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",isbn:"978-1-83881-111-2",printIsbn:"978-1-83880-992-8",pdfIsbn:"978-1-83881-112-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"acb2875b3bfc189c9881a9b44b6a5184",bookSignature:"Dr. Abdo Abou Jaoudé",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11865.jpg",keywords:"Linear Operators, Normal Operators, Spectral Theorem, Applications, Differential Operators, Integral Operators, Functional Calculus, Complex Variables, Complex Analysis, Theory, Recent Advances, Latest Trends",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 13th 2022",dateEndSecondStepPublish:"June 21st 2022",dateEndThirdStepPublish:"August 20th 2022",dateEndFourthStepPublish:"November 8th 2022",dateEndFifthStepPublish:"January 7th 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"6 days",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Abdo Abou Jaoudé is a pioneering Associate Professor of Mathematics and Statistics at Notre Dame University-Louaizé. He holds two PhDs in Mathematics and Prognostics from the Lebanese University and Aix-Marseille University. His research interests are in the field of mathematics.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"248271",title:"Dr.",name:"Abdo",middleName:null,surname:"Abou Jaoudé",slug:"abdo-abou-jaoude",fullName:"Abdo Abou Jaoudé",profilePictureURL:"https://mts.intechopen.com/storage/users/248271/images/system/248271.jpg",biography:"Abdo Abou Jaoudé has been teaching for many years and has a passion for researching and teaching mathematics. He is currently an Associate Professor of Mathematics and Statistics at Notre Dame University-Louaizé (NDU), Lebanon. He holds a BSc and an MSc in Computer Science from NDU, and three PhDs in Applied Mathematics, Computer Science, and Applied Statistics and Probability, all from Bircham International University through a distance learning program. He also holds two PhDs in Mathematics and Prognostics from the Lebanese University, Lebanon, and Aix-Marseille University, France. Dr. Abou Jaoudé's broad research interests are in the field of applied mathematics. He has published twenty-three international journal articles and six contributions to conference proceedings, in addition to seven books on prognostics, pure and applied mathematics, and computer science.",institutionString:"Notre Dame University - Louaize",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Notre Dame University – Louaize",institutionURL:null,country:{name:"Lebanon"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"15",title:"Mathematics",slug:"mathematics"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"252211",firstName:"Sara",lastName:"Debeuc",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/252211/images/7239_n.png",email:"sara.d@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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The prevalence keeps increasing with age and it is commonly identified in elderly populations. Approximately 20% of adults in their second to fourth decades are affected by this disease. Yeasts contribute to 24–50% cases of onychomycosis with
The prevalence of onychomycosis differs based on geographical location with worldwide prevalence of approximately 10% [5]. The incidence onychomycosis in North America ranges from 8.7–13.8% while the prevalence in Southeast Asia ranges from 2–6% [2, 3]. Higher prevalence is reported in countries with humid climates, such as Greece (27.99%) and Ethiopia (60,4%), [6, 7]. While there are three groups of fungi responsible for onychomycosis, dermatophytes are the most common cause of onychomycosis (60–70%) [3].
Yeasts, most commonly identified as
In assessing the treatment outcome of CO patients, there are three types of cure to be considered, which area mycological cure, clinical cure, and complete cure. Clinical cure is described as a previously infected nail without signs and symptoms of onychomycosis. Mycological cure is described as negative results on both direct microscopic examination and culture. Complete cure is described as achieving both clinical and mycological cure [8]. Various prognostic factors have been identified for the treatment outcome of onychomycosis. In general, they can be divided into three groups, which are patient’s characteristics, nail features, and the infectious agents (Table 1) [9].
Poor Prognostic Factors | |
---|---|
Patient’s characteristics | Male gender |
Increasing age | |
History of nail trauma | |
History of onychomycosis | |
Poor immune status | |
Poor peripheral circulation | |
Uncontrolled diabetes mellitus | |
Repeated exposure to water and detergents | |
Repeated exposure to mud and soil | |
Barefoot walking | |
Nail features | Subungual hyperkeratosis >2 mm |
Fingernail and toenail involvement | |
More than 3 infected nails | |
Matrix involvement | |
Significant lateral disease | |
Dermatophytoma | |
Nail plate involvement >50% | |
Slowly growing nails | |
Hallux involvement | |
Severe onycholysis | |
Paronychia | |
Melanonychia | |
Total dystrophic onychomycosis | |
Infectious agents | Fungal and bacterial coinfections |
Yeasts | |
Non-dermatophytes molds |
Most studies reported that the onychomycosis is more commonly diagnosed in men. Male patients are associated with poor outcome because they are more likely to be exposed to repeated nail trauma and they usually do not seek health care until the disease becomes too advanced. Furthermore, they are more likely to have low compliance; hence, male patients become more resilient when it comes to treatment and have 2,6 times risk of not achieving clinical cure [8]. Increasing age is also known to be associated with poor prognosis in onychomycosis patients because elderly populations usually suffer from poor circulation system, poor immune status, decreased nail growth, and mixed fungal infections. Hence, their response to therapy might be lacking and they have 3,7 times risk of not achieving clinical cure [8, 9].
Nail trauma can exert significant and irreversible damage which will predispose patients to onychomycosis. Patients who have abnormal nails with positive mycology examination had 5,4 times risk of developing onychomycosis [9]. Other poor prognostic factor is history of onychomycosis. Patients with prior infection have 2,3 times risk of not achieving clinical cure. These patients are more likely not to respond standard treatment course since they have been treated before. There might also be involvement of genetic susceptibility in the development of recurrent onychomycosis [8].
As most fungi are opportunistic agents, poor immune status can predispose patients to onychomycosis, especially in HIV patients with CD4 count <400/mm3. The onychomycosis is more likely to involve fingernails and toenails also more severe [9]. Patients with hand and foot involvement have 1.1 times risk of not achieving complete cure and if the patients have more than 3 infected nails, they have 1.5 times risk of not achieving complete cure [4]. Furthermore, hallux involvement presents as poor prognostic sign because it is more likely to suffer repeated trauma lead to predisposition of continuous infection.
In addition, poor peripheral circulation caused by chronic venous disease is associated with poor prognosis. Chronic venous disease can cause nail dystrophy, hyperkeratosis, discoloration, hyperplastic nail bed, and onychogryphosis. Only 25% of patients treated with itraconazole are cured [9]. Poor peripheral circulation can also identified in patients with uncontrolled diabetes mellitus which associates with secondary infections and nonhealing ulcers. This population is also reported to have more severe onychomycosis, high recurrence rate and longer duration to achieve complete cure [9].
Repeated exposure to water and detergents will predispose patients to chronic paronychia and affect the drug delivery since the tissue is more edematous and inflamed. While repeated exposure to mud and soil, also barefoot walking will predispose the patients to repeated minor trauma. Most fungi are saprophytic; hence, they can invade nails easily in this condition. This often happened in tropical countries [10].
Subungual hyperkeratosis is host’s reaction towards fungal infection by thickening the stratum corneum. The thick debris presents as a barrier to antifungal agents, both systemic and topical agents [9]. Furthermore, patients with matrix involvement have 2.1 times risk of not achieving complete cure [8]. Matrix is known to be the nail’s origin [11]. Hence, matrix involvement in onychomycosis will affect the nail growth and drug delivery [8]. In addition, the slow nail growth is also a poor prognostic factor since the patients shed the infected portion of the nail more slowly. This association is also described in elderly populations. Slow nail growth is also seen in significant nail plate involvement. Greater surface involved is associated with greater fungi load; hence, lower cure rates [9].
Significant lateral disease affects the treatment outcome since there is poor attachment of the lateral edge to the nail groove. This can reduce the drug delivery about two thirds of normal nail. Similar cases are seen in severe onycholysis [9]. Patients with lateral disease have 3,5 times risk of not achieving complete cure [8]. Another poor prognostic factor is dermatophytoma, a dense thick-walled fungal elements presenting as white to yellow patch or longitudinal streak in nail plate. This dense mass is difficult to be penetrated by antifungal agents. Therefore, the patients with dermatophytoma have 2.9 times risk of not achieving clinical cure [8, 9].
Melanonychia is black pigmentation identified on the nail plate. This feature is associated with poor prognosis in onychomycosis. However, the association has not been elucidated yet. Total dystrophic onychomycosis (TDO) is the final destructive stage of onychomycosis, in which there is thickened nail bed, crumbling nail plate, and significant involvement of nail matrix. Patients with TDO have 1.1 times risk of not achieving complete cure [4, 9].
As for the infectious agents, CO and NDMs onychomycosis indicate poor prognosis. CO is associated with immunosuppression, especially in case of chronic mucocutaneous candidiasis (CMC) and HIV patients. While NDMs infections are difficult to be diagnosed and lack of data for treatment course. In addition, fungal and bacterial infections can complicate the treatment. Therefore, these factors can implicate in poor prognosis of onychomycosis patients [9].
In order to aid the clinicians in have better treatment outcome, several instruments have been developed to predict the prognosis in onychomycosis patients. The first developed instrument was Scoring Clinical Index for Onychomycosis (SCIO Index). This scoring assesses the nail’s clinical component based on its clinical form, nail involvement, and subungual hyperkeratosis. In addition, it assesses the growth component based on the patient’s age and location of onychomycosis. As the score increases, the onychomycosis might be more difficult to treat [12]. However, this scoring has not been validated and has other limitations, such as exclusion of important prognostic factors and complex calculation [9].
Another scoring was developed by Baran et al. (Table 2). The higher the score, the more likely the treatment failure will happen [13]. Albeit being the most comprehensive instrument, this index has not been validated and time-consuming [9].
Descriptor | Subdivision | Score | |
---|---|---|---|
1 | Extent of involvement | Distal one-third of nail plate | 1 |
Distal two-thirds of nail plate | 2 | ||
Proximal nail plate involvement | 3 | ||
2 | Diffuse nail plate thickening | Mild or moderate | 1 |
Associate with onychogryphosis | 3 | ||
3 | Nail plate thickening associated with the appearance of linear streaks – includes the change confined to the lateral border | One streak only | 2 |
Two or more streaks | 3 | ||
If the streaks are black do not score but see 7 | |||
4 | Onycholysis | Affecting the distal two-thirds of nail plate | 2 |
5 | Location | Any one of: | |
Second to fifth toes or thumb | 1 | ||
Great toenail | 2 | ||
6 | Paronychia associated with nail plate disease | With diffuse melanonychia | 3 |
With melanonychia at the lateral edges of the nail | 3 | ||
7 | Melanonychia (without paronychia) | With one or more longitudinal streaks | 3 |
Diffuse pigmentation | 4 | ||
8 | Age of patient | Under 7 years | 3 |
7–25 years | 1 | ||
25–60 years | 2 | ||
Over 60 years | 3 | ||
9 | Presence of the following predisposing factors | Diabetes mellitus | 1 |
Known severe trauma to affected nail | 2 | ||
Immunosuppression (due to therapy, e.g., prednisolone, or disease, e.g., AIDS) | 4 | ||
Symptomatic peripheral vascular disease | 2 | ||
10 | Causative organism | 4 | |
Other mold fungi | 2 | ||
Yeasts | 1 |
The most commonly used instrument is Onychomycosis Severity Index (OSI). OSI is simpler by assessing three major components, which are area of involvement, proximity of disease to matrix, presence of dermatophytoma or subungual hyperkeratosis >2 mm (Table 3). The score is multiplication of score for area of involvement with score for proximity of disease and addition of score for the presence of dermatophytoma or subungual hyperkeratosis >2 mm. Score 1–5 indicates mild onychomycosis; 6–15 indicates moderate onychomycosis; and 16–35 indicates severe onychomycosis [14]. This index has been validated with high reliability. However, this index only assesses one nail, does not correlate the severity of disease with treatment outcome, and excludes other important prognostic factor [9].
Predictor | Subdivision | Score |
---|---|---|
Area of involvement (%) | 0 | 0 |
1–10 | 1 | |
11–25 | 2 | |
26–50 | 3 | |
51–75 | 4 | |
76–100 | 5 | |
Proximity of disease to matrix | <1/4 | 1 |
1/4–1/2 | 2 | |
>1/2–3/4 | 3 | |
>3/4 | 4 | |
Matrix involvement | 5 | |
Presence of dermatophytoma or subungual hyperkeratosis >2 mm | No | 0 |
Yes | 10 |
The most common causative agent of yeast onychomycosis is candida species. Fingernails are the predilection site of CO, especially in patients who are regularly submerging their hands in water [3]. Candida species are a commensal part of the normal skin flora, which are present in nature. However, these species may exhibit opportunistic quality in an immunocompromised host. Candida species can be either primary or secondary causative agent in onychomycosis. Primary CO can be commonly encountered in a severe immunocompromised host, for example, in HIV patient. On the contrary, secondary CO is usually related to predisposing diseases or circumstances, for instance, diabetes mellitus, malnutrition, peripheral vascular disease, chronic nail trauma, smoking, and vulnerable age (elderly and children). Particular occupations such as housekeepers, fishers, and farmers are also at risk of CO due to the frequent trauma and excessive moisture on the nails, exposure to contaminants, and contact with chemicals [2].
Instead of appearing as individual spores and hyphae, fungal organisms tend to integrate, forming a biofilm which is a syntrophic group of fungi adhering to the host’s surface. When not infiltrating a substrate, fungi may fluctuate between free-floating types and parts of a superficial biofilm. This particular feature provides benefits for fungi development while being surrounded by extracellular matrix (ECM). The surrounding ECM defends fungi from the host’s immune response and antifungal treatments. ECM also supports fungi to distribute nutrients to the biofilm. Fungi biofilm contributes to the rationale of why onychomycosis is relatively refractory to antifungal treatment and challenging to eliminate the spores in chronic manifestation entirely [3].
The biofilm development by
There are 3 definite stages of
In addition to biofilm, yeast factors that contribute to the virulency of CO are synthetization of hydrolytic enzymes, including proteinase, hemolysin, and phospholipase, which are unique between each type of Candida species. Moreover, proteinase plays a part in the breakdown of protein and phospholipase contributes to the destruction of the host cell, allowing
Most CO cases involve fingernails compared to toenails, with an estimated prevalence of up to 50% of onychomycosis cases in fingernails. Women at risk of developing CO are typically wet workers due to the recurrent moist in the hands, exposure to trauma, regular contact with washing liquids, and contamination to vaginal flora during cleansing, which ultimately provides a suitable niche for the development of Candida species [2].
Clinical presentations that are predictive for CO are nail plate dystrophy and off-white discoloration, commonly followed by pigmentation. Melanisation, one of the virulence factors for Candida, suggests an indication of progressive resistance to antifungal treatment. Classification of CO is established because of the complex etiopathogenesis and diverse clinical presentations. The first clinical classification of CO was suggested based on the clinical presentation, the affected location, and the infection route, which are Candida paronychia, Candida granuloma, and Candida onycholysis [2].
The most frequent type of CO is paronychia. Humidity plays an essential role in the development of Candida paronychia. Clinical manifestation of Candida paronychia comprises erythema and swelling in the nail folds followed by gradual dystrophy in the nail plate accompanied by paronychia and Beau lines, which is depicted by an oblique dent in the nail plate suggesting parasite infestation on the nail matrix. The most severe type of CO is granuloma, which is frequently observed in patients with chronic mucocutaneous candidosis. Clinical manifestation of Candida granuloma displays brittle nails and a deformity resembling drumstick which is also referred to as pseudoclubbing. The last type of CO is onycholysis. Clinical manifestation of Candida onycholysis is characterized by subungual distal hyperkeratosis, which further develops into a group of keratosis separating the nail plate from the bed. Moreover, a recent classification was proposed, including four clinical groups of CO, which are chronic paronychia with secondary nail dystrophy, distal onychomycosis, chronic mucocutaneous candidosis, and secondary candidosis [17].
Chronic paronychia initially emerges from the proximal nail fold, although lateral nail folds are occasionally affected in the beginning. Swelling of the periungual skin and a noticeable gap between the fold and nail plate is observed, followed by the nail plate involvement. Marks with a white, green, or black color can be detected at the lateral and distal parts, respectively. The longitudinal ridges and opaqueness appear on the nail that develops into a brittle and easily detached nail. Pressure and movement on the nail can be painful in contrast to dermatophyte infections. A superimposed infection caused by bacteria into the subcuticular space usually occurs, leading to a vicious cycle. Chronic paronychia usually appears in adults whose occupations regularly contact water and children because of the thumb sucking habit [17].
Distal candida nail infection manifests as subungual hyperkeratosis along with onycholysis. Differentiating the clinical manifestation with dermatophytosis can be challenging, however the candida results in less extent damage to the nail compared to dermatophyte. In addition, the predilection of CO usually affects the fingernails, while most dermatophytes invade the toenails. The prevalence of distal candida nail infection is infrequent and most of the cases are related to vascular problems, such as Raynaud’s phenomenon [17].
Total dystrophic onychomycosis occurs in patients with chronic mucocutaneous candidosis. The organism invasion on the nail plate results in hyperkeratotic and gross thickening of the nail. Chronic mucocutaneous candidosis has multifaceted etiology which results in the weakened cell-mediated immunity. The variety of clinical appearance depends on the severity of immunosuppression; however, thickening of the nails can be observed in advanced cases due to the Candida granuloma. In addition, the involvement of the mucous membrane is nearly presented in most cases [17].
Secondary candida onychomycosis results because of other diseases involving the nail apparatus, most commonly psoriasis [17].
Common tests utilized in the diagnosis of onychomycosis are potassium hydroxide (KOH) preparation, fungal culture, histopathology, polymerase chain reaction (PCR), and flow cytometry (Table 4). The combination tests are usually performed; however, the gold standard of diagnostic tests are microscopy and culture [3].
Dissolved large keratinocytes result in the flattening of nail segment and decreasing reflection from cell borders. Examined with microscopy | Quick, on-the-spot | Low sensitivity | No | No | |
Cleaned and clipped subungual debris of the nail are scraped into the gauze. Culture developed in the agar with or without cycloheximide. Examined with microscopy | Precise | Results obtained in ≥3 weeks, high false-negative rate | Yes | Yes | |
Stained by hematoxylin and eosin to depict the elements of the fungi. Periodic acid-Schiff or Grocott’s methenamine-silver can be utilized to enhance the appearance of hyphae | Validate the presence of fungus | Involves specific laboratory equipment | No | No | |
Employ a target gene part of ribosomal DNA or chitin synthase genes | Quick, 48 hours | Costly | Yes (real-time PCR) | Yes | |
Employ granulosity, cell volume, DNA, and protein markers to produce definite profiles for fungi | Very specific | Involves great sample size, costly | No | Yes |
Onychoscopy can also be used for initial diagnosis of onychomycosis. The most common findings in onychomycosis are jagged edge with spikes of the proximal part of the onycholysis, parallel bands of various color resembling aurora borealis pattern, and ruin appearance at the subungual part [3].
KOH microscopy and fungal culture are presently the gold standards to establish the diagnosis of onychomycosis. However, it remains questionable because KOH microscopy demonstrates a false-negative rate between 5% to 15% and false-positive for evaluating the medication, given that KOH microscopy visualizes both live and dead hyphae which are identical through microscope. Furthermore, fungal culture has a wide-ranging sensitivity from 30% to 57% and requires incubation for weeks. Latest studies comparing a variety of diagnostic tests indicate that histopathology staining has higher sensitivity than KOH microscopy or culture, although another study suggests PCR for a quicker and precise alternative for fungal culture, particularly in NDM onychomycosis. Therefore, the combination of diagnostic tests is recommended to diagnosis onychomycosis accurately. A feasible option can be a KOH microscopy and PCR (or culture in a resource-limited setting) if the KOH shows positive results [3].
In the case of CO, obtaining sample for KOH microscopy and culture can be performed from the proximal and lateral parts of the nail. Nevertheless, sample can be obtained from the distal part in the case of onycholysis. Culture result may reveal creamy-whitish colonies on Sabouraud dextrose agar media or primary isolation can also be attained using chromogenic media, for instance CHROMagar Candida®. Anti-fungal susceptibility should be performed following the identification of the isolated strains to achieve the most effective therapy. Histopathological results of CO usually display hyphae and pseudomycelia on the nail through Schiff’s periodic acid stains or Grocott’s methenamine silver stains. PCR can also be utilized for further identification [2].
Defining the resolution of onychomycosis can be achieved through clinical, mycological, and complete cure. Clinical cure is described as 100% improvement depicted by clear nail, while mycological cure is described as negative KOH microscopy and negative fungal culture, respectively. Ultimately, complete cure comprises 100% clear nail and mycological cure. The goal of treating onychomycosis for physicians and affected stakeholders are achieving the complete cure. However, it is difficult for an infected nail to return into an utterly normal appearance, particularly in advanced stage although mycological cure has been attained [3].
The treatment choices (Figure 1) available for managing onychomycosis are oral medication, topical therapy, and devices. Oral antifungals (Table 5) are the first-line therapy because they result in high success rates. Nevertheless, oral antifungals are contraindicated in patients with chronic or active liver disease, congestive heart failure, and kidney failure. Besides, oral antifungals may interact with other pharmacological agents, which can trigger a severe adverse reaction. These setbacks urged the request for the safer option which leads to the awareness of topical therapy. Topical treatments (Table 6) are indicated in mild–moderate cases and patients with contraindication for oral antifungals. However, they also have limitations which are smaller cure rate, prolonged therapy and difficulty applying for patients with mobility problems. Ultimately, lasers are FDA-approved device therapy for short-term clearance and/or nail enhancement. However, laser therapy is lacking conclusive guidance and its efficacy demonstrates notable disparities among all treatment modalities. Topical antifungals eradicate the fungus from the outward penetrating the dorsal part of the nail, whereas oral antifungals eliminate from the inward infiltrating the ventral part of the nail [3].
Treatment algorithm of onychomycosis [
Trade name | Lamisil | Sporanox | Diflucan | |
Chemical structure | Allylamine | Triazole | Triazole | |
Molecular formula | C21H25N•HCl | C35H38Cl2N8O4 | C13H12F2N6O | |
Mass (g/mol) | 291.3 | 705.64 | 306.27 | |
Mechanism of action | Squalene epoxidase inhibitor | Lanosterol 14α-demethylase inhibitor | Lanosterol 14α-demethylase inhibitor | |
CYP+ inhibition | CYP2D6 | CYP3A4 | CYP2C9, CYP2C19, CYP3A4 | |
Spectrum of action | Dermatophytes, some activity against NDMs | Dermatophytes, NDMs, and | Dermatophytes, some NDMs, and | |
Efficacy | MC | 70% | 54% | 47–62% |
CC | 38% | 14% | 28–36%* | |
Approval | US–1996 | US–1995 | US–1990† | |
EU–1991 | EU–1989 | EU (UK)–1988 | ||
Canada–1993 | Canada–1993 | EU (Finland)–1993 | ||
China–1993 | ||||
Canada–1990* | ||||
FDA pregnancy class | B | C | D |
Summary of available oral antifungal [3].
Data provided are clinical cure rates.
Fluconazole was FDA-approved for use in humans in 1990, but is not yet approved for treatment of onychomycosis in the US or Canada.
CYP, cytochrome P450; NDM, non-dermatophyte molds; MC, mycological cure; CC, complete cure.
Cited as is from Gupta et al. [3].
Trade name | Jublia | Kerydin | Penlac | Loceryl | |
Chemical structure | Triazole | Oxaborole | Hydroxypyridone | Morpholine | |
Molecular formula | C18H22F2N4O | C7H6BFO2 | C14H24N2O3 | C21H35NO | |
Mass (g/mol) | 348.39 | 151.93 | 207.27 | 317.51 | |
Mechanism of action | Lanosterol 14α-demethylase inhibitor | Aminoacyl †RNA synthetase inhibitor | Chelation of polyvalent heavy metal ions | Δ14-sterol reductase and cholestenol | |
Δ-isomerase inhibitor | |||||
Spectrum of action | Dermatophytes, NDMs, and | Dermatophytes, NDMs, and yeasts | Dermatophytes, | Dermatophytes, NDMs, and yeasts | |
Efficacy | MC | 53.4–55.3% | 31.1–35.9% | 29–36% | 60%125 |
CC | 15.2–18.8122 | 6.5–9.1%121 | 5.5–8.5%123 | ||
Approval | US–2014 | US–2014 | US–1999 | EU–1991 | |
Canada–2013 | Canada–2004 | Australia–1996 | |||
Japan–2014 | |||||
FDA pregnancy class | C | C | B | Poor systemic absorption, safe in animals, no studies in pregnant women† |
Another proposed treatment algorithm is based on the severity of onychomycosis assessed with SCIO (Table 7) [12].
SCIO | Treatment approach |
---|---|
1–3 | Topical treatment: remove (cut or scrape off) affected marginal parts of the nail |
Use topical antifungals until healthy nail regrows | |
3–6 | Topical treatment with lower success, which often depends on growth rate |
Systemic therapy recommended in slower-growing nails or proximal onychomycosis type | |
6–9 | Systemic therapy. Use scheme proposed for fingernails (e.g., itraconazole: 2 pulses of 200 mg bid) |
9–12 | Systemic therapy. Use scheme proposed for toenails (e.g., itraconazole: 3 pulses of 200 mg bid) |
12–16 | Systemic therapy. Use scheme proposed for fingernails with any antifungal (e.g., 4–5 pulses of itraconazole, 200 mg bid) |
16–20 | Combination therapy (systemic antifungal + topical measures) |
Adequate keratolytic treatment recommended | |
20–30 | Consider nail avulsion (e.g., with urea paste), continue with systemic therapy |
As CO commonly recurs with overall onychomycosis recurrence rate of 10–53%, additional measures should be implemented to prevent this recurrence. For the clinicians, it is imperative to confirm the diagnosis and identify the infectious agent before providing treatment. Assessing and treating the comorbidities is also crucial since some comorbidities are risk factors for onychomycosis, also portend as poor prognostic factors. Tinea pedis should be treated properly as the infected skin can play a role as reservoir for the pathogens [3].
When the patients are diagnosed, the clinicians should provide them with optimal onychomycosis therapy, provide counseling on the expectations and adherence to treatment. The patients should also be provided with information to maintain hand and foot hygiene, avoid occlusive shoes, trim the nails regularly, use broad toed shoes with absorbent materials, and avoid barefoot walking in locations with abundant fungal density (e.g., swimming pool, communal showers, gymnasium floors). Good sanitization measures should be taken for previous infected socks and shoes. Socks should be washed with hot water (60 °C) for 45 minutes and shoes should be exposed to ultraviolet rays or ozone or can be sprayed with antifungal sprays. The close contacts or family members of the patients should be examined and treated if they suffer from onychomycosis or tinea pedis [3, 18].
Prophylaxis can be considered for patients with high probability to suffer from recurrence. Topical antifungal agent in the form of solution or lacquer can be applied once daily for a month then twice weekly for at least two years after the cure have been achieved [3].
CO is a common nail infection affecting people worldwide. Establishing the diagnosis of CO becomes a challenge for the clinicians since
The authors declare no conflict of interest.
Chronic Mucocutaneous Candidiasis Candida Onychomycosis Human Immunodeficiency Virus potassium hydroxide Non-Dermatophyte Molds Polymerase Chain Reaction Scoring Clinical Index of Onychomycosis Total Dystrophic Onychomycosis
The permanent harm, dysfunction, and failure of multiple human body parts, like eyes, kidneys, heart, nerves and blood vessels could be caused by persistent hyperglycemia [1].
The risk of the diabetes raises seven times in older age (55+) than it is in younger age (20 to 34 years old). So, it is really important to gear up to control diabetes in midlife. Specially minimizing the spread of type 2 Diabetes Mellitus is crucial for individuals and even the societies. The importance of eradication of
Healthy lifestyle and body-weight control in midlife plays a crucial role in avoiding or postponing manifestation of type 2 Diabetes Mellitus since lifestyle interventions seem more durable concerning their protective potential in this part of life. The different pharmaceutical approaches to eradicate type 2 Diabetes Mellitus are not effective after they root out the disease for the first time. Also, such approaches have so many side effects on the patients going through such techniques. Therefore, for the time being, no drug is licensed for diabetes prevention.
Nonetheless, novel medicaments’ attempts for diabetes prevention and supporting healthy aging are under scientific investigation. The diabetes can result in severe hypoglycemia, premature cardiovascular complications, other severe problems and even death. So, every possible step should be taken in order to eradicate this. The lifestyle of the patient should be changed to fight diabetes. All possible pharmaceutical techniques should also be applied to control the ailment. Diabetes prevention has a vital influence in the making of health policy [2].
Numerous pathogenic processes are responsible of the growth of diabetes. These range from autoimmune demolition of the pancreatic β-cells with subsequent insulin shortage to anomalies that result in confrontation to insulin action. Lacking insulin action results from insufficient insulin emission and/or reduced tissue responses to insulin at one or more points in the complex paths of hormone action. The basis of the abnormalities in carbohydrate, fat, and protein metabolism in diabetes is deficient action of insulin on target tissues. Weakening of insulin secretion and defects in insulin action frequently coexist in the same patient, and it is mostly uncertain which anomaly, if either alone, is the main reason of the glucose excess in blood [1].
When we take the meal, the glucose levels in blood rise that activates insulin secretion. This results in a rise in biotransformation, transport and storage of insulin in fat tissues and muscles. During fasting, liver provides the glucose in blood that is used by the brain, without any dependence on insulin. Besides storing glucose, insulin also hinders the secretion of glucagon and drops the quantity of serum fatty acids resulting in a downfall in production of glucose in liver [3]. Inadequate insulin or confrontation to insulin in the body results in lessened uptake of glucose by tissues that has intracellular hypoglycemia and extracellular hyperglycemia as its outcome. The glucogenesis is caused by intracellular hypoglycemia and gluconeogenesis that results in breakdown of fats (resulting in diabetic ketoacidosis) and reduces synthesis of gamma globulins and protein (resulting in polyphagia, cachexia and reduced wound healing), while osmotic dieresis and hyperglycemic coma are caused by the extracellular hyperglycemia [4].
A deficiency of insulin secretion occurs in Insulin dependent Diabetes Mellitus (IDDM). It is because of the autoimmune demolition of pancreatic beta cells that results in metabolic disorders associated with Insulin Dependent Diabetes Mellitus [4]. The last stage of β-cell demolition shows the beginning of clinical ailment resulting in type 1 diabetes mellitus. There the infiltrating lymphocytes, monocytes and a blend of pseudo atrophic islets form along with a few cells emitting glycogen, somatostatin and polypeptide from pancreas. This results in an immunogenic process whose outcome is the ailment [5, 6, 7]. Genetic makeup, autoimmunity and environmental factors are accountable for islets cell demolition [8].
Many healthy operations are impaired in Non-Insulin dependent diabetes mellitus (NIDDM). This lessens the adjustment of tissue acceptance to insulin which results in reduced insulin influence via insulin confrontation and reduced insulin emission by the beta cells of pancreas [9].
Several genetic imperfections, and some environmental factors like overweightness are important in this type of diabetes. They are accountable for peripheral tissue insulin reluctance and beta cell problems [8].
As indicated by ongoing appraisals, the human populace overall seems, by all accounts, to be amidst a pestilence of diabetes. Notwithstanding the incredible steps that have been made in the comprehension and the executives of diabetes, the infection and sickness related difficulties are expanding continuously. Along with this, ongoing improvements in comprehension of the pathophysiology of the ailment procedure has unlocked a few new roads to distinguish and create novel treatments to battle the epidemic of diabetes [10]. The cure of diabetes with artificial medications is expensive and odds of reactions are so many. Phytomedicine has been utilized since old occasions in different regions around the globe where access to up-to-date drugs is restricted. Therapeutic plants and phytochemicals assume a significant job in the administration of diabetes mellitus particularly in under-developed nations where assets are small. Utmost pervasive amongst phytochemical bunches are the glycosides, alkaloids, polysaccharides and phenolics, for example, terpenoids, steroids and flavonoid. Regardless of impressive advancement in the improvement of artificial medications, the disclosure of phytomedicine as an elective treatment is increasing [11]. Simultaneously, phytochemicals recognized from customary medical plants are exhibiting an energizing open door for the improvement of new kinds of therapeutics. This has quickened the worldwide exertion to saddle and gather those restorative plants that bear significant number of potential phytochemicals appearing advantageous impacts in battling diabetes and diabetes-related entanglements. In this manner, as the malady is advancing continuously, there is a critical need of recognizing native resources occurring in nature so as to get them, and concentrate in detail, their potential on various recently distinguished focuses so as to create them as new treatments [10]. The improvement of type 2 diabetes might be decreased by the admission of cancer prevention agents in the eating routine [12].
Nutrients are the natural mixes needed by our body which are termed as mandatory ingredients required in definite quantities. They cannot be made in adequate quantity by the human body, and thus, should be gotten from the eating routine. Thirteen distinct kinds of vitamins are found that are ordered by their organic and substance action; every one of them keeps a particular job in human body [13].
Vitamins are termed as either fat-dissolvable or water-solvent. There are thirteen vitamins found in nature. Nine of them could dissolve in water (8 B Vitamins and Vitamin C) whereas, four of them could dissolve in fat (A, D, E, and K). The water-solvent Vitamins effectively make solution in water and are discharged from the body quickly since they could not be kept for quite a while, aside from nutrient B12 [14]. Whereas, fat-solvent Vitamins are caught up in the digestive system within the existence of lipid and they are bound to be kept in the body. As they are kept for quite a while, they can prompt hypervitaminosis more than the water-dissolvable vitamins; a few nutrients are necessary for the body cell development and improvement (for instance folate and vitamin B12).
Folate is known as vitamin B9 which has significant functionality in human body. We need folate for the repair, creation and methylation of DNA [16]. In a study in America, it was seen that the
Besides, it goes about as a helper in numerous fundamental natural responses. Folic Acid has a significant job in cell division and it is particularly required amid early stages and pregnancy. Our body needs folic acid so as to avoid iron deficiency and create sound RBCs (Red Blood Cells), while Vitamin B12 assumes a significant job in providing basic methyl bunches for protein and DNA amalgamation. Vitamin B12 is bound to the protein in our meal and hydrochloric acid in the stomach discharges B12 from it amid ingestion. Once discharged, vitamin B12 consolidates with an ingredient known as intrinsic factor [18].
The type 2 Diabetes Mellitus is a heterogenous malady which is usually connected to vital chemical reactions, especially starch and fat administration in the living being. Be that as it may, most micronutrients are likewise associated with some route either as a component of the reason or impact of this perpetual pathology. The outcomes and problems of diabetes are the aftereffect of a disparity between free radical development and their control by common cancer prevention agents [19]. Thus, those micronutrients that have an antioxidant function are very important in the development of the disease and its complications, while other non-antioxidant vitamins have also shown a relationship.
Vitamins A, C and E, which have antioxidant properties are discovered diminished in diabetic patients, may be because of an expanded need to limit the extraordinary oxidative pressure created by irregularities in glucose digestion. Then again, retinol binding protein applies a tweaking impact, as it has adipokine capacities. As for the B complex Vitamins, pyridoxine, thiamin and biotin have been discovered diminished though the systems are not obvious, whereas using its supplements has demonstrated some betterment of the metabolic control in individuals suffering from diabetes. The assimilation of folate and Vitamin B12 is critically diminished by the prolonged utilization of metformin, which is the most used medicine in simple diabetes, subsequently these two supplements have been discovered insufficient in the ailment and most presumably should be administered consistently. Whereas, Vitamin D is viewed as a hazard for the improvement of diabetes just as its difficulties, especially those related to heart and blood vessels. Though a few examinations have discovered a relationship of Vitamin K admission with sugar digestion which require more research. Research on the utilization of multivitamin supplements have indicated uncertain outcomes. The individuals utilizing metformin amid delayed periods may require folate and Vitamin B12 [20].
Vitamin B12 is a non-protein ingredient in the single-carbon metabolic pathways, engaged with the making of methionine, pyrimidine and purine bases. Its deficiency due to DNA damage or faulty repair is involved in cancer, vascular diseases and some birth defects, while a consequent hyperhomocysteinemia, also related to folic acid deficiency; it has been recognized as a risk for hypertension and atherosclerosis [21].
The water-soluble vitamin is
These compounds are listed as [26].
Hydroxocobalamin
Methyl cobalamin
5-deoxyadenosylcobalamin and Adenosyl cobalamin
Cyanocobalamin
It is essential of the suitable RBCs development, neurological role, and DNA synthesis. Vitamin B12 acts as a cofactor for methionine synthase and L-methyl malonyl-CoA mutase. Methionine synthase activates the alteration of homocysteine to methionine [26, 27]. Methionine is vital for the development of S-adenosylmethionine which is a general methyl donor for roughly 100 different substrates, including RNA, DNA, hormones, lipids and proteins. L-methyl malonyl-CoA mutase transforms L-methyl malonyl-CoA to succinyl-CoA during destruction of propionate [22, 26, 27], which is an important biochemical reaction in metabolism of protein and fat. Succinyl-CoA is also necessary for the making of hemoglobin.
It is present within the protein of food and may be free through action of gastric protease and HCl during digestion. When artificial vitamin B12 is mixed in prepared meals and nutritional supplements, it is now in free form and, therefore, does not involve this detachment process. Free vitamin B12 joins with intrinsic factor which is a glycoprotein released by the gastric tube’s parietal cells. The complex formed as a consequence experiences ingestion inside the distal ileum by the help of receptor-mediated endocytosis [26, 28].
It can be in particular main component to keep strong nerve cells as well as this assists for making of RNA and DNA hereditary matter of body [28].
Its mechanism is directly with vitamin B9 as well-known as folic acid or folate, to aid build RBCs and hence keep anemic conditions from building up in the body. Folic acid and Vitamin B12 play role jointly for making S-adenosylmethionine (SAMe), a chemical compound concerned in immunity related functions and person’s mood changes.
Vitamins B12, Vitamin B6 as well as B9 act mutually for the management of status of the homocysteine amino acid. Elevated status for homocysteine is linked by heart disease. Though, scientists do not have confidence that homocysteine can be reason for heart disease otherwise only an indicator which shows the risk of heart attack.
Vitamin B12 has a key role in the production of energy in the body. It keeps the cells fit. Without it, cells become weak.
The heart as well as whole cardiovascular system requires B12. It has functions of eliminate hazardous protein known as homocysteine. When homocysteine becomes tolerable so that it stays throughout blood, this devastates arteries results in swelling as well as heart disease.
Research works explain people having osteoporosis can contain elevated status for homocysteine as well as decreased status for B12 as compared to persons having strong and fit bones [29].
Nerves contain defensive cover for their protection from pollutants as well as free radicals within blood. Devoid of casing, known as myelin sheaths, bare nerves are injured as well as might expire. Such deceased nerves disturb signals toward and away from brain as well as might take part in function in nerve associated circumstances. Vitamin B12 assists approach by which the body replenishes this defending casing [30].
The Vitamin B12 is found within organic foodstuffs, as well as in meat, fish, eggs, poultry, milk products and milk itself. It does not find within plants and its products only in very small quantity, but prepared breakfast cereals may be easily accessible resource for vitamin B12 having elevated availability for vegetarians [26]. Some dietary yeast foodstuffs also have vitamin B12.
Prepared foodstuffs have different formulation and this may be essential understand tags of manufactured goods find out the nutritional ingredients. Various food origins of vitamin B12 are enlisted in the Table 1 [31].
Food | Micrograms (mcg) per serving | Percent DV* |
---|---|---|
Beef | 70.7 | 1,178 |
Breakfast cereals, fortified with 100% of the DV for vitamin B12, 1 serving | 6.0 | 100 |
Trout | 5.4 | 90 |
Salmon | 4.8 | 80 |
Tuna fish | 2.5 | 42 |
Cheeseburger, twofold pastry as well as bread roll, 1 sandwich | 2.1 | 35 |
Milk | 1.2 | 18 |
Yogurt, fruit | 1.1 | 18 |
Cheese, Swiss | 0.9 | 15 |
Egg | 0.6 | 10 |
Chicken | 0.3 | 5 |
Different sources of vitamin B12 [31].
* Percent Daily Value. A guide to the nutrients in one serving of food
The Vitamin B12 is utilized by us in two ways, as methyl cobalamin or 5-deoxyadenosyl cobalamin. Methionine synthase is an enzyme which needs methyl cobalamin as a cofactor. It is usually responsible of the transformation of the amino acid homocysteine to methionine, whereas methionine, is needed for the methylation of DNA. 5-Deoxyadenosyl cobalamin is a helper enzyme needed by those enzymes which transform l-methyl malonyl CoA into succinyl CoA. This transformation is a primary point in the taking out of energy from fats and proteins. Additionally, succinyl CoA is needed for the making of hemoglobin which is the compound that is a carrier of oxygen molecules in red blood cells [32].
The connection between diabetes and vitamin B12 can be explained as:
Diabetes Type 1 is an automatic immune state which is the outcome from auto immune devastation for insulin releasing from beta cells of pancreas. This can be consistently related to new organ as well as non-organ particular auto immune plus endocrine situations results in growth of autoimmune polyglandular disorders [33].
Pernicious anemia due to chronic autoimmune gastritis can be very much widespread amongst people having type 1 diabetes. Pernicious anemia and Chronic autoimmune gastritis are present within almost 2% as well as up to 1% common people correspondingly. Amongst people having type 1 diabetes, incidence raises 3 to 5 times [34]. vitamin B12 shortage because of pernicious anemia present repeatedly amongst individuals having type 1 diabetes.
Individuals suffering from type 1 diabetes show parietal cell antibodies (PCA) plus auto antibodies to intrinsic factor (AIF) type 1 as well as 2 (De Block
Main autoimmune hypothyroidism as well as celiac ailment is common comorbidities between people having type 1 diabetes [36] and directly influence vitamin B12 metabolism. Vitamin B12 shortage between people having autoimmune hypothyroidism is described as existence of gastric parietal cell antibodies as well as intrinsic factor, decreased ingestion by mouth because of thyroid hormone insufficiency as well as flawed assimilation because of bowel wall edema, decreased bowel motility and increased growth of bacteria [37]. Celiac disease can be greatly widespread autoimmune mediated gastrointestinal state happen within 1–16% people having type 1 diabetes in contrast to 0.3–1% of common people. Intake for wheat gluten as well as further associated proteins is recognized as activator for situation within genetically liable persons. Because of linked enteropathy, people frequently stop to thrive, anemia and chronic diarrhea owing to micronutrient (mainly folate, vitamin B12) malabsorption [38].
Due to lack for contradictions such as renal as well as hepatic dysfunction, current guiding principles support utilization of metformin like primary line glucose reducing mediator parallel to changes in way of life [39]. Regardless of better glycemic reducing influence, metformin is revealed for reduction of vitamin B12 status. The possibility for having metformin coupled vitamin B12 deficit can be deeply affected of growing age, metformin dosage as well as period of use. The given methods for clarification of metformin induced vitamin B12 shortage amongst people having type 2 diabetes comprise: variations of small bowel motility that induces increased growth of bacteria as well as resulting vitamin B12 deficit, viable reduction and vitamin B12 malabsorption, changes within intrinsic factor status as well as contact to tubulin endocytic receptor. Metformin hamper calcium bound assimilation for complex of vitamin B12-IF at the terminal ileum. Such inhibition consequence could be inverted using calcium medication [40].
The term folate includes 150 components of the family of pteroilglutamate, which participate in cell replication by enzymatic activity in purine base synthesis for DNA and are a primary co-factor for transamination in the transformation of amino acids, particularly homocysteine into methionine. Folates are present in animal tissue, leafy vegetables, legumes and nuts and their deficiency has been associated to megaloblastic anemia, neural tube defects, cardiovascular disease, cancer and senile dementia [41].
Implication of folate in pathogenesis of type 2 DM is linked with vitamin B12 shortage and its consequent hyperhomocysteinemia, and although its deficiency is not widespread, supplementation trials have been carried out in diabetic patients [42].
Folates are made up of 4[(2-amino-4-oxo-1,4-dihydropteridin-6-yl) methylamino] benzoic acid, pteroic acid which is bonded with multiple or single monomers of L-glutamate. They lie in the family of heterocyclic organic compounds group [43].
There are eight different types of B vitamins. They are collectively called as B complex vitamins. Folate i.e., Vitamin B9 is also one of them. The naturally present folate forms are also based on vitamin B9. Many of the foods contain B vitamins. Many of folates are also taken from foods. They are generally made up of a mix of reduced folates. Reduced folates are any type of pteroyl mono glutamates, or an amalgam of pteroyl glutamates. They have a peculiar degree of pteridine ring reduction. Also, they have a different number of glutamates remains and one-carbon replacements [44]. The seven of total eight B vitamins can dissolve in water and hence cannot be kept by our body. We must constantly get their supply in our daily diet. Folates (vitamin B9) have that property. We can get them from foods like beans (and other legumes), salmon, citrus fruits, whole grains, leafy vegetables, meat and dairy etc. If we fail to fulfill our need of folate form our daily diet then we can take supplements which contain artificially synthesized folate to fulfill our needs. Folate fortification is also done to increase the folic acid intake by people. A number of commercially sold synthetic forms of folates are even better as compared to the natural ones [45]. They could be easily broken down chemically, especially reduced type of unsubstituted tetra and di-hydro forms are chemically stable. Tetrahydrofolates are usually found as the unsubstituted poly glutamates and tetrahydrofolates, that is, 5-methyl, 5,10-methylene, and 10-formyl etc. [46]. Reduced substituted forms of vitamins are prone to the chemical changes. Oxidative reactions occur in them which results in the activeness loss of vitamins. There are no acknowledged undesired effects of folates. An excess intake of them is not dangerous for human beings. The maximum usage limit of synthetic folates is capped to 1 mg daily. It is advised because excessive administration of folates may cover up the vitamin B12 deficiency [47].
Folic acid is considered to be an essential nutrient for our body. Folic Acid derivatives are necessary components for the DNA production. They are also needed for the erythrocyte synthesis. The biosynthesis of some amino acids needs tetrahydrofolates as a crucial ingredient. They are needed in the biosynthesis of precursors of DNA also [48]. Folic acid is necessary for the production of deoxyribose nucleic acid (DNA). They even aid maintenance of the process of methylation [49]. They also participate as helper molecules in some biological reactions. The cell division in our body essentially needs folate. We need it even more during pregnancy and infancy. It is needed in multiple crucial processes like quick cell growth and proliferation. The production of RBCs also needs folate. This acts to keep from anemia [50]. Nucleotide synthesis is the most important function of folate. It is required for the production and repair of DNA. Folates are also responsible of the production of methionine by alteration of Homocysteine in the procedure of re-methylation. Methionine is a useful amino acid which is in turn used to produce other necessary proteins. It may get converted to an important methyl donor i.e., S-adenosylmethionine [51].
The deficiency of folate is not common in developed countries. But it is reported in many of the third-world countries. Folate deficiency could be due to multiple reasons. The poor diet and erroneous metabolism of vitamins could be responsible for it [52]. The US government along with that of many other countries has made fortification of food with folate to be mandatory for their nationals. This helps in eradication of NTDs worldwide. Mostly they use floor for the fortification because it is widely used by the public. The routine ingestion of folate is examined by taking the blood samples and measuring the folate levels in them. If the level of folate is low in blood samples then it means the folate is not taken up to required level [51].
We can fulfill our folate requirement by taking folate fortified diet. Artificial folate supplements are also available in the market which can serve the purpose. But the availability of any of the options of folate intake vary in different regions of world. The folate absorption also differs for every supplement used. Dietary Folate Equivalent (DFE) is the amount of folate our body can absorb out of the supplement taken per serving. Every DFE unit is considered to be one micro gram of folates or 0.6 micro grams of artificially made folate [50].
Loss of appetite along with decrease in body weight may occur due to deficiency in folate. The deficiency might be faced when one’s need of folate increases or diet is reduced from a certain level. It is reported as a key health issue in some countries. Though it is rare in developed countries which enforce folate fortification of foods. Folate and vitamin B12 deficiency impacts all public of all ages. It is related to many diseases like neural tube defects in infants, diarrhea, anemia and other birth defects etc. [52].
The loss of methyl groups from DNA is termed as DNA hypomethylation. This could be affected by the deficiency of folate. The folate ingestion can fix such problems [53]. The overall methylation and DNA synthesis processes could also be negatively affected by the deficiency of folate in human body. Thymidyl acid, dTMP (Deoxythymidine monophosphate), is used as a monomer in DNA. Its supply in body becomes limited due to increased rate of removal of dUMP (Deoxy uridine Monophosphate) from the molecule of DNA. This is increased due to defective methylation cycle as a result of folate deficiency. DNA repair reactions start due to these problems which in turn declines the required cell division [45].
Folic acid is inactive biochemically, it is transformed by dihydrofolate reductase into methyl tetrahydrofolate and tetrahydro folic acid. These folate congeners are carried by receptor-mediated endocytosis through body cells. There they are required to generate and use format, and synthesize thymidylate nucleic acids and purine, methylate tRNA, keep general erythropoiesis, interconvert amino acids. Utilizing vitamin B12 as a helper enzyme, folate can standardize high homocysteine quantities by re-methylation of homocysteine to methionine via methionine synthetase [16].
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Integrity - We are consistent and dependable, always striving for precision and accuracy in the true spirit of science.
\n\nOpenness - We communicate honestly and transparently. We are open to constructive criticism and committed to learning from it.
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Kapp, Alexander Gantman and Elizabeth A. Laugeson",authors:[{id:"43405",title:"Dr",name:"Elizabeth",middleName:"A",surname:"Laugeson",slug:"elizabeth-laugeson",fullName:"Elizabeth Laugeson"},{id:"46932",title:"Mr.",name:"Steven",middleName:null,surname:"Kapp",slug:"steven-kapp",fullName:"Steven Kapp"},{id:"46933",title:"Dr.",name:"Alexander",middleName:null,surname:"Gantman",slug:"alexander-gantman",fullName:"Alexander Gantman"}]},{id:"48416",doi:"10.5772/60662",title:"Examining Sex and Gender Differences in Anxiety Disorders",slug:"examining-sex-and-gender-differences-in-anxiety-disorders",totalDownloads:3682,totalCrossrefCites:16,totalDimensionsCites:26,abstract:"Several studies have examined sex differences in different anxiety disorders. Females are repeatedly found to be more likely than males to suffer from anxiety in general and to be diagnosed with most anxiety disorders, including agoraphobia (AG), panic disorder (PD), separation anxiety (SA), specific phobia (SP), social anxiety disorder (SAD), generalised anxiety disorder (GAD), obsessive-compulsive disorder (OCD), and acute and posttraumatic stress disorder (ASD and PTSD), although the latter three are technically no longer categorised as anxiety disorders according to DSM-5. This chapter provides an overview of research on sex and gender differences in anxiety disorders ranging from the well-established female preponderance in prevalence and severity to possible sex differences in the risk and protective factors associated with anxiety, sex differences in the clinical presentation of anxiety disorders, and potential sex differences in the effectiveness of different treatments. The chapter contains suggestions for future research, including important questions that remain to be answered.",book:{id:"4651",slug:"a-fresh-look-at-anxiety-disorders",title:"A Fresh Look at Anxiety Disorders",fullTitle:"A Fresh Look at Anxiety Disorders"},signatures:"Dorte M. Christiansen",authors:[{id:"113525",title:"MSc.",name:"Dorte",middleName:null,surname:"M. Christiansen",slug:"dorte-m.-christiansen",fullName:"Dorte M. Christiansen"}]},{id:"48585",doi:"10.5772/60711",title:"Impact of Anxiety and Depression Symptoms on Scholar Performance in High School and University Students",slug:"impact-of-anxiety-and-depression-symptoms-on-scholar-performance-in-high-school-and-university-stude",totalDownloads:4397,totalCrossrefCites:17,totalDimensionsCites:20,abstract:"Emotional processes are important to survive. The Darwinian adaptive concept of stress refers to natural selection since evolved individuals have acquired effective strategies to adapt to the environment and to unavoidable changes. If demands are abrupt and intense, there might be insufficient time to successful responses. Usually, stress produces a cognitive or perceptual evaluation (emotional memory) which motivates to make a plan, to take a decision and to perform an action to face successfully the demand. Between several kinds of stresses, there are psychosocial and emotional stresses with cultural, social and political influences. The cultural changes have modified the way in which individuals socially interact. Deficits in familiar relationships and social isolation alter physical and mental health in young students, producing reduction of their capacities of facing stressors in school. Adolescence is characterized by significant physiological, anatomical, and psychological changes in boys and girls, who become vulnerable to psychiatric disorders. In particular for young adult students, anxiety and depression symptoms could interfere in their academic performance. In this chapter, we reviewed approaches to the study of anxiety and depression symptoms related with the academic performance in adolescent and graduate students. Results from available published studies in academic journals are reviewed to discuss the importance to detect information about academic performance, which leads to discover in many cases the very commonly subdiagnosed psychiatric disorders in adolescents, that is, anxiety and depression. With the reviewed evidence of how anxiety and depression in young adult students may alter their main activity in life (studying and academic performance), we discussed data in order to show a way in which professionals involved in schools could support students and stablish a routine of intervention in any case.",book:{id:"4651",slug:"a-fresh-look-at-anxiety-disorders",title:"A Fresh Look at Anxiety Disorders",fullTitle:"A Fresh Look at Anxiety Disorders"},signatures:"Blandina Bernal-Morales, Juan Francisco Rodríguez-Landa and\nFrank Pulido-Criollo",authors:[{id:"45701",title:"Dr.",name:"Blandina",middleName:null,surname:"Bernal-Morales",slug:"blandina-bernal-morales",fullName:"Blandina Bernal-Morales"},{id:"45702",title:"Dr.",name:"Juan Francisco",middleName:null,surname:"Rodríguez-Landa",slug:"juan-francisco-rodriguez-landa",fullName:"Juan Francisco Rodríguez-Landa"},{id:"175891",title:"MSc.",name:"Frank",middleName:null,surname:"Pulido-Criollo",slug:"frank-pulido-criollo",fullName:"Frank Pulido-Criollo"}]},{id:"17574",doi:"10.5772/19919",title:"The Loss of Glutamate-GABA Harmony in Anxiety Disorders",slug:"the-loss-of-glutamate-gaba-harmony-in-anxiety-disorders",totalDownloads:9495,totalCrossrefCites:4,totalDimensionsCites:19,abstract:null,book:{id:"510",slug:"anxiety-disorders",title:"Anxiety Disorders",fullTitle:"Anxiety Disorders"},signatures:"Joanna M Wierońska, K. Stachowicz, G. Nowak and A. Pilc",authors:[{id:"36779",title:"Prof.",name:"Andrzej",middleName:null,surname:"Pilc",slug:"andrzej-pilc",fullName:"Andrzej Pilc"},{id:"36785",title:"Dr.",name:"Joanna",middleName:null,surname:"Wieronska",slug:"joanna-wieronska",fullName:"Joanna Wieronska"},{id:"36786",title:"Mr.",name:"Katarzyna",middleName:null,surname:"Stachowicz",slug:"katarzyna-stachowicz",fullName:"Katarzyna Stachowicz"}]}],mostDownloadedChaptersLast30Days:[{id:"62216",title:"Subtypes of Psychotic-Like Experiences and Their Significance for Mental Health",slug:"subtypes-of-psychotic-like-experiences-and-their-significance-for-mental-health",totalDownloads:3169,totalCrossrefCites:2,totalDimensionsCites:4,abstract:"More recently, the interest in studying subclinical psychosis has increased, as it might provide critical information regarding mechanisms that are implicated in the exacerbation of subclinical symptoms and the maintenance of mental health. However, psychosis research has tended to focus on clinical outcomes and not to differentiate between subtypes of psychotic-like experiences (PLE) that might differ regarding their psychopathological significance. Importantly, this might have obscured a more accurate picture of the complex structure of psychosis and the significance of particular risk and protective factors. Notably, while studies point toward a continuity of psychotic experiences and accompanying factors across the general population, there is evidence indicating that some PLE in healthy individuals might also be associated with a weaker expression of other subclinical symptoms, increased well-being and even resilience to some degree. Importantly, such findings might have implications on strategies in psychosis prevention and therapy, early detection, as well as the construction of continuum models of psychosis. The present chapter aims at drawing together findings that necessitate a more differentiated view and assessment of PLE. It intends to provoke new questions that might offer starting points for future investigations, such as longitudinal studies investigating the interplay of subclinical symptoms.",book:{id:"7117",slug:"psychosis-biopsychosocial-and-relational-perspectives",title:"Psychosis",fullTitle:"Psychosis - Biopsychosocial and Relational Perspectives"},signatures:"Lui Unterrassner",authors:[{id:"245870",title:"Ph.D. Student",name:"Lui",middleName:null,surname:"Unterrassner",slug:"lui-unterrassner",fullName:"Lui Unterrassner"}]},{id:"18334",title:"Challenges and Opportunities in Diagnosis and Management of Generalized Anxiety Disorder in Primary Care",slug:"challenges-and-opportunities-in-diagnosis-and-management-of-generalized-anxiety-disorder-in-primary-",totalDownloads:3916,totalCrossrefCites:0,totalDimensionsCites:0,abstract:null,book:{id:"236",slug:"anxiety-and-related-disorders",title:"Anxiety and Related Disorders",fullTitle:"Anxiety and Related Disorders"},signatures:"Mehtap Kartal",authors:[{id:"33369",title:"Dr.",name:"Mehtap",middleName:null,surname:"Kartal",slug:"mehtap-kartal",fullName:"Mehtap Kartal"}]},{id:"67627",title:"Borderline Personality Disorder and Childhood Trauma: The Posited Mechanisms of Symptoms Expression",slug:"borderline-personality-disorder-and-childhood-trauma-the-posited-mechanisms-of-symptoms-expression",totalDownloads:1231,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Traumatic events are reported in a large percentage of the population, however, only in some individuals it will lead to a diagnosable trauma-related disorder. Borderline personality disorder (BPD) is deemed to be a form of acute reaction to childhood trauma. Therein experiences of childhood abuse and neglect take on an important etiological role, generating severely disorganized attachment relationships, which in turn affect the development of emotional regulation systems, and significantly inhibit the development of mentalization and metacognitive skills. Furthermore, the last decade has seen important contribution of neuroscientific research in shedding light on the neurobiological correlates of traumatic experiences. A wealth of scientific literature links the onset of BPD to the combination between genetic and environmental factors (G×E), in particular between biological vulnerabilities and the exposure to traumatic experiences during childhood. Although no research can predict with certainty which trauma will translate into symptoms, there are indications as to who is more at risk of developing a trauma-related disorder. Herein we describe the psychological and epigenetic mechanisms affected by childhood trauma and altered in BPD patients.",book:{id:"7834",slug:"psychological-trauma",title:"Psychological Trauma",fullTitle:"Psychological Trauma"},signatures:"Maria Uscinska, Nicolo’ Gagliano, Andrea Polla Mattiot and Silvio Bellino",authors:[{id:"285336",title:"Dr.",name:"Maria",middleName:null,surname:"Uscinska",slug:"maria-uscinska",fullName:"Maria Uscinska"},{id:"288179",title:"Dr.",name:"Andrea",middleName:null,surname:"Polla Mattiot",slug:"andrea-polla-mattiot",fullName:"Andrea Polla Mattiot"},{id:"302735",title:"Dr.",name:"Nicolo'",middleName:null,surname:"Gagliano",slug:"nicolo'-gagliano",fullName:"Nicolo' Gagliano"}]},{id:"69569",title:"Introductory Chapter: Psychological Trauma",slug:"introductory-chapter-psychological-trauma",totalDownloads:953,totalCrossrefCites:0,totalDimensionsCites:0,abstract:null,book:{id:"7834",slug:"psychological-trauma",title:"Psychological Trauma",fullTitle:"Psychological Trauma"},signatures:"Ana Starcevic",authors:[{id:"182584",title:"Dr.",name:"Ana",middleName:null,surname:"Starcevic",slug:"ana-starcevic",fullName:"Ana Starcevic"}]},{id:"67251",title:"A Relational Perspective on Psychological Trauma: The Ghost of the Unspent Love",slug:"a-relational-perspective-on-psychological-trauma-em-the-ghost-of-the-unspent-love-em-",totalDownloads:1250,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Psychological trauma is central to the practice of all psychological therapies and is possibly one of the most frequently uttered terms in the history of psychology since its philosophical inception by the Ancient Greeks. Despite the abundance of scholarship devoted to the study and conceptualization of trauma, it remains a perplexing phenomenon given that the majority of contemporary studies focus on post-traumatic symptomatology and allied diagnostic pathology. While the psychopathology of post-traumatic ramifications has been thoroughly examined, the pathopsychology of trauma remains an arena of ongoing exploration and debate. The purpose of the current chapter is to offer an overview of the most predominant conceptual frameworks of psychological trauma residing in the psychodynamic school of thought, which not only addresses the intrapsychic and interpersonal origins of traumatic pathology but also provides a normative framework of healthy human development. Alongside that, a clinical case vignette will be presented to illustrate the interventions, processes, and outcome of psychodynamic treatment for complex trauma. 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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. 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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"}}},{id:"334239",title:"Prof.",name:"Leung",middleName:null,surname:"Wai Keung",slug:"leung-wai-keung",fullName:"Leung Wai Keung",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Hong Kong",country:{name:"China"}}}]}},subseries:{item:{id:"4",type:"subseries",title:"Fungal Infectious Diseases",keywords:"Emerging Fungal Pathogens, Invasive Infections, Epidemiology, Cell Membrane, Fungal Virulence, Diagnosis, Treatment",scope:"Fungi are ubiquitous and there are almost no non-pathogenic fungi. Fungal infectious illness prevalence and prognosis are determined by the exposure between fungi and host, host immunological state, fungal virulence, and early and accurate diagnosis and treatment. \r\nPatients with both congenital and acquired immunodeficiency are more likely to be infected with opportunistic mycosis. Fungal infectious disease outbreaks are common during the post- disaster rebuilding era, which is characterised by high population density, migration, and poor health and medical conditions.\r\nSystemic or local fungal infection is mainly associated with the fungi directly inhaled or inoculated in the environment during the disaster. The most common fungal infection pathways are human to human (anthropophilic), animal to human (zoophilic), and environment to human (soilophile). Diseases are common as a result of widespread exposure to pathogenic fungus dispersed into the environment. \r\nFungi that are both common and emerging are intertwined. In Southeast Asia, for example, Talaromyces marneffei is an important pathogenic thermally dimorphic fungus that causes systemic mycosis. Widespread fungal infections with complicated and variable clinical manifestations, such as Candida auris infection resistant to several antifungal medicines, Covid-19 associated with Trichoderma, and terbinafine resistant dermatophytosis in India, are among the most serious disorders. \r\nInappropriate local or systemic use of glucocorticoids, as well as their immunosuppressive effects, may lead to changes in fungal infection spectrum and clinical characteristics. Hematogenous candidiasis is a worrisome issue that affects people all over the world, particularly ICU patients. CARD9 deficiency and fungal infection have been major issues in recent years. Invasive aspergillosis is associated with a significant death rate. Special attention should be given to endemic fungal infections, identification of important clinical fungal infections advanced in yeasts, filamentous fungal infections, skin mycobiome and fungal genomes, and immunity to fungal infections.\r\nIn addition, endemic fungal diseases or uncommon fungal infections caused by Mucor irregularis, dermatophytosis, Malassezia, cryptococcosis, chromoblastomycosis, coccidiosis, blastomycosis, histoplasmosis, sporotrichosis, and other fungi, should be monitored. \r\nThis topic includes the research progress on the etiology and pathogenesis of fungal infections, new methods of isolation and identification, rapid detection, drug sensitivity testing, new antifungal drugs, schemes and case series reports. It will provide significant opportunities and support for scientists, clinical doctors, mycologists, antifungal drug researchers, public health practitioners, and epidemiologists from all over the world to share new research, ideas and solutions to promote the development and progress of medical mycology.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/4.jpg",hasOnlineFirst:!0,hasPublishedBooks:!1,annualVolume:11400,editor:{id:"174134",title:"Dr.",name:"Yuping",middleName:null,surname:"Ran",slug:"yuping-ran",fullName:"Yuping Ran",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9d6QAC/Profile_Picture_1630330675373",biography:"Dr. Yuping Ran, Professor, Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China. Completed the Course Medical Mycology, the Centraalbureau voor Schimmelcultures (CBS), Fungal Biodiversity Centre, Netherlands (2006). International Union of Microbiological Societies (IUMS) Fellow, and International Emerging Infectious Diseases (IEID) Fellow, Centers for Diseases Control and Prevention (CDC), Atlanta, USA. Diploma of Dermatological Scientist, Japanese Society for Investigative Dermatology. Ph.D. of Juntendo University, Japan. Bachelor’s and Master’s degree, Medicine, West China University of Medical Sciences. Chair of Sichuan Medical Association Dermatology Committee. General Secretary of The 19th Annual Meeting of Chinese Society of Dermatology and the Asia Pacific Society for Medical Mycology (2013). In charge of the Annual Medical Mycology Course over 20-years authorized by National Continue Medical Education Committee of China. Member of the board of directors of the Asia-Pacific Society for Medical Mycology (APSMM). Associate editor of Mycopathologia. Vice-chief of the editorial board of Chinses Journal of Mycology, China. Board Member and Chair of Mycology Group of Chinese Society of Dermatology.",institutionString:null,institution:{name:"Sichuan University",institutionURL:null,country:{name:"China"}}},editorTwo:null,editorThree:null,series:{id:"6",title:"Infectious Diseases",doi:"10.5772/intechopen.71852",issn:"2631-6188"},editorialBoard:[{id:"302145",title:"Dr.",name:"Felix",middleName:null,surname:"Bongomin",slug:"felix-bongomin",fullName:"Felix Bongomin",profilePictureURL:"https://mts.intechopen.com/storage/users/302145/images/system/302145.jpg",institutionString:null,institution:{name:"Gulu University",institutionURL:null,country:{name:"Uganda"}}},{id:"45803",title:"Ph.D.",name:"Payam",middleName:null,surname:"Behzadi",slug:"payam-behzadi",fullName:"Payam Behzadi",profilePictureURL:"https://mts.intechopen.com/storage/users/45803/images/system/45803.jpg",institutionString:"Islamic Azad University, Tehran",institution:{name:"Islamic Azad University, Tehran",institutionURL:null,country:{name:"Iran"}}}]},onlineFirstChapters:{paginationCount:14,paginationItems:[{id:"82103",title:"The Role of Endoplasmic Reticulum Stress and Its Regulation in the Progression of Neurological and Infectious Diseases",doi:"10.5772/intechopen.105543",signatures:"Mary Dover, Michael Kishek, Miranda Eddins, Naneeta Desar, Ketema Paul and Milan Fiala",slug:"the-role-of-endoplasmic-reticulum-stress-and-its-regulation-in-the-progression-of-neurological-and-i",totalDownloads:5,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Updates on Endoplasmic Reticulum",coverURL:"https://cdn.intechopen.com/books/images_new/11674.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}},{id:"80954",title:"Ion Channels and Neurodegenerative Disease Aging Related",doi:"10.5772/intechopen.103074",signatures:"Marika Cordaro, Salvatore Cuzzocrea and Rosanna Di Paola",slug:"ion-channels-and-neurodegenerative-disease-aging-related",totalDownloads:6,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Ion Channels - From Basic Properties to Medical Treatment",coverURL:"https://cdn.intechopen.com/books/images_new/10838.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}},{id:"81647",title:"Diabetes and Epigenetics",doi:"10.5772/intechopen.104653",signatures:"Rasha A. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. 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