\r\n\tThe formation and development of seagrass meadows take many years. Among all the plant habitats in the world, the most carbon storage feature belongs to seagrass with 2000 tons/ha. Posidonia oceanica is the most important seagrass species for primary production and is endemic to the Mediterranean. This species is a perennial herb that spreads to a depth of 45 meters on the Mediterranean coast and can live up to 30 years. Their presence is indicative of clean seas.
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1. Introduction
\n
Social relationships represent a very important dimension during adolescence [1]; for this reason social withdrawal is an actual phenomenon that needs to be examined in detail. As very little is known about it, the risk that may contribute to the formation of a mental health disease may be ignored. Additionally, it is critical to remember that social withdrawal may also occur as a complication of an existing mental health disorder. Social withdrawal is defined as the lack of social relations with one’s family and friends. This situation may create very important damages in interpersonal relations and social relations at an individual level and that may affect the society in general. Barzeva et al. [2] in line with Rubin et al. [3] report that it is “an umbrella term referring to an individual’s voluntary self-isolation from familiar and/or unfamiliar others through the consistent display of solitary behaviors such as shyness, spending excessive time alone, and avoiding peer interaction.”
\n
The intensive use of the Internet or video games is also associated with social withdrawal. This may be indicative of a form of adaptation of social isolation, but it becomes a real addiction. The use of interactive media for games is very frequent among adolescents, and is increasingly on the rise [4, 5]. It is estimated that the number of teenagers using smartphones have rapidly increased in recent years, the percentage has gone from 73 to 95% in the last 4 years. In particular, the use is associated with video games and the use of social media such as YouTube (85%), Instagram (72%), and Snapchat (69%) [4, 5].
\n
The frequency of Internet addiction that has been estimated in various countries is very different in Western and Asian cultures with respect to social norms and the culture of using social media [6, 7], varying from 0.8% in Italy to 14% in China and from 12% and up to 26.7% in Hong Kong.
\n
\n\n
2. Social withdrawal
\n
In recent years, a new social phenomenon has been observed. Many adolescents voluntarily isolate themselves by withdrawing, and become recluses in their families, and in their social environment. Until 2008, this manifestation was considered as a symptom of other psychopathological situations in DSM-IV * (Statistical diagnostic manual of mental disorders) [8, 9] such as psychosis. Although this state of social withdrawal leads to such a serious consequence in adults, the adolescents who show a social withdrawal do not meet the criteria for a diagnosis.
\n
The phenomenon of well-known social withdrawal in Japan is called Hikikomori, a term coined by a psychiatrist, Saito. Saito [10, 11] described Hikikomori as withdrawing from contact with family, having almost no friends, and not attending school for adolescents. Beginning from late 1970s, Hikikomori has been a silent epidemic among teens and young adults in Japan. Currently, Japanese scholars differentiate the phenomenon of Hikikomori from social withdrawal as being as a consequence of a psychiatric psychopathology that occurs together with the diagnosis of depression, personality disorder, anxiety disorder etc. Social withdrawal and the difficulty in creating social relationships do not manifest themselves as a primary symptom but do not meet the criteria of diagnostic labels so far theorized by international psychiatry [12]. To overcome this diagnostic gap, the Japanese Ministry of Health created guidelines in 2003 to help identify the Hikikomori phenomenon, by establishing the presence of certain criteria:
home-confined lifestyle;
lack of motivation to attend school or work;
absence of criteria for the other psychiatric diagnoses such as agoraphobia, schizophrenia, etc.
duration of symptoms more than 6 months.
\n\n
The phenomenon of social withdrawal in Italy has been handled from a different perspective than that of the Japanese Hikikomori. Initially, the attention to adolescent withdrawal was addressed as a consequence of the even more extensive phenomenon of Internet addiction. For example, in Italian literature [13], Internet users differ in their action: (a) those who use the Web to achieve economic, relational, or social success and are the socially overexposed and (b) Internet addicts who use the Web to escape from anxieties and depressive experiences. The latter are social retreats.
\n
\n\n
3. Social withdrawal: the symptom of a block in the growth process
\n
Berne [14] defines the script as: “A life plan bases on a decision taken during childhood, reinforced by parents, justified by subsequent events, and culminating in a final choice.” During childhood, each child creates a script of life that becomes the supporting structure of the identity with which the person gives form and meaning to himself and to the world [14]. In his life script, the child will insert the expectations, injunctions, and thrusts that come from the most important attachment figures. The injunctions are the limits that the person perceives in childhood from the attitudes of the parental figures who exercise restrictions in being able to freely express themselves. The pushes, also called orders, are prescriptive commands, insistent, that the parental figures send verbally to their children. Current families are often composed of a single child; it may happen that parents pour out numerous projections and expectations in the line of “being perfect” and they push the child to try desperately. Thus the child is required to be precise in everything he does; in school and in relationships, inaccuracies are not tolerated. These inducing attitudes may be accompanied by injunctive messages sent by parents during childhood. The cognitive structures of parents, often formed before the birth of the baby, are too full of fantasies and expectations that they unwittingly create a deep predisposition to make things go wrong. These parental messages may generate feelings of shame. Shame is an emotion of a relational nature in which the person oscillates between the desire to be admired by the other and the fear of failing, between the desire to be accepted and the feeling of being excluded [15]. Sometimes shame may become a process of protection to avoid feeling the emotions of humiliation and vulnerability linked to the loss of the relationship with the other. Shame may lead to a denial of anger to allow the child/adolescent to keep the relationship with the person who carried out the humiliating transactions. When anger is denied, an important need of the person is lost, that of being taken seriously, with respect, and being important to others. Self-esteem may remain extremely compromised. The emotions of sadness and fear are also hidden in the feeling of shame. Some examples may be the sadness of not being accepted, with one’s needs, desires and behaviors and the fear of being abandoned, of losing the relationship with the other because of what one is [16]. During puberty, the antiscript is experienced [14]; the exact opposite of the Life script that the child together with the parents and the environment was built during the first years. Experiencing the opposite is a healthy strategy to try and find the right balance between extremes. But it may happen that the boy in this attempt to experience his tolerance or his possibilities of decision arrives at extreme behaviors, such as solitude and isolation [17]. From the existential crisis, the boy can find new ideas about his identity or he may get stuck in the copycat decisions made in childhood. In scripts where parental injunctions have unwittingly created a strong feeling of shame, it may happen that the child considers his body and his abilities to face the world to be unsuitable. All the expectations that parents and the child had built in childhood collapse. This transactional analytical perspective agrees with other psychological theories in which therapeutic work with the child is considered necessary to help him in the long work of building an identity capable of tolerating confrontation with others.
\n
\n\n
4. Social withdrawal in Italy
\n
In recent years, a new social phenomenon has been observed in Italy. Unlike the first Japanese Hikikomori who adopted a lifestyle of social exclusion long before the arrival of the Internet, in Italy, social withdrawal has been studied as a consequence of Internet addiction because this condition is often accompanied by the use and abuse of the network. This is the obvious symptom that alarms parents and forces them to ask for help. Therefore, the abuse of the network was studied as a cause of social withdrawal initially. Currently, scholars claim that the abuse of the Internet is linked to social withdrawal as a strategy to survive an extreme lifestyle. The use of the Internet as well as allowing access to information allows the symbolization of the world through the construction of avatars and role-playing games and allows a protected relationship with others, in which it is not necessary to use the body, for example in online games [18].
\n
Living virtually allows being in relationships with others maintaining the considered right distance by secluded teenager, which allows them to keep away the feeling of anxiety and the sense of inadequacy that comes from inter-relational confrontation [19]. Two important components need to be considered: the age of onset of seclusion and gender. The debut usually takes place in two timelines that coincide with two important changes in the life of the students: the first is the passage in the secondary school between the first degree (middle school) and the second degree (high school); the second delicate passage occurs at the end of high school with a leap into the university world. Depending on the time of onset, the setting and the therapeutic work change. Dealing with the gender components, social withdrawal appears predominantly as a male symptomatology. It seems that the two disorders are complementary, even though in recent years the cases of male anorexia and female social withdrawal are increasingly widespread [19].
\n
\n\n
5. Reactivate the growth process: interdisciplinary intervention
\n
Taking charge of the withdrawn social adolescent requires special attention given the complexity of the phenomenon. Currently, there are no guidelines shared by the different theoretical approaches, as is the case for other clinical pictures such as attempted suicide and anorexia. The point on which the different approaches converge is that the treatment of social withdrawal consists in a global management of the adolescent’s life context and that it is necessary to work on the relational emptiness that the boy has created around him. If on the one hand, the secluded teenager tends to eliminate and abandon relationships and spaces of movement, the parents try to create, expand, and add both physical and mental space, respecting the boy’s timing and propensity to change [20].
\n
In Italy, there are public and private services such as associations, cooperatives, foundations, and various types of organizations that deal with socially isolated adolescents. The interventions for social withdrawal cases in Italy vary. Despite the diversity of approach, generally an open intervention is addressed both to the boy and the context. The family is invited, then the detailed anamnesis is taken including not only the parents but also other significant persons in the family environment. The sessions are carried out by psychotherapists, in some cases the collaboration with a neuropsychiatrist to foresee and to exclude possible psychopathologies or to place side by side, if necessary, a pharmacological cure. Professional educators within the multi-professional team are those who perform home interventions in the most extreme situations in which significant social isolation makes an intervention outside the family setting impossible.
\n
\n\n
6. An Italian example of clinical intervention
\n
Different kinds of interventions vary depending on the theoretical approach and the different tools available including public and private practices in Italy. One of the consolidated interventions is implemented in a private clinic in Milan, at the Minotauro Institute. The ultimate goal is to reactivate the evolutionary path where the adolescent resides. The first step is the alliance with the boy and his lifestyle, a symptom of anguish and unacceptable pain. The assumption of the Minotauro team is that the unconscious drive to live pushes these teenagers to find alternative, albeit virtual, ways to madness or death. In fact, in the most serious cases, withdrawal is the only way to manage the fragility, saving one’s own body. The escape of one’s body is the decision taken by the secluded boy to remain alive, both psychologically and physically. For this reason, the alliance with the symptom is fundamental for the Minotauro method. Only in this way is a therapeutic path possible in which the boy rediscovers the real self with the resources and the evolutionary capacities that allow him to imagine and therefore invest in a future perspective. The therapist explores the adolescent’s signals and communications, helps him to transform anguish and pain into words, to promote the transformation of family dynamics and to create alternatives for eliminating the voluntary withdrawal [19].
\n
The experience of the Minotaur indicates as a first step the taking in charge of the parents who usually turn to the center without being accompanied by the boy. Parental care provides with extreme attention the figure of the father who plays a fundamental role in the context of social withdrawal. The intervention method foresees that parents follow individual psychotherapy.
\n
\n\n
7. Social withdrawal and social brain
\n
During puberty, the neurophysiological development of the prefrontal cortex occurs very quickly [1]. The prefrontal cortex deals with not only cognitive abilities such as planning and executive functions [21], but also the regulation and management of emotions. In particular, it deals with regulating behavior with respect to the emotions evoked by group dynamics such as the sense of belonging to one’s own group [22, 23]. In other words prefrontal cortex corresponds to a social brain. Spear [24] stresses that during this period there is a qualitative change in social relations with an increase in contacts with peers, in particular, in salience of social rewards. From the hormonal point of view, the adolescent’s brain responds differently to that of adults. According to the Walker et al. [25], an adolescent’s stress may interfere with the regulatory development of the brain system that includes the area associated with social rewards. In fact, a dysregulation of these involves an alteration of the functioning activated by addictive behaviors like that of electronic devices—Internet. The same structures are involved in substance abuse cases. Even if it has not been included in the DSM-5, “Internet addiction (IA)” is a global issue [26], a behavioral dependence derived from the human-machine interaction with serious consequences such as loss of control and feelings of anger. Internet addiction may favor a clinically severe condition.
\n
\n\n
8. Conclusion
\n
The aim of this chapter is to give some information on interdisciplinary interventions such as clinical psychology, educational approach, and social neuroscience practices in order to contribute a better understanding of the social withdrawal concept. This can help to better understand the potential risk for mental and physical health. In accordance with the information given in this chapter, working with secluded adolescents has revealed that their families should be included in the therapeutic relationship. It has been also detected that the characteristics found in the secluded adolescents can be traced back to relationships within the family. For example, there is often an intense mother/child relationship that promotes dependence and obstacle in the natural processes of separation and individuation, a distant or absent paternal figure who initially idealizes and places numerous expectations in the child and when that happens, when these expectations are not satisfied, it becomes debasing. Following the evolutionary theory, it is possible to observe a block in the growth process and in the realization of the evolutionary tasks accompanied by a narcissistic fragility in the boy, lacking not only the evolutionary task of separation-individuation necessary for the construction of identity but also a process in mentalization of the body and a block in the social birth outside the family nucleus [19]. In addition to the family aspect, environmental and cultural factors that may affect and support vulnerable adolescents on such important aspects should also be addressed. Considering interdisciplinary aspects may preserve the social exclusion processes [27]. In this regard, an interdisciplinary point of view can lay the foundations for opening new theoretical and intervention perspectives on the phenomenon.
\n
\n\n',keywords:"social withdrawal, adolescents, health, psycho-educative intervention, social neuroscience, mental health",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/70694.pdf",chapterXML:"https://mts.intechopen.com/source/xml/70694.xml",downloadPdfUrl:"/chapter/pdf-download/70694",previewPdfUrl:"/chapter/pdf-preview/70694",totalDownloads:965,totalViews:0,totalCrossrefCites:1,totalDimensionsCites:3,totalAltmetricsMentions:2,introChapter:null,impactScore:3,impactScorePercentile:85,impactScoreQuartile:4,hasAltmetrics:1,dateSubmitted:"July 1st 2019",dateReviewed:"December 2nd 2019",datePrePublished:"February 12th 2020",datePublished:"April 8th 2020",dateFinished:"December 31st 2019",readingETA:"0",abstract:"Social isolation may be considered as a risk factor for health. It may contribute to the development of a mental health disease. In this chapter, social withdrawal is defined as voluntary isolation prolonged in time that involves the cessation of any form of social relationship and contact with people and the outside. Clinical psychology, psycho-educational interventions, and social neuroscience research \ufefftries to understand what happens when social isolation is experienced. Therefore an interdisciplinary perspective can help to better understand this phenomenon. \ufeffThe deepening of these aspects can help to create new forms of theoretical perspective and of a clinical and psycho-educational intervention to better \ufeffarrange for this new type of maladaptive condition.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/70694",risUrl:"/chapter/ris/70694",book:{id:"7818",slug:"social-isolation-an-interdisciplinary-view"},signatures:"Rosalba Morese, Sara Palermo, Carlotta Torello and Francesca Sechi",authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Social withdrawal",level:"1"},{id:"sec_3",title:"3. Social withdrawal: the symptom of a block in the growth process",level:"1"},{id:"sec_4",title:"4. Social withdrawal in Italy",level:"1"},{id:"sec_5",title:"5. Reactivate the growth process: interdisciplinary intervention",level:"1"},{id:"sec_6",title:"6. An Italian example of clinical intervention",level:"1"},{id:"sec_7",title:"7. Social withdrawal and social brain",level:"1"},{id:"sec_8",title:"8. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'[\nMorese R, Palermo S, Defedele M, Nervo J, Borraccino A. Vulnerability and social exclusion: Risk in adolescence and old age. In: The New Forms of Social Exclusion. IntechOpen; 2019. DOI: 10.5772/intechopen.85463. Available from: https://www.intechopen.com/books/the-new-forms-of-social-exclusion/vulnerability-and-social- exclusion-risk-in-adolescence-and-old-age\n]'},{id:"B2",body:'[\nBarzeva SA, Meeus WHJ, Oldehinkel AJ. Social withdrawal in adolescence and early adulthood: Measurement issues, normative development, and distinct trajectories. Journal of Abnormal Child Psychology. 2019;47:865. DOI: 10.1007/s10802-018-0497-4\n]'},{id:"B3",body:'[\nRubin KH, Coplan RJ, Bowker JC. Social withdrawal in childhood. In: Annual Review of Psychology. Vol. 60. Palo Alto: Annual Reviews; 2009. pp. 141-171\n]'},{id:"B4",body:'[\nAnderson M, Jiang J. Teens, Social Media & Technology 2018. Washington, D.C.: Pew Research Center; 2018\n]'},{id:"B5",body:'[\nLenhart A. Teens, Social Media and Technology Overview 2015. Washington, D.C.: Pew Research Center; 2015\n]'},{id:"B6",body:'[\nPoli R, Agrimi E. Internet addiction disorder: Prevalence in an Italian student population. Nordic Journal of Psychiatry. 2012;66(1):55-59. DOI: 10.3109/08039488.2011.605169\n]'},{id:"B7",body:'[\nShek DTL, Yu L. Adolescent internet addiction in Hong Kong: Prevalence, change, and correlates. The Journal of Pediatric and Adolescent Gynecology. 2016;29(Suppl 1):S22-S30. DOI: 10.1016/j.jpag.2015.10.005\n]'},{id:"B8",body:'[\nAmerican Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. text rev. 2000. DOI:10.1176/appi.books.9780890423349\n]'},{id:"B9",body:'[\nAmerican Psychiatric Association. Cautionary statement for forensic use of DSM-5. In: Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: Author; 2013. DOI: 10.1176/appi.books.9780890425596\n]'},{id:"B10",body:'[\nSaitō T. Shaikaiteki hikikomori: Owaranaishishunk [Hikikomori: Adolescence without end]. Tokyo: PHP Kenkyuujo; 1998\n]'},{id:"B11",body:'[\nSaitō T. Hikikomori no hyouka shien ni kansuru gaidorain [Guideline on evaluation and support of hikikomori]. Tokyo: Ministry of Health, Labour & Welfare; 2010\n]'},{id:"B12",body:'[\nSuwa M, Suzuki K. The phenomenon of “hikikomori” (social withdrawal) and the socio-cultural situation in Japan today. Journal of Psychopathology. 2013;19:191-198\n]'},{id:"B13",body:'[\nCantelmi T, Talli M. Anatomia di un problema, una review sui fenomeni psicopatologici Internet-correlati. Psicotech. 2007;5:7-31\n]'},{id:"B14",body:'[\nBerne E. What do you say after you say hello?, trad. it. “Ciao!”… E poi?, La psicologia del destino umano. Milano: Bompiani; 1972\n]'},{id:"B15",body:'[\nBattacchi MW. Vergogna e senso di colpa: in psicologia e nella letteratura. Milano: Raffaello Cortina Editore; 2002\n]'},{id:"B16",body:'[\nErskine RG. A gestalt therapy approach to shame and self-righteousness: Theory and methods. British Gestalt Journal. 1995;4:107-117\n]'},{id:"B17",body:'[\nFilanti S, Romanini AS. l modello dell’analisi transazionale. Dai fondamenti teorici all’intervento. Milano: Franco Angeli; 2017\n]'},{id:"B18",body:'[\nDi Lorenzo M, Lancini M, Suttora C, Zanella TE. La dipendenza da internet in adolescenza tra normalità e psicopatologia: uno studio italiano. Psichiatria e psicoterapia. 2013;2:101-135\n]'},{id:"B19",body:'[\nLancini M. Il ritiro sociale negli adolescenti. La solitudine di una generazione iperconnessa. Cortina: Milano; 2019\n]'},{id:"B20",body:'[\nSpiniello R, Piotti A, Comazzi D. Il corpo in una stanza. Adolescenti ritirati che vivono di computer. Milano: Franco Angeli; 2015\n]'},{id:"B21",body:'[\nPalermo S, Morese R, Zibetti M, Dematteis F, Sirgiovanni S, Stanziano M, et al. Impulse control disorder and response-inhibition alterations in Parkinson’s disease. A rare case of totally absent functionality of the medial-prefrontal cortex and review of literature. Journal of Advanced Research. 2017;8:713-716. DOI: 10.1016/j.jare.2017.09.004\n]'},{id:"B22",body:'[\nLo Gerfo E, Gallucci A, Morese R, Vergallito A, Ottone S, Ponzano F, et al. The role of ventromedial prefrontal cortex and temporo-parietal junction in third-party punishment behavior. NeuroImage. 2019;200:501-510. DOI: 10.1016/j.neuroimage.2019.06.047\n]'},{id:"B23",body:'[\nMorese R, Rabellino D, Sambataro F, Perussia F, Valentini MC, Bara BG, et al. Group membership modulates the neural circuitry underlying third party punishment. PLoS One. 2016;11(11):e0166357\n]'},{id:"B24",body:'[\nSpear LP. The adolescent brain and age-related behavioral manifestations. Neuroscience and Biobehavioral Reviews. 2000;24:417-463. DOI: 10.1016/s0149-7634(00)00014-2\n]'},{id:"B25",body:'[\nWalker DM, Cunningham AM, Gregory JK, Nestler EJ. Long-term behavioral effects of post-weaning social isolation in males and females. Frontiers in Behavioral Neuroscience. 2019;13:66. DOI: 10.3389/fnbeh.2019.00066\n]'},{id:"B26",body:'[\nCerniglia L, Zoratto F, Cimino S, Laviola G, Ammaniti M, Adriani W. Internet addiction in adolescence: Neurobiological, psychosocial and clinical issues. Neuroscience and Biobehavioral Reviews. 2017;76:174-184\n]'},{id:"B27",body:'[\nMorese R, Palermo S. Introductory chapter: Do you feel bad if i exclude you? From marginalization to suicide. In: The New Forms of Social Exclusion. IntechOpen; 2019. DOI: 10.5772/intechopen.86192. Available from: https://www.intechopen.com/books/the-new-forms-of-social-exclusion/introductory-chapter-do-you-feel-bad-if-i-exclude-you-from-marginalization-to-suicide\n\n]'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Rosalba Morese",address:"rosalba.morese@usi.ch",affiliation:'- Faculty of Communication Sciences, Università della Svizzera italiana, Switzerland
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'},{corresp:null,contributorFullName:"Sara Palermo",address:null,affiliation:'- Department of Psychology, University of Turin, Italy
'},{corresp:null,contributorFullName:"Carlotta Torello",address:null,affiliation:'- CDSR Identi-Kit, Coop Interactive, Italy
'},{corresp:null,contributorFullName:"Francesca Sechi",address:null,affiliation:'- Transactional Clinical Analysis in Psychology Practice for Children and Adolescent, Italy
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Introduction
Restoration of calcium levels is essential for the human body, which leads to proper function such as enzyme activity, hormone secretion, neurological stimulation, and/or muscle function. Calcium homeostasis is in relationship with different tissues and structures such as bone, parathyroid gland, and kidney. Regulation of calcium-homeostasis-related events begins with rapid changes in the parathormone (PTH) release from parathyroid gland cells. Hypocalcemic or hypercalcemic responses are controlled by a specific receptor that senses the changes in serum calcium levels [1]. If calcium levels decrease, the mechanism provides a rapid increase in the PTH level to maintain proper calcium levels. Once calcium is balanced to the normal values, continual calcium release suppresses the PTH through a negative-feedback mechanism. Major and pulsatile events occur during the process itself through calcium-sensing receptors (CaSRs) [2]. This G-protein-coupled receptor is a unique part of the parathyroid gland function to monitor changes in serum calcium levels. This process is carried out by two main mechanisms which are, respectively, stimulation of the kidneys and intestine to increase the absorption of calcium and stimulation of the bones to release calcium into the blood [3, 4].
PTH mRNA expression levels are suppressed by the 1-25OH2D modulation, despite CaSR expression with its effect on the modulation of the PTH release. Ritter et al. report that PTH release decreased by 1–25(OH)2D, 1 hydroxy-vitamin D, and 25(OH)D in mice parathyroid cells in culture [5, 6, 7, 8, 9, 10, 11]. Earlier in this study, Kim et al. showed a lack of upregulation of PTH transcription in the Vitamin D Receptor (VDR) knockout mice, and lack of suppression of PTH transcription by 1,25(OH)2D administration [12]. Consistent with both researcher and current literature, the 1–25(OH)2D reduces the PTH mRNA expression and has an antiproliferative effect on parathyroid cells from uremic rats, subsequently enhancing the VDR expressions. Acute changes in the calcium levels of sHPT patients enhance the CaSR and Klotho expressions by Vitamin D [5, 13].
The location of the parathyroid glands is on the posterior side of the thyroid gland. Mostly there are four glands and rarely supernumerary glands [14]. Starting from the early phases of embryogenesis, the pharyngeal pouches give rise to parathyroid glands along with many organs [15, 16]. The third and the fourth pharyngeal pouches particularly emerge as parathyroid glands [17]. Inferior and superior parathyroid glands develop with thymus and a portion of the thyroid respectively [15]. Different cell adhesion after separation from the pharyngeal pouch modulates the formation of parathyroids, while the thymus continues to migrate above the heart [16]. Separation of the superior parathyroid glands is carried out during the seventh week of the development and after detaching the pharyngeal wall, the parathyroid fuses with the posterior surface of the thyroid [14].
The parathyroid glands are derived from the endoderm during embryogenesis. Endoderm consists of a high amount of actin fibers that provide formation and expansion to the ectoderm. Numerous signaling molecules and proteins maintain the progression of morphogenesis. Particularly, Glial cell missing 2 (GCM2), Homeobox A3 (HOXA3), Forkhead box protein N1 (FOXN1), Eyes Absent Homolog 1 (Transcriptional Coactivator And Phosphatase 1—EYA1), T-Box Transcription Factor 1 (TBX1), GATA binding protein 3 (GATA3), Paired box 1 (PAX1), and Paired box 9 (PAX9) genes are the leading transcription factors that initiate the parathyroid morphogenesis [16, 17]. Among them, GCM2 is particularly important as the early transcription factor of parathyroid formation [18]. The developmental stage includes another important transcription factor: V-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) [19].
In order to understand the development of the parathyroid gland, extensive research on murine models is performed. To identify the involving molecules and signaling processes, researchers have proven most of the downstream and upstream mediators. The remaining unknown factors remain to be elucidated. In current practice, the known factors involving the development and maturation of the parathyroid glands are evaluated in murine models and related parathyroid disorders. This chapter summarizes the molecular findings based on the cell type distribution of parathyroid and pathophysiology up to the present.
2. Cellular distribution of parathyroid gland
The vascular structure of the parathyroid glands is separated from the outside by a fibrous thin capsule. Such capsules contain thin fibrous bands that disperse toward the inner parts by fibrous structures. This provides access to the blood vessels, lymphatics, and nerves to provide nutrients to the tissue [20, 21]. Macroscopic appearances may vary depending on cell type, cell/organelle amount, blood supply status, and the amount of fat content of the tissue [1, 22].
In literature, cell-type distribution in the parathyroid tissue has been reported based on either two or three different cell types. In some reports, it has been stated as two: oxyphil and chief cells [14], while another group of researchers has elucidated histological evidence that there are water-clear cells besides oxyphil and chief cells [23]. Besides, there is another group of cell types that are observed with disease and/or age-related changes, which are not yet classified as a specific cell type. Although this type is not yet classified, the transitional chief cells are present and particularly reported as chief cell-to-oxyphil cell transdifferentiated cell group [23, 24]. These four types of cells do not have distinctive markers yet. Their variations in size and number per tissue originate from different parathyroid pathophysiology, which is the main unknown aspect of parathyroid cell biology. Hence, this chapter prioritizes the three main cell types in the parathyroid gland.
2.1 Water-clear cells
Water-clear cells contain many glycogen granules in their cytoplasm and are rarely seen. These cells are clinically encountered in the tissues of patients with secondary hyperparathyroidism (sHPT) and primary hyperparathyroidism (pHPT) [25]. In 1992, Emura’s study on rabbit parathyroid tissue stated that water-clear cells contained a large number of vacuoles in the parathyroid tissue sections, which were observed with electron microscopy and were found scattered around the chief cells. Water-clear cells reside in between the perivascular space and the basal lamina that have been observed to have a desmosomal connection with chief cells [26]. In 2013, Ezzat et al. showed that these cells were not associated with PTH secretion and serum calcium levels. In addition, they reported that only 0.3% of pHPT cases had “water-clear cell hyperplasia” or “water-clear cell adenomatosis” [27]. A recent report presented that the water-clear cell hyperplasia ratio is less than 1% of all pHPT cases [28]. Distinct features or changes in the water-clear cell accumulation in parathyroid tissue or relation with disorders remain to be elucidated.
2.2 Chief cells
The chief cells constitute the cellularly dominant cell type of parathyroid tissue, and it was described by Baker in 1942 [29]. Baker describes these cells as the dark “primary cells” with distinctive cytoplasmic structures. Their rod-shaped mitochondria are homogeneously distributed throughout the cytoplasm [20]. In addition, Trier reported that he did not observe the dark and pale stained oxyphil cells, neither with light nor with electron microscopy, which Baker mentioned in his notes in 1942.
The chief cells are usually rich in intracellular fat content. Cells are supported by a thin connective tissue and accordingly are located more closely to the capillaries [30]. Although the chief cells may contain more than one nuclei (multinucleic cells), the nuclear matrix structures are densely arranged [31]. Chief cells are considered the main cell type, and cells are mostly spherical or oval-shaped with long nuclei and narrow cytoplasm [32]. The knowledge about the cell shapes of the chief cells is mostly obtained from histological examinations. Besides, observations by using live imaging or confocal microscopy are either absent or limited. Since it has been reported that single chief cell diameters are 0.2 μm wide according to electron microscope images [33, 34] and 6–8 μm histologically [23]. The agranular membrane structure of the Golgi body of the chief cells was first visualized in 1957 [35]. Due to the eosinophilic cytoplasm, they may appear dark or light in color at the time of staining.
To date, the parameters such as age, disease history, and drug use, which are the definitive features of parathyroid function, may affect cytoplasm amount or changes in the cytoplasm content or nucleus size for all processes [32, 36, 37]. In brief, functional activity and cytoplasm content are the two related main chief cell behaviors of the parathyroid. The most distinctive feature of the chief cells is that they contain a large number of secretory vesicles. These membrane-covered vesicles mostly contain PTH [38].
As is known, the main function depends on the chief cells, which are responsible cell type for PTH release. These cells play an important role in calcium homeostasis, thanks to the CaSR expression on its surface. The receptor detects the low amount of extracellular calcium changes and releases the appropriate amount of PTH to balance the calcium in the blood [23, 39].
2.3 Oxyphil cells
Oxyphil cells are the cells with well-circumscribed eosinophilic cytoplasm and pycnotic nuclei [1, 20, 39]. Between 1952 and 1953, Parade compared monkey, equine, and human parathyroid tissues and reported that the size and number of mitochondria in oxyphil cells varied between species. In addition, the variability in the number of mitochondria in human oxyphilic cells is also associated with age [23, 33, 34]. As of note, rat parathyroid tissue does not contain oxyphil, oxyphil-like, or mitochondria-rich cell groups [32]. In 1958, Trier observed that some of the oxyphilic cells were stained “dark” and some were “pale.” He described pale-stained oxyphilic cells as having “low” mitochondrial content, and dark-staining oxyphil cells as having “excessive” mitochondrial content [20]. Both studies have confirmed the outcome of oxyphil cells.
In 1981, Allen and Thorburn examined the activity of oxyphil cells in abnormal parathyroid tissue of 114 patients with sHPT due to chronic kidney disease. The absence and presence of oxyphil cells in human parathyroid tissues were evaluated in this retrospective study, in which histological evaluation was associated with clinical practice. They reported that hyperparathyroidism was seen in more than one parathyroid tissue in 55% of the cases, and adenoma was found in one of the four parathyroid glands in 69% of the cases. They also reported that oxyphil cells were found in 91% of the cases, and the number of oxyphilic cells was positively correlated with serum calcium level [40].
In 1990, Suzuki et al. reported oxyphil cell function in 148 parathyroid tissues from patients who are taking hemodialysis. They calculated for each tissue by proportioning the area occupied by oxyphilic cells by morphometric measurements concerning the total parathyroid cross-sectional area (oxyphil cell area/total area). Additionally, it has been reported that serum PTH levels do not have a statistically significant relationship with age and the dialysis duration; however, the total tissue size is positively correlated with PTH release. Based on the results, they concluded that the oxyphil cell/total tissue area was not effective in PTH release in patients with chronic renal failure [41].
In 1996, Tanaka et al. used 22 sHPT tissues to understand oxyphil cell function. The study reported that 10 of these tissues had oxyphil cells and the mRNA expression of PTH was found to increase. Then, performed heterotransplantation in mice to determine oxyphilic cell function by evaluating serum PTH levels. As a result, the change in PTH levels was positively correlated with transplanted tissue size, not the cell number or type [42].
Despite the reported studies, there is no definite information about the exact function of oxyphil cells, but this question was clarified in many ways by Ritter and Brown et al. [5, 6, 23, 39]. Histologically, increased eosinophilic content from the chief cell through oxyphil cell, suggesting that oxyphil cells are formed by “transition.” As evidence, the oxyphil cells have been shown to express PTH [42] and GCM2, which is a parathyroid-specific transcription factor [18] and has a role in parathyroid tissue development. It has been observed that oxyphil cells are more numerous in patients with chronic renal failure, and the amount of oxyphil cells is much higher than in the tissues of healthy individuals [43, 44]. Although studies have shown that oxyphil cells express the parathormone-dependent protein (PTHrP) [45, 46] and that protein is involved in PTH release [42], the amount/mechanism of PTH release is not yet known. The proposed function of the PTHrP on parathyroid cells may be responsible for autocrine or paracrine signaling while affecting PTH release or parathyroid maturation [23].
On the one hand, the CaSR expression levels of oxyphil cells are statistically found higher than other parathyroid cells. On the second hand, there was no significant difference in Vitamin D Receptor (VDR) expression [5, 39]. The higher mitochondrial content of oxyphil cells indicates that energy requirements are much higher than in chief cells. Mitochondria are also responsible for VDR function. One study by Ritter et al. elucidated that 25-hydroxyvitamin D-1α-hydroxylase (1αOHase) is highly expressed and this is the inactive form of Vitamin D [5]. In addition, the amount of 1αOHase in human parathyroid tissue was directly proportional to calcium levels. The study reported that calcimimetic therapy in patients with chronic renal failure causes a significant increase in the amount of 1αOHase in oxyphil cells [5, 6].
A recent commentary also highlighted Ritter’s findings after 5 years. Metabolic changes of parathyroid tissue are significantly affected by changes in tissue volume and/or cell type, cell count rate due to drug use, or changes in serum calcium level. Concomitant CaSR induction and its persistence are also known to affect the expression profile [47]. Thus, in terms of PTH expression, it has been clarified that oxyphil cells contain more PTH than chief cells. Some of these data also confirm the findings of Allen and Thorburn in 1981 [40].
3. Cellular variations in parathyroid research and related diseases
Calcium or di-/trivalent cations induce the activation of CaSR, which triggers the PTH release [48]. Definitive research studies have demonstrated the outcomes from direct or indirect approaches so far. The comparisons and the evaluations were mainly performed with the diseased tissues, not the healthy parathyroids due to the difficulties in retrieval processes. There is only a limited number of papers that compare/evaluate healthy parathyroid tissue expression profiles of cellular content. Particularly, the location and the size of the parathyroid gland make it difficult to obtain from healthy individuals. Researchers, surgeons, and physicians reported different approaches to finding and/or distinguishing the parathyroid tissue during thyroid operation [49, 50, 51]. This challenge still exists, and suggested techniques such as near-infrared autofluorescence [52] are not readily available for the use of numerous surgeons. Essentially, it is a fact that even if healthy tissue is donated, it will take a long time to reach the appropriate sample size required to conduct various studies. Therefore, a limited number of healthy parathyroid tissues either used or to be used in studies for comparisons.
The further part of this chapter continues with parathyroid tissue from the primary and secondary hyperparathyroidism patients (adenoma and hyperplasia tissues respectively) were compared according to their cellular content. The changes in their expression profiles were evaluated with different stages of the related diseases.
Starting 25 years ago, most of the papers evaluated the CaSR, PTH, proliferation markers, and transcription factors expression changes by mRNA and/or protein levels (mostly immunohistochemistry, western blot, ELISA methods). The clinical characteristics and the cell content of the parathyroid tissue were compared by Yamaguchi et al. in 1997. Samples are retrieved from patients who have secondary hyperparathyroidism and cell proliferation specific marker PCNA (proliferating cell nuclear antigen) expression was compared between normal, adenoma, and hyperplasia parathyroid tissues. This study divided the cell content in each tissue group including dark-stained chief cells, clear chief cells, vacuolated chief cells, transitional oxyphil cells, and oxyphil cells [53]. This divided cell type classification was very similar to the report by Trier in 1958 [20]. Among 27 out of 40 normal parathyroid tissues were found positive for PCNA, and no correlation between age and expression levels is observed. Cell content was reported as clear-chief>dark-chief>oxyphil cells, respectively. However, the normal parathyroid tissue was obtained from thyroid cancer patients, and a definite interpretation should not be made without ignoring this situation. Adenoma tissue showed remarkably higher PCNA expression levels, and the cell content included mostly clear chief cells and less commonly transitional oxyphil cells. In 129 parathyroid hyperplasia tissue samples, all of the divided cell types of this study were found distinguishable. The PCNA expression was found significantly higher in the nodular type from the glandular structure of the parathyroid. The authors concluded that clear chief cells are the most proliferative cell group in all samples, and the dark chief cell group was found the lowest proliferative group [53]. Yamaguchi’s study alone is one of the rare studies that evaluate the highest number of parathyroid tissues in its related field.
In 2000, Corbetta et al. demonstrated that 27 parathyroid adenoma tissues contain only chief cells. Cell isolation, cultivation under different calcium concentrations, PTH levels, and CaSR expression levels were evaluated. Additionally, it is stated that there was no correlation between different calcium sensitivity and pathology. Furthermore, PTH and CaSR mRNA and protein levels were significantly reduced when compared with normal tissue, and the authors concluded that defective calcium sensing occurs in abnormal parathyroid tissue [54]. This study may be considered as a starting point for understanding the defects in the sensing mechanism of the CaSR. Failure to obtain the expected changes in the PTH level under different calcium concentrations should not be interpreted as a resistance mechanism.
In 2006, Brown et al. stated that three different Vitamin D prodrugs, which are lacking side-chain hydroxyl groups, were treated with bovine parathyroid cells and showed that PTH levels decreased based on the related concentrations. The prodrugs have different affinities to the VDR; however, utilization of the VDR decreases PTH synthesis for treatment of secondary hyperparathyroidism [7]. The inhibition of PTH synthesis was performed in vitro using prodrugs at that time of the work, and this indicates a new aspect of parathyroid research. Continued with Ritter et al. in 2006, by the same research group, competitive VDR binding of the vitamin D analogs was examined. In this report, two main conclusions were included. One is the 25(OH)D3 has the highest affinity to the VDR among other analogs, and direct action mechanisms through VDR suppress PTH [8]. The PTH regulation versus VDR activation may be explained by a compensatory mechanism model. Although the authors did not exclude other regulatory systems such as the negative feedback mechanism of the PTH [10]. Studies conducted between 2005 and 2011 mostly did not focus on cell-type-specific changes. Instead, the relationships between VDR and PTH were investigated in terms of regulation mechanism, especially in bovine, rat, and other knockout-animal models.
In 2012, Ritter et al. defined the differential mRNA expression of parathyroid glands by cell types. In this paper, histological examination was provided and the size of the chief, oxyphil, and transdifferentiated oxyphil cells was reported. Consistent with previous reports, the high oxyphil cell amount was reported in chronic kidney diseased patients, accordingly higher PTH and CaSR expression was elucidated as well. In addition, oxyphil cells showed GCM2 expression, which is a specific parathyroid transcription factor. Therefore, in order to understand parathyroid pathophysiology in patients with secondary hyperparathyroidism, oxyphil cell secretomes may help to define their role other than chief cells [23]. This study still has important outcomes that shaped the perspective to a particular point for chief and oxyphil cell features. Future studies including isolation of oxyphil and chief cells separately with the assessment of secretory features will justify each cell type’s function.
In 2014, Shi et al. demonstrated a flow cytometric cell sorting of 20 parathyroid adenoma tissues from primary hyperparathyroidism patients. They divided the cells into three distinct populations including the chief, oxyphil, and lymphocytes. The cutting-edge research from Shi et al. provided electron microscopy images of each population and also demonstrated the immunofluorescence staining of CaSR and mRNA expressions of CASR and PTH by comparing oxyphil and chief cells. At end of this unique study, they reported that oxyphil cells respond to calcium faster than chief cells by releasing higher PTH and did not find differences in their CaSR expression profiles. They also reported that the feature of oxyphil cells provides an important function to the parathyroid tissue as a piece of solid evidence [55].
In 2015, Howson et al. investigated the oxyphil-cell-rich adenoma tissues from primary hyperparathyroidism patients. During the 10-year follow-up period, among obtained 2739 tissues, 91 of the parathyroid adenoma were found oxyphil cell adenoma type. About 80% of these patients were symptomatic and most commonly had higher serum calcium and PTH levels than the classical type of adenoma. On the contrary, the frequency of oxyphilic adenomas was not rare, and patients trend toward a higher rate of morbidity and potential mortality if left untreated [56].
In 2017, two different groups presented water-clear cell-type adenoma and hyperplasia cases. The clinical symptoms of the adenoma patient were unintentionally led and treated for hyperparathyroidism due to the clinical features. However, after surgical removal of the two adenoma tissues from the same patient, the histopathological evaluation showed water-clear cell double parathyroid adenomas [57]. This is followed by another case report that presents primary hyperparathyroidism clinically. Contrary to the clinic, the histopathological results showed enormous unilateral water-clear cell hyperplasia in parathyroid [28]. Both of the cases concluded that despite ultrasonography, biochemical, and clinical follow-up, these extremely rare cases unintentionally misled the physicians [28, 57]. In the same year, another study by Ritter et al. was reported. In that study, parathyroid hyperplasia tissues were retrieved from chronic kidney patients and grouped according to their calcimimetic treatment (cinacalcet versus paricalcitol versus cinacalcet+paricalcitol). The effects of treatment processes on the cell type of the parathyroid tissue were compared with four healthy parathyroid tissues. According to the histopathological evaluation, parathyroid oxyphil cell content was found to increase significantly for the cinacalcet-treated patients [58]. The role of the CaSR activation possibly led to a new comprehension to understand the outcome of conventional treatment with vitamin D analogs or calcimimetics on the cellular composition of the parathyroid.
In 2020, Ding et al. provided a comparison of clinical characteristics and oxyphil cell proportion through 78 patients. In total, 295 parathyroid tissue samples were retrieved from 78 patients who did not have cinacalcet treatment. Clinical characteristics included serum calcium, phosphorus, alkaline phosphatase, age, dialysis duration, and preoperative PTH levels. The samples were divided based on the mean oxyphil cell ratio (high oxyphil cell content and low oxyphil cell content, respectively). Subsequently, etiopathogenesis and histological examinations were evaluated. They reported that preoperative PTH levels of the patients were found lower than the oxyphil cell-rich group [37]. This finding contradicts the previous study by Howson [56]. Furthermore, Ding et al. reported that if parathyroid tissue contains more oxyphil cells, it became lighter than the tissue with fewer oxyphil cells. As of note, weight comparison was performed between parathyroid hyperplasia tissues [37].
At the beginning of 2021, Altinay et al. demonstrated the cellular composition of the hyperplasia and adenoma tissues while comparing normal parathyroid glands. Furthermore, PTH, GATA3, and PAX8 levels were evaluated histologically. As a result, expression of GATA3 and PTH was found more prominent in pathologic parathyroid tissues when compared with normal. Particularly the GATA3 staining has shown positive only for parathyroid, not thyroid tissue. Chief cell amount was high in adenoma and hyperplasia tissues; however, PTH staining was found low when compared with normal tissue. In addition, adenoma displayed less PTH and GATA3 expression histologically [59].
Another study from Rodriguez et al. reported the clinicopathological outcome of the oxyphil cell clusters, which were detected in parathyroid adenoma tissue. The main idea is to define the particular effect of the oxyphil cell content-rich/poor tissue composition and localization. Despite clinic versus histopathological comparisons so far, this study has a similar manner with distinct oxyphil cell subgroups [60]. Rodriguez’s team investigated histopathological function with symptomatology, and this could depend on the changes in the percentage of the oxyphil cells. Clinically, observations included age, sex, body mass index, and symptomatic reasons for surgical initiation such as nephrocalcinosis, osteoarticular and/or neuropsychiatric and/or cardiovascular symptoms. Biochemical parameters were as follows: ionic calcium, corrected serum calcium, albumin, PTH, 25-OH Vitamin D, alkaline phosphatase, creatinine, glomerular filtration rate (GFR), and urinary calcium excretion. Additionally, oxhyphil cell percentages were divided into the following four categories: 0–24, 25–49, 50–74, and 75–100% [60]. In terms of variables, this is the most comprehensive evaluation to date associated with clinical (including both biochemical and symptomatic) and parathyroid cell groups. In total 261 parathyroid tissues obtained from 238 patients were used. Eventually, 77% of tissues have less than 25% in the percentage of oxyphil cells and 8% of tissues are greater than 75% in terms of percentage of oxyphil cells. No significant difference was found in terms of biochemical parameters such as calcium, phosphorus, alkaline phosphatase, PTH, and 25-OH vitamin D. In addition, the localization of the adenoma tissues did not show significant changes when compared between inferior and superior glands. Different distributions of the oxyphil cell clusters among varied cell percentages showed no significant changes. Although, increased thyroid nodularity and higher prevalence in cardiovascular symptoms are shown within the less oxyphil cell groups (<25%). Imaging tests also justified a correlation between better localization with increased oxyphil cell group (>75%). Nevertheless, preoperative GFR and urinary calcium excretion significantly worsen the patients’ symptoms that were altered in parathyroid tissues containing high oxyphil cells. Findings in the non-pathological tissue samples from normocalcemic patients showed an absence/low level in the oxyphil cells [60]. These conditions are still controversial.
3.1 Exception: parathyroid carcinoma
Parathyroid carcinomas influence the laboratory values, which are similar to those with hyperparathyroidism (primary or secondary). For instance, increased serum PTH levels are around thousands, and a palpable mass may be detected in the neck region. Currently, carcinoma can be observed in any (upper or lower) of the glands and is not considered to have any priority within the four existing glands while the invasion of the adjacent thyroid gland is observed [61]. The histological resemblance of parathyroid adenoma causes a challenge for diagnosis. Observations in parathyroid carcinoma tissue include increased mitotic potential, necrosis, formation of encapsulated structures, and spread from the capsule through adjacent tissues [62].
Studies on parathyroid cancer are gaining attention. A recent study evaluated whether tumor volume and tumor size were associated with disease severity [63]. Another study determined circulating miRNA expression levels as a potential diagnostic biomarker in parathyroid carcinomas [64, 65].
Despite all these findings, in terms of cell type, water-clear, oxyphil, and chief cells do not provide a differential diagnosis. The prime reasons are a rarity, and it is not possible to impose a limitation in terms of cell composition.
4. Conclusion
To further understand the parathyroid gland function and development, studies were carried out by numerous researchers. Indicated contributions already shaped the required future studies for this composite tissue. The parathyroid gland is a relatively small tissue while the behavior and changes in its composition provide a fine balance in terms of its function. Thus, this has enabled us to come a little closer to elucidating the actual mechanisms. Foremost, the mechanisms that maintain certainty in all research results can be listed as the following:
Parathyroid cells mostly contain three types of cells; chief, oxyphil, and water-clear cells.
Depending on the circumstances such aging and diseases may affect and increase the oxyphil cell amount.
The cells that switch between chief through oxyphil cells can affect different mechanisms, which are still uncategorized.
Categorization of the differentiating cells may explain the influence of autocrine/paracrine effect on tissue behavior.
So-called “transdifferentiated cells” can be classified as another cell type that will provide a separate diagnosis criterion such as prognosis, degree, or etiology of parathyroid-related-diseases.
Expression patterns of the same transcription factors such as GCM2, MAFB, and RXR are the most difficult part of distinguishing the cell-type-specific features. Even with all the findings in the literature, one question still remains; where does the border of differential cellular diagnosis end? The answer to this question is still unknown.
The role of autocrine and paracrine effects in parathyroid cell differentiation cannot be ignored. Each person’s metabolism balances this process individually; therefore, studies should include larger cohorts. More collaborative studies are required between researchers. The lack of oxyphil cells in some murine models is another challenge. This indicates that understanding the cellular composition/regulation of parathyroid tissue behavior is mandatory, particularly for primary human parathyroid tissue cell studies.
The emergence of oxyphilic cells is perhaps a defense mechanism that is developed from the parathyroid tissue against external signalings, which was first reported by Christi in 1955 [31]. However, this is yet to be confirmed. Another remark can be made from the state of immunogenicity, which is considered as a defense mechanism or after pathological disturbances leads to adverse circumstances, and as a result, the oxyphil cells differentiate from chief cells. Nevertheless, several studies have focused on the presence of other immunological markers for parathyroid tissue. Verified studies to date have limited definitions for the expression of immunological markers such as human leukocyte antigens (HLAs) [66, 67, 68, 69]. Revealing the possible relationship of immunological and/or defense mechanisms in parathyroid cell composition requires more studies such as different co-culture models. This can be a starting point for future studies.
A few important subjects that have not been finalized yet in terms of parathyroid tissue are:
Histological studies are contributing to the field; however, more biomarker research is required for the specific differential prognosis of related diseases.
The inverse relationship between the increased oxyphilic cell and the lighter tissue structure is still not understood, whereas the studies that determine weight through cell composition of the parathyroid tissue could provide paramount importance.
In conclusion, the approaches that have been proposed in the literature paved the way for future research objectives. Differentiating points obtained by comparing the outcomes and the data of different researchers raise new questions. The exact mechanism for basic parathyroid biology requires new in vitro and in vivo approaches, and mostly, primary tissue culture systems are essential to understand such a mechanism.
Acknowledgments
The author would like to thank Prof. Emrah Yucesan for his valuable feedbacks. This chapter is dedicated to all patients undergoing treatment for parathyroid-related diseases who agreed to participate in the studies from many researchers highlighted in this section. This chapter was supported by the Research Fund Unit of the Bezmialem Vakif University.
Conflict of interest
The authors declare no conflict of interest.
\n',keywords:"parathyroid gland, hyperplasia, adenoma, oxyphil cells, chief cells, water-clear cells",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/82779.pdf",chapterXML:"https://mts.intechopen.com/source/xml/82779.xml",downloadPdfUrl:"/chapter/pdf-download/82779",previewPdfUrl:"/chapter/pdf-preview/82779",totalDownloads:8,totalViews:0,totalCrossrefCites:0,dateSubmitted:"January 22nd 2022",dateReviewed:"June 30th 2022",datePrePublished:"July 22nd 2022",datePublished:null,dateFinished:"July 22nd 2022",readingETA:"0",abstract:"The parathyroid tissue is composed of the chief, oxyphil, and water-clear cells. The cell type in each parathyroid gland is highly heterogeneous between different pathologies. The parathyroid oxyphil cells are markedly increased in secondary hyperparathyroidism due to chronic kidney diseases. These cells include more eosinophil than oxyphil cells, but they are closer in size to the chief cells. Studies reported that the oxyphil cells are derived from chief cells, and this presents another cell type that occurs as “transitional oxyphilic cells.” As is known, calcium-sensing receptor (CaSR) is expressed abundantly in the chief cells. Expression of CaSR is elevated in disparate parathyroid tissues, which is possibly related to differential expression levels of parathyroid-specific transcription factors including GCM2 (Glial Cells Missing Transcription Factor 2), MAFB (V-maf musculoaponeurotic fibrosarcoma oncogene homolog B), GATA3 (GATA Binding Protein 3), RXR (The retinoid X receptor), and even VDR (Vitamin D Receptor). The pathways that connect CaSR to parathyroid cell proliferation are precisely not known yet. Evaluation of oxyphil and chief cells of parathyroid glands and their differential expression patterns are important to understand the parathyroid function and its behavioral changes due to related diseases. This chapter presents a summary of the current literature on the cell type distribution of parathyroid and pathophysiology by comparing the expression patterns.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/82779",risUrl:"/chapter/ris/82779",signatures:"Beyza Goncu",book:{id:"11262",type:"book",title:"Parathyroid Glands",subtitle:null,fullTitle:"Parathyroid Glands",slug:null,publishedDate:null,bookSignature:"Ph.D. Beyza Goncu",coverURL:"https://cdn.intechopen.com/books/images_new/11262.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-472-3",printIsbn:"978-1-80355-471-6",pdfIsbn:"978-1-80355-473-0",isAvailableForWebshopOrdering:!0,editors:[{id:"316670",title:"Ph.D.",name:"Beyza",middleName:null,surname:"Goncu",slug:"beyza-goncu",fullName:"Beyza Goncu"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"316670",title:"Ph.D.",name:"Beyza",middleName:null,surname:"Goncu",fullName:"Beyza Goncu",slug:"beyza-goncu",email:"bsgoncu@gmail.com",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/316670/images/system/316670.jpg",institution:{name:"Bezmiâlem Vakıf Üniversitesi",institutionURL:null,country:{name:"Turkey"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Cellular distribution of parathyroid gland",level:"1"},{id:"sec_2_2",title:"2.1 Water-clear cells",level:"2"},{id:"sec_3_2",title:"2.2 Chief cells",level:"2"},{id:"sec_4_2",title:"2.3 Oxyphil cells",level:"2"},{id:"sec_6",title:"3. Cellular variations in parathyroid research and related diseases",level:"1"},{id:"sec_6_2",title:"3.1 Exception: parathyroid carcinoma",level:"2"},{id:"sec_8",title:"4. Conclusion",level:"1"},{id:"sec_9",title:"Acknowledgments",level:"1"},{id:"sec_12",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'[Baloch ZW, LiVolsi VA. Parathyroid glands, pathology. In: Reference Module in Biomedical Sciences. 3rd ed. Philadelphia, PA, USA: Elsevier; 2014. p. 474]'},{id:"B2",body:'[Chiavistelli S, Giustina A, Mazziotti G. Parathyroid hormone pulsatility: Physiological and clinical aspects. Bone Research. 2015;3:14049]'},{id:"B3",body:'[Hall JE. 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Boston: Academic Press; 2018. pp. 687-693]'},{id:"B33",body:'[Palade GE. An electron microscope study of the mitochondrial structure. The Journal of Histochemistry and Cytochemistry. 1953;1(4):188-211]'},{id:"B34",body:'[Palade GE. The fine structure of mitochondria. The Anatomical Record. 1952;114(3):427-451]'},{id:"B35",body:'[Lever JD. Fine structural appearances in the rat parathyroid. Journal of Anatomy. 1957;91(1):73-81]'},{id:"B36",body:'[Javadov M, Karatay E, Ulusan K, Ozpek A, Idiz O, Duren M, et al. Number of cells in parathyroid tissue in primary hyperparathyroidism cases and its relationship with serum calcium value. Medicine (Baltimore). 2021;100(46):e27530]'},{id:"B37",body:'[Ding Y, Zou Q , Jin Y, Zhou J, Wang H. Relationship between parathyroid oxyphil cell proportion and clinical characteristics of patients with chronic kidney disease. International Urology and Nephrology. 2020;52(1):155-159]'},{id:"B38",body:'[Eroschenko VP, Fiore MSH. 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\n\nRegistration is requested only to download the PDF of the chapter/article. There are no subscription fees and there is no charge to user groups.
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\n\nAuthors may post published works to any repository or website with no delay, and Authors and Editors of IntechOpen books have direct access to the PDF of the full book.
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Aalborg University has Two Satellite Campuses, one in Copenhagen (Aalborg University Copenhagen) and the other in Esbjerg (Aalborg University Esbjerg).\n· He is a member of prestigious IEEE (Institute of Electrical and Electronics Engineers), and IAENG (International Association of Engineers) organizations. \n· He is the chief Editor of the Journal of Software Engineering.\n· He is the member of the Editorial Board of International Journal of Computer Science and Software Technology (IJCSST) and International Journal of Computer Engineering and Information Technology. \n· He is also the Editor of Communication in Computer and Information Science CCIS-20 by Springer.\n· Reviewer For Many Conferences\nHe is the lead person in making collaboration agreements between Aalborg University and many universities of Pakistan, for which the MOU’s (Memorandum of Understanding) have been signed.\nProfessor Akbar is working in Academia since 1990, he started his career as a Lab demonstrator/TA at the University of Sussex. After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. 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\r\n\r\n\t
\r\n\r\n\t2. Health and Wellbeing focusing on SDG 3 on Good Health and Wellbeing and SDG 6 on Clean Water and Sanitation
\r\n\r\n\t
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\r\n\r\n\t
\r\n\r\n\t4. Climate Change and Environmental Sustainability comprising SDG 13 on Climate Action, SDG 14 on Life Below Water, and SDG 15 on Life on Land
\r\n\r\n\t
\r\n\r\n\t5. Urban Planning and Environmental Management embracing SDG 7 on Affordable Clean Energy, SDG 9 on Industry, Innovation and Infrastructure, and SDG 11 on Sustainable Cities and Communities.
\r\n\r\n\t
\r\n\r\n\tThe series also seeks to support the use of cross cutting SDGs, as many of the goals listed above, targets and indicators are all interconnected to impact our lives and the decisions we make on a daily basis, making them impossible to tie to a single topic.
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He was elected a Yangtze River Scholars Distinguished Professor in 2013, a member of the International Statistical Institute (ISI) in 2016, a member of the board of the International Chinese Statistical Association (ICSA) in 2018, and a fellow of the Institute of Mathematical Statistics (IMS) in 2021. He received the ICSA Outstanding Service Award in 2018 and the National Science Foundation for Distinguished Young Scholars of China in 2012. He serves as a member of the editorial board of Statistics and Its Interface and Journal of Systems Science and Complexity. He is also a field editor for Communications in Mathematics and Statistics. His research interests include biostatistics, empirical likelihood, missing data analysis, variable selection, high-dimensional data analysis, Bayesian statistics, and data science. He has published more than 190 research papers and authored five books.",institutionString:"Yunnan University",institution:{name:"Yunnan University",country:{name:"China"}}},{id:"1177",title:"Prof.",name:"António",middleName:"J. R.",surname:"José Ribeiro Neves",slug:"antonio-jose-ribeiro-neves",fullName:"António José Ribeiro Neves",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1177/images/system/1177.jpg",biography:"Prof. António J. R. Neves received a Ph.D. in Electrical Engineering from the University of Aveiro, Portugal, in 2007. Since 2002, he has been a researcher at the Institute of Electronics and Informatics Engineering of Aveiro. Since 2007, he has been an assistant professor in the Department of Electronics, Telecommunications, and Informatics, University of Aveiro. He is the director of the undergraduate course on Electrical and Computers Engineering and the vice-director of the master’s degree in Electronics and Telecommunications Engineering. He is an IEEE Senior Member and a member of several other research organizations worldwide. His main research interests are computer vision, intelligent systems, robotics, and image and video processing. He has participated in or coordinated several research projects and received more than thirty-five awards. He has 161 publications to his credit, including books, book chapters, journal articles, and conference papers. He has vast experience as a reviewer of several journals and conferences. As a professor, Dr. Neves has supervised several Ph.D. and master’s students and was involved in more than twenty-five different courses.",institutionString:null,institution:{name:"University of Aveiro",country:{name:"Portugal"}}},{id:"11317",title:"Dr.",name:"Francisco",middleName:null,surname:"Javier Gallegos-Funes",slug:"francisco-javier-gallegos-funes",fullName:"Francisco Javier Gallegos-Funes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/11317/images/system/11317.png",biography:"Francisco J. Gallegos-Funes received his Ph.D. in Communications and Electronics from the Instituto Politécnico Nacional de México (National Polytechnic Institute of Mexico) in 2003. He is currently an associate professor in the Escuela Superior de Ingeniería Mecánica y Eléctrica (Mechanical and Electrical Engineering Higher School) at the same institute. His areas of scientific interest are signal and image processing, filtering, steganography, segmentation, pattern recognition, biomedical signal processing, sensors, and real-time applications.",institutionString:"Instituto Politécnico Nacional",institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"428449",title:"Dr.",name:"Ronaldo",middleName:null,surname:"Ferreira",slug:"ronaldo-ferreira",fullName:"Ronaldo Ferreira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/428449/images/21449_n.png",biography:null,institutionString:null,institution:{name:"University of Aveiro",country:{name:"Portugal"}}},{id:"165328",title:"Dr.",name:"Vahid",middleName:null,surname:"Asadpour",slug:"vahid-asadpour",fullName:"Vahid Asadpour",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/165328/images/system/165328.jpg",biography:"Vahid Asadpour, MS, Ph.D., is currently with the Department of Research and Evaluation, Kaiser Permanente Southern California. He has both an MS and Ph.D. in Biomedical Engineering. He was previously a research scientist at the University of California Los Angeles (UCLA) and visiting professor and researcher at the University of North Dakota. He is currently working in artificial intelligence and its applications in medical signal processing. In addition, he is using digital signal processing in medical imaging and speech processing. Dr. Asadpour has developed brain-computer interfacing algorithms and has published books, book chapters, and several journal and conference papers in this field and other areas of intelligent signal processing. He has also designed medical devices, including a laser Doppler monitoring system.",institutionString:"Kaiser Permanente Southern California",institution:null},{id:"169608",title:"Prof.",name:"Marian",middleName:null,surname:"Găiceanu",slug:"marian-gaiceanu",fullName:"Marian Găiceanu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/169608/images/system/169608.png",biography:"Prof. Dr. Marian Gaiceanu graduated from the Naval and Electrical Engineering Faculty, Dunarea de Jos University of Galati, Romania, in 1997. He received a Ph.D. (Magna Cum Laude) in Electrical Engineering in 2002. Since 2017, Dr. Gaiceanu has been a Ph.D. supervisor for students in Electrical Engineering. He has been employed at Dunarea de Jos University of Galati since 1996, where he is currently a professor. Dr. Gaiceanu is a member of the National Council for Attesting Titles, Diplomas and Certificates, an expert of the Executive Agency for Higher Education, Research Funding, and a member of the Senate of the Dunarea de Jos University of Galati. He has been the head of the Integrated Energy Conversion Systems and Advanced Control of Complex Processes Research Center, Romania, since 2016. He has conducted several projects in power converter systems for electrical drives, power quality, PEM and SOFC fuel cell power converters for utilities, electric vehicles, and marine applications with the Department of Regulation and Control, SIEI S.pA. (2002–2004) and the Polytechnic University of Turin, Italy (2002–2004, 2006–2007). He is a member of the Institute of Electrical and Electronics Engineers (IEEE) and cofounder-member of the IEEE Power Electronics Romanian Chapter. He is a guest editor at Energies and an academic book editor for IntechOpen. He is also a member of the editorial boards of the Journal of Electrical Engineering, Electronics, Control and Computer Science and Sustainability. Dr. Gaiceanu has been General Chairman of the IEEE International Symposium on Electrical and Electronics Engineering in the last six editions.",institutionString:'"Dunarea de Jos" University of Galati',institution:{name:'"Dunarea de Jos" University of Galati',country:{name:"Romania"}}},{id:"4519",title:"Prof.",name:"Jaydip",middleName:null,surname:"Sen",slug:"jaydip-sen",fullName:"Jaydip Sen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/4519/images/system/4519.jpeg",biography:"Jaydip Sen is associated with Praxis Business School, Kolkata, India, as a professor in the Department of Data Science. His research areas include security and privacy issues in computing and communication, intrusion detection systems, machine learning, deep learning, and artificial intelligence in the financial domain. 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He has been listed among the top 2% of scientists in the world for the last three consecutive years, 2019 to 2021 as per studies conducted by the Stanford University, USA.",institutionString:"Praxis Business School",institution:null},{id:"320071",title:"Dr.",name:"Sidra",middleName:null,surname:"Mehtab",slug:"sidra-mehtab",fullName:"Sidra Mehtab",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002v6KHoQAM/Profile_Picture_1584512086360",biography:"Sidra Mehtab has completed her BS with honors in Physics from Calcutta University, India in 2018. She has done MS in Data Science and Analytics from Maulana Abul Kalam Azad University of Technology (MAKAUT), Kolkata, India in 2020. Her research areas include Econometrics, Time Series Analysis, Machine Learning, Deep Learning, Artificial Intelligence, and Computer and Network Security with a particular focus on Cyber Security Analytics. Ms. Mehtab has published seven papers in international conferences and one of her papers has been accepted for publication in a reputable international journal. She has won the best paper awards in two prestigious international conferences – BAICONF 2019, and ICADCML 2021, organized in the Indian Institute of Management, Bangalore, India in December 2019, and SOA University, Bhubaneswar, India in January 2021. Besides, Ms. Mehtab has also published two book chapters in two books. Seven of her book chapters will be published in a volume shortly in 2021 by Cambridge Scholars’ Press, UK. Currently, she is working as the joint editor of two edited volumes on Time Series Analysis and Forecasting to be published in the first half of 2021 by an international house. Currently, she is working as a Data Scientist with an MNC in Delhi, India.",institutionString:"NSHM College of Management and Technology",institution:{name:"Association for Computing Machinery",country:{name:"United States of America"}}},{id:"226240",title:"Dr.",name:"Andri Irfan",middleName:null,surname:"Rifai",slug:"andri-irfan-rifai",fullName:"Andri Irfan Rifai",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226240/images/7412_n.jpg",biography:"Andri IRFAN is a Senior Lecturer of Civil Engineering and Planning. He completed the PhD at the Universitas Indonesia & Universidade do Minho with Sandwich Program Scholarship from the Directorate General of Higher Education and LPDP scholarship. He has been teaching for more than 19 years and much active to applied his knowledge in the project construction in Indonesia. His research interest ranges from pavement management system to advanced data mining techniques for transportation engineering. He has published more than 50 papers in journals and 2 books.",institutionString:null,institution:{name:"Universitas Internasional Batam",country:{name:"Indonesia"}}},{id:"314576",title:"Dr.",name:"Ibai",middleName:null,surname:"Laña",slug:"ibai-lana",fullName:"Ibai Laña",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314576/images/system/314576.jpg",biography:"Dr. Ibai Laña works at TECNALIA as a data analyst. He received his Ph.D. in Artificial Intelligence from the University of the Basque Country (UPV/EHU), Spain, in 2018. He is currently a senior researcher at TECNALIA. His research interests fall within the intersection of intelligent transportation systems, machine learning, traffic data analysis, and data science. He has dealt with urban traffic forecasting problems, applying machine learning models and evolutionary algorithms. He has experience in origin-destination matrix estimation or point of interest and trajectory detection. Working with large volumes of data has given him a good command of big data processing tools and NoSQL databases. He has also been a visiting scholar at the Knowledge Engineering and Discovery Research Institute, Auckland University of Technology.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"314575",title:"Dr.",name:"Jesus",middleName:null,surname:"L. Lobo",slug:"jesus-l.-lobo",fullName:"Jesus L. Lobo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314575/images/system/314575.png",biography:"Dr. Jesús López is currently based in Bilbao (Spain) working at TECNALIA as Artificial Intelligence Research Scientist. In most cases, a project idea or a new research line needs to be investigated to see if it is good enough to take into production or to focus on it. That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:'"Politechnica" University Timişoara',institution:null},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"310576",title:"Prof.",name:"Erick Giovani",middleName:null,surname:"Sperandio Nascimento",slug:"erick-giovani-sperandio-nascimento",fullName:"Erick Giovani Sperandio Nascimento",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y00002pDKxDQAW/ProfilePicture%202022-06-20%2019%3A57%3A24.788",biography:"Prof. Erick Sperandio is the Lead Researcher and professor of Artificial Intelligence (AI) at SENAI CIMATEC, Bahia, Brazil, also working with Computational Modeling (CM) and HPC. He holds a PhD in Environmental Engineering in the area of Atmospheric Computational Modeling, a Master in Informatics in the field of Computational Intelligence and Graduated in Computer Science from UFES. He currently coordinates, leads and participates in R&D projects in the areas of AI, computational modeling and supercomputing applied to different areas such as Oil and Gas, Health, Advanced Manufacturing, Renewable Energies and Atmospheric Sciences, advising undergraduate, master's and doctoral students. He is the Lead Researcher at SENAI CIMATEC's Reference Center on Artificial Intelligence. In addition, he is a Certified Instructor and University Ambassador of the NVIDIA Deep Learning Institute (DLI) in the areas of Deep Learning, Computer Vision, Natural Language Processing and Recommender Systems, and Principal Investigator of the NVIDIA/CIMATEC AI Joint Lab, the first in Latin America within the NVIDIA AI Technology Center (NVAITC) worldwide program. He also works as a researcher at the Supercomputing Center for Industrial Innovation (CS2i) and at the SENAI Institute of Innovation for Automation (ISI Automação), both from SENAI CIMATEC. He is a member and vice-coordinator of the Basic Board of Scientific-Technological Advice and Evaluation, in the area of Innovation, of the Foundation for Research Support of the State of Bahia (FAPESB). He serves as Technology Transfer Coordinator and one of the Principal Investigators at the National Applied Research Center in Artificial Intelligence (CPA-IA) of SENAI CIMATEC, focusing on Industry, being one of the six CPA-IA in Brazil approved by MCTI / FAPESP / CGI.br. He also participates as one of the representatives of Brazil in the BRICS Innovation Collaboration Working Group on HPC, ICT and AI. He is the coordinator of the Work Group of the Axis 5 - Workforce and Training - of the Brazilian Strategy for Artificial Intelligence (EBIA), and member of the MCTI/EMBRAPII AI Innovation Network Training Committee. He is the coordinator, by SENAI CIMATEC, of the Artificial Intelligence Reference Network of the State of Bahia (REDE BAH.IA). He leads the working group of experts representing Brazil in the Global Partnership on Artificial Intelligence (GPAI), on the theme \"AI and the Pandemic Response\".",institutionString:null,institution:null},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. She is a member of Indian Mathematical Society.",institutionString:null,institution:null},{id:"417317",title:"Mrs.",name:"Chiedza",middleName:null,surname:"Elvina Mashiri",slug:"chiedza-elvina-mashiri",fullName:"Chiedza Elvina Mashiri",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Midlands State University",country:{name:"Zimbabwe"}}},{id:"352140",title:"Dr.",name:"Edina",middleName:null,surname:"Chandiwana",slug:"edina-chandiwana",fullName:"Edina Chandiwana",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Midlands State University",country:{name:"Zimbabwe"}}},{id:"342259",title:"B.Sc.",name:"Leonard",middleName:null,surname:"Mushunje",slug:"leonard-mushunje",fullName:"Leonard Mushunje",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Midlands State University",country:{name:"Zimbabwe"}}},{id:"347042",title:"Mr.",name:"Maxwell",middleName:null,surname:"Mashasha",slug:"maxwell-mashasha",fullName:"Maxwell Mashasha",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Midlands State University",country:{name:"Zimbabwe"}}},{id:"2941",title:"Dr.",name:"Alberto J.",middleName:"Jorge",surname:"Rosales-Silva",slug:"alberto-j.-rosales-silva",fullName:"Alberto J. Rosales-Silva",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"437913",title:"Dr.",name:"Guillermo",middleName:null,surname:"Urriolagoitia-Sosa",slug:"guillermo-urriolagoitia-sosa",fullName:"Guillermo Urriolagoitia-Sosa",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"435126",title:"Prof.",name:"Joaquim",middleName:null,surname:"José de Castro Ferreira",slug:"joaquim-jose-de-castro-ferreira",fullName:"Joaquim José de Castro Ferreira",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Aveiro",country:{name:"Portugal"}}},{id:"437899",title:"MSc.",name:"Miguel Angel",middleName:null,surname:"Ángel Castillo-Martínez",slug:"miguel-angel-angel-castillo-martinez",fullName:"Miguel Angel Ángel Castillo-Martínez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"289955",title:"Dr.",name:"Raja",middleName:null,surname:"Kishor Duggirala",slug:"raja-kishor-duggirala",fullName:"Raja Kishor Duggirala",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jawaharlal Nehru Technological University, Hyderabad",country:{name:"India"}}}]}},subseries:{item:{id:"15",type:"subseries",title:"Chemical Biology",keywords:"Phenolic Compounds, Essential Oils, Modification of Biomolecules, Glycobiology, Combinatorial Chemistry, Therapeutic peptides, Enzyme Inhibitors",scope:"Chemical biology spans the fields of chemistry and biology involving the application of biological and chemical molecules and techniques. In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. This topic will closely deal with all emerging trends in this discipline.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11411,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. 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In many cases, these diseases have adapted so well that they have developed efficient resilience methods in the human host and can live in the host for years. Others, particularly some blood parasites, can cause very acute diseases and are responsible for millions of deaths yearly. Many parasitic diseases are classified as neglected tropical diseases because they have received minimal funding over recent years and, in many cases, are under-reported despite the critical role they play in morbidity and mortality among human and animal hosts. The current topic, Parasitic Infectious Diseases, in the Infectious Diseases Series aims to publish studies on the systematics, epidemiology, molecular biology, genomics, pathogenesis, genetics, and clinical significance of parasitic diseases from blood borne to intestinal parasites as well as zoonotic parasites. We hope to cover all aspects of parasitic diseases to provide current and relevant research data on these very important diseases. 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