Medications used in the treatment of obesity and their classification.
\\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:"1642",leadTitle:null,fullTitle:"Continuum Mechanics - Progress in Fundamentals and Engineering Applications",title:"Continuum Mechanics",subtitle:"Progress in Fundamentals and Engineering Applications",reviewType:"peer-reviewed",abstract:"Continuum Mechanics is the foundation for Applied Mechanics. There are numerous books on Continuum Mechanics with the main focus on the macroscale mechanical behavior of materials. Unlike classical Continuum Mechanics books, this book summarizes the advances of Continuum Mechanics in several defined areas. Emphasis is placed on the application aspect. The applications described in the book cover energy materials and systems (fuel cell materials and electrodes), materials removal, and mechanical response/deformation of structural components including plates, pipelines etc. Researchers from different fields should be benefited from reading the mechanics approached to real engineering problems.",isbn:null,printIsbn:"978-953-51-0447-6",pdfIsbn:"978-953-51-6184-4",doi:"10.5772/2103",price:119,priceEur:129,priceUsd:155,slug:"continuum-mechanics-progress-in-fundamentals-and-engineering-applications",numberOfPages:168,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"3c300d90c090f3c7a639265e3caf3bd7",bookSignature:"Yong X. 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Gan, joined the Department of Mechanical, Industrial and\r\nManufacturing Engineering at The University of Toledo (UT) in 2007\r\nas Assistant Professor. Before he came to UT, he was with Department\r\nof Mechanical Engineering at Cooper Union as Assistant Professor\r\nfrom September 2005 to August 2007. He received his undergraduate\r\ndegree in Chemical Engineering in 1984 from Hunan University,\r\nChangsha, China. He received his MS and D.Eng. in Materials Science\r\nand Engineering from Beijing University of Aeronautics and\r\nAstronautics (BUAA), Beijing, China in 1987 and 1992, respectively.\r\nHe received his M.Phil. in 2004 and Ph.D. in Mechanical Engineering\r\nin 2005, both from Columbia University. His major teaching and\r\nresearch activities are on materials processing, and microstructure\r\nand property characterization. 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\r\n\tPlate tectonics associated with subsurface and surficial processes defines the restless and dynamic nature of our planet Earth. The evolution of the Earth throughout geological time can be understood by exploring the terrain and imaging sub-surface data set through implementing multidisciplinary scientific approaches. Earlier researchers have made several efforts to understand the internal and crustal geodynamics of the planet. However, due to limitations in modern technology and associated understanding, several concepts of plate tectonics are still in heated debate. In the last couple of decades, notable improvements have been made in the field of instrumentation, such as Geophysical investigation, Geodesy, Seismology, Geochemistry and Geochronology, which ultimately helped earth scientists explore the unravelling ambiguities of the planet. Therefore, there is a solid need to gather updated scientific information related to advancement in the field of plate tectonics. Thus, the present volume is proposed to invite the key chapters from researchers throughout the globe to contribute their findings and advanced research propositions. The book will undoubtedly focus on the better understanding of debated topics related to plate tectonics and will also pave opportunities for future earth scientists to explore the elements of the restless planet Earth.
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Thakkar",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11490.jpg",keywords:"Rift Basins, Plate Boundaries, Structures and Tectonics, Seismic Activities, Magmatism, Active Tectonics, Geochemistry, Geochronology, Cratons, Orogenic Belts, Siesmotectonics, Geophysics, Rheology, Geodesy, RS, GIS Application",numberOfDownloads:12,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 2nd 2022",dateEndSecondStepPublish:"April 5th 2022",dateEndThirdStepPublish:"June 4th 2022",dateEndFourthStepPublish:"August 23rd 2022",dateEndFifthStepPublish:"October 22nd 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"3 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"An active researcher in the field of structures and tectonics working mainly in the Kachchh Rift Basin, South Asia. 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\nPolycystic ovary syndrome—in spite of many years of research—is still a controversial topic. We have come to know in detail its clinical manifestations such as metabolic disorders, menstrual and ovulatory dysfunctions, and clinical hyperandrogenism. However, not knowing its etiology, most of the treatments suggested to patients with PCOS are symptomatic, not addressing to the underlying cause, but rather each symptom in part.
\nFollowing numerous studies and research on PCOS and despite that the exact mechanism is not completely understood, the conclusions of most researchers are the same; lifestyle change and weight loss have beneficial effects on the entire panel of symptoms associated with this syndrome.
\nUnder the metabolic disorders, which are commonly encountered in patients with PCOS, it is worth mentioning: obesity, insulin resistance, metabolic syndrome, dyslipidemia, and type 2 diabetes mellitus.
\nSome researchers state that the obesity rate in the case of the women with PCOS is even up to 70%, but most agree that at least half of the women with PCOS suffer from obesity (body mass index (BMI) = 19–25 kg/m2) [2] and in most cases, it is of a central distribution (waist circumference > 88 cm) [3]. Of the nonobese patients, one-third has increased intra-abdominal fat [4]. There is no specific data on why the prevalence of obesity is much higher in women with PCOS, but most researchers attribute it to the hyperinsulinemia resulting from the insulin resistance, an important factor of adipogenesis, lipogenesis, and lipolysis inhibition [5].
\nInsulin resistance and reactive hyperinsulinemia are definitely implicated in the physiopathological mechanism of PCOS. With respect to insulin resistance, some authors consider it to be uncorrelated to the degree of the obesity [6], while others argue that the obesity, especially the central one, seems to increase the metabolic and clinical features of insulin resistance [7]. Although obese patients seem to be more affected by insulin resistance, this also occurs in the cases of nonobese patients with PCOS [8].
\nThe metabolic syndrome is commonly associated with PCOS, with a prevalence ranging between 33 and 47% [9]. Both PCOS and the metabolic syndrome have features that generate an increased risk of cardiovascular diseases–if this risk is independent of PCOS or it is caused by its association with the metabolic syndrome, it is still a topic of debate [10]. Studies demonstrate that in patients with PCOS, even if the criteria for the metabolic syndrome are not fully met, there is at least one component of the metabolic syndrome [11].
\nThe research in the field demonstrates the presence of the risk factors for the metabolic syndrome in women with PCOS. Of these, the following appear to be important: the level of fasting insulin (which in these patients is doubled [12]) and obesity (an independent risk factor for the metabolic syndrome).
\nImpaired glucose tolerance (IGT) or even type 2 diabetes mellitus (T2DM) are common in patients with PCOS with a prevalence rate of 30–40% for impaired glucose tolerance and 7.5–10% for type 2 diabetes mellitus [13, 14]. The risk of patients with PCOS to develop these pathologies is considerably higher than in healthy patients. In these cases as well obesity appears to play an important role–impaired glucose tolerance and diabetes mellitus have an increased prevalence in obese patients (31.3% IGT and 7.5% T2DM) in comparison to nonobese patients (10.3% IGT and 1.5% T2DM) suffering from PCOS.
\nIt is not known exactly to what extent PCOS would be an independent risk factor for cardiovascular diseases but, unquestionably, through associated pathologies (obesity, increased resistance to insulin, IGT, T2DM, and/or dyslipidemia), it contributes to an increased risk [15].
\nMost experts consider that hyperandrogenism is the main characteristic of PCOS [16], whether is biochemically or clinically identified. Alteration in insulin action as well as enzymatic defaults has been discussed as possible pathogenic theories.
\nStudies suggest that the androgenic hyper-responsiveness that characterizes women with PCOS is probably due to the factors controlled by insulin sensitization rather than luteinizing hormone (LH), adrenocorticotropin hormone (ACTH), or ovarian steroids
The clinical correspondence of this intricate biochemical processes have incredible impact on patients’ quality of life and psychological status. Virilising signs and symptoms, acne and hirsutism are most often the first elements to lead to the clinical suspicion of PCOS.
\nObesity is a key metabolic entity in some PCOS patients. Because of its undeniable influence on insulin resistance, it has become a target to treat when identified. PCOS women, who are obese tend to have higher hirsutism and acne scores than their lean counterparts [16]. The consequent importance of weight loss is therefore essential to be taken into account. It is certified in medical literature that a weight loss of 5–10% can reduce hyperandrogenism and insulin levels [17]. Lifestyle modifications reside once again as the first step therapeutical management in patients with PCOS.
\nThe modified metabolic background associated with PCOS is basically characterized by unbalanced estrogen serum levels due to lack of progesterone production. Left untreated, the main effects of this modified environment leads to atypical endometrial hyperplasia, and endometrial dysfunction-induced infertility [18].
\nEven though progesterone-based oral contraceptive therapy is often efficacious [19], approximately 30% of women with PCOS fail to respond to such treatment [20] and progress to the development of atypical hyperplasia and further transformation to endometrial cancer [21].
\nThe mechanism of progesterone resistance is determined at molecular level and based on the imbalance of two progesterone receptor (PR) isoforms PRA and PRB. Patients with PCOS have a modified ratio of PRA to PRB receptors present on stromal and epithelial cells of endometrium [21].
\nProgesterone resistance is associated with insulin resistance [20] and this way, a new perspective in the prevention of endometrial hyperplasia can be contoured: targeted therapy on reducing insulin resistance may benefit both endometrial tissue and serum hyperinsulinemia.
\nAlthough most of PCOS-diagnosed patients complain about the inability to pursue a pregnancy, it is important to have in mind the situation when women diagnosed and treated for PCOS do not want to obtain a pregnancy.
\nA recent study states that in women aged 28–33 years old, women with PCOS were less likely to be using contraception (61 versus 79%, P < 0.001) and more likely to be trying to conceive (56 versus 45%, P < 0.001), compared with women not reporting PCOS [22]. However, the same study mentions that fewer women with PCOS (61%) were using contraception than women without PCOS (79%) (P = 0.001) [22].
\nBecause women with oligomenorrhea ovulate intermittently and rarely use contraception-unwanted pregnancy may occur.
\nAs part of the PCOS, infertility secondary to anovulation is usually the main complaint of patients diagnosed with this metabolic disorder.
\nPathological basis of infertility in this particular medical situation resides in the low Follicle-stimulating hormone (FSH) serum level, which is responsible for the impossibility of ovarian follicles to reach maturity due to their persistence in final growth stages.
\nAiming to treat this frequent cause of anovulation, there are two ways to ensure the wellbeing of the patient based on each woman’s choice: evaluating the options for further contraception or starting a therapeutical plan for inducing ovulation.
\nWith respect to the latter, inducing ovulation still remains a medical challenge in some patients with PCOS. There are a few known therapeutical approaches for achieving this: medical treatment with clomiphene citrate, tamoxifen, aromatase inhibitors, metformin, glucocorticoids, or gonadotropins or surgically management by laparoscopic ovarian drilling [23]; in vitro fertilization is also taken into consideration when all the other options failed to induce pregnancy.
\nTaking into account the morpho-clinical picture of the patients with PCOS and common sense, lifestyle changes and weight loss would, at first glance, be effective. It seems simple that by adopting a healthy lifestyle and weight loss, as with the patients who do not suffer from this pathology, it would improve the metabolic profile, reduce the risk of diabetes mellitus, cardiovascular disease or endometrial hyperplasia. Moreover, there are studies that discuss the complete or at least partial disappearance of the symptoms [24] and PCOS phenotype after weight loss.
\nStudies with various degrees of evidence have been conducted in an attempt to quantify their effect in patients with PCOS. While some parameters are certainly improved, there are still others involved in a series of controversies.
\nAn improved lifestyle will undoubtedly improve the distribution of the adipose tissue and will in most cases lead to weight loss. A weight loss of between 5 and 10% will ameliorate IGT and will decrease the prevalence of the metabolic syndrome and diabetes mellitus [25].
\nResearch suggests that these interventions are associated with lower fasting insulin levels and insulin resistance [26], and consequently a decreased risk for metabolic syndrome, cardiovascular disease, and diabetes mellitus [27].
\nIt has been shown that improvement of the lipid profile resulting from weight loss and lifestyle changes is nonuniform. Thus, in the case of some patients, a significant decrease in cholesterol levels will be observed while in others the change will be insignificant [24]. However, in all cases there will be a significant increase of high density lipoprotein (HDL)–cholesterol levels (thus reducing the risk of cardiovascular disease) and a decrease of triglyceride levels [24].
\nDuring the treatment, we also seek to improve the hormonal profile since PCOS being a pathology with deep hormonal implications. Unanimously, studies describe a decrease in the total testosterone level [28] and in androstenedione [29] as a result of lifestyle changes and weight loss. There is, however, controversy in terms of improving the level of SHBG and free androgen index (FAI) [29]. However, in all cases, an improvement in hirsutism will result when using the Ferriman-Gallwey (FG) score as an objective measuring method.
\nWhile the level of FSH increases as a result of lifestyle changes and weight loss, more by means of physical exercise than a result of diet [29], the level of LH does not seem to be improved by following a hygienic-dietary diet.
\nIn PCOS treatment, we aim to restore both normal menstrual function and fertility. In some cases, there may also be a decrease in ovarian volume and a reduction in the number of follicles [30] following weight loss and lifestyle changes. Ovulatory menstrual cycles can be obtained for obese women with PCOS, even when the weight loss is relatively low [31], thus increasing considerably the chances of getting pregnant. However, not all patients equally respond to these measures even if their weight loss is similar [24]. Hollmann et al. describe an 80% improvement in ovulation rate and 29% in the pregnancy rate in the case of a 10% weight loss [32].
\nAlthough the last decades have been revolutionary in terms of understanding this pathology, its etiology is not elucidated, hence we cannot talk about the existence of a curative treatment, but rather of symptomatic treatments. The spectacular evolution in this field also refers to the many symptomatic treatments, whose efficiency, although relatively high, address each symptom in part and not the pathology as a whole. The change in lifestyle, with all the developments in the last decades, still seems the most approachable and most effective treatment method, at the same time covering a broad spectrum of symptoms.
\nWhen we talk about lifestyle changes, we refer to a healthy lifestyle that involves exercise and weight loss. Although in many cases, patients are able to lose weight and lead a healthy lifestyle for a while, the difficulty they encounter is to maintain this lifestyle and their weight in the long run.
\nA solution to this problem is the behavioral treatment by “Burtyn and co.” designed specifically to help with this–a complex program that not only helps patients to lose weight efficiently but also to maintain their weight in the long term or even continue to lose more over time. Patients undergo this program for a period of 4–6 months under the supervision of a group of specialists: nutritionists and psychologists [33]. Patients learn how to choose healthy foods, how to ration their portions and how to get social support. After setting objective targets in terms of daily caloric intake, time spent on physical exercise and other behavioral changes, patients share in weekly or bi-weekly group sessions the obtained results. Specialists recommend patients to expect a weight loss of 0.5–1 kg per week, mentioning that the final target is a 10% decrease in weight relative to their initial weight [33]. They argue that by a comprehensive behavioral approach, patients manage to decrease 8–10 kilograms in weight and that about 80% of patients starting this program manage to complete it [34]. However, specialists mention that in the absence of weight maintenance therapy, regaining weight will be inevitable.
\nThe National Institute of Health also recommends psychotherapeutic and social support for these patients in order to manage to maintain their weight in the long run or even to further lose weight.
\nRegarding the type of diet, there are no clinically relevant data to prove the efficacy of any of them in the case of patients suffering from PCOS. However, based on food principles and taking into account that a decrease in carbohydrate intake would lead to a decrease in hyperinsulinemia, which in turn would lower insulin resistance, low-carbohydrate diets would be favored. Nevertheless, a comparative study between a high protein/low carbohydrate diet (40% carbohydrate, 30% protein, and 30% fat) and a low protein/high carbohydrate diet (55% carbohydrate, 15% protein, and 30% fat) proved the same efficacy in both cases [26] in terms of weight loss, waist circumference decrease and effects on insulin sensitivity. The same study emphasizes the importance of a calorific deficit in PCOS treatment, noting that the differences in dietary compounds are relatively insignificant when comparing their effect on metabolic and reproductive improvements [26]. A meta-analysis of 48 clinical trials involving a total of 2886 patients concludes that regardless of the type of diet and macronutrient on which they are based, there will be a relatively comparative weight loss–the same thing happening with maintaining weights at follow-up for 6 months and 12 months [35]. The impact of the type of macronutrients used in the diet is still debated. What is certain is that less energy intake than energy consumption will result in a weight loss. Thus, high-level metabolic studies conclude that a caloric intake of less than 1000 kcal/day will show results in all cases, with no exception.
\nNew diet hypothesis have emerged over the last few years, and here we want to mention the fast-paced ones, which are still under investigation and seem to be ground-breaking. Researchers believe that patients with PCOS might have significant benefits in terms of PCOS symptoms but also complications in the medium to long term if approaching this type of diets. The data we currently have on intermittent fasting diet obtained on rodent models are promising in terms of results. Thus, intermittent fasting diets, as compared to diets based on energy restriction of continued iso-energetic type, improve insulin sensitivity [36], provide protection for the cardiovascular system [37], and increase the lifespan of the rodent in the model. [38] Moreover, 3 days or more of the fasting will result in at least a 30% decrease in circulating insulin levels, glucose levels, and insulin-like growth factor 1 (IGF-1), which plays a key role in the metabolic homeostasis and changes associated with aging [39]. Current theories take into account the possibility that this type of diet can improve the symptoms of hyperandrogenism, based on the argument that improving insulin resistance would reduce compensatory hyperinsulinemia and ultimately the excess of androgen involved in the PCOS symptomatology.
\nFinally, we want to emphasize the importance of weight loss, pointing out the uselessness of this fact if the patients fail to maintain their long-term weight.
\nPhysical exercise is definitely a part of the lifestyle changes. Studies show that the type, frequency or duration of the exercise do not influence the results that patients get from it. It has been shown that regular, aerobic exercise of moderate intensity does not only contribute to weight loss and improved insulin resistance, but also improves reproductive outcomes, including ovulation and regulation of menstrual cycles. The recommendation for patients with PCOS in view of the improve reproductive and cardio metabolic outcomes is – aerobic physical activity of moderate intensity for 90 minutes per week [40].
\nIn a relatively recent past, following multiple clinical trials, medical journals supported the benefit of adding anti-obesity drugs to lifestyle changes–both in terms of maintaining weight in the long-term and reducing associated co-morbidities. Drugs such as sibutramine, orlistat, and rimonabant have been shown to be effective in improving the lipid profile, lowering blood pressure, glycosylated hemoglobin (in diabetics), and pro-inflammatory cytokine levels, thus reducing cardiovascular risk [41]. Meanwhile, it has been shown that the majority of these drugs instead of lowering cardiovascular risk have the opposite effect, which has led to their removal from the market [42].
\nCurrently, drugs used in the treatment of obesity are–orlistat, lorcaserin, phentermine-topiramate, bupropion naltrexone, liraglutide and noradrenergic sympathomimetic drugs but there are no specific studies with patients suffering from PCOS. A list of medication used to treat obesity is shown in \nTable 1\n.
\nDrugs that alter fat digestion | \nOrlistat | \n
---|---|
Serotonin agonists | \nLorcaserin | \n
Sympathomimetic drugs | \nPhentermine Diethylpropion Benzphetamine Phendimetrazine | \n
Antidepressants and antiepileptic drugs | \nBupropion Venlafaxine Desvenlafaxine Topiramate Zonisamide Lamotrigine Ziprasidone | \n
Diabetes drugs | \nMetformine Pramlintidine Exenatide Liraglutide | \n
Combination drugs | \nPhentermine-topiramate Bupropion-naltrexone | \n
Medications used in the treatment of obesity and their classification.
Orlistat, being an inhibitor of pancreatic and gastric lipases, inhibits the hydrolysis of triglycerides from the diet by up to 30%, thus reducing total caloric intake [41]. Hence, weight loss is not significant using this medication only and requires a calorie-restricted regimen. The X-PERT study establishes a 3-month weight loss that exceeds 5% of the initial weight as an accurate predictor of long-term weight loss. A 12-month meta-analysis concludes that patients undergoing lifestyle changes that also associate orlistat as an adjuvant medication will lose an average of 8–10 kg over 12 months as opposed to those who associate lifestyle change with a placebo who will lose an average of 3–6 kg [43]. In addition to weight loss, it has positive effects in reducing cardiovascular risk factors due to its effects on triglyceride and LDL cholesterol [41]. Moreover, in Orlistat treatment, a better glycemic control with decreasing fasting glucose and glycosylated hemoglobin is noticed [44]. This is considered to be a relatively safe drug, with adverse effects mainly upon the intestinal tract such as increased defecation, fatty stools, and fecal urgency.
\nLorcaserin is believed to activate serotonin 5-HT2c receptors stimulating pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus. Thus, it increases alpha-melanocortin stimulating hormone resulting in satiety and consequently in a decreased food intake [45]. Lorcaserin is indicated for the treatment of obesity when it is associated with at least one comorbidity such as type 2 diabetes mellitus, high blood pressure, high cholesterol or sleep apnea [46]. This is an alternative to orlistat, with similar efficacy but fewer side effects. In addition to weight loss, studies show that it lowers: blood pressure, heart rate, total cholesterol, LDL cholesterol, fasting glucose, and insulin levels.
\nNoradrenergic sympathomimetics, of which we currently find phentermine, diethylpropion, benzphetamine, and phendimetrazine, cause early satiety and reduce food cravings. Although they have increased effectiveness and their use is widespread, they are indicated for a treatment of a maximum of 12 weeks and have large potential for abuse. We must mention that all sympathomimetic drugs have side effects such as tachycardia, increased blood pressure, cause insomnia, constipation, nervousness, and dry mouth. In fact, their side effects on the cardiovascular system were those that caused the withdrawal of some drugs of this class from the market, such as sibutramine (removed from the market in 2010 [47] after it was shown to increase the risk of myocardial infarction and stroke [48]) or phenylpropanolamine (removed from the market due to association with increased risk of hemorrhagic stroke in women [49]).
\nAntidepressants and antiepileptics can affect weight in different ways, while some lead to weight gain, others to loss. Among the drugs that lead to weight loss, we mention: bupropion, venlafaxine, desvenlafaxine, topiramate, zonisamide, lamotrigine, and ziprasidone [45].
\nBupropion is an antidepressant commonly used in cases of smoking cessation, to prevent weight gain [50]. It can also be used in combination with naltrexone, although there are currently no data on an augmenting the effect of bupropion by naltrexone.
\nTopiramate is an antiepileptic agent that blocks neuronal voltage-dependent sodium channels, enhances gamma-aminobutyric acid (GABA) A activity and inhibits carbonic anhydrase, generating appetite suppression and satiety enhancement. Amongs its adverse effects, we mention paresthesia, somnolence, and metabolic acidosis. Studies recommend its use in combinations with other substances and not as a sole agent in the treatment of obesity.
\nZonisamide is another antiepileptic with serotoninergic and dopaminergic activity, which has effect on weight loss. Randomized trials in obese patients demonstrate that zonisamide at high doses is superior to placebo, while at low doses has effects similar to placebo [51].
\nMetformin is an anti-hyperglycemic biguanide, used in the treatment of type 2 diabetes mellitus. It reduces liver production and intestinal absorption of glucose and therefore insulin secretion. By its anti-lipolytic effect, free fatty acid concentrations and gluconeogenesis decrease [52, 53]. Numerous studies have been performed on obese patients with PCOS, who received metformin. While the first studies seemed to demonstrate its effects in terms of weight loss, decreased serum androgen levels (and implicitly hirsutism), restoration of menstrual cycles, and induction of ovulation [54], further studies concluded its ineffectiveness in treating hirsutism or increasing live birth rates, even if it is effective in increasing the ovulatory rates and pregnancy rates. Metformin is no longer used as a first-line treatment for oligomenorrhea or weight loss.
\nPramlintide is a synthetic analog of human amylin whose effect in terms of weight loss is relatively modest, due to its slowing effect on gastric emptying and the reduction in postprandial blood glucose concentration it causes.
\nExenatide is a long-acting synthetic peptide (GLP-1 -glucagon-like polypeptide-1-agonist receptor), the effect of which is the increased secretion of dose-dependent and glucose-dependent insulin. Its’ use is avoided because of the relatively low weight loss effect in conjunction with its mode of administration by subcutaneous injection [45].
\nLiraglutide, like exenatide, is a GLP-1 analog with significant weight-reducing effects. Studies in obese, non-diabetic patients have shown better efficacy against placebo at normal doses and even orlistat when administered in high doses [55]. Among its adverse effects when administered at high doses are included nausea and vomiting, which may in part contribute to the weight-loss effect [55]. This drug is quite often avoided due to its route of administration (subcutaneous injection) but also due to its potential adverse effects, that although rare, they are severe (pancreatitis, renal impairment and gallbladder disease). Further, we consider important to mention that rodent studies have demonstrated the association of this drug with the increased frequency of thyroid C-cell tumors (benign and malignant), which is why it is not recommended in the case of the patients with personal or family history of medullary thyroid cancers [56].
\nThe combination of phentermine and topiramate is another two drug combination with good effect in terms of weight loss, being pharmacologically included in the sympathomimetic anorexia class. Being a two drug combination, it has a complex mechanism of action. Thus, phentermine, which is a sympathomimetic amine, like amphetamines, will reduce the appetite after the stimulation of the hypothalamus and the release of the norepinephrine. Topiramate also has appetite suppressing effects and causes rapid satiety. Studies show that after a 1-year administration, the effect of this combination drug on weight loss decreases, but nevertheless it seems to contribute in maintaining the weight obtained up to that point [57, 58]. Side effects of this drug include dry mouth, constipation, paresthesia, psychiatric and cognitive impairment. It is also contraindicated during pregnancy, having teratogenic effects [59].
\nThe bupropion-naltrexone combination, though effective in weight loss, seems to have cardiovascular side effects, such as high blood pressure or tachycardia, so if it would be administered it would fail in addressing the underlying reason for initiating this therapy.
\nBariatric surgery is indicated in cases of morbid obesity (BMI = 40 kg/m2 or BMI greater than or equal to 35 kg/m2 associated with different comorbidities). A study that enrolled obese patients who underwent bariatric surgery divided the treated patients into 3 groups; obese with PCOS, obese with hyperandrogenemia characteristics but with regular menstrual cycles and a third group with obese patients without hyperandrogenic traits. After applying the exclusion criteria, the group of patients with PCOS was studied in detail and the results were surprising. Within 12 +/− 5 months, the weight loss was of 41 +/− 9 kg, associated with the improvement of clinical and biochemical markers of hyperandrogenism. It was noted that an improvement in hirsutism had been observed and from a biochemical point of view markers such as: free testosterone, total testosterone, androstenedione and dehydroepiandrostenedione sulfate have been normalized while the level of SHBG increased. From a metabolic point of view, the improved insulin sensitivity was proved by the decrease in fasting insulin levels. With regard to the reproductive system, the restoration of regular menstrual cycles and ovulation were noticed [60].
\nA newer study, conducted in 2012, concludes that weight loss after bariatric surgery is not associated with significant changes in the menstrual cycle, the luteal phase length or the amount of blood lost during menstruation. A relatively modest improvement was found with respect to biochemical hyperandrogenism but without effects on the clinical markers of hyperandrogenism. Instead, an 8–9 day follicular phase shortening associated with decreased fertility, was observed. What was new in this study was the finding that patients undergoing bariatric surgery after weight loss improve their sex life [61].
\nWe consider to be of major importance the adoption of a healthy lifestyle, composed of a hypo caloric diet and physical exercise that will generate weight loss. Unlike any other treatment, weight loss without adjuvant medication (which brings various side effects) in many cases leads to at least partial resolution of PCOS symptoms. Although in this chapter by enlarge we have approached the subject of slimming medications, we consider it important to use them only in carefully selected cases, lifestyle changes continue to be the first-line treatment.
\nThe authors certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this chapter.
Behçet’s disease (BD; MIM 109650) is an autoinflammatory disease characterized by with recurrent oral aphthae, genital ulcers and vasculitis involving the skin, joints, eyes, veins, arteries, nervous and gastrointestinal systems [1]. BD is diagnosed worldwide, although its highest prevalence coincides with the countries stretching from Japan to the Mediterranean region along the ancient trading route “Silk Route”. Among the affected countries, the prevalence of BD varies between Western (0.12–7.5 per 100,000) and Eastern countries (6.3–14 per 100,000) [2]. The prevalence of BD is the highest in Turkey (80–420 cases per 100,000) [3]. Although the pathogenesis remains uncertain, it is thought that both genetic and environmental factors contribute to the onset and progression of the BD [4]. The first reported susceptibility genetic region for BD was found in the human leukocyte antigen (HLA) region, or the major histocompatibility complex (MHC) on chromosome [5]. HLA-B51 antigen was recognized as the strongest evidence of a BD genetic background [6]. Multiple other putative genes outside the HLA region have also been identified.
The MHC, also known in humans as the human leukocyte antigen (HLA) region encodes several molecules that play key roles in the immune system [7]. A strong association was established between the HLA regions and autoimmune disorders. Among them, HLA-B51 has been shown to be the strongest risk allele for BD in multiple studies and in different ethnic populations [6, 8, 9, 10, 11]. Several other HLA class I and class II alleles including HLA-A26, HLA-B15, HLA-B5701, HLA-B2702, HLA-B3901, HLA-B52, HLA-B56, HLA-DRB104, and HLA-DRB107 have been also associated with BD in different populations [12, 13, 14, 15]. The several HLA alleles including HLA-A03, -B15, -B35, -B49, -B58 were reported BD-protective [1, 16, 17]. In addition to susceptibility, HLA alleles were also associated with reflect clinical outcomes of BD. The HLA-A26:01 was associated with poor visual prognosis and high incidence of posterior uveitis in previous studies [15, 18]. There were significant associations found between clinical manifestations of BD and some HLA alleles such as HLA-A26:01 with uveitis, HLA-A*02:07 with skin lesions and arthritis, and HLA-A*30:04 with vascular lesions, genital ulcers, and positive pathergy test [17]. These findings indicate that HLA alleles may be associated clinical manifestations and prognosis and the specific HLA alleles are can be used as genetic markers for diagnostic or prognostic classification of BD patients.
The HLA class II transactivator gene (CIITA), encodes an important transcription factor that regulates the MHC class II genes, IL-4, IL-10 and other immune-mediating genes [19]. CIITA is implicated in various autoimmune and autoinflammatory diseases [20]. In a recent study of a Chinese Han population, the GG genotype and G allele of the CIITA gene (rs12932187) were correlated with risk factor for BD, and the GG carriers had a higher expression of the CIITA gene [21].
Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an essential enzyme to optimizing the length of peptides to bind with MHC-class I molecules by trimming their N-terminal in the ER [22]. The association between ERAP1 and BD was first reported in a Turkish population. The rs10050860 and rs17482078 SNPs of the ERAP1 gene were found to confer risk to BD in Turkish population [23]. Zhang et al. reported the rs1065407 and rs10050860 polymorphisms might be associated with increased risk of BD in a Chinese cohort [24]. Sousa et al. studied in an Iranian cohort and reported that rs10050860 and rs13154629 of ERAP1 might contribute to the genetic susceptibility of BD [25]. A functional study indicated that the expression of ERAP1 was found to be significantly lower in active BD patients. The patients carrying AA genotype of rs1065407 and CC genotype of the rs10050860, respectively, were found a higher expression level of the ERAP1 gene than the patients carrying AC or CC and CT or TT genotypes of the SNPs, respectively, in response to lipopolysaccharide stimulation [24, 26].
The major histocompatibility complex class I chain related gene A (MICA) is a gene that functions in immune activation under cellular stress conditions, such as infections, tissue injury, pro-inflammatory signals, and malignant transformation [27]. MICA*009 and *019 alleles were found strongly associated with BD in a Spanish population [28]. The MICA-A6 allele has been reported to increase the risk of BD in Japanese and Korean populations. In a recent study, the MICA*049 allele was found to be significantly higher in BD patients than in controls in a Chinese cohort [29]. On the other hand, Eyerci et al. reported the MICA*006 (MICA-A6) and MICA*009 alleles were associated with BD susceptibility in the HLA-B*51 positive Turkish population. [30]. MICA-A5.1 was indicated a negative correlation with ocular lesions and iridocyclitis in BD patients [31].
IL-1 gene family is composed of IL-1α, IL-1β, and IL-1Ra [32]. Interleukin-1α and -1β, are pleiotropic cytokines with primarily proinflammatory effects, which induce acute phase responses, activate endothelial cells, and lead to expression of adhesion molecules and coagulation factors [33]. IL-1Ra acts as an antagonist of IL-1 by blocking the IL-1 receptor [34]. Previous studies have shown that the IL-1α (-889) C allele is significantly associated with BD risk [35, 36]. Alayli et al. also reported that the frequency of IL-1β (−511) CC genotype is significantly higher in BD patients compared to controls [35]. In another study showed that IL-1Ra mspa1l 1100 CT and IL-1Ra mspa1l 1100 TT promoter polymorphisms could be confer susceptibility to BD in Turkish population [37]. Barış et al. found IL-1RN2 gene polymorphism was correlated with the presence of articular involvement and the IL-1β gene polymorphism was correlated with the presence of an ocular lesion [38].
Interleukin-4 (IL-4) is a key cytokine secreted by Th2 lymphocytes. It has cytotoxic, anti-tumor effects, inhibits induction of nitric oxide synthase, and also has role in chemotaxis, formation of endothelial cell adhesion molecules and hematopoiesis [39]. IL-4 gene 70 bp VNTR polymorphism was first reported to be associated with BD in the Turkey. The P1 allele of the IL-4 gene 70 bp VNTR polymorphism was found to constitute a risk for developing BD in a Turkish population. In the same study, P2P2 genotype was associated deep venous thrombosis and ocular involvement in the BD patients [40]. The IL-4 -1098 G, IL-4 -590 T alleles and IL-4 TTC haplotypes were showed more common in the patients with BD when compared with healthy controls in an another Turkish cohort. They also demonstrated that IL-4Rα (+1902) gene polymorphism was associated with the Pathergy test positivity in BD patients [41].
IL-10 is an anti-inflammatory cytokine, which is secreted by T lymphocytes (mainly Th2 subsets), B lymphocytes, NK cells, monocytes, and macrophages, plays critical roles in modulating immune response and preventing inflammatory and autoimmune pathologies [42]. IL-10 may inhibit the antigen-presenting process by downregulating the expression of HLA molecules on the surface of a cell and suppressing the expression of multiple proinflammatory cytokines, such as TNF-α, IL-1, IL-6, and IL-8 [43]. The first reported SNP of the IL10 gene was rs1800871 that found to be an association with BD in the UK and Middle Eastern cohorts [44]. The -1082A > G (rs1800896), −819 T > C (rs1800871), and -592A > C (rs1800872) SNPs of IL-10 gene were found to be association with BD susceptibility in different populations including Chinese, Japanese, Korean and Iranian [45, 46, 47, 48].
IL-12A is a gene which encodes for IL-35 that is a subunit of the heterodimeric cytokines IL-12 (encoded by IL-12B) and IL-35 [49]. It binds to a heterodimeric IL-12 receptor (IL-12R) which consists of IL-12Rβ1 (encoded by IL-12 RB1) and IL-12Rβ2 (encoded by IL-12RB2) [50]. IL-12A gene variants (rs1780546 and rs17810458) were revealed to be associated with BD susceptibility in a Turkish cohort [23]. In a study with a Chinese cohort rs3212227/IL-12B genotype CC and C allele was found involved in the susceptibility to BD [51]. IL-23 is a member of the IL-12 cytokine family that plays important roles in the development process of the Th17 cells [52, 53]. The IL-23 receptor consists of two subunits encoded by the IL-23R and IL-12RB1 genes [54]. A meta-analysis of the association data (including a total of 2430 BD cases and 2660 controls) provided strong evidence for associations of the IL23R/IL12RB2 loci with BD [55]. The IL-23R/IL-12RB2 genes were associated with BD, in multiple reports with different populations including Japanese, Chinese, and Korean [56, 57, 58].
IL-17 is a pleiotropic inflammatory cytokine that plays a pivotal role in a variety of pathologic conditions by inducing numerous inflammatory molecules and the recruitment of neutrophils [59]. This cytokine is produced by CD + T helper, hematopoietic cells, Th17 cells and neutrophils and consists of a family of cytokines from IL-17A to IL-17F [60]. Jang et al. reported the allele and genotype frequencies of A126G SNP of IL-17 were significant differences between BD and controls [61]. The another genetic study in a Korean population, the IL17A rs8193036C > T variant was associated with the risk of intestinal BD [62]. In another study, the IL-17A gene rs2275913 polymorphism has been showed it might be associated with intestinal involvement in patients with BD [63]. IL-18 is a proinflammatory cytokine that mediates T-helper (Th)-1-polarized immune responses. Lee et al. found that IL-18 − 607 C/A promoter polymorphism was significantly associated with BD and also age at disease onset [64]. IL-18 gene −607 promoter site polymorphism was associated with patients with BD in Egyptian patients. Moreover, they found GG genotype at position −137 had a higher risk of developing ocular manifestations in patients with BD [65].
IL-29, IL-28A and IL-28B are subgroups of Type III IFNs known as IFN-λs that induce activation of the Jak/STAT signaling pathway and modulating the Th1/Th2 response [66, 67]. The first relationship between IL-28 and IL-29 and BD was investigated in a study from Turkey. Genc et al. showed that the GG genotype of rs8099917 (IL28 G/T) might be a protective factor against BD. They also found a significant difference between patients with and without central nervous system (CNS) involvement in rs12979860 (IL28 C/T) polymorphism [68].
IL-33 is a member of the IL-1 cytokine family that expressed by various types of immune cells such as mast cells, macrophages and dendritic cells, that drives production of Th2-associated cytokines [69, 70]. The rs7044343 and rs11792633 variants of IL-33 gene were associated with the decreased risk of BD in Turkish patients [71]. Talei et al. showed that a significantly higher prevalence of the IL-33 SNP rs1342326 T/G in BD patients. They showed also this genotype was also associated with increased IL-33 expression in patients with BD compared to healthy controls [72].
C–C chemokine receptor type 1 (CCR1) and C–C chemokine receptor type 3 (CCR3) encode the chemokine receptor belonging to the G protein-coupled receptor super family. These receptors play an important role in the accumulation and activation of inflammatory cells [73, 74]. The rs7616215 SNP located in the CCR1-CCR3 locus was showed to be associated with BD in a Turkish population [25]. The CCR1 gene was associated to susceptibility with BD in multiple cohorts including Turkish, Japanese, and Iranian cohorts [23, 25]. Hou et al. reported that the CCR1-CCR3 (rs13084057 in the 30 UTR of CCR1; rs13075270 and rs13092160 in the intergenic region between CCR1 and CCR3) polymorphisms also associated with BD in a Chinese population [75].
The Fc receptor-like (FCRL) family is a recently recognized potential immunoregulatory cell surface molecule. FCRL3 is predominantly expressed in germinal centers of lymphoid organs and has been linked to B cell maturation [76]. FCRL3 may be involved in the mechanisms regulating Treg dysfunction, which may in turn contribute to the loss of self-tolerance and development of autoimmunity [77]. The -110 G allele and CGCG haplotype of FCRL3 were found to be associated with BD, while the ATCG haplotype was found to be protective for BD in a Chinese population [78]. In a study with Iranian BD patients, there was a significant difference demonstrated between groups at position -169 (rs7528684) of FCRL3 gene [79].
The Mediterranean fever (MEFV) protein also named pyrin is an is an significant regulator of innate immunity and the inflammatory response to IL-1β and IFN-γ. Some clinical findings and geographic distribution of FMF and BD seem to be similar [80]. Touitou et al. who first suggested a possible implication of MEFV mutations in BD, reported higher frequencies of four mutations such as M694V, V726A, E148Q, and L110P mutations [81]. The MEFV SNPs rs61752717 Met694Val, rs28940580 Met680Ile, and rs3743930 Glu148Gln were reported conferred risk to both of FMF and BD [80, 82, 83, 84].
IRF-1 is originally identified to be a regulator of the interferon (IFN)–β gene family. It plays an important role in various biologic functions such as innate immunity to viral infection, lymphocyte development, macrophage cytotoxicity, induction of apoptosis and tumor suppression [85, 86]. A study by Lee et al. showed that a significant association between BD and IRF-1 gene polymorphisms (-415 C/A, -410 A/G, and -300 A/G, and 3’-untranslated region (UTR) A/G) [87]. Interferon Regulatory Factor (IRF) 8 is a transcription factor of a member of Interferon (IFN) Regulatory Factor (IRF) family that it regulates expression of type I IFN stimulated genes and the development and function of a variety of immune cells [88, 89]. The rs17445836 and rs11642873 polymorphisms of the IRF8 gene were associated with BD and these SNPs appeared to regulate IRF8 expression and cytokine production in a Chinese cohort [90]. The other SNPs (rs11117433, rs142105922 and rs7203487) of the IRF8 gene were reported BD-associated in multiple cohorts including Turkish, Iranian, and Japanese populations [91].
TNFAIP3 gene encodes A20 protein, which is a key regulator of the nuclear factor (NF)-κB signaling pathway, toll-like receptor (TLR), interleukin 1 receptor (IL1R), and nucleotide-binding oligomerization domain containing 2 (NOD2) [92]. A genetic linked between the TNFAIP3 gene SNPs (rs9494885, rs10499194 and rs7753873) and BD was reported in Chinese BD patients [93].
Toll-like receptor (TLR) proteins are a family receptors that recognize pathogen molecules and have a critical role in both innate and adaptive immune systems [94]. TLRs are thought to be one of the links between infection and autoinflammatory or autoimmune disease [95]. The TLR2 rs2289318 CC genotype and rs3804099 CT genotype were significantly associated with ocular BD in a Chinese population [96]. The associations of the TLR4 gene with BD have been found to be contradictory in different studies. It was not found an association between TLR4 gene polymorphisms and BD in Italian and Chinese patients [97, 98]. Horie et al. showed that the TAGCGGTAA haplotype of TLR4 gene was significantly associated with BD susceptibility and BD arthritis in a Korean cohort [99]. A Japanese study indicated that the TLR4 gene may confer susceptibility to BD [100]. Fernández et al. revealed the rs2407992 and the rs5744067 of TLR8 were associated with susceptibility to BD in Spanish patients [101]. An Asian study revealed a significant association between the TLR7 rs5743733 and rs3853839 and BD and it showed also an association of TLR9 rs352140 with BD [102].
The GIMAP (GTPase of the immune associated nucleotide binding protein) gene family have been suggested as being involved in different aspects of the immune system in different species. These events appear to be associated with cell regeneration and proliferation and apoptosis [103]. The SNPs in GIMAP1 (rs2286900), GIMAP2 (rs10266069 and rs10256482), and GIMAP4 (rs1916012, rs1522596, and rs1608157) were associated with BD in a study of Korean and Japanese populations, but they were not found to be associated in a study with European cohort [104].
Nod-like receptors (NLRs) are a member of pattern-recognition receptor molecules (PRRs) can capable to sense several pathogens or endogenous danger signals [105]. In a Chinese study, the C allele (major) of the NOD1 SNP rs2075818 was associated with BD susceptibility [21]. In a recent study indicated that the CC genotype of rs2075818 (NOD1 G/C) increased the risk of BD by 3.780-fold and the AA genotype of rs2075820 (NOD1 G/A) was increased the risk of cardiovascular involvement in BD 4.286-fold. In addition, they did not find the NOD2 gene variants (R334Q and R334W) in nor the BD patients and neither control groups [106]. Multiple reports have demonstrated that a Crohn’s disease-associated polymorphism, Arg702Trp of the NOD2 rs2066844 was protective to BD [107, 108].
Signal transducer and activator of transcription-4 (STAT4) is a transcription factor that activates gene expression involved in differentiation of naïve T cells into Th1 and Th17 cells, natural killer (NK) cells, mast cells, and dendritic cells [109, 110, 111]. The association between the BD and STAT4 gene appears to be consistent in many independent reports including Korean, Turkish, and Iranians [23, 25]. The functional studies have shown that risk allele A of STAT4 rs897200 correlates clinically with BD disease score due to increased mRNA level of STAT4 gene and expression of IL-17 [112].
FOXP3 is a key transcription factor in the development and function of T(reg) cells. Recent reports have shown the FOXP3 SNPs contribute to the susceptibility to some autoimmune and autoinflammatory disorders. The FOXP3 SNP rs3761548 (-3279 C/A) was significantly associated with BD in the Iranian patients [113]. The FOXP3 (-3279 C/A) A allele has been reported to be associated with neural involvement in BD in Egyptian patients [114]. A low copy number variant of the FOXP3 gene was shown to increase risk in female BD patients in a Chinese cohort [115].
FUT3 (Fucosyltransferase) gene is responsible for the formation of histo-blood group antigens, it might affect the intestinal microbiota composition and modulate innate immune responses [116]. Recent studies indicated that the association between the FUT2 gene variants (rs632111, rs601338, rs602662, rs492602, rs681343, and rs281377) and BD was reported in Iranian and Turkish populations [117].
The renin-angiotensin system (RAS) is important in vascular tone and inflammatory processes. It has been suggested that DD genotype of ACE gene I/D polymorphism might be a genetic marker for BD in Turkish populations [118, 119]. In the other hand, the ACE gene I/D polymorphism was not associated with BD patients in a Iranian cohort and in an another Turkish population [120, 121]. VEGF is a potent angiogenic factor exhibiting various endothelial cell effects, including endothelial cell survival, proliferation, migration and tube formation, and also acts as a proinflammatory cytokine [122, 123]. The carriers of the -634C (3’untranslated region UTR) and I (insertion/deletion) alleles of VEGF gene were associated with a susceptibility to BD in Italian patients [124].
Ubiquitin-associated domain containing 2 (UBAC2) encodes an ubiquitination-related structural domain that is implicated in ubiquitination and proteasomal degradation. The association of the UBAC2 gene polymorphisms (rs9513584, rs9517723, rs7999348) with BD were found in multiple cohorts found including Turkish, Chinese Han, Italian, and Japanese populations [125, 126, 127, 128]. The LACC1 (Laccase domain-containing 1), also known as multicopper oxidoreductases, encodes an oxidoreductase that promotes fatty-acid oxidation. It known functions in activation of inflammasome, bactericidal activity of macrophages, and production of mitochondrial and NADPH-oxidase-dependent reactive oxygen species. SNP rs9316059 of the LACC1 was associated with BD in all the populations tested including Chinese Han, Turkish, Iranian and Japanese [91, 129].
Small ubiquitin-like modifier 4 (SUMO4) has been shown to have the potential to down-regulate NF-kappaB signal, leading to decreased transcription of pro-inflammatory cytokines [130, 131]. The association between the SUMO4 gene (rs237024 and rs237026) polymorphisms and BD was first reported in a Chinese cohort, and they showed the GGAC haplotype was protectively associated with BD in HLA-B51 positive patients [132]. The association was replicated in Tunisian and Korean cohorts for the rs237024 and rs237026 polymorphisms of SUMO4 gene. This study also showed this polymorphisms were associated with disease severity and also some clinical manifestations such as skin lesions, and vascular involvement [133, 134].
The Rho-kinase (ROCK) family members, consisting of ROCK1 and ROCK2, play significant roles in the actin cytoskeleton organization and regulate a wide range of fundamental cellular functions, such as adhesion, migration, motility, cell proliferation, apoptosis, and multiple inflammatory responses [135, 136]. Oguz et al. showed the SNPs rs73963110, rs112130712, rs111874856, rs112108028 might increase the susceptibility to Behçet’s disease, but they failed for the other SNPs such as rs35996865, rs111312709 and rs2271255 [137]. In addition, the ROCK2 gene rs35768389 (Asp601Val) polymorphism was showed to be associated with BD and the C allele was significantly higher in BD patients compared to controls [138].
The proven role of vitamin D in innate and adaptive immune responses has led to an increase in studies on the relationship between vitamin D and autoinflammatory diseases. The VDR gene encodes the VDR protein, a member of the nuclear receptor superfamily, that is essential for the biological functions of vitamin D [139, 140]. Karray et al. found that the VDR gene (rs1544410 and rs2228570) polymorphism were associated with BD in Tunisian patients [141]. In a study with a Turkish cohort, the VDR gene rs1544410 A allele and rs2228570 C allele were reported to be a risk factor for BD susceptibility [142]. In a meta-analysis, the role of the four common VDR polymorphisms has been investigated and it was suggested that rs731236 polymorphism might be a risk factor for BD [143].
Epigenetics is the study of stable and heritable changes in the function of genes which occur without altering the DNA sequence and include DNA methylation, histone modification, and microRNAs [144]. MicroRNAs (miRNAs) are short noncoding RNAs are crucial in regulating multiple cellular processes, such as development, proliferation and apoptosis [145]. Several miRNAs have been associated with the susceptibility of BD disease, which includes many different inflammatory pathways [146]. Zhou et al. revealed miR155 expression was significantly decreased in dendritic cells from patients with BD with active compared to inactive uveitis [147]. In addition, the many SNPs in miRNA have been showed to be a risk for BD in association studies. Both of the TT genotype and T allele of rs11614913 located at pre-miR196a2 were found had increased frequency in patients with BD [148]. The microRNA-146a rs2910164 was associated with decreased frequency of CC genotype and C allele in patients with BD, whereas GG genotype was significantly increased in an Egyptian cohort [149]. Also, TT genotypes and T allele of rs3746444 miRNA-499 exhibited a significantly higher risk in patients with BD in a study of Turkish population [150]. In a Spanish cohort, the relative promoter methylation level of the IL-6 mRNA was found significantly lower in BD patients compared to controls [151]. The variant in the pre-miRNA region of miR-196a2, rs11614913, was associated with BD susceptibility, as well as BD arthritis [148]. In an Epigenome-wide association study with Chinese BD patients, the genetic variants of 10 CpG-SNPs were not associated with BD susceptibility [152].
From a genetic perspective, several molecules involved in the response to pathogens and multiple genes that activate or regulate inflammation appear to be critical in the etiopathogenesis of BD. However, the precise pathogenic mechanisms of these genes on BD are still unclear. In addition, it is unknown how genetic components as well as other associated risk factors such as bacterial and viral pathogens affect the developmental process of BD. Genome-wide association studies (GWAS) have become a very important step in understanding BD pathogenesis. GWASs with satisfactory numbers of subjects in regions where BD is prevalent revealed a strong association between BD and inflammatory cytokines such as IL-1, IL-4, IL-6, IL-10, IL-17, and IL-23–IL-12RB2. Some association studies, for example TNFAIP3, TLRs and miRNAs, appear to be conflict in different study groups and/or populations. The conflicting results of these genes associated with BD suggest that they may be ethnically specific or have occurred due to sample selection bias. In the future, similar studies in different populations with a higher number of patients will provide significant advances in the etiopathology of BD. We proposed that genetic factors located at loci outside the MHC region (IL1A-IL1R, IL10, CCR1-CCR3, ERAP1, IRF8, RIPK2, FUT2, IL-28, IL-29, NOD1, NOD2, VEGF and etc.…) contributed to BD susceptibility by playing a role in host defense and immune responses to pathogens in inflammation pathways. Moreover, specific gene polymorphisms have been linked with clinical presentation of BD such as ocular lesions, neurological and intestinal and cardiovascular involvement. The future direction will guide possible therapeutic approaches by understanding the functional significance of BD-associated gene polymorphisms, as well as insights into the pathogenesis of the disease.
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He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. 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He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. 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