Metabolic disorders in PCOS.
\\n\\n
IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\\n\\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\\n\\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\\n\\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\\n\\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\\n\\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\\n\\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\\n\\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\\n\\nFeel free to share this news on social media and help us mark this memorable moment!
\\n\\n\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/237"}},components:[{type:"htmlEditorComponent",content:'
After years of being acknowledged as the world's leading publisher of Open Access books, today, we are proud to announce we’ve successfully launched a portfolio of Open Science journals covering rapidly expanding areas of interdisciplinary research.
\n\n\n\nIntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\n\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\n\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\n\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\n\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\n\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\n\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\n\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\n\nFeel free to share this news on social media and help us mark this memorable moment!
\n\n\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"2467",leadTitle:null,fullTitle:"Metal Forming - Process, Tools, Design",title:"Metal Forming",subtitle:"Process, Tools, Design",reviewType:"peer-reviewed",abstract:"Different aspects of metal forming, consisting of process, tools and design, are presented in this book.\nThe chapters of this book include the state of art and analysis of the processes considering the materials characteristics.\nThe processes of hydroforming, forging and forming of sandwich sheet are discussed. 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Polycystic ovary syndrome (PCOS) is emerging as one of the most common endocrine disorders, affecting about 5–14% of the women of reproductive age and a leading cause of infertility [1, 2, 3]. In recent decades, there has been a wealth of evidence that the disease is a typical example of a female sex specific metabolic syndrome (MetS) due to IR, with obesity having an additional aggravating effect [4, 5, 6]. The interest in PCOS, from its first description in 1935 by Stein and Leventhal as a combination of bilaterally enlarged polycystic ovaries with manifest hirsutism, obesity, amenorrhea/oligomenorrhea, and infertility in a group of women [7], is an ever increasing one, becoming interdisciplinary, as affected girls and young women are at increased risk of cardiovascular disease (CVD) compared to age-matched healthy women [8, 9, 10]. This opinion is based mainly on the metabolic disorders established in PCOS (Table 1).
Overweight/obesity (android type) |
Insulin resistance/hyperinsulinemia |
Impaired fasting glucose (IFG)/impaired glucose tolerance (IGT)/ Diabetes mellitus (DM) type 2 |
Gestational diabetes mellitus |
Dyslipidemia (↓HDL-cholesterol; ↑ triglycerides) |
Arterial hypertension/Arterial hypertension during pregnancy |
Hypercoagulation |
Hyperuricemia |
Metabolic disorders in PCOS.
PCOS is a complex disorder that results from the interaction of diverse genetic and environmental factors. Heritable factors include polycystic ovarian morphology due to functional ovarian steroidogenic defects, hyperandrogenemia, IR, and insulin secretory defects. Acquired obesity is a major postnatal unfavorable factor [11] (Figure 1).
Mechanisms by which obesity may determine the obese PCOS phenotype (adаpted according to [
The major atherogenic risk factor is IR, since excluding all other pathological abnormalities, weight included, the hyperinsulinemic women with PCOS have a 5-fold higher incidence of CVD risk factors than the normoinsulinaemic ones. But the latter, in turn, remain at a significantly higher CVD risk than their age-and BMI-matched healthy controls [12]. This fact supports the main impact of the disease itself. The role of hyperandrogenemia as an independent determinant of CVD risk in PCOS is controversial—there are studies supporting [13] and rejecting [14] the direct link; moreover, elevated androgen levels are interpreted by most authors as being secondary to an underlying IR [15, 16, 17].
Not only does the presence of hyperandrogenemia and IR/compensatory hyperinsulinemia in PCOS elucidate such important pathogenetic mechanisms of the disease, but some clinical observations show that, in fact, the late metabolic complications are more deleterious than the reproductive dysfunction itself. Moreover, recent data from a long-term prospective study indicate that hyperinsulinemia and IR tend to deepen spontaneously in PCOS women, even without worsening of the hyperandrogenism [18]. PCOS is a markedly heterogeneous disease that is why the results of numerous studies on CVD risk assessment in the PCOS women are controversial. This is due to some differences in research trial designs and the characteristics of PCOS women cohorts in terms of weight and anthropometric variables, presence or absence of IR, and other metabolic disorders [19].
Glucose tolerance in women with PCOS was systematically investigated for the first time by Dunaif et al. in 1987 [20]. A number of studies involving large populations of PCOS women reported incidence of
In general, the incidence of a
The PCOS women are more predisposed to development of
Following the initial evidence of Burghen et al. concerning the presence of hyperinsulinemia in PCOS [34], many other investigators obtained similar results demonstrating that both lean and obese PCOS women are characterized by IR and hyperinsulinemia [35, 36]. It has been proved that PCOS women have a more marked IR as compared to age- and BMI-matched healthy women, the difference becoming greater with the increase in BMI [33, 34, 35, 36, 37]. The use of insulin sensitizers significantly improved the characteristic metabolic and endocrine features of PCOS, ovulatory function, menstrual cyclicity, and fertility [19, 38, 39, 40, 41].
It is generally accepted that obese PCOS women are insulin-resistant. The obese PCOS women have higher insulin levels and/or more marked IR, as compared to obese controls and normal-weight PCOS women [42]. Still debatable is the issue whether IR in PCOS depends on weight and/or the android redistribution of adipose tissue, or it is intrinsic to the disease, since there is evidence in both directions [35, 43, 44, 45, 46]. Studies differing in design have obtained similar results, showing that both obese and lean PCOS women have IR and hyperinsulinemia. Some of these differences are due mainly to nonstandardized criteria for diagnosing both PCOS and IR. Family history of DM type 2 is not always taken into account. In addition, there are certain racial and ethnic peculiarities, which become more and more distinct regarding not only the individual characteristics of PCOS, but also the insulin sensitivity and the MetS itself [47, 48, 49].
It is important to know that irrespective of the occurrence of multiple risk factors, DM develops only in the presence of
As it was stated above, the PCOS women have an
With a view to further elucidate post-receptor defects, a reduction in insulin-dependent receptor tyrosine autophosphorylation has been found in isolated fibroblasts of about 50% of PCOS women, as well as an increase in noninsulin dependent receptor serine phosphorylation, i.e., receptor tyrosine kinase activity is inhibited. A factor extrinsic to the insulin receptor, probably serine/threonine kinase, induces serine phosphorylation of the insulin receptor, which results in signal inhibition [57, 58]. This defect leads to IR in the early stages of insulin-receptor-mediated signal transduction. This unique PCOS characteristic distinguishes it from the other clinical conditions with IR [57]. The resultant hyperinsulinemia, arising as it seems upon triggering of puberty, may involve the system of ovarian insulin-like growth factors (IGFs), influence the liver production of the IGF binding protein-1(IGFBP-1), and is probably a pathogenetic factor in the development of the disease [59].
Serine phosphorylation seems to modulate the activity of the key regulatory enzyme of androgen biosynthesis—Р450с17, present in both ovarian and adrenal steroidogenic tissue. In this way, serine phosphorylation enhances enzymatic activity and increases androgen synthesis [60]. It is interesting to note that serine phosphorylation of insulin receptor substrate-1 (IRS-1) is also the mechanism of the TNF-α-mediated IR in obesity [61]. Thus, one and the same defect—serine phosphorylation—is likely to result in both IR and hyperandrogenism. This is a very tempting hypothesis explaining the syndrome pathogenesis; unfortunately, it is valid for only a part (about 50%) of the population of PCOS women.
With view to establishing a defect in insulin action after binding to the receptor, Book and Dunaif [62] investigated the metabolic and mitogenic effects of insulin and IGF-1 in a culture of skin fibroblasts from PCOS women and healthy controls. The authors found that in PCOS, a selective defect was present involving insulin metabolic but not mitogenic signaling pathways; a similar defect was found in the action of IGF-1 (this fact shows that insulin and IGF-1 stimulate glycogen synthetase by one and the same post-receptor pathways) [62]. Poretsky et al. demonstrated that the inhibition of PI-3-kinase activity did not alter insulin-induced stimulation of progesterone production in cultures of human ovarian cells [63]. On the other hand, insulin-stimulated PI-3-kinase activity in skeletal muscles of PCOS women was damaged [64]. The results suggest that the insulin regulation of steroidogenesis and glucose metabolism uses different signaling pathways, the first one remaining functionally active and probably even overstimulated by the increased insulin levels in women with IR [4] (Figure 2).
Role of insulin in the pathogenesis of PCOS.
The hypothesis of presence of a post-receptor defect in insulin action in PCOS is consistent with the results of investigations performed on a molecular level, which have not found structural anomalies in the insulin receptor [65, 66, 67]. What exactly the defect is remains to be elucidated. An evidence provided by Ek et al. [68] suggests a selective impairment in the function of the protein kinase A-dependent hormone-sensitive enzyme lipase, which regulates the lipolytic response to catecholamines in visceral adipose tissue in lean PCOS women with mild IR. An abnormal post-receptor sensitivity to catecholamines has been observed while the antilipolytic sensitivity to insulin is preserved [68]. This anomaly differs from the impaired balance occurring in the MetS between the lipolytic β3- and the antilipolytic α2-adrenoreceptors [69]. It is still unclear whether this unique defect found in PCOS is primary or secondary to other factors, such as increased serum androgen levels.
Thus, the logical question arises—if IR and hyperinsulinemia play a major pathogenetic role in PCOS, why all women with hyperinsulinemia (e.g., with DM type 2) are not hyperandrogenic as well? IR and reproductive disturbances are probably indicative of single genetic defects and IR unmasks the syndrome in genetically predisposed individuals. Because of the fact that PCOS-related IR is a selective one and involves the metabolic but not the mitogenic and signaling pathways, we can explain the paradox of a persistent biological insulin action on reproductive processes on the background of systemic IR [70]. In general, studies have shown that predominantly PCOS women with both hyperandrogenism and chronic anovulation seem to be insulin-resistant. Women with only hyperandrogenism or a morphological finding of polycystic ovaries who have normal ovulation are less likely to develop IR [20, 71].
To sum up,
Schematic representation of the factors regulating ovarian steroidogenesis.
The possible mechanism of insulin-induced enhanced ovarian steroidogenesis is supported by the higher incidence of PCOS in women with DM type 1—the ovaries of the affected women are exposed to hyperinsulinemia resulting from the availability of exogenously administered insulin in the systemic circulation [76].
In approximately 40% of the women diagnosed with PCOS in conformity with the NIH (National Institute of Health) criteria, an IGT or DM type 2 developed as sequelae of IR in the fourth decade of life, the age and weight gain having an unfavorable effect on glycemic control [27, 77, 78, 79, 80]. In addition, a study based on the Rotterdam diagnostic criteria, 2003 reported IR in 71.54% of the studied PCOS women [81].
The incidence of IR, however, differed considerably among the various phenotypes—80.4% in the “classical” one (phenotypes А and В), 65% in the women with normal ovulation (phenotype С) and 38.1% in the group with normoandrogenemia (phenotype D). The classical phenotype and to a lesser degree the phenotype without ovulatory dysfunction were independently associated with IR, whereas in the normoandrogenic phenotype no IR was found [81]. This was confirmed by another study, showing that the number of women with PCOS and a HOMA-index >3.8 is considerably higher in the hyperandrogenic phenotypes, as compared to the normoandrogenic one [82]. That is why the nature and course of carbohydrate disturbances in women with different phenotypic presentations of PCOS require establishing a precise and timely diagnosis, as well as proper behavior by changing one’s lifestyle and dietary regimen, weight reduction whenever needed, with view to reducing the risk of developing DM and/or its complications.
The risk factors for developing carbohydrate disturbances in PCOS are presented in Table 2.
Confirmed | Possible |
---|---|
Age Obesity Abdominal deposition of adipose tissue Insulin resistance β-cell dysfunction Family history of DM type 2 | Chronic anovulation Hyperandrogenemia Dyslipidemia (hypertriglyceridemia) Ethnicity (certain risk populations) |
Risk factors for developing carbohydrate disturbances in PCOS.
Having in mind the incidence of carbohydrate disturbances in the general population of women aged 20–44 (7.8% for IGT and 1.0% for newly diagnosed DM type 2) and the average prevalence of PCOS (about 5%), it can be extrapolated that PCOS-associated IR contributes approximately to 20% of IGT and 40% of DM type 2 in women of reproductive age, which gives prominence to the social importance of this syndrome. In the light of this evidence in 2006, the Аmerican Association of Clinical Endocrinologists (ААСЕ) [83] recommended screening for presence of DM in all PCOS women after the age of 30, irrespective of weight—normal or overweight. Under certain risk circumstances, screening has been recommended before that age as well [83]. Considering the fact that DM type 2 can develop with age progression, the women who have had initially a negative result should be followed-up periodically.
The methods for evaluation of insulin sensitivity are presented in Table 3.
Euglycemic insulin clamp technique |
Minimal model—multiple determination from i.v. GTT |
Sensitivity insulin infusion tests
|
Insulin parameters in oral glucose tolerance test (oGTT)
|
Baseline insulin and derivative indexes, according to baseline blood sugar
|
Methods for evaluation of insulin sensitivity.
In the routine clinical practice a measurement of basal and during oGTT glucose and insulin levels is most frequently used.
The association between PCOS and obesity is complex. In the USA, it was reported that obesity affects from 30 to 75% of PCOS women [41, 84], which is higher than the percentage found in Europe [85, 86]. In a systematic review and meta-analysis of the literature, Lim et al. concluded that in PCOS women, as compared to the age-matched controls, a higher incidence of overweight and obesity was found [87]. In addition, the carriers of the syndrome of the Caucasian origin were found to be more overweight than their counterparts from the Asian origin [87]. These results are compromised to a certain extent by the fact that in most of the published studies, the patients have been selected from clinical practices on the basis of a subjective evaluation and local diagnostic methods. In general, overweight women are more often referred to a specialist for searching PCOS. However, in independent population samples, the incidence of obesity in PCOS does not seem as high as the one found in clinically targeted populations [27, 88]. Furthermore, PCOS incidence, based on the diagnostic criteria of NIH, is relatively stable throughout the world, irrespectively of the variable incidence of obesity in different populations [89].
In one of our studies, we found obesity in 51% and overweight of 22% in an unselected Bulgarian population of 142 women with PCOS [27]. Obesity incidence in our patients was higher than 38% found in women with PCOS from the island of Lesbos, Greece [90], and closer to the one found in England, where around 60% of the studied PCOS women were obese [71]. According to many studies including ours, PCOS women have higher ratio of central to peripheral redistribution of adipose tissue in comparison to controls [27, 91, 92, 93, 94]. Obesity, of visceral type mainly, plays a key role in developing and maintaining the syndrome [95, 96] and influences significantly its severity as well as metabolic and CVD risk, since it is a well-known risk factor for IGT and DM type 2, IR and dyslipidemia [91, 97, 98]. In this respect, insulin sensitizers may exert complex positive effects on both metabolic consequences and clinical manifestations of hyperandrogenism in women with PCOS [19, 47, 48, 83, 91] (Figure 4).
Role of insulin sensitizers in the treatment of PCOS.
Obesity may promote the onset and exacerbate other long-term sequalae of PCOS, including metabolic disorders, the occurrence of some types of carcinoma, potentiated by chronic unopposed estrogen secretion, and leads to further impairing of the quality of life (QOL), low self-esteem, and worsened social adaptation, which may even potentiate occurrence of mental disorders. Obese PCOS women have a more severe clinical picture with higher incidence of IR, hyperinsulinemia, carbohydrate and lipid disturbances, and hyperandrogenism. Many studies, including ours, have shown that overweight PCOS women possess a higher degree of IR in comparison to the lean ones [27, 91, 92, 93, 94].
Data exist that even normal-weight carriers of the syndrome show unfavorable abdominal redistribution of adipose tissue and IR [99]. In a study of young normal-weight PCOS women (mean age 15.9 ± 1.8 years, mean BMI 22.7 ± 2.3 kg/m2) Cree-Green et al. found reduced insulin sensitivity and mitochondrial dysfunction in the muscles, relative postprandial hyperinsulinemia, abnormal glucose disposal, and increased hepatic fat in comparison to healthy controls [100].
PCOS women frequently have decreased
In conclusion, the concomitant obesity, especially of an android type, is associated with an increase in the long-term metabolic risk in women with PCOS.
In the last decades, visceral adipose tissue is perceived as a source of biologically active substances—adipocytokines [103]. Commonly, PCOS women have increased amount of visceral adipose tissue and associated metabolic disorders. The influence of adipose tissue hormones on IR processes, carbohydrate, lipid, and atherogenic disorders in PCOS women is a subject of increased research interest [104].
A close relationship between IR and hyperleptinemia in PCOS women was found irrespective of their weight [105, 106] but the results are mostly controversial due to the differences in the studies designs and the lack of data on the independent effect of obesity, as well as the presence of various phenotype expressions of PCOS. In one of our studies [107], we found higher leptin levels with borderline significance in PCOS women in comparison to age-, weight-, waist circumference-, and WHR-matched healthy controls. Significant correlation of leptin was found with BMI, waist circumference, WHR, percentage of adipose tissue, as well as with basal insulin and HOMA-index in the PCOS group [107]. These findings were confirmed and complemented by our more recent studies of women with IR syndromes, including PCOS [108, 109]. Thus, leptin exhibited significantly positive correlation with BMI, WHR, percentage of adipose tissue, basal glucose and insulin, HOMA-index, total cholesterol, triglycerides, plasma atherogenic index, Castelli I, and Castelli II indexes. A significant negative correlation was found of leptin with Matsuda index, QUICKI-index, and adiponectin [108, 109].
Mohiti-Ardekani et al. [110] also found a positive correlation between free and total leptin levels and HOMA-index in PCOS women (r = 0.78, Р < 0.001; r = 0.84, Р = 0.003, respectively), as well as in healthy controls (r = 0.86, Р < 0.001; r = 0.69, Р < 0.001, respectively). Similar results were reported by authors from Australia [111], Brazil [112], Canada [113], Finland [114], Italy [115], Sweden [116], Turkey [117] and the USA [118, 119]. In a more recent study of PCOS women (mean age 34.30 ± 2.08 years, mean BMI 34.84 ± 4.77 kg/m2) and normally ovulating controls with comparable BMI (mean age 28.10 ± 4.61 years, mean BMI 33.59 ± 1.23 kg/m2) Nomair et al. [120] found higher leptin concentrations in PCOS women in comparison to controls (P = 0.005), significant differences being found in intergroup comparative analysis between the insulin-resistant and non-insulin-resistant PCOS women as well (P = 0.044). In women with PCOS a positive correlation between leptin and BMI (P = 0.049) was found. Authors also consider BMI and IR the two chief factors associated with leptin levels [120].
Our results, as well as those from the above-mentioned studies, are indisputable proof for the role of leptin in the pathogenesis of IR in PCOS.
Adiponectin is a model of an anti-inflammatory adipocytokine. A negative correlation was found between its serum levels and the degree of obesity, IR, IGT, dyslipidemia, and atherosclerosis [121, 122, 123]. The increased amount of visceral adipose tissue results in hypoadiponectinemia due to reduced expression of adiponectin genes. This leads to suppression of the insulin activity in the liver, muscles, and other peripheral tissues. Conversely, the high adiponectin levels are an independent factor for an increased insulin sensitivity and reduced risk for DM type 2. On the basis of the effects on insulin sensitivity and its anti-inflammatory properties, adiponectin is perceived as an antiatherogenic factor. The decreased adiponectin is also combined with increased production of pro-inflammatory proteins IL-6, С-reactive protein (CRP). A positive correlation between the reduced levels of the hormone and the development of ischemic heart disease has been registered [124]. It was established that adiponectin production is suppressed in conditions of IR—DM type 2 and obesity [125]. Low adiponectin levels in obesity are probably due to the process of “down”-regulation mediated by the increased amount of adipose tissue. In a study of a large population in Japan [126] and American Pima Indians [127], adiponectin levels were found to be in negative correlation with the indexes of IR even if the factors age and BMI were excluded.
Initial studies of the levels of this antiatherogenic adipocytokine in women with PCOS were conducted by Orio et al. [128] and Panidis et al. [129]. Orio et al. [128] determined serum adiponectin levels in 60 PCOS women (30 normal-weight and 30 overweight) and in 60 age- and BMI-matched healthy women. Adiponectin levels were significantly lower in obese women in comparison to normal-weight women in the PCOS group, as well as in the control group. A significant difference in adiponectin levels between PCOS women and healthy women was not found, its levels in both groups correlated negatively with BMI and HOMA-index. The authors concluded that adiponectin concentrations vary depending on the quantity of the adipose tissue and that insulin sensitivity does not play a key role in controlling adiponectin levels in PCOS women [128]. Although in other IR conditions adiponectin was found to be decreased, both cited studies reported that in normal-weight PCOS women with IR and hyperinsulinemia its levels did not differ from those in the controls [128, 129].
However, in PCOS women with severe IR, Sepilan et al. found that it was the insulin sensitivity but not the weight that was the chief determinant for adiponectin levels [130]. This fact was confirmed by one of our more recent studies [131], which revealed higher adiponectin levels in non-insulin resistant PCOS women in comparison to insulin resistant ones. In addition, insulin levels and HOMA-index proved to be higher in the group of obese PCOS women in comparison to BMI-matched controls while adiponectin levels were similar in both obese groups. On the other hand, adiponectin concentrations were significantly higher in PCOS women with normal BMI in comparison to those with obesity. In PCOS women a negative correlation between adiponectin and body weight, BMI, waist circumference, hip circumference, WHR, blood glucose at 60 and 120 min, IRI at 0, 60, and 120 min of oGTT, HOMA-index, triglycerides, triglycerides/HDL-cholesterol ratio, plasma atherogenic index, and leptin was found. We observed also a positive correlation of adiponectin with Matsuda and QUICKI indexes [109, 131]. Most probably the relation between adiponectin and IR is confined to the ability of this adipokine to stimulate glucose utilization and to reduce glucose production by the liver [71, 114]. The established significant correlation of adiponectin and androstenedione in PCOS which presupposes some interrelation between this hormone and ovarian steroidogenesis is very interesting and needs further elucidation [11, 131].
It is believed that the
There is controversial data in studies among PCOS women concerning resistin levels in terms of a lack of association with the syndrome [138, 139], or an increase in PCOS [140]. Thus, Panidis et al. [139] did not confirm an active role of resistin in the pathogenesis of PCOS. The authors compared anovulatory PCOS women (obese and non-obese) and healthy controls with normal weight. Resistin was significantly higher only in the obese PCOS women in comparison to the other two groups irrespectively of the differences in insulin levels and the glucose/insulin ratio. Resistin did not correlate with any hormonal or metabolite index in our Bulgarian population of PCOS women with overweight [135]. Pangaribuan et al. [141] also did not find significant difference in serum resistin levels between PCOS women and controls. Meanwhile, the authors did not find significant correlation between resistin, BMI and HOMA-index [141]. Similar serum resistin levels in normal-weight women with or without PCOS were found by Seow et al. [142]. But resistin iRNA expression in adipocytes was twice as high in PCOS women. Probably, the overexpression of the resistin gene plays a role as a local factor [142].
Olszanecka-Glinianowicz et al. [143] studied the association of adiponectin and resistin with the process of IR in PCOS women and controls. All study participants were divided into two subgroups—obese and normal-weight. Comparable serum resistin concentrations between the two subgroups of PCOS women and controls were observed. No correlations between the adipokines, HOMA-index and androgen levels were found [143]. Lewandowski et al. published similar data [144]. The authors did not find a correlation between adiponectin and resistin with the parameters of IR (basal IRI, HOMA-index, QUICKI) [144]. Yilmaz et al. obtained different results—higher resistin in PCOS women in comparison to controls, however, they observed that resistin levels remained independent of the degree of IR and BMI [145] which supports the data of some of the above-mentioned studies.
The results from our studies in adipocytokines in PCOS [47, 48, 104, 107, 108, 109, 146] showed similar resistin levels in PCOS women and metabolically healthy obese women, higher resistin levels in insulin-resistant PCOS women in comparison to non-insulin resistant ones, lack of significant difference among the different subgroups of PCOS women, divided according to BMI. Resistin correlated positively with IRI at 0 and 120 min during oGTT, HOMA-index and negatively with Matsuda and QUICKI indexes [109, 146]. Wang et al. [147] registered significantly higher resistin levels in PCOS women (obese and normal-weight) in comparison to clinically healthy women. In similarity with our data, the authors reported a positive correlation of resistin with HOMA-index and a negative one with adiponectin [147]. Resistin in our study showed a positive correlation with IL-6 [109, 146]. Our data is peculiar in this aspect since it is considered that IL-6 is the main adipocytokine which regulates resistin levels. An
A number of studies on the relation of resistin with obesity, IR, MetS, CVD risk in different age populations have been conducted so far, which, though being controversial in some respects, lead to further clarification of the role of resistin in the processes of atherogenesis [149, 150]. It was found that with the increase in the number of MetS components, serum levels of resistin and other pro-inflammatory markers increase as well [150]. These and a number of other results fully support the hypothesis on the relation between circulating resistin levels and the degree of IR. Having in mind that PCOS is considered a prototype of female specific MetS in young age populations, the role of resistin has to be clarified.
A meta-analysis [153] encompassing a study among 1341 women (695 with PCOS and 646 controls) showed higher visfatin levels in PCOS women without a significant correlation between it and BMI, HOMA-index, and testosterone. The authors concluded that high circulating visfatin can be perceived as a specific characteristic of PCOS, which even presupposes a role for this adipokine as a potential diagnostic biomarker for PCOS [153]. Kowalska et al. [154] found higher visfatin levels and a reduced insulin sensitivity in both normal-weight and obese PCOS women in comparison to healthy controls. Visfatin correlated negatively with parameters of IR, this correlation being well-expressed in normal-weight PCOS women, but missing in obese ones. It must be noted that in some circumstances visfatin does not succeed in exhibiting its beneficial effects on carbohydrate metabolism [154]. A hypothesis that the increase in serum visfatin levels is a secondary process aiming to prevent IR exists. On the other hand, insulin possesses the property to inhibit visfatin expression from the adipocytes so that the observed interrelationship could be explained as an inability of insulin to inhibit visfatin production in an already developed insensitivity to its action [155]. In this context, in the study of Kowalska et al. a positive correlation of visfatin with total testosterone and free androgen index (FAI) in the lean PCOS women was established [154]. The study of Tan et al. [156] also confirmed higher visfatin levels in PCOS women in comparison to age- and weight-matched healthy women. The researchers found a stimulated process of expression of visfatin mRNA and of the protein precursor of visfatin both in subcutaneous and visceral adipose tissue in PCOS women. Plasma visfatin levels were in a positive correlation with basal IRI (Р < 0.01), HOMA-index (Р < 0.01), testosterone (Р = 0.03), and estradiol (Р = 0.046). After performing a multiple regression analysis, the researchers found that the HOMA-index was the only predictive factor for visfatin levels. In contrast to plasma visfatin levels, the expressed visfatin mRNA in subcutaneous and visceral adipose tissue correlated positively with BMI and WHR [156].
In our Bulgarian studies [109, 131], we found higher serum visfatin levels in insulin-resistant PCOS women in comparison to non-insulin resistant ones. Visfatin levels in the PCOS women with obesity/overweight and in the BMI-matched metabolically healthy controls did not differ significantly. In our PCOS women, a negative correlation of visfatin with HDL-cholesterol and Matsuda index was found as well as a positive one with diastolic arterial pressure [109, 131]. In similarity to our results, Kowalska et al. reported a negative correlation between visfatin and HDL-cholesterol (r = −0.27, Р = 0.004) [154]. Such negative correlation (r = −0.349, Р = 0.013) was confirmed also by El-Said et al. [157] in insulin resistant PCOS women. In addition, the authors reported a positive correlation of visfatin with BMI, waist circumference, HOMA-index, FAI and a negative one with LH, total testosterone and sex hormone-binding globulin (SHBG
It appears that there is controversy with respect to the relation of visfatin with insulin sensitivity indexes in women with IR and namely with PCOS and MetS. The main action of visfatin is intended at prevention of IR development as it was already pointed out, and this can explain its increase in PCOS women. The negative correlation of visfatin with IRI and HOMA-index and respectively the positive one with atherogenic indexes QUICKI and Matsuda in women with overt MetS registered in our studies is in support of this suggestion. Visfatin secretion control is a subject of increased research interest that arises much debate. Up till now, the conducted clinical studies comprising insulin resistant individuals with obesity and MetS, exhibit controversial results. The changes in this adipocytokine in PCOS women with different phenotypes are still to be clarified in targeted studies.
Adipose tissue is an important source of factors of low-grade inflammation not only due to the production of various cytokines by the adipocytes themselves, but also because of tissue infiltration with pro-inflammatory macrophages. The adipose tissue macrophages are responsible for the production of almost the entire amount of
Elevated levels of TNF-α have been observed in PCOS women, which correlated positively with BMI and negatively with insulin sensitivity [166]. Gonzalez et al. [167] found elevated levels of TNF-α in normal-weight PCOS women as compared to controls. However, in all obese women in this study, despite the absence/presence of PCOS, TNF-α levels were similar. Direct correlation of TNF-α was detected with BMI, but with insulin such a correlation was found only in the healthy women. Apparently, factors other than obesity were the cause of TNF-α increase in normal-weight PCOS women. On the other hand, this cytokine did not correlate with testosterone, LH, and DHEA-S in the PCOS women [167].
We found significantly higher TNF-α concentrations in PCOS women compared to BMI-matched controls [109, 131]. In our studies, we did not establish a significant difference when comparing serum levels of TNF-α between insulin-resistant and non-insulin-resistant PCOS women. Higher levels of TNF-α were registered in obese PCOS women as compared to overweight PCOS women, but not to normal weight PCOS women. No correlations between TNF-α and the parameters of IR were established in the PCOS women [109, 131]. Contrary to our results are those of Soares et al., who did not detect a significant difference in the TNF-α levels between PCOS women and BMI-matched controls [168].
Data are controversial regarding the role of
Mohlig et al. [174] studied IL-6 and CRP in PCOS women and in age-matched controls, analyzing the influence of C-174G-IL-6 gene polymorphism on the IL-6 and androgens levels, and on the degree of obesity. The authors did not find elevated CRP and IL-6 levels in PCOS women (both lean and obese) compared to the controls. In PCOS women the anthropometric variables (BMI, WHR, amount of adipose tissue) and the parameters of IR, but not the markers of hyperandrogenic condition, showed significant correlation with IL-6 and CRP. In addition, a 6-month metformin treatment resulted in a significant decrease in the body weight, the amount of adipose tissue and total testosterone levels, but did not affect the levels of IL-6 and CRP. Using multivariate linear regression analysis, it was established that in PCOS women BMI but not HOMA-index constituted a dominant factor explaining 18% and 24% of the variations in IL-6 and CRP levels, respectively [174].
This fact was also confirmed by another study conducted in pre-menopausal women [175]. In the study of Mohlig et al. [174], no link between the C-genotype and the IL-6 and BMI levels was found. However, the heterogeneous GC genotype was associated with lower levels of androstenedione [174]. The C-174G polymorphisms of the IL-6 gene promoter could be expected to modify its activity in certain
Our studies [107, 108, 109, 131] showed similar levels of IL-6 between the groups of PCOS women—insulin-resistant
In a study of Tarkun et al. [181] in PCOS women and age- and weight-matched healthy women, a comparative analysis of TNF-α and IL-6 was made, with an assessment of their role in IR pathogenesis. Higher concentrations of TNF-α and IL-6 were found in PCOS women compared to controls. A positive correlation was observed between TNF-α and BMI, waist circumference, triglycerides, basal insulin and HOMA-index (P < 0.001). IL-6 correlated positively with basal glucose and degree of IR (P < 0.05). The authors concluded that TNF-α and IL-6 have a pathogenetic role in the development of IR in PCOS [181].
In another study consisting of obese PCOS women, weight-matched healthy women and normal weight controls Vgontzas et al. [182] determined basal cytokine concentrations and conducted an 8-h nocturnal polysomnography searching for obstructive sleep apnea syndrome. Higher IL-6 plasma concentrations were observed in PCOS women as compared to obese and normal-weight controls (4.75 ± 0.5; 3.65 ± 0.4; 1.84 ± 0.3 pg/mL, respectively, P < 0.01). TNF-α levels were somewhat higher in the obese PCOS and control women compared to the normal-weight women, but the differences did not reach statistical significance (4.05 ± 0.3; 3.79 ± 0.2; 3.14 ± 0.2 pg/mL, respectively, P = 0.103). IL-6 and TNFα correlated positively with BMI (P < 0.01) in the obese healthy women, but not in the obese PCOS women. In addition, a stronger correlation of IL-6 and TNF-α levels with IR indexes (HOMA and QUICKI) was established in the PCOS women than in the obese controls. The authors came to the conclusion that IL-6 may be elevated in PCOS women, irrespectively of obesity and presence of obstructive sleep apnea, and may have a role in the process of IR in this syndrome [182].
Grimaldi Barcellos et al. [183] investigated the impact of PCOS and obesity on the levels of TNFα, IL-6 and CRP in young PCOS women and age- and BMI-matched women with a normal menstrual cycle without CVD risk factors (DM, dyslipidemia, arterial hypertension). The authors did not establish a significant difference in the levels of TNF-α, IL-6 and CRP between the PCOS women and the controls (2.1
The pathogenesis of an inflammatory process development in MetS, and in particular in PCOS, has not yet been fully clarified. In scientific terms, the most logical and most widespread is the explanation that the higher amount of adipose tissue in case of obesity leads to increased excretion of IL-6 and TNF-α in the circulation, which in turn causes increased production of CRP by the liver. There is another hypothesis highlighting IR as the primary cause of the higher production of cytokines [184].
Women with PCOS, combining IR and hyperandrogenism are carriers of an unfavorable cardiovascular risk profile. However, data concerning the long-term risk of cardiovascular morbidity and mortality are scarce, controversial and this issue has not yet been addressed appropriately in targeted large prospective studies. However, since there is compelling evidence of the presence of MetS components and early stages of atherosclerotic processes in young PCOS women that are still reversible, it is essential that they must be diagnosed on the basis of the current knowledge in order to administer adequate complex treatment to prevent late consequences of IR.
The future of psychiatry is neurodevelopmental. One of the tragedies of the twentieth century, more particularly in child and adolescent psychiatry, is the tradition of blaming families and particularly mothers for psychiatric problems. Tragically, we had “schizophrenogenic mothers” as “causes” of schizophrenia and “refrigerated mothers” as “causes” of autism. Even more recently, tragically, John Bowlby [1], in discussing “causal factors” in relation to autism, mentioned “inappropriate mothering”. This is another mother-blaming idea. The current understanding of these disorders, intellectual disability, ADHD, autism, Asperger’s syndrome, tics, etc., is a neurodevelopmental disorder with schizophrenia and bipolar disorder also being neurodevelopmental, and all have significant neurobiological inputs. Some personality disorders should also be considered as being on the neurodevelopmental spectrum. The neurodevelopmental trajectory will include the addition of more neurodevelopmental disorders, e.g., bipolar, schizophrenia and depression as the person gets older.
\nAll diagnoses of autism have to take a developmental history from childhood, which will include persistent deficits in social communication and social interaction from the early developmental period, as well as restricted, repetitive patterns of behaviour causing clinically significant impairment in functioning (American Psychiatric Association [2]). The problem with adult autism diagnosis will include getting a relatively early history from an informant which may be a parent or other, the problem of camouflaging because of treatment or just life experience which makes it more difficult to diagnose the adult with autism. They may have learned about eye contact, etc. School reports or home videos sometimes help. They will often present with comorbidities, for example, depression, (70%), anxiety (40%), attention deficit disorder or psychosis. Mazefsky and White [3] “caution against excessive reliance on ADOS (Autism Diagnostic Observation Scale), Lord et al. [4] for diagnosis”.
\nSchizophrenia and bipolar disorder are now seen as neurodevelopmental disorders with a widening of the neurodevelopmental spectrum.
\nEvans [5] states that the diagnosis of “schizophrenia, psychosis and autism in children, were largely interchangeable during the 1940s and 1950s” [6]. They were described as separate by Kolvin et al. [7]. This view was not supported [8].
\nAccording to Scull [9], Steven Hyman, the former director of NIMH stated that DSM 5 “was totally wrong in the way it’s authors could not have imagined. So in fact, what they produced was an absolute scientific nightmare. Many people who got one diagnosis got five diagnoses, but they did not have five diseases—they have one underlying condition”. Thomas Insel [9], who was also the director of the NIMH stated that DSM 5 showed “a lack of validity … as long as the research community takes DSM 5 to be a bible, we will never make progress. People think that everything has to match DSM 5 criteria, but what you know … biology never the book, and he went on to point out that in future the NIMH would be, “re-orientating into research away from DSM 5 categories … patients with mental illness deserve better”. Indeed, the NIMHS, under their director, Insel, gave up on this and aimed at a transdiagnostic study of psychiatric problems, and further studies should be based on biomarkers, neuroimaging and laboratory tests. This is a good aspiration and research efforts are being made in that direction. Clearly, Hyman and Insel were absolutely correct. He [9] proposed Research Domain Criteria to collect “genomic, cellular, imaging, social and behavioural information”, and he also recommended focusing on the brain and “connectopathies”. Thomas Insel noted that psychiatrists “actually believe, (that their diagnoses) are real, but there’s no reality. They are just constructs”. The first step is to analyse the huge spectrum of empathy and diagnosis.
\nRutter [10] states that “the concept of autism as a variety of schizophrenia is very probably wrong”. The real answer is that they overlap and are not watertight categories. Rutter [11] stated that “infantile autism is not anything to do with schizophrenia, is not primarily a disorder of social relationship”. This is incorrect because they do overlap and autism is primarily a disorder of social relationships. Sullivan et al. [8] point out that “ASD, schizophrenia and bipolar disorder share common aetiological factors”. This would be supported by Abel [12] who points out that “it has been suggested that, (as for common genetic variants), many of the candidate genes identified may not be coding for schizophrenia per se, but for a broader construct such as psychosis, or neurocognitive deficits which occur in schizophrenia and other conditions”. Rapaport et al. [13] states that many individually rare genetic abnormalities affect common pathways containing hundreds of genes that affect neuronal development and regulation. Carroll et al. [14] point out that some of the specific genetic loci implicated encode proteins, such as neurexins and neuroligins, which function in synaptic development and plasticity and therefore represent a common biological pathway for disorders. Fatemi [15] points out the pathological involvement of Reelin gene or its protein product in autism and schizophrenia. Reelin is a glycoprotein that helps guide brain development in an orderly fashion [15]. Fatemi [15] notes that Reelin deficits may cause abnormal corticogenesis and alter synaptic plasticity. In addition, Burbach et al. [16] note that contact in associated protein affects receptor/signalling units and are thought to mediate neuron-glial cell interactions, neuron migration and dendritic orientation. Contactin is a member of the neurexin family, and there are deletions and disruptions in neurexin 1 in autism and schizophrenia.
\nRutter [17] points out that “adult schizophrenia is rare in both parents and brothers and sisters of autistic children”. This is incorrect. Stone et al. [18] pointed out that there’s evidence that parental diagnosis of schizophrenia was associated with elevated rates of autism offspring. Rapaport et al. [13] points out that familial schizophrenia like psychosis is a risk factor for “narrowly defined autism”.
\nBoth autism and schizophrenia can show formal thought disorder with poverty of content, illogical and loose associations. Solomon et al. [19] pointed out that when patients with first episode psychosis were compared to patients with ASD, they showed problems with semantics, syntax and coherence, although these deficits are more severe in ASD. They also noted that social interactional deficits are part of both conditions. Both have theory of mind deficits and problems with eye to eye gaze. In addition, they both have problems reading emotions from faces. Chris Frith [20] points out that “social withdrawal, stereotyped behaviour, and lack of communication are all typical features of childhood autism and chronic ‘negative’ schizophrenia”. He emphasised mentalisation deficits in schizophrenia, which also occur in autism. In fact, they both show a disturbed sense of self. In comparison with schizophrenia, persons with autism show greater problems in reading faces, greater poverty of speech, as well as content and more perseveration of language, including echolalia and pronominal reversal, and more problems with set shifting and preservation of sameness. In comparison with autism, persons with schizophrenia show greater illogicality of thought, show more positive symptoms of psychosis, have mostly later onset (different from autism), run a more elapsing remitting course, show less stereotyped and repetitive behaviour, show less resistance to change, show less challenging behaviour as on an in-patient ward and show more jumping to conclusions.
\nCraddock and Owen [21] discuss a gradient of neurodevelopmental psychopathology from mental retardation to autism to schizophrenia to schizoaffective disorder to bipolar disorder. Nevertheless, the developmental process underlying these similar end points in autism and schizophrenia may be very different. Sporn et al. [22] suggest that “autistic behaviour may be a non-specific response to a variety of early developmental insults, and thus pre-morbid PDD (Pervasive Developmental Disorder) features in early onset schizophrenia may be an exaggeration of neurodevelopmental abnormalities seen in adult schizophrenia” and that “autism may reflect a separate additive risk factor for schizophrenia with very early onset”. Certainly, psychotic risk factors are very similar to autistic symptoms, as is the case with schizotaxia, schizotypal personality disorder and schizoid personality disorder.
\nRutter [23] states that delusions and hallucinations “are quite rare in autistic children, even when they reach adolescence and early adult life”. This has not been my clinical experience, having diagnosed about 5000 children and adults and currently being involved with over 100 persons with autism in in-patient and out-patient settings.
\nSimple schizophrenia Kolb [24] is simply autism spectrum disorder. In my view, the so-called simple schizophrenia involves a disturbance of emotion, disturbance of interest, disturbance of activity, impoverishment of personality, shallowness of emotions and eccentricities. This would be classical high-functioning autism or what was called Asperger’s syndrome in former classifications ICD 10 [25]. This is currently being updated.
\nKanner [26] was correct when he pointed out that “the extreme isolation from people … infantile autism bears so close a resemblance to schizophrenic withdrawal that the relationship between the two conditions deserves serious consideration”. Of course other times, he described them as very separate. Asperger [27] pointed out that “the schizophrenic patient seems to show progressive loss of contact, the children we diagnose (now called Asperger’s syndrome), lack contact from the start”. The problem here is that some of the patients with autism do follow this pattern, but others have regressive autism, where they develop normally and then regress with loss of language, etc. I’ve seen this occurring up to 3 or 4 years of age.
\nRutter [11] states that “the social class of parents of autistic children is most unlike that of the parents of schizophrenics. A high proportion of the parents of autistic children are of above average intelligence and superior socio-economic states”. This is incorrect, as shown by Gillberg and Schumann [28]. In my clinical practice, I constantly see patients from every social class with autism and observe schizophrenia, bipolar disorder, etc. in their family histories.
\nUsing narrow criteria of autism ADI-R, etc., Baird et al. [29] found a prevalence of 25 per 10,000, but when the broader autism spectrum criterium was used, a prevalence of 116 per 10,000 was found. This unfortunately means that over three quarters of the persons with autism in the community have what I would call “real” autism or clinical autism (autism spectrum disorder) and were missed by these narrow-based instruments. Currently, the prevalence of autism is 1/59 CDC and 1/37 males [30].
\n\nSee Table 1 attached.
\nAsperger syndrome (DSM-IV) diagnostic criteria | \nImpairment in use of eye-to-eye gaze, facial expression, body postures | \nFailure to develop peer relationships to developmental level | \nLack of spontaneous seeking to share enjoyment | \nLack of social and emotional reciprocity | \npre-occupation with one or more stereotyped pattern of interest | \nInflexible adherence to specific non-functional routines or rituals | \nStereotyped and repetitive motor mannerisms | \nPersistent pre-occupation with parts of objects | \nClinically significant impairment in social or occupational functioning | \nNo clinically significant delay in language development | \nNo clinically significant delay in cognitive development or self-help skills | \n
---|---|---|---|---|---|---|---|---|---|---|---|
Schizoid personality in childhood | \n\n | Yes | \nYes | \nYes | \nYes | \nYes | \n\n | \n | Yes | \nYes | \nYes | \n
Obsessive compulsive personality disorder | \n\n | \n | Yes, often | \nYes, often | \nYes | \nYes | \n\n | \n | Yes | \nYes | \nYes | \n
Schizotypal disorder | \n\n | Yes | \nYes | \nYes | \nYes, sometimes | \n\n | \n | \n | Yes | \nYes | \nYes | \n
Avoidant personality disorder | \nYes | \nYes | \nYes | \nYes | \n\n | Yes | \n\n | \n | Yes | \nYes | \nYes | \n
Differential diagnosis of neurodevelopmental disorders (Asperger’s syndrome).
Canitano et al. [31] showed that 22% of ASDs presented with tic disorder, but there was a “difficulty in discriminating complex tics and OCD symptoms, and ASD symptoms”. Nevertheless, the overlap between neurodevelopmental disorders is consistent. This equates with clinical experience and clinical reality. Maybe we need a subcategory called ASD plus tics and another category ASD without tics, another category with tics with ADHD and another category tics without ADHD, tics without OCD, etc. Stein [32] notes the overlap between autism, tics and stereotypic movement disorder. There is considerable neurobiological data in relation to OCD spectrum disorder. Stein [32] again emphasises the “possibly overlapping phenomenological and neurobiological features”. Stein [32] points out that “there is increasing evidence that a sub-set of OCD may be genetically related to Tourette’s Disorder, manifests with tics or OCD and involving both the serotonin or dopamine systems and the basal ganglia”. Meir et al. [33] showed that “individuals diagnosed with OCD displayed a nearly four-fold higher risk to be diagnosed with ASD in later life” and that “the high co-morbidity sequential risk and shared familial risks between OCD and ASD’s are suggestive of partially shared etiological mechanism”. It would appear then that some neurosis (OCD) could be neurodevelopmental in origin, at least partly. This again shows the lack of sharp delineation between psychiatric diagnoses.
\nThere is a very high comorbidity between autism and ADHD. Child psychiatric disorders have a comorbidity more than expected by chance [34]. Attention and hyperactivity are common in many disorders and, indeed, many more disorders in child psychiatry, and there is clearly poor separation of condition at a clinical level. Measurement issues are common. In relation to comorbidity, there are shared risks factors and one disorder creating an increased risk for another disorder. Neil et al. [35] pointed out that there are correlated liabilities where the risk factors of the two disorders correlate. There are social deficits in both ADHD and autism with overlap from an etiological point of view, but with ADHD the social deficits are more impulsive, and with autism, the social deficits can again be impulsive, but also, they can be due to lack of social know-how and theory of mind deficits. There is no sharp division here.
\nIn a study of ADHD combined type, with one or more siblings, the diagnosis of autism was excluded at the beginning, and siblings with ADHD were compared with siblings without ADHD by Mulligan et al. [36]. They wrote that phenotypic correlation of ADHD and autism symptoms was 0.71 and that 32% of this correlation was due to shared familial characteristics but with a higher percentage for male ADHD probands. There was a trend for children with high ADHD symptoms to have high autism symptoms, as measured by the Social Communication Questionnaire. ADHD probands with definite language disorder or motor disorder had significantly higher symptoms of autism than those without. This study showed that autism symptoms as part of the ADHD phenotype were partly true. These were familial. Probands with autistic traits tend to have siblings with autistic traits, and probands without autistic traits tend to have affected siblings without autistic traits. Finally, latent class analysis of SCQ symptoms in probands with ADHD combined type showed the following clusters of autism symptoms: 31% with few or no symptoms of autism, 22.5% with repetitive and stereotyped behaviour, 21% with communication domain symptoms, 18.5% communication and reciprocal interaction domains and 7% who had symptoms in all three domains.
\nThe percentage of phenotypic correlation due to shared familial influences (autistic symptoms and ADHD) was 35% for the whole group and 62% for males and 12% for females. In a family with a male child with ADHD and comorbid autistic symptoms, a second child with ADHD is also likely to have comorbid autistic symptoms (not so female), which suggest a different aetiology according to sex. Gillberg’s [37] disorder of attention, motor control and perception would be showing similar findings. Fifty percent of children with DAMP had autistic features.
\nChildren with oppositional defiant disorder and conduct disorder have more autistic traits than children without these comorbid disorders and ADHD [38]. Children with ADHD have more subthreshold symptoms of autism. Children with combined ADHD and social communication deficits are at increased risk of motor and language disorders. Overall, this shows the massive heterogeneity that is evident in child psychiatry classifications, and clearly, ADHD is not a homogenous disorder. Forty two percent of children with ADHD had few symptoms of autism. That autism symptoms are part of the ADHD phenotype is partly true. Autistic traits in ADHD are familial. This again supports the lack of a sharp overlap between neurodevelopmental disorders, here, autism and ADHD.
\nIf I was to plan an assessment programme in child psychiatry again from the start, I would assess the following dimensions: social reciprocity, pragmatic language, oppositionality, working memory, delinquency, attention, impulsivity, activity, capacity to read non-verbal behaviour, preservation of sameness and fixations.
\nThis would be a transdiagnostic approach.
\nA not insignificant number of personality disorders are developmental disorders. This will require further research. One example is schizoid personality disorder. Another is paranoid personality disorder and, another, borderline personality disorder. Obsessive compulsive personality disorder could be also included in this group. There’s quite a good case for narcissistic personality disorder to be included. An older term, anankastic personality disorder [39], could also be included. Many individuals with psychopathy have a developmental disorder, and a group of these have been called criminal autistic psychopathy [40]. There is a clear overlap between psychopathy and autism spectrum disorders. This is despite some research showing that persons with psychopathy have good theory of mind skills, while persons with autism don’t. Nevertheless, more recent research has shown that particularly persons with high IQ can have good theory of mind skills while, at the same time, having autism.
\nBlair [41] stated that “cognitive empathy or theory of mind is intact in individuals with psychopathy”. These ideas have been very seriously undermined by Drayton et al. [42] in relation to automatic perspective taking. Previous research did not take the complexity of cognitive empathy into account, and this led to serious misunderstandings of cognitive empathy. Drayton et al. [42] point out that “automatic theory of mind processes are engaged when an individual unintentionally represents the perspective of another person,” also called “altercentric interference”. Drayton et al. [42] suggest that “psychopathic individuals have a diminished propensity to automatically think from another’s perspective, which may be the cognitive root of their deficits in social functioning and moral behaviour”. Drayton et al. [42] raise, for this author, the possible failure of previous research on theory of mind and psychopathy, failing “to tap into a critical component of normal theory of mind processing; or tendency to take other’s perspective automatically”. Drayton et al. [42] defined “automatic theory of mind processes” as an individual representing “the thoughts and feelings of another person without intending to do so”. They also point out that psychopathic individuals have a previously unobserved cognitive deficit that might explain their patterns of destructive and anti-social behaviour, that is, … failure “to automatically take the perspective of others, but can deliberately (controlled), take the perspective of others”. These findings suggest that psychopathic individuals have the ability to take the perspective of others but lack the propensity to do so. It seems they can pass theory of mind tasks in the research situation but fail to do so in the real world situation. This is one of the endless problems of laboratory research not translating into the “real world,” that is, the clinical world. This lack of generalisation can be a serious flaw in academic psychological research. Drayton et al. [42] note that “psychopathic individuals do show deficits in their ability to understand what others are feeling but this capacity to represent other feelings appears to be distinct from capacity to represent what others see and believe”. They also point out that “psychopathic individuals appear to represent other’s perspective in a relatively typical manner when doing so. It is goal-conducive and yet is able to ignore other’s perspective when it is not conducive”. This means that all previous theory of mind research on psychopathy missed the fundamental point of the deficit of automatic perspective of others. Drayton et al. [42] point out that “this combination of relatively intact deliberative Theory of Mind but impaired spontaneous theory of mind may allow psychopathic individuals to use information about others’ mental states to achieve their own ends, while at the same avoid the, ‘cost,’ of automatically representing other’s mental states, resulting in callous and chronic criminal behaviour”. They have no empathic interest in other minds, except getting their own egocentric desires met.
\nIn relation to psychiatry, there’s a sharp difference between findings in university laboratories and the findings in clinical practice. Research groups are very rarefied and very often do not represent what is found in the general population, clinically. An example is autism defined by the Autism Diagnostic Interview or Autism Diagnostic Observational Scale which give you a very narrow definition of autism, very unlike what you find in the general population which is the broader autism phenotype [43].
\nAsperger originally defined persons with autism as being autistic psychopaths, which Frith [44] described as autistic psychopathy or autistic personality disorder. In actual fact, there is a lot of truth in Asperger’s [27] definition of autistic psychopaths. This has been brought back now with the terms criminal autistic psychopathy [40, 45]. Indeed, the following could be seen as synonyms, autistic psychopathy, autistic personality disorder, high-functioning autism and Asperger’s syndrome.
\nThe kind of criminality seen in autism (criminal autistic psychopathy) would include arson, stalking, sex offences and strange repetitive crimes. According to the Centers for Disease Control [30], developmental disorders are characterised by problems with language, mobility, self-help and independent living. There is a myth that ASD and personality disorder and psychopathy are completely different. There is also a myth that autism and Asperger’s syndrome have little or no relationship with criminality and serious murder. Patricia Howlin [46] stated “little, if any significant association between autism and criminal offending”. This is clearly not supported by my reading of the literature [40]. Sipponma [47] pointed out that 27% of adult offenders in her study met criteria for autism spectrum disorder. These could be called criminal autistic psychopathy. Ashead and Sarkar [48] described correctly personality disorders as “developmental in nature”, and they noted that personality regulates social relationships, arousal impulsivity and emotions, as well as self-directedness and self-soothing as well as verbal and non-verbal communication problems. What is of interest is that all of these areas are abnormal in ASD and personality disorder.
\nAshead and Sarkar [48] note the following clusters of personality disorders: odd, eccentric behaviour; anti-social, borderline and narcissistic personality disorders; fearful and anxious behaviour; and avoidant, dependent and obsessive compulsive.
\nAll these clusters, clearly at a descriptive level, overlap with ASD. Ashead and Sarkar [48] describe the following features of personality disorder:
Emotional indifference
Anger, suspicion and fearfulness
Fears of others attacking and threatening them
Brief psychotic episodes
Odd beliefs
Magical thinking
Preoccupation and ruminations
Identity confusion
Empathy problems
Major problems in in-patient units
Failure to confirm to social norms
Social relationship problems
Social reciprocity problems
Impulsivity
Irrationality
Disregard for safety of self and others
Reduced reaction to upset in other people
Preoccupation with one or more stereotyped patterns of behaviour
Problems with emotional processing
Emotional detection problems
Reduced observing self
Reduced self-awareness and capacity to decentre the self
Egocentricity
Low affiliation and harm avoidance
All of these features also occur in autism spectrum disorders. Of course, in a way, this is not surprising since the boundaries between most psychiatric disorders are fluid and we do not have an accurate, categorical diagnosis at this point in time, assuming we ever will.
\nIt’s interesting that Wolfe [49], in her group of schizoid disorder overlapping with Asperger’s syndrome, found “fraudulent behaviour and pathological lying”; in that, 5 out of 13 had “falsely reported their parents of being cruel to them” and “had used aliases”.
\nThere is a myth that persons with high-functioning autism cannot lie. This is utterly false, as from a clinical perspective, many parents complain to me about their children with high-functioning autism being what they call “inveterate liars”. Of course, the great majority of persons with autism are the opposite and are incredibly honest, open, moral, etc. These features of autism spectrum disorder occur in the general population, as do features of personality disorder. It’s only when you get to a certain threshold that you would get a diagnosis of autism or personality disorder. In truth, we need a new classification system in psychiatry again. The problem is that most of our current disorders overlap and are therefore not independent. We need to go back from a classificatory point of view, to a pre-Kraepelin period and, in a way, that is, what the NIMH is stating with their transdiagnostic research.
\nThere are a number of phrases associated with personality disorder, which could also be associated with autism spectrum disorder:
Schizoid personality, “you can knock, but nobody’s home” [50].
Schizotypal personality, “I’m eccentric, different, strange” [50].
Paranoid personality, “you can’t trust anybody” [50].
Borderline personality, “I will be very angry, if you try to leave me” [50].
The sadistic personality, “I will savour your suffering” [50]. This particularly refers to criminal autistic psychopathy and serial killers.
Narcissistic personality, “my command is your wish” [50].
The future of psychiatry will be neurodevelopmental. Psychiatrists will focus on these conditions. Mild psychiatric conditions will be dealt with by psychiatric counsellors and psychologists, using psychotherapeutic interventions. This will allow psychiatrists to become neuropsychiatrists which they are all already moving towards. The “blaming” culture of attributing these disorders to mothers’ inadequacies will then be at an end. The neurodevelopmental spectrum is far wider and far more important than suggested by DSM 5 [2, 3].
\nIntechOpen - where academia and industry create content with global impact
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\n\nSara Uhac, COO
\n\nSara Uhac was appointed Managing Director of IntechOpen at the beginning of 2014. She directs and controls the company’s operations. Sara joined IntechOpen in 2010 as Head of Journal Publishing, a new strategically underdeveloped department at that time. After obtaining a Master's degree in Media Management, she completed her Ph.D. at the University of Lugano, Switzerland. She holds a BA in Financial Market Management from the Bocconi University in Milan, Italy, where she started her career in the American publishing house Condé Nast and further collaborated with the UK-based publishing company Time Out. Sara was awarded a professional degree in Publishing from Yale University (2012). She is a member of the professional branch association of "Publishers, Designers and Graphic Artists" at the Croatian Chamber of Commerce.
\n\nAdrian Assad De Marco
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\n\nDr Alex Lazinica
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She is also Invisalign certified. She’s working as a Senior Lecturer in the Department of Orthodontics, SRM Dental College since November 2019. She is actively involved in teaching orthodontics to the undergraduates and the postgraduates. Her clinical research topics include new orthodontic brackets, fixed appliances and TADs. She’s published 4 articles in well renowned indexed journals and has a published patency of her own. Her private practice is currently limited to orthodontics and works as a consultant in various clinics.",institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"323731",title:"Prof.",name:"Deepak M.",middleName:"Macchindra",surname:"Vikhe",slug:"deepak-m.-vikhe",fullName:"Deepak M. Vikhe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/323731/images/13613_n.jpg",biography:"Dr Deepak M.Vikhe .\n\n\t\n\tDr Deepak M.Vikhe , completed his Masters & PhD in Prosthodontics from Rural Dental College, Loni securing third rank in the Pravara Institute of Medical Sciences Deemed University. He was awarded Dr.G.C.DAS Memorial Award for Research on Implants at 39th IPS conference Dubai (U A E).He has two patents under his name. He has received Dr.Saraswati medal award for best research for implant study in 2017.He has received Fully funded scholarship to Spain ,university of Santiago de Compostela. He has completed fellowship in Implantlogy from Noble Biocare. \nHe has attended various conferences and CDE programmes and has national publications to his credit. His field of interest is in Implant supported prosthesis. Presently he is working as a associate professor in the Dept of Prosthodontics, Rural Dental College, Loni and maintains a successful private practice specialising in Implantology at Rahata.\n\nEmail: drdeepak_mvikhe@yahoo.com..................",institutionString:null,institution:{name:"Pravara Institute of Medical Sciences",country:{name:"India"}}},{id:"204110",title:"Dr.",name:"Ahmed A.",middleName:null,surname:"Madfa",slug:"ahmed-a.-madfa",fullName:"Ahmed A. Madfa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204110/images/system/204110.jpg",biography:"Dr. Madfa is currently Associate Professor of Endodontics at Thamar University and a visiting lecturer at Sana'a University and University of Sciences and Technology. He has more than 6 years of experience in teaching. His research interests include root canal morphology, functionally graded concept, dental biomaterials, epidemiology and dental education, biomimetic restoration, finite element analysis and endodontic regeneration. Dr. Madfa has numerous international publications, full articles, two patents, a book and a book chapter. Furthermore, he won 14 international scientific awards. Furthermore, he is involved in many academic activities ranging from editorial board member, reviewer for many international journals and postgraduate students' supervisor. Besides, I deliver many courses and training workshops at various scientific events. Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Univeristy of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:null},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:null},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. Her knowledge of English is at an advanced level.",institutionString:null,institution:null},{id:"332914",title:"Dr.",name:"Muhammad Saad",middleName:null,surname:"Shaikh",slug:"muhammad-saad-shaikh",fullName:"Muhammad Saad Shaikh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jinnah Sindh Medical University",country:{name:"Pakistan"}}},{id:"315775",title:"Dr.",name:"Feng",middleName:null,surname:"Luo",slug:"feng-luo",fullName:"Feng Luo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sichuan University",country:{name:"China"}}},{id:"423519",title:"Dr.",name:"Sizakele",middleName:null,surname:"Ngwenya",slug:"sizakele-ngwenya",fullName:"Sizakele Ngwenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419270",title:"Dr.",name:"Ann",middleName:null,surname:"Chianchitlert",slug:"ann-chianchitlert",fullName:"Ann Chianchitlert",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419271",title:"Dr.",name:"Diane",middleName:null,surname:"Selvido",slug:"diane-selvido",fullName:"Diane Selvido",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419272",title:"Dr.",name:"Irin",middleName:null,surname:"Sirisoontorn",slug:"irin-sirisoontorn",fullName:"Irin Sirisoontorn",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"355660",title:"Dr.",name:"Anitha",middleName:null,surname:"Mani",slug:"anitha-mani",fullName:"Anitha Mani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"355612",title:"Dr.",name:"Janani",middleName:null,surname:"Karthikeyan",slug:"janani-karthikeyan",fullName:"Janani Karthikeyan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"334400",title:"Dr.",name:"Suvetha",middleName:null,surname:"Siva",slug:"suvetha-siva",fullName:"Suvetha Siva",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}}]}},subseries:{item:{id:"38",type:"subseries",title:"Pollution",keywords:"Human activity, Pollutants, Reduced risks, Population growth, Waste disposal, Remediation, Clean environment",scope:"\r\n\tPollution is caused by a wide variety of human activities and occurs in diverse forms, for example biological, chemical, et cetera. In recent years, significant efforts have been made to ensure that the environment is clean, that rigorous rules are implemented, and old laws are updated to reduce the risks towards humans and ecosystems. However, rapid industrialization and the need for more cultivable sources or habitable lands, for an increasing population, as well as fewer alternatives for waste disposal, make the pollution control tasks more challenging. Therefore, this topic will focus on assessing and managing environmental pollution. It will cover various subjects, including risk assessment due to the pollution of ecosystems, transport and fate of pollutants, restoration or remediation of polluted matrices, and efforts towards sustainable solutions to minimize environmental pollution.
",coverUrl:"https://cdn.intechopen.com/series_topics/covers/38.jpg",hasOnlineFirst:!1,hasPublishedBooks:!0,annualVolume:11966,editor:{id:"110740",title:"Dr.",name:"Ismail M.M.",middleName:null,surname:"Rahman",slug:"ismail-m.m.-rahman",fullName:"Ismail M.M. Rahman",profilePictureURL:"https://mts.intechopen.com/storage/users/110740/images/2319_n.jpg",biography:"Ismail Md. Mofizur Rahman (Ismail M. M. Rahman) assumed his current responsibilities as an Associate Professor at the Institute of Environmental Radioactivity, Fukushima University, Japan, in Oct 2015. He also has an honorary appointment to serve as a Collaborative Professor at Kanazawa University, Japan, from Mar 2015 to the present. \nFormerly, Dr. Rahman was a faculty member of the University of Chittagong, Bangladesh, affiliated with the Department of Chemistry (Oct 2002 to Mar 2012) and the Department of Applied Chemistry and Chemical Engineering (Mar 2012 to Sep 2015). Dr. Rahman was also adjunctly attached with Kanazawa University, Japan (Visiting Research Professor, Dec 2014 to Mar 2015; JSPS Postdoctoral Research Fellow, Apr 2012 to Mar 2014), and Tokyo Institute of Technology, Japan (TokyoTech-UNESCO Research Fellow, Oct 2004–Sep 2005). \nHe received his Ph.D. degree in Environmental Analytical Chemistry from Kanazawa University, Japan (2011). He also achieved a Diploma in Environment from the Tokyo Institute of Technology, Japan (2005). Besides, he has an M.Sc. degree in Applied Chemistry and a B.Sc. degree in Chemistry, all from the University of Chittagong, Bangladesh. \nDr. Rahman’s research interest includes the study of the fate and behavior of environmental pollutants in the biosphere; design of low energy and low burden environmental improvement (remediation) technology; implementation of sustainable waste management practices for treatment, handling, reuse, and ultimate residual disposition of solid wastes; nature and type of interactions in organic liquid mixtures for process engineering design applications.",institutionString:null,institution:{name:"Fukushima University",institutionURL:null,country:{name:"Japan"}}},editorTwo:{id:"201020",title:"Dr.",name:"Zinnat Ara",middleName:null,surname:"Begum",slug:"zinnat-ara-begum",fullName:"Zinnat Ara Begum",profilePictureURL:"https://mts.intechopen.com/storage/users/201020/images/system/201020.jpeg",biography:"Zinnat A. Begum received her Ph.D. in Environmental Analytical Chemistry from Kanazawa University in 2012. She achieved her Master of Science (M.Sc.) degree with a major in Applied Chemistry and a Bachelor of Science (B.Sc.) in Chemistry, all from the University of Chittagong, Bangladesh. Her work affiliations include Fukushima University, Japan (Visiting Research Fellow, Institute of Environmental Radioactivity: Mar 2016 to present), Southern University Bangladesh (Assistant Professor, Department of Civil Engineering: Jan 2015 to present), and Kanazawa University, Japan (Postdoctoral Fellow, Institute of Science and Engineering: Oct 2012 to Mar 2014; Research fellow, Venture Business Laboratory, Advanced Science and Social Co-Creation Promotion Organization: Apr 2018 to Mar 2021). The research focus of Dr. Zinnat includes the effect of the relative stability of metal-chelator complexes in the environmental remediation process designs and the development of eco-friendly soil washing techniques using biodegradable chelators.",institutionString:null,institution:{name:"Fukushima University",institutionURL:null,country:{name:"Japan"}}},editorThree:null,series:{id:"25",title:"Environmental Sciences",doi:"10.5772/intechopen.100362",issn:"2754-6713"},editorialBoard:[{id:"252368",title:"Dr.",name:"Meng-Chuan",middleName:null,surname:"Ong",slug:"meng-chuan-ong",fullName:"Meng-Chuan Ong",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRVotQAG/Profile_Picture_2022-05-20T12:04:28.jpg",institutionString:null,institution:{name:"Universiti Malaysia Terengganu",institutionURL:null,country:{name:"Malaysia"}}},{id:"63465",title:"Prof.",name:"Mohamed Nageeb",middleName:null,surname:"Rashed",slug:"mohamed-nageeb-rashed",fullName:"Mohamed Nageeb Rashed",profilePictureURL:"https://mts.intechopen.com/storage/users/63465/images/system/63465.gif",institutionString:null,institution:{name:"Aswan University",institutionURL:null,country:{name:"Egypt"}}},{id:"187907",title:"Dr.",name:"Olga",middleName:null,surname:"Anne",slug:"olga-anne",fullName:"Olga Anne",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBE5QAO/Profile_Picture_2022-04-07T09:42:13.png",institutionString:null,institution:{name:"Klaipeda State University of Applied Sciences",institutionURL:null,country:{name:"Lithuania"}}}]},onlineFirstChapters:{paginationCount:20,paginationItems:[{id:"80964",title:"Upper Airway Expansion in Disabled Children",doi:"10.5772/intechopen.102830",signatures:"David Andrade, Joana Andrade, Maria-João Palha, Cristina Areias, Paula Macedo, Ana Norton, Miguel Palha, Lurdes Morais, Dóris Rocha Ruiz and Sônia Groisman",slug:"upper-airway-expansion-in-disabled-children",totalDownloads:35,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Oral Health Care - An Important Issue of the Modern Society",coverURL:"https://cdn.intechopen.com/books/images_new/10827.jpg",subseries:{id:"1",title:"Oral Health"}}},{id:"80839",title:"Herbs and Oral Health",doi:"10.5772/intechopen.103715",signatures:"Zuhair S. 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