxidant response.
Lipid peroxides are not bystanders when it comes to the destruction of cellular membranes, cell-matrix and the accelerators in the development of conditions such as atherosclerosis in arthritis especially rheumatoid arthritis. The destruction of the cell membrane can cause the leakage of cellular content, thereby inducing an inflammatory response as the phagocytic cells attempt to clean the debris. The process of debris clearance can percussively cause tissue damage. During this process two sets of macrophages are activated, the first set is M1 which is classically activated, and the second set is M2, which is alternatively activated. M1 is known for excessive production of toxic production which M2 tries to resolve by producing molecules like EVG and VEGF. The difference in function is made vivid by the distinction in the cytokine profile of the two sets. M1 releases excessive proinflammatory cytokines IL1, IL6 and ROS which ultimately causes cell death by activating death receptors and/or caspases. M2 on the other hand releases anti-inflammatory cytokines like IL-4 and IL-10. In situations that lead to excessive tissue injury, there is little to no anti-inflammatory response as compared to proinflammatory. Aside from this, oxidation of low-density lipoproteins can cause the upregulation of chemokines, adhesion molecules and glycan end-products, thereby inducing an increased inflammatory response. Inflammation in the presence of oxidative stress is known to result in the nonenzymatic degradation of proteins through glycoxidation. Glycoxidation of immunoglobins produces modified immunoglobins which can induce a systemic inflammatory response. Neo-epitopes created by protein modifications can be recognized by toll-like receptor-4, advanced glycan end-product receptors, and scavenger receptors as invasive and can induce pathogen-associated molecular patterns in the immune system that will ultimately lead to autoimmunity. Additionally, there is a correlation between ROS-altered biomolecules and the severity score of autoimmune and inflammatory diseases.
SLE is a complex autoimmune disease that affects at least 0.04% - 0.2% of every 100,000 people. The disease has a high prevalence in childbearing age women. This disease is marked by the increased presence of autoantibodies that target nuclear components and inflammation. This usually occurs in organs like the lungs, kidney, and joints. Although the exact cause of SLE remains not fully understood, a genetic predisposition that promotes the formation of lupus has been purported. Additionally, single nucleotide polymorphism in the Ncf2 gene that causes reduced ROS production is known to increase the likelihood of SLE occurrence. The promoting role of ROS deficiency in lupus-like phenotype has been demonstrated in mice where mutation of the Ncf1 shows high levels of anti-DNA, anti-histone, and anti-RNA antibodies with elevated deposits of Ig G and complement C3 in the glomeruli [43]. This contributes to the development of clinical signs of Arthritis, lung hemorrhage and enhanced glomerulonephritis. Increased risk of atherosclerosis is another feature of SLE. Atherosclerosis is developed due to endothelial dysfunction which is linked to a diminished bioavailability of nitric oxide and an increased generation of ROS. Studies in lupus-prone mice have shown increased activity of NADPH oxidase coupled with elevated systolic blood pressure and renal disease, a typical symptom of lupus [44]. ROS in SLE can play a double role depending on the stage of the disease. On one hand, it can be essential in the prevention of autoimmune diseases during the early stage, but it may exacerbate damage during the late stage of the disease.
Type 1 diabetes is a metabolic disease that results from the dysregulation of insulin due to the autoimmune destruction of β-cells in the pancreas. The disease emerges at an early age and is manifested as high levels of blood sugar. The hyperglycemia-induced onset of diabetes has been linked to excessive oxidative stress damage. Mouse model-based experiments have demonstrated that ROS plays a key role in disease development of the disease [45]. For example, non-obese diabetic mice that produce is prone to type1 diabetes, contrary to their ROS deficient counterparts [46]. Reducing the ROS levels is known to help in transforming macrophages to M2 phenotype. Unlike M1, M2 is not a proinflammatory phenotype and does not cause diabetes mellitus. Cells taken from diabetic patients have been found to exhibit increased production of singlet oxygen molecules and a depletion of antioxidants or loss of antioxidant enzymes activity. Hyperglycemia coupled with oxidative stress can lead to macromolecule damage such as protein damage, DNA, and lipids. Islet β-cells are highly susceptible to this damage, which displaces the activation of signaling pathways [47].
Rheumatoid arthritis is an autoimmune and inflammatory disorder characterized by persistent joint inflammation, which can result in the production of autoantibodies, destruction of the bone and cartilage at the site of inflammation. Mutations in the genes that encode components involved in oxidative stress have been found to play a role in the progression of rheumatoid arthritis. By using murine-induced arthritis, pristine-induced arthritis (PIA), gene regions that are involved in the regulation of different phases of the disease and its severity have been identified using mouse models [48]. The loss of NOX2 function due to polymorphism of the
The protective role of ROS in rheumatoid arthritis seems to oppose its destructive role in joint inflammation. During arthritic inflammation, reactive species can exacerbate inflammation while contributing to tissue damage via collagen degradation. Overproduction of ROS is also known to cause cartilage degradation in osteoarthritis. This is achieved by inducing apoptosis in the chondrocytes, cells that are essential for the formation and function of the cartilage [50]. The prevalence of ROS coupled with inflammation causes the disruption of tissue homeostasis and depletion of antioxidants. Hydrogen peroxide and hydroxyl species react with membrane lipids, causing lipid peroxidation and promoting cartilage degeneration while inhibiting self-repair [51]. Cartilage degeneration is achieved by affecting the structures of the structural proteins found on the joint, such as collagen and proteoglycan, causing the chondrocytes to enter the stage of senescence or cell death, which can eventually lead to subchondral sclerosis and meniscal and ligament damage. ROS and inflammatory cells are contained in the synovial fluid in the joint. Their intense activity not only causes the thinning of the proteoglycan layer and collagen fiber but can also cause functional impotence to the DNA mismatch repair system. This activates the NF-kB and the overproduction of metalloproteinase and DNA adducts such as 8-oxo-hydroxy-7,8-dihydro-2′-deoxyguanosine there by contributing to DNA damage and cell arrest. With reduced antioxidant activity, arthritis progression is favored.
Chronic granulomatous disease (CGD) also known as Bridges-Good or Quie syndrome is a rare inheritable immunodeficiency disorder that affects phagocytes such as neutrophils, monocytes and macrophages. These phagocytes lose their capability to form reactive oxygen compounds such as superoxides, and their capability to eliminate invasive pathogens will therefore, become greatly reduced. CGD is characterized by recurrent bacterial or fungal infection and other dysregulated inflammatory responses, leading to the formation of granulomatous and development of other inflammatory disorders such as colitis. Clinical manifestation of CGD includes pneumonia, adenitis, subcutaneous and hepatic cellulitis, lymphadenitis, osteomyelitis, and sepsis. Clinical studies have also shown the involvement of the genitourinary system and gastrointestinal tract in granulomas [52]. CGD is caused by a reduction in ROS production due to defective activity of the NADPH complex’s NOX2. The defect is a result of mutations in the NOX2 catalytic subunit gene gp91phox. About 70% of all reported CGD cases are found in males and they are X-linked. Mutations in the Ncf1 and Ncf2 which are recessive autosomal inherited account for a large number of cases [53]. These mutations can cause reduced ROS production and disable the ability to form NETs, leading to reduced efficiency in pathogen elimination. Interestingly, CGD patients have reduced long term memory immunity. A reduced long term memory in CGD patients and mice may can be due to the relation between the number of neutrophils, NOX2 normal activity and percentage of memory B cells. ROS is known to directly influence the process of memory B cells, and hence a loss of function of NOX2 will reduce this process. Contrary to a reduced number of memory B cells, Cd19+ B cells and immature Ig, the D + CD27- B cells availability increases in patients [54]. ROS also plays a role in the activation and proliferation of B cells. According to
In septic patients, the loss of redox balance is usually the common cause of severe inflammatory response syndrome. The inflammation is caused by the reactive species from neutrophils and macrophages. The inflammation phase of the disease is marked by reduced mitochondrial ATP synthesis and continuous uptake of antioxidants by affected cells. The antioxidants aim to fight the deleterious activity of ROS and RNS such as reversible and irreversible oxidative modifications of nucleic acids, lipids, and proteins. The oxidative modification of complex lipids of the mitochondrial inner membrane such as cardiolipin worsens the mitochondrial dysfunction by causing the release of cytochrome c [56, 57]. This causes further reduction of ATP synthesis while elevating the production of reactive species. Excessive and persistent ROS in turn inhibits the translocation of Nrf2, which jeopardizes the antioxidant response mechanism.
Psoriasis is an immune-mediated chronic inflammatory skin disease that speeds up the growth cycle of skin cells. The disease comprises numerous comorbidities and the multifactorial etiology of cardiovascular diseases, metabolic syndrome, and type 2 diabetes [58]. The pathogenesis of psoriasis is heavily marked by oxidative stress. However, ROS is reported to have protective effects in psoriasis. In mice models with induced psoriasis, elevated levels of ROS will increase the functionality of T regulator cells as well as the expression of indoleamine 2,3-dioxygenase. Increased functionality of T regulator cells results in the reduction of circulating Th17 cells [20]. The protective effects of ROS are further supported by evidence showing the exacerbation of Psoriasis in Ncf1 mutated mice [59]. This suggests that the normal functionality of NOX2 plays a role in the attenuation of psoriasis.
Gout is one of the most understood and manageable systemic rheumatoid diseases. It is a disorder of purine metabolism that results in the formation of monosodium urate crystals that are deposited in and around the joints. This is mostly due to longstanding hyperuricemia. The urate crystals can induce the release of inflammatory cytokines from monocytes and neutrophils, which cause immense inflammation [60]. The onset of gout attack can last for at most 10 days and then disappear, but the crystals remain present in the joint area. These crystals can induce the formation of large NETs aggregates that end up trapping and degrading the pro-inflammatory mediators. This in turn will limit and resolve the inflammation [61]. The formation of NETs in gout is dependent on the availability of ROS, and a deficiency in ROS can result in a chronic state for the disease. Therefore, a functional oxidative burst is critical for the maintenance of immune tolerance and the resolution of inflammation in gout.
The effects of ROSs autoimmunity appears to be more complicated than previously anticipated. ROS is thought to be solely a by-product of the process involved in the cellular response to inflammation or infectious stimuli. However, recent findings have attributed ROS to have vital roles in cellular regulatory and inflammation restraining processes. As their role in numerous cell functions is elaborated, it is now understood that these functions cannot occur without the presence of ROSs. Despite this, the tissue, cell type and time point on which ROS act as anti-inflammatory and immunoregulators are not yet elucidated.
The deficiency of NOX2 has been found to play a key role in the induction of multiple autoimmunity conditions. This is true even in severe bacterial and fungal infections. Inflammatory and autoimmune diseases such as Corhn-like inflammatory disease, idiopathic arthritis and CGD can co-occur. Animal model experiments as well as genome-wide studies have shown a relationship between the polymorphism of Ncf1 and the occurrence of many arthritic diseases [62]. Ncf1 is a cytosolic subunit of NOX2 whose polymorphism signifies diminished production of superoxide. Mutation in the Ncf1 gene which results in loss of NOX2 function has been reported to increase susceptibility to T cell autoreactive activation, cartilage oligomeric matric protein-induced arthritis, and collagen-induced arthritis among others [28]. Additionally, NOX2 derived ROS have been found to have regulatory roles in T-cell dependent nervous system diseases such as multiple sclerosis and Guillan-barre syndrome. Interestingly, NOX2 is also a regulator of autoantibody production and autoimmune inflammation. Therefore, NOX2 activity, especially ROS generation has a crucial preventative effect on the development of autoimmunity and can regulate chronic inflammation [63]. However, it is important that NOX2 is viewed not as a regulator of disease susceptibility but as a regulator of disease severity.
The protective role of ROS in inflammatory and autoimmunity is not universal. In type 1 diabetes, ROS deficiency is associated with safeguarding from diseases, especially in non-obese diabetic animal model. Thayer et al. reported the essential role of macrophage ROS in mediating effector function for CD4+ T cells autoreactivity and autoimmune diabetes pathogenesis [64]. NOX2 generated ROS is also vital in the execution of islet reactivity. However, mutations in the Ncf1 gene which eventually leads to NOX2 malfunction and reduced ROS availability has been found to significantly alter the effector function of macrophages and T-cell subsets [43]. Additionally, collagen antibody transfer which develops independently of phagocytic immune cells can induce arthritis. This phenomenon can be exacerbated by an increase of Ncf1 gene expression. Furthermore, non-classical autoimmune diseases such as monosodium urate crystal-induced inflammation and zymosan show signs of increased inflammation even in the absence of NOX2 and ROS [41, 63]. This shows that certain cases ROS deficiency can be linked to the protection against disease.
The development of autoimmunity is defied by a wide range of mechanisms, regulatory cells and tolerance mechanism, which when not properly functioning or are inefficient, fail to decelerate the effects of the interplay of environmental, genetic, and immunological factors. Faults in the immune tolerance mechanism consequentially leads to inappropriate cell death or survival or failure to clear debris which are involved in the pathogenesis of autoimmune diseases. The failure of these systems and the eventual development of autoimmune diseases is aided by inflammatory modulators. Interestingly, this process occurs before the full development of diseases, making the modulators a potential therapeutic target. As such, they can also be used as control points to prevent the exacerbation of the autoimmune diseases. Targeting inflammatory modulators can, therefore, offer opportunities for the development of novel diagnostic methods and effective therapy in the future.
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He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",institutionURL:null,country:{name:"Canada"}}}]}]},openForSubmissionBooks:{paginationCount:3,paginationItems:[{id:"11580",title:"Recent Advances in Canine Medicine",coverURL:"https://cdn.intechopen.com/books/images_new/11580.jpg",hash:"1806716f60b9be14fc05682c4a912b41",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"March 23rd 2022",isOpenForSubmission:!0,editors:[{id:"258334",title:"Dr.",name:"Carlos Eduardo",surname:"Fonseca-Alves",slug:"carlos-eduardo-fonseca-alves",fullName:"Carlos Eduardo Fonseca-Alves"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"11579",title:"Animal Welfare - New Insights",coverURL:"https://cdn.intechopen.com/books/images_new/11579.jpg",hash:"12e4f41264cbe99028655e5463fa941a",secondStepPassed:!1,currentStepOfPublishingProcess:2,submissionDeadline:"June 1st 2022",isOpenForSubmission:!0,editors:[{id:"51520",title:"Dr.",name:"Shao-Wen",surname:"Hung",slug:"shao-wen-hung",fullName:"Shao-Wen Hung"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"11578",title:"Antibiotics and Probiotics in Animal Food - Impact and Regulation",coverURL:"https://cdn.intechopen.com/books/images_new/11578.jpg",hash:"3731c009f474c6ed4293f348ca7b27ac",secondStepPassed:!1,currentStepOfPublishingProcess:2,submissionDeadline:"June 3rd 2022",isOpenForSubmission:!0,editors:[{id:"225390",title:"Dr.",name:"Asghar Ali",surname:"Kamboh",slug:"asghar-ali-kamboh",fullName:"Asghar Ali Kamboh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},onlineFirstChapters:{paginationCount:1,paginationItems:[{id:"81831",title:"Deep Network Model and Regression Analysis using OLS Method for Predicting Lung Vital Capacity",doi:"10.5772/intechopen.104737",signatures:"Harun Sümbül",slug:"deep-network-model-and-regression-analysis-using-ols-method-for-predicting-lung-vital-capacity",totalDownloads:0,totalCrossrefCites:null,totalDimensionsCites:0,authors:null,book:{title:"Decision Science - Recent Advances and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/11604.jpg",subseries:{id:"86",title:"Business and Management"}}}]},subseriesFiltersForOFChapters:[{caption:"Business and Management",value:86,count:1,group:"subseries"}],publishedBooks:{paginationCount:1,paginationItems:[{type:"book",id:"11392",title:"Leadership in a Changing World",subtitle:"A Multidimensional Perspective",coverURL:"https://cdn.intechopen.com/books/images_new/11392.jpg",slug:"leadership-in-a-changing-world-a-multidimensional-perspective",publishedDate:"May 11th 2022",editedByType:"Edited by",bookSignature:"Muhammad Mohiuddin, Bilal Khalid, Md. Samim Al Azad and Slimane Ed-dafali",hash:"86a6d33cf601587e591064ce92effc02",volumeInSeries:1,fullTitle:"Leadership in a Changing World - A Multidimensional Perspective",editors:[{id:"418514",title:"Dr.",name:"Muhammad",middleName:null,surname:"Mohiuddin",slug:"muhammad-mohiuddin",fullName:"Muhammad Mohiuddin",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038UqSfQAK/Profile_Picture_2022-05-13T10:39:03.jpg",institutionString:null,institution:{name:"Université Laval",institutionURL:null,country:{name:"Canada"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Business and Management",value:86,count:1}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:1}],authors:{paginationCount:249,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, Kuwait. His research interests include optimization, computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, and intelligent systems. Prof. Sarfraz has been a keynote/invited speaker at various platforms around the globe. He has advised/supervised more than 110 students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He has authored and/or edited around seventy books. Prof. Sarfraz is a member of various professional societies. He is a chair and member of international advisory committees and organizing committees of numerous international conferences. He is also an editor and editor in chief for 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:"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:"Beijing University of Technology",institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"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:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRZkkQAG/Profile_Picture_2022-05-09T12:55:18.jpg",biography:null,institutionString:null,institution:null},{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:"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"}}},{id:"147824",title:"Mr.",name:"Pablo",middleName:null,surname:"Revuelta Sanz",slug:"pablo-revuelta-sanz",fullName:"Pablo Revuelta Sanz",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:"12",type:"subseries",title:"Human Physiology",keywords:"Anatomy, Cells, Organs, Systems, Homeostasis, Functions",scope:"Human physiology is the scientific exploration of the various functions (physical, biochemical, and mechanical properties) of humans, their organs, and their constituent cells. The endocrine and nervous systems play important roles in maintaining homeostasis in the human body. Integration, which is the biological basis of physiology, is achieved through communication between the many overlapping functions of the human body's systems, which takes place through electrical and chemical means. Much of the basis of our knowledge of human physiology has been provided by animal experiments. Because of the close relationship between structure and function, studies in human physiology and anatomy seek to understand the mechanisms that help the human body function. 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His interest later turned to the molecular mechanism and attenuating strategy of sarcopenia (age-related muscle atrophy). His opinion is to attenuate sarcopenia by improving autophagic defects using nutrient- and pharmaceutical-based treatments.",institutionString:null,institution:{name:"Tokyo Institute of Technology",institutionURL:null,country:{name:"Japan"}}},editorTwo:null,editorThree:{id:"331519",title:"Dr.",name:"Kotomi",middleName:null,surname:"Sakai",slug:"kotomi-sakai",fullName:"Kotomi Sakai",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000031QtFXQA0/Profile_Picture_1637053227318",biography:"Senior researcher Kotomi Sakai, Ph.D., MPH, works at the Research Organization of Science and Technology in Ritsumeikan University. She is a researcher in the geriatric rehabilitation and public health field. She received Ph.D. from Nihon University and MPH from St.Luke’s International University. 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In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. 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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. 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