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Cortisol levels in fingernail samples are known to represent cumulative hormone levels. However, findings on the association between fingernail cortisol and perceived stress have been inconsistent. Since the effect of confounding factors cannot be excluded in cross-sectional studies, this study longitudinally examined the effects of perceived stress and negative life events on changes in fingernail cortisol levels over a period of six months. In total, 113 university students rated their perceived stress and negative life events twice, fingernail samples were collected every 15 days during a six-month period. Furthermore, fingernail cortisol levels were quantified according to each stress and negative life event assessment. We conducted longitudinal multilevel analyses to estimate the effects of perceived stress and negative life events in changes within an individual (within-person change) as well as individual differences of them over the study period (between-person level) on changes in fingernail cortisol levels. Within-person increase in perceived stress and negative life events did not significantly predict within-person increase in fingernail cortisol levels. In the between-person level, higher average levels of negative life events did not significantly predict the rate of increase in fingernail cortisol levels than those with lower levels. However, individuals with higher average levels of perceived stress showed a steeper slope of time in fingernail cortisol levels. These findings suggest that prolonged high levels of perceived stress may be associated with fingernail cortisol levels., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The terms "onychofibroblast" (nail-specific fibroblast) and onychodermis (nail-specific dermis) were first introduced in 2006 and 2012, respectively, based on distinctive histologic and immunohistochemical features from the dermis of the surrounding skin and have been demonstrated in multiple studies. Recently, based on molecular research, the definition of onychodermis containing onychofibroblasts has been expanded to encompass the area located between the nail matrix and bed epithelium and periosteum. Single-cell RNA sequencing and in situ hybridization demonstrated that onychofibroblasts within the onychodermis express the genes including RSPO4, MSX1, WIF-1, and BMP5, which are implicated in nail formation and/or in disorders with nail phenotype. A mutation in RSPO4, a component of the Wnt signaling pathway, causes anonychia congenita. Nail matrix onychodermis and nail bed onychodermis share many similar characteristics which differ from the surrounding normal dermis of the skin. Comparative spatial transcriptomic and single-cell analyses of human nail units and hair follicles suggest that onychodermis is the counterpart of follicular dermal papilla, which plays a key role in hair follicle growth and morphogenesis. Onychomatricoma, as a nail-specific tumor, has been demonstrated to be a mesenchymal tumor that originates from onychofibroblasts and is associated with the upregulation of Wnt signaling. Collectively, the onychodermis and onychofibroblasts play crucial roles in nail development and these specialized nail mesenchymal elements are key components in the pathogenesis of onychomatricoma. The concept of onychodermis containing onychofibroblasts is very important for nail biology and pathology., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To evaluate the potential of compound-specific isotope analysis of amino acids (CSIA-AA) for investigating infant feeding practices, we conducted a long-term study that compared infant and maternal amino acid (AA) nitrogen isotope ratios., Materials and Methods: Fingernail samples were collected from a single mother-infant dyad over 19 months postpartum. Carbon and nitrogen stable isotope ratios were measured in the bulk keratin of the fingernail samples. Selected samples were then hydrolyzed and derivatized for compound-specific nitrogen isotope analysis of keratin AAs., Results: As in previous studies, infant bulk keratin nitrogen isotope values increased during exclusive breastfeeding and fell with the introduction of complementary foods and eventual cessation of breastfeeding. Infant trophic AAs had elevated nitrogen isotope values relative to the mother, while the source AAs were similar between the mother and infant. Proline and threonine appeared to track the presence of human milk in the infant's diet as the isotopic composition of these AAs remained offset from maternal isotope values until the cessation of breastfeeding., Discussion: Although CSIA-AA is costly and labor intensive, it appears to hold potential for estimating the duration of breastfeeding, even after the introduction of complementary foods. Through the analysis of a full suite of AAs, it may also yield insights into infant physiology and AA synthesis., (© 2024 The Author(s). American Journal of Biological Anthropology published by Wiley Periodicals LLC.)

Hair and nail cortisol is increasingly studied as a physiologic proxy for chronic stress response. Glucocorticoid use is an expected confounder for cortisol measurement, yet there remains little evidence of whether external cortisol use should be subject to exclusion in study subjects. In a group of 209 youth (15-22 year-olds), we analyzed hair and fingernail cortisol concentrations. We assessed topical, nasal, oral, and injectable glucocorticoid use via a questionnaire. Extensively validated methods were used for hair and nail cortisol extraction and measurements. The median value of hair cortisol was 10.2 pg/mg (n=200), and the median value of nail cortisol was 7.06 pg/mg (n=203). Topical glucocorticoid use significantly increased hair and nail cortisol concentrations (p<0.005). Hair and nail cortisol concentrations were positively associated (p<0.0001, n=194). Spearman correlation coefficients demonstrated that the positive correlation between hair and nail cortisol values was higher in participants who used external glucocorticoids. Topical glucocorticoids moderated the association between hair and nail cortisol values (p=0.006). Based on these findings, we recommend that the assessment of topical glucocorticoid use must be performed when collecting hair/nail samples and that subjects reporting glucocorticoid use should be excluded from all future hair and nail cortisol studies; also, all outliers must be excluded to account for glucocorticoid medication underreporting and yet-unknown confounders., Competing Interests: Declaration of Competing Interest All authors declare no conflict of interest. KB declares a significant financial interest in Stress Bioanalytics, LLC, which currently performs HCC and NCC measurements in numerous projects. The present work was completed a year before the creation of Stress Bioanalytics LLC., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Comprehensive genomic sequencing is becoming a critical component in the assessment of hematologic malignancies, with broad implications for patients' management. In this context, unequivocally discriminating somatic from germline events is challenging but greatly facilitated by matched analysis of tumor:normal pairs of samples. In contrast to solid tumors, in hematologic malignancies conventional sources of normal control material (peripheral blood, buccal swabs, saliva) could be highly involved by the neoplastic process, rendering them unsuitable. In this work we describe our real-world experience using cell-free DNA (cfDNA) isolated from nail clippings as an alternate source of normal control material, through the dedicated review of 2,610 tumor:nail pairs comprehensively sequenced by MSK-IMPACT-heme. Overall, we found that nail cfDNA is a robust germline control for paired genomic studies. In a subset of patients, nail DNA may be contaminated by tumor DNA, reflecting unique attributes of the hematologic disease and transplant history. Contamination is generally low level, but significantly more common among patients with myeloid neoplasms (20.5%; 304/1,482) than among those with lymphoid diseases (5.4%; 61/1,128) and particularly enriched in myeloproliferative neoplasms with marked myelofibrosis. When identified in patients with lymphoid and plasma-cell neoplasms, mutations commonly reflected a myeloid profile and correlated with a concurrent/evolving clonal myeloid neoplasm. Donor DNA was identified in 22% (11/50) of nails collected after allogeneic stem-cell transplantation. In this cohort, an association with a recent history of graft-versus-host disease was identified. These findings should be considered as a potential limitation to the use of nails as a source of normal control DNA but could also provide important diagnostic information regarding the disease process.

Background: Nail squamous cell carcinoma (NSCC) is the most frequent ungual malignant tumor, but its incidence remains low. The histopathological description is sparse. We aim to characterize NSCC histopathological aspects, search for a correlation with clinical subtypes, and investigate immunohistochemistry expression of p16, p53, and Ki67., Methods: This retrospective study collected NSCC diagnosed in our dermatology department between 2007 and 2021. The histopathological features were correlated with the clinical signs and immunohistochemistry., Results: A total of 48 patients were included, and immunohistochemistry was available for 36 of them. Two histopathological patterns became prominent: a blue-basaloid type characterized by koilocytosis (p < 0.001), and a pink-keratinizing type. Mean ages were similar when comparing basaloid and periungual versus keratinizing and subungual (p < 0.001). p16 was positive in 31 of 36 cases: 18 basaloid and 13 keratinizing (p = 0.167). p53 and Ki67 were all abnormal., Conclusions: Our study described two histopathological NSCC subtypes and associated them with the two clinical subtypes: the blue-basaloid type, HPV-induced, in situ, of periungual localization in younger males; and the pink-keratinizing type, non-HPV-induced, invasive, of subungual site, in elderly. Immunohistochemistry was not contributing on its own, but p16 positivity associated with basaloid histopathological profile helps support HPV etiology., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Inhalation of welding fumes can cause metal accumulation in the brain, leading to Parkinsonian-like symptoms. Metal accumulation and altered neurochemical profiles have been observed using magnetic resonance imaging (MRI) in highly exposed welders, being associated with decreased motor function and cognition. While MRI is impractical to use as a health risk assessment tool in occupational settings, toenail metal levels are easier to assess and have been demonstrated to reflect an exposure window of 7-12 months in the past. Yet, it is unclear whether toenail metal levels are associated with brain metal levels or changes in metabolism, which are the root of potential health concerns. This study investigates whether toenail manganese (Mn) and iron (Fe) levels, assessed at several time points, correlate with brain Mn and Fe levels, measured by MRI, as well as brain GABA, glutamate (Glu), and glutathione (GSH) levels, measured by Magnetic Resonance Spectroscopy (MRS), in seventeen Mn-exposed welders. Quantitative T1 and R2* MRI maps of the whole brain, along with GABA, Glu, and GSH MRS measurements from the thalamus and cerebellum were acquired at baseline (T0). Toenail clippings were collected at T0 and every three months after the MRI for a year to account for different exposure periods being reflected by toenail clippings and MRI. Spearman correlations of toenail metal levels were run against brain metal and metabolite levels, but no significant associations were found for Mn at any timepoint. Cerebellar GSH positively correlated with toenail Fe clipped twelve months after the MRI (p = 0.05), suggesting an association with Fe exposure at the time of the MRI. Neither thalamic GABA nor Glu correlated with toenail Fe levels. In conclusion, this study cannot support toenail Mn as a proxy for brain Mn levels or metabolic changes, while toenail Fe appears linked to brain metabolic alterations, underscoring the importance of considering other metals, including Fe, in studying Mn neurotoxicity., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ulrike Dydak reports a relationship with American Regent Inc that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Coxsackievirus A10 (CV-A10) infection, a prominent cause of childhood hand-foot-and-mouth disease (HFMD), frequently manifests with the intriguing phenomenon of onychomadesis, characterized by nail shedding. However, the underlying mechanism is elusive. Here, we found that CV-A10 infection in mice could suppress Wnt/β-catenin signaling by restraining LDL receptor-related protein 6 (LRP6) phosphorylation and β-catenin accumulation and lead to onychomadesis. Mechanistically, CV-A10 mimics Dickkopf-related protein 1 (DKK1) to interact with Kringle-containing transmembrane protein 1 (KRM1), the CV-A10 cellular receptor. We further found that Wnt agonist (GSK3β inhibitor) CHIR99021 can restore nail stem cell differentiation and protect against nail shedding. These findings provide novel insights into the pathogenesis of CV-A10 and related viruses in onychomadesis and guide prognosis assessment and clinical treatment of the disease., (© 2024 Cui et al.)

Background: Nails accumulate the alcohol metabolite, ethyl glucuronide (ETG), and the cannabis metabolite, carboxy- delta-9-THC over 3-6 months. Few studies have examined nail toxicology testing's sensitivity and specificity and the agreement between nail testing and self-reported alcohol and marijuana use., Methods: In an ongoing clinical trial, 1101 veterans completed initial telephone questionnaires and were then asked to mail nail clippings for substance use analysis. We examined sensitivity and specificity of ETG and carboxy- delta-9-THC in nails compared to self-report of alcohol use patterns (the AUDIT-C) and substance-related harms (alcohol and THC subscales of the ASSIST). We then examined factors associated with discordance between nails and self-report., Results: Almost two-thirds (707/1101) of respondents mailed in nail clippings. Those with returned nails were disproportionately married, white race, older, and less depressed. At a threshold of 8pg/mg, sensitivity was only.50 to detect risky alcohol use and.49 to detect alcohol-related issues. Sensitivity for marijuana issues was only.61. Specificity was greater than.77 for all measures. Factors associated with positive nails/negative self-report (i.e. false positives) for risky alcohol use on the Audit-C included more pain and being unmarried; false positive nails for alcohol-related issues on the ASSIST were associated with being unmarried and non-Hispanic ethnicity. False positive nails for THC-related issues on the ASSIST were associated with being African American, Hispanic, and having had legal issues., Conclusions: At standard cut-offs, nail measures had low sensitivity and higher specificity. The groups who disproportionately submit positive nails/negative self-report could have substance use patterns not adequately captured by self-report, inaccurate self-report due to social pressures, or distinct drug metabolism., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest with respect to the content of this manuscript., (Copyright © 2024. Published by Elsevier B.V.)

Commercial topical formulations containing itraconazole (poorly water soluble), for mycotic infections, have poor penetration to infection sites beneath the nails and skin thereby necessitating oral administration. To improve penetration, colloidal solutions of itraconazole (G1-G4) containing Poloxamer 188, tween 80, ethanol, and propylene glycol were prepared and incorporated into HFA-134-containing sprays. Formulations were characterized using particle size, drug content, and Fourier-transform infrared spectroscopy (FTIR). In vitro permeation studies were performed using Franz diffusion cells for 8 h. Antimycotic activity on Candida albicans and Trichophyton rubrum was performed using broth micro-dilution and flow cytometry, while cytotoxicity was tested on HaCaT cell lines. Particle size ranged from 39.35-116.80 nm. FTIR and drug content revealed that G1 was the most stable formulation (optimized formulation). In vitro release over 2 h was 45% for G1 and 34% for the cream. There was a twofold increase in skin permeation, fivefold intradermal retention, and a sevenfold increase in nail penetration of G1 over the cream. Minimum fungicidal concentrations (MFC) against C. albicans were 0.156 and 0.313 µg/mL for G1 and cream, respectively. The formulations showed optimum killing kinetics after 48 h. MFC values against T. rubrum were 0.312 and 0.625 µg/mL for the G1 and cream, respectively. Transmission electron microscopy revealed organelle destruction and cell leakage for G1 in both organisms and penetration of keratin layers to destroy T. rubrum. Cytotoxicity evaluation of G1 showed relative safety for skin cells. The G1 formulation showed superior skin permeation, nail penetration, and fungicidal activity compared with the cream formulation., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

The nail matrix containing stem cell populations produces nails and may contribute to fingertip regeneration. Nails are important tissues that maintain the functions of the hand and foot for handling objects and locomotion. Tumor chemotherapy impairs nail growth and, in many cases, loses them, although not permanently. In this report, we have achieved the successful differentiation of nail stem (NS)-like cells from human-induced pluripotent stem cells (iPSCs) via digit organoids by stepwise stimulation, tracing the molecular processes involved in limb development. Comprehensive mRNA sequencing analysis revealed that the digit organoid global gene expression profile fits human finger development. The NS-like cells expressed Lgr6 mRNA and protein and produced type-I keratin, KRT17, and type-II keratin, KRT81, which are abundant in nails. Furthermore, we succeeded in producing functional Lgr6-reporter human iPSCs. The reporter iPSC-derived Lgr6-positive cells also produced KRT17 and KRT81 proteins in the percutaneously transplanted region. To the best of our knowledge, this is the first report of NS-like cell differentiation from human iPSCs. Our differentiation method and reporter construct enable the discovery of drugs for nail repair and possibly fingertip-regenerative therapy., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Inomata et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Luliconazole-loaded microemulgels containing different permeation enhancers were formulated for transungual drug delivery for the management of onychomycosis, onychomycosis, which affects nails. The physicochemical properties like droplet size, zeta potential, pH, viscosity, spreadability, extrudability, oil binding capacity, drug content, and microscopic study were evaluated. The Pseudo-ternary phase diagram was constructed for the formulation of microemulsions (MEs) by keeping the K m ratio constant at 3:1 and characterized for clarity, mean droplet size, zeta potential, viscosity, pH, transmittance, refractive index, and stability. The ME mean droplet size and zeta potential were found in the range of 38.78 to 171.4 nm, and 0.00 to - 6.6 mV, respectively. Prepared MEs were converted into microemulgel by adding a 2.5% gelling agent (Carbapol 934) in the external phase, and a drug release study was conducted. Formulation E3 showed better drug release and was chosen as the control. Four different penetration enhancers were added separately within E3 and further evaluated for pH, viscosity, spreadability, extrudability, oil binding capacity, drug content, microscopic study, Compatibility study, XRD, and DSC. A favorable docking score was observed between luliconazole and Lanosterol 14-alpha-demethylase. In-vitro cumulative drug release at the end of 24 h from E3-SS, containing sodium sulfide as a penetration enhancer, was found to be 94.70% and was 2 times more than the control formulation. Ex-vivo transungual permeation studies through cutting nail clippings were found to be in the range of 28.18 - 36.52 µg/mm 2 . The microemulgels tagged as E3, E3-SS, and E3-SL showed a significant zone of inhibition against Candida albicans and Aspergillus fumigatus as compared to the marketed formulation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Iron status is often assessed in epidemiologic studies, and toenails offer a convenient alternative to serum because of ease of collection, transport, and storage, and the potential to reflect a longer exposure window. Very few studies have examined the correlation between serum and toenail levels for trace metals. Our aim was to compare iron measures using serum and toenails on both a cross-sectional and longitudinal basis. Using a subset of the US-wide prospective Sister Study cohort, we compared toenail iron measures to serum concentrations for iron, ferritin and percent transferrin saturation. Among 146 women who donated both blood and toenails at baseline, a subsample (59%, n = 86) provided specimens about 8 years later. Cross-sectional analyses included nonparametric Spearman's rank correlations between toenail and serum biomarker levels. We assessed within-woman maintenance of rank across time for the toenail and serum measures and fit mixed effects models to measure change across time in relation to change in menopause status. Spearman correlations at baseline (follow-up) were 0.08 (0.09) for serum iron, 0.08 (0.07) for transferrin saturation, and - 0.09 (- 0.17) for ferritin. The within-woman Spearman correlation for toenail iron between the two time points was higher (0.47, 95% CI 0.30, 0.64) than for serum iron (0.30, 95% CI 0.09, 0.51) and transferrin saturation (0.34, 95% CI 0.15, 0.54), but lower than that for ferritin (0.58, 95% CI 0.43, 0.73). Serum ferritin increased over time while nail iron decreased over time for women who experienced menopause during the 8-years interval. Based on cross-sectional and repeated assessments, our evidence does not support an association between serum biomarkers and toenail iron levels. Toenail iron concentrations did appear to be moderately stable over time but cannot be taken as a proxy for serum iron biomarkers and they may reflect physiologically distinct fates for iron., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Introduction: Onychomycosis, a multifactorial fungal infection of the nails, shows a global prevalence of about 5.5% and is responsible for 50% of all nail infections. To develop effective management strategies, it is necessary to understand the etiology, pathophysiology, and risk factors of onychomycosis. Oral route of drug delivery is one of the routes utilized to deliver anti-fungal agents, but, has its own limitations like longer duration of treatment, increased adverse effects, and potential for drug interaction. The ungual route has received greater attention due to its localized, non- invasive action and improved patient compliance., Areas Covered: This review comprehensively discusses conventional onychomycosis therapies and patented novel drug delivery systems for the management of onychomycosis including chemical permeation enhancers, non-particulate drug delivery systems, penetration enhancing devices etc., Databases such as PubMed, ResearchGate, and Google Patents were searched by using the keywords onychomycosis and trans-ungual drug delivery., Expert Opinion: Enormous research has been conducted and is still ongoing to find the best possible novel drug delivery system for onychomycosis management. Approaches like incorporation of herbal constituents in nano-formulations, inkjet printing, laser devices, iontophoretic techniques, etc. can be employed to make safe and effective drug delivery systems which are regulatory compliant.

Background: The growth of Diabetes Mellitus (DM) is a serious public health issue which is more prevalent in developing countries. The main problems related to DM are the gradual changes in the structural and functional integrity of tissues caused by hyperglycemia, which calls for early diagnosis and periodic monitoring exams. Recent studies suggest that the quality of the nail plate has great potential to assess the secondary complications of DM. Hence, this study aimed to determine the biochemical characteristics of the nails of individuals with DM2 by Raman confocal spectroscopy (CRS)., Methods: We collected fragments from the distal region of the fingernails of 30 healthy volunteers and 30 volunteers with DM2. The samples were analyzed by CRS (Xplora - Horiba) coupled to a 785 nm laser., Results: Alterations in different biochemical components, such as proteins, lipids, amino acids, and final agents of advanced glycation, and alterations in the disulfide bridges, which are important in stabilizing keratin in nails were identified., Conclusion: The spectral signatures and new DM2 markers in nails were identified. Therefore, the possibility of acquiring biochemical information by evaluating the nails of diabetics, a simple and easily acquired material associated with the CRS technique, may allow health complications to be detected quickly., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

The nail unit and hair follicle are both hard keratin-producing organs that share various biological features. In this study, we used digital spatial profiling and single-cell RNA sequencing to define a spatially resolved expression profile of the human nail unit and hair follicle. Our approach showed the presence of a nail-specific mesenchymal population called onychofibroblasts within the onychodermis. Onychodermis and follicular dermal papilla both expressed Wnt and bone morphogenetic protein signaling molecules. In addition, nail matrix epithelium and hair matrix showed very similar expressions profile, including the expression of hard keratins and HOXC13, a transcriptional regulator of the hair shaft. Integration of single-cell RNA sequencing and digital spatial profiling data through computational deconvolution methods estimated epithelial and mesenchymal cell abundance in the nail- and hair-specific regions of interest and revealed close transcriptional similarity between these major skin appendages. To analyze the function of bone morphogenetic proteins in nail differentiation, we treated cultured human nail matrix keratinocytes with BMP5, which are highly expressed by onychofibroblasts. We observed increased expressions of hard keratin and its regulator genes such as HOXC13. Collectively, our data suggest that onychodermis is the counterpart of dermal papilla and that BMP5 in onychofibroblasts plays a key role in the differentiation of nail matrix keratinocytes., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Elemental homeostasis is essential for maintaining normal metabolic processes. Elements in the toenails are now considered in the diagnosis or screening and used as biomarkers of several metabolic disorders. The incidence of obesity is more prevalent in females than males globally. At the same time, females appeared more susceptible to elemental alterations than males. This study aimed to evaluate the variation in the levels of several elements in toenails as possible biomarkers of health conditions associated with obesity in young Saudi females. A cross-sectional study was performed, between February-November 2019. The study enrolled 79 young females divided into two groups: participants with obesity (n=39) and non-obese (n=40). The toenail was analyzed to estimate Fe, I, K, Na, Cd, Cr, Mn, Ca, Mg, Cu, Co, and Se levels. The study showed a significant elevation in the levels of Fe, Ca, K, and Na in the toenail sample of female participants with obesity compared to the non-obese group. The levels of Mn, Cd, Co, Cu, and Cr, were significantly decreased in the toenail of participants with obesity. Moreover, other elements ( i.e ., Mg, I, and Se) were not significantly lower in the female group with obesity. Our findings confirmed the alterations of several elements among Saudi females with obesity. The toenail elemental analysis may become a useful diagnostic technique in monitoring the nutritional status, predicting some metabolic disorders, and environmental exposure., (© 2022 JOURNAL of MEDICINE and LIFE.)

The nail plate is one of the essential structures of the nail apparatus and is highly keratinized, making it difficult to handle this tissue experimentally. Different types of nail consistency were identified by applying distal pressure to the nail plate. To analyze the relationship between the keratins expressed in the nail plate and nail consistency, we chose a sample of 32 adult individuals (age 49.81±3.21 y) with the same number of each sex, who had a similar percentage of nail consistency types (56.25% hard consistency nails and 43.75% soft consistency nails). Immunohistochemical analyses showed that hard consistency nails contain more keratin 17 than soft consistency nails (P=0.026). These novel results allow nail consistency to be defined by the differential expression of keratins in the nail plate, and have potential clinical implications for the diagnosis of possible nail disorders and/or systemic disease., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Psoriasis is a chronic inflammatory disease in which T helper 1 (Th1) and Th17 cells play a major role in its pathogenesis. Studies have shown that keratinocytes in psoriatic tissue are resistant to apoptosis and have a high proliferation rate. Survivin is a multifunctional protein belonging to an apoptosis inhibitor family, which has significant effects on the immune system, such as activation of dendritic cells and T cells and immunomodulation., Objectives: To investigate a possible relationship between serum survivin levels and psoriasis disease characteristics and severity., Materials and Methods: The present study included 84 patients with psoriasis who did not receive any systemic treatment for psoriasis in the last three months and 84 volunteers without psoriasis. Demographic data, smoking status, and alcohol consumption of the participants were questioned, and body mass index (BMI) was calculated. In the patient group, disease duration, family history, accompanying arthritis, and nail involvement were questioned and psoriasis area severity index (PASI) scores were calculated. Serum survivin levels were measured in all subjects., Results: Serum survivin level was significantly higher in the patients compared to the controls (p = 0.008). There was no relationship between serum survivin level and disease duration, family history, joint involvement, nail involvement, BMI, and PASI score (all p-values > 0.05). Serum survivin levels were significantly higher in smokers than non-smokers and in alcohol consumers than patients that did not drink alcohol in the psoriasis group (p = 0.034 and p = 0.006, respectively)., Conclusion: Serum survivin levels were higher in psoriasis patients than the control group. This finding suggests that this molecule, which is both immunomodulatory and an apoptosis inhibitor, may play a role in the pathogenesis of psoriasis. Significantly high serum survivin level in psoriasis patients who smoke suggests that smoking may act through survivin. More comprehensive studies are needed to evaluate the role of survivin in the pathogenesis of psoriasis and its relationship with smoking., (© 2021 Wiley Periodicals LLC.)

Diagnostic, monitoring, response, predictive, risk, and prognostic biomarkers of disease are all widely studied, for the most part in biological fluids or tissues, but there is steadily growing interest in alternative matrices such as nails. Here we comprehensively review studies dealing with molecular or elemental biomarkers of disease, as opposed to semiological, pharmacological, toxicological, or biomonitoring studies. Nails have a long history of use in medicine as indicators of pathological processes and have also been used extensively as a matrix for monitoring exposure to environmental pollution. Nail clippings are simple to collect noninvasively as well as to transport and store, and the matrix itself is relatively stable. Nails incorporate, and are influenced by, circulating molecules and elements over their several months of growth, and it is widely held that markers of biological processes will remain in the nail, even when their levels in blood have declined. Nails thus offer the possibility to not only look back into a subject's metabolic history but also to study biomarkers of processes that operate over a longer time scale such as the post-translational modification of proteins. Reports on ungual biomarkers of metabolic and endocrine diseases, cancer, and psychological and neurological disorders will be presented, and an overview of the sampling and analytical techniques provided.

A nail patch is an attractive option for the topical treatment of onychomycosis, although no product is commercially available. We previously identified optimal nail patch formulations for two anti-onychomycotic drugs, based on their properties, as well as those of the other patch components. In this paper, our aim was to further investigate the potential of the patch formulations as topical nail medicines, in particular, whether the drug-in-adhesive patches release drug which then permeates into and through the nail plate and show anti-fungal efficacy, and whether and to what extent they remain adhered to the human nail plate in vivo when tested over 2 week durations. In addition, the influence of the drug (amorolfine HCl, ciclopirox olamine) and PSA (Duro-Tak 2852 or Duro-Tak 202A) on these parameters was determined. We found that both the nature of the drug and of the PSA influenced in vitro drug release. The nature of the drug, but not that of the PSA, influenced ungual drug permeation through human nail clippings, with considerably greater (almost double) permeation for ciclopirox olamine, the smaller and less lipophilic molecule. In vivo residence, tested with 3 out of the 4 patches, excluding the patch where ciclopirox olamine degraded with time, showed greater residence on toenails compared to fingernails reflecting their far lesser exposure to environmental stresses during daily activities. In vivo residence was enhanced when the patch was cut to the shape of the nail, was applied at bedtime, and when a clear colourless nail varnish was applied on top of the patch to 'seal' it into place on the nail. Comparison of the patches indicated greater residence of Duro-Tak 202A containing patches over those containing Duro-Tak 2852. Amorolfine HCl in Duro-Tak 202A based patch also showed antifungal efficacy in contrast to Duro-Tak 2852-based patch, and is particularly promising for further development as a potential toenail medicine, remaining almost fully adhered to toenails for at least two weeks., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The main purpose of this work was to determine if the use of hybrid nail polishes causes changes in concentration of the most important sulfur amino acids that build nail plate structures, cysteine and methionine. We found that the average contents of cysteine and methionine in studied samples before the use of hybrid manicure were 1275.3 ± 145.9 nmol mg -1 and 111.7 ± 23.8 nmol mg -1 , respectively. After six months of hybrid manicure use, the average amount of these sulfur amino acids in studied samples were 22.1% and 36.5% lower in the case of cysteine and methionine, respectively. The average amounts of cysteine and methionine in nail plate samples after the use of hybrid manicures were 992.4 ± 96.2 nmol mg -1 and 70.9 ± 14.8 nmol mg -1 , respectively. We also confirmed that in studied women the application of UV light varnishes reduced the thickness of the nail plate, from 0.50 ± 0.12 mm before to 0.46 ± 0.12 mm after the use of the hybrid manicure.

Background: COVID-19 is a pandemic disease worldwide. Although cutaneous manifestations may present in affected patients, there have been limited studies on the cutaneous findings and hair and nail abnormalities after discharge., Objective: To establish the cutaneous manifestations, hair and scalp disorders, and nail abnormalities in patients who recovered from COVID-19 infections., Methods: A retrospective chart review and telephone interviews were conducted to determine the cutaneous manifestations, hair and scalp disorders, and nail abnormalities of patients aged over 18 years who were diagnosed with COVID-19 infections at Siriraj Hospital, Bangkok, Thailand, between January and June 2020., Results: Ninety-three patients with prior COVID-19 infections participated in the study. The COVID-19 severity had been mild for most (71%). Cutaneous manifestations were reported in 8 patients (8.6%), with the common skin conditions being maculopapular rash and urticaria. The onsets of the skin conditions were before admission (1%), during admission (4.3%), and after discharge (3.2%). Increased hair shedding was also reported in 22 patients (23.7%), with a female predominance. Three patients were affected during admission, while the others were affected after discharge. The patients with moderate, severe, and critical COVID-19 infections experienced significantly more hair shedding than those with asymptomatic and mild diseases. Only 2 patients with mild COVID-19 disease reported nail abnormalities (chromonychia and brittle nails)., Conclusions: Cutaneous manifestations, hair disorders, and nail abnormalities can occur in patients with COVID-19 after their discharge from hospital. Patients should therefore be followed up in anticipation of dermatological problems., Competing Interests: All authors declare that there are no conflicts of interest related to this study., (Copyright © 2021 Rattapon Thuangtong et al.)

Research on human nail tissue has been limited by the restricted access to fresh specimen. Here, we studied transcriptome profiles of human nail units using polydactyly specimens. Single-cell RNAseq with 11,541 cells from 4 extra digits revealed nail-specific mesenchymal and epithelial cell populations, characterized by RSPO4 (major gene in congenital anonychia) and SPINK6, respectively. In situ RNA hybridization demonstrated the localization of RSPO4, MSX1 and WIF1 in onychofibroblasts suggesting the activation of WNT signaling. BMP-5 was also expressed in onychofibroblasts implicating the contribution of BMP signaling. SPINK6 expression distinguished the nail-specific keratinocytes from epidermal keratinocytes. RSPO4 + onychofibroblasts were distributed at close proximity with LGR6 + nail matrix, leading to WNT/β-catenin activation. In addition, we demonstrated RSPO4 was overexpressed in the fibroblasts of onychomatricoma and LGR6 was highly expressed at the basal layer of the overlying epithelial component, suggesting that onychofibroblasts may play an important role in the pathogenesis of onychomatricoma.

Urea has been incorporated into several topical ungual formulations to hydrate and soften the nail plate. In this study, we employed various characterization techniques (visual observation, scanning electron microscopy, measurement of thickness, transonychial water loss, nail electrical resistance, and mechanical study) to investigate the effect of urea concentration on the hydration of bovine hoof membranes - an in vitro model of infected human nails. We obtained inconsistent results in the thickness, transonychial water loss, nail electrical resistance, and scanning electron microscopy studies. In the mechanical study using a modified Texture Analyzer method, we reported an inverse and linear correlation between urea concentrations in the formulations and the force required to puncture the treated membrane ( R 2 = 0.9582, n  ≥ 8). As the urea concentration decreased from 4x to 2x, 1x, and 0x % w/w, the puncture force increased significantly from 0.47 ± 0.07 to 0.77 ± 0.07, 0.91 ± 0.09, and 1.33 ± 0.26 N, respectively ( p   <  0.05). Thus, urea provided a positive softening effect on the membranes and the puncture force could indicate the urea level in topical formulations. In this study, we provided a novel, efficient, and reliable tool to evaluate the hydration level and physical properties of bovine hoof membranes.

Low selenium status may be associated with increased risk of prostate cancer (PC), particularly aggressive PC, and variation in selenoprotein genes may constitute an important modifying factor. We aimed to investigate the association between two selenium status biomarkers [toenail selenium, plasma selenoprotein P (SELENOP)] and risk of advanced, high-grade and advanced-stage PC. We further studied whether variations in selenoprotein genes were associated with PC risk and selenium biomarker concentrations. In the "Diet, Cancer and Health" cohort, 27 178 men aged 50 to 65 years were enrolled from 1993 to 1997. Between baseline and 2012, 1160 cohort participants were diagnosed with advanced PC; among these 462 had high-grade and 281 had advanced-stage disease at diagnosis. Each case was risk set-matched to one control. Toenail selenium and plasma SELENOP concentrations were measured by neutron activation analysis and a SELENOP-ELISA, respectively, and genotyping was performed for 27 selected single nucleotide polymorphisms (SNPs) in 12 selenium pathway genes (including seven selenoproteins) by allele-specific PCR. Toenail selenium and circulating SELENOP concentrations were not associated with advanced, high-grade or advanced-stage PC. After adjustment for multiple testing, none of the genes were associated with PC risk. Neither toenail selenium nor plasma SELENOP was associated with advanced, high-grade or advanced-stage PC., (© 2020 UICC.)

Melatonin plays multiple physiological roles in the human body. Evaluation of melatonin production by the determination of urinary 6-sulfatoxymelatonin in 24-h samples has important drawbacks which hinder the successful evaluation of melatonin production in large cohorts. Here, we evaluated the potential of nail analysis for estimating melatonin production. Firstly, mass spectrometry methodology for the determination of melatonin in nails was optimized and successfully validated. The method was found to be linear in the range 6.5-830 fg/mg with intraday and interday accuracy in the range 100-104 %, precision below 15 % and a LOD of 3.5 fg/mg. Secondly, nail melatonin concentrations from 84 volunteers (age 5-96) were determined. The expected correlation between melatonin and age was obtained (correlation coefficient -0.615; p < 0.001). Additionally, we showed that fingernails are preferable to toenails to determine nail melatonin content. Finally, fingernails collected for 180 days after melatonin administration (two volunteers, 1.9 mg/night during 5 days) were analyzed. Nail melatonin concentrations immediately rose after administration and went back to pre-administration values after ≈100 days in both volunteers. Our results suggest that melatonin determination in nails is a suitable non-invasive tool for the estimation of global melatonin production. Due to the easy collection and storage of nails, the long-term information obtained and the multiple functions of melatonin, nail melatonin content might complement dim light melatonin onset, which is commonly measured from plasma/saliva samples, paving the way for melatonin research.

Iontophoresis is a widely used drug delivery technique that has been used clinically to improve permeation through the skin for drugs and other actives in topical formulations. It is however not commonly used for the treatment of nail diseases despite its potential to improve transungual nail delivery. Instead, treatments for nail diseases are limited to relatively ineffective topical passive permeation techniques, which often result in relapses of nail diseases due to the thickness and hardness of the nail barrier resulting in lower permeation of the actives. Oral systemic antifungal agents that are also used are often associated with various undesirable side effects resulting in low patient compliance. This review article discusses what is currently known about the field of transungual iontophoresis, providing evidence of its efficacy and practicality in delivering drug to the entire surface of the nail for extended treatment periods. It also includes relevant details about the nail structure, the mechanisms of iontophoresis, and the associated in vitro and in vivo studies which have been used to investigate the optimal characteristics for a transungual iontophoretic drug delivery system. Iontophoresis is undoubtedly a promising option to treat nail diseases, and the use of this technique for clinical use will likely improve patient outcomes.Graphical abstract.

Psoriasis is a chronic inflammatory disease associated with immune system dysfunction that can affect nails, with a negative impact on patient life quality. Usually, nail psoriasis is associated with skin psoriasis and is therefore relatively simple to diagnose. However, up to 10% of nail psoriasis occurs isolated and may be difficult to diagnose by means of current methods (nail biopsy, dermoscopy, video dermoscopy, capillaroscopy, ultrasound of the nails, etc.). Since the nail is a complex biological tissue, mainly composes of hard α-keratins, the structural and morphological techniques can be used to analyze the human fingernails. The aim of this study was to corroborate the information obtained using Raman spectroscopy with those obtained by scanning electron microscopy (SEM) and X-ray diffractometry and to assess the potential of these techniques as non-invasive dermatologic diagnostic tools and an alternative to current methods.

Onychomycosis is considered a stubborn nail fungal infection that does not respond to conventional topical antifungal treatments. This study aimed to develop and characterize novel solid lipid nanoparticles (SLNs) formulae containing terbinafine HCl (TFH) and loaded with different nail penetration enhancers (nPEs). Three (nPEs) N-acetyl-L-cysteine, thioglycolic acid, and thiourea were used. Characterization of the prepared formulae was done regarding particle size, zeta potential, polydispersity index (PDI), entrapment efficiency (EE%), physical stability, in vitro release study, infrared (FT-IR), and their morphological structures. The selected formulae and the marketed cream Lamifen® were compared in terms of their antifungal activity against Trichophyton rubrum as well as their nail hydration and their drug uptake by the nail clippers. Thiourea was the nPE of choice; formulae (N2 and N8), with thiourea, were considered the optimum TFH SLNs containing nPEs. They were selected for their optimum particle size of 426.3 ± 10.18 and 450.8 ± 11.45 nm as well as their highest EE% of 89.76 ± 1.25 and 90.35 ± 1.33, respectively. The in vitro microbiological screening of the antifungal activity of these two formulae showed significantly larger zones of inhibition in comparison with the marketed product. The ex vivo screening of the drug uptake of the two selected formulae was significantly higher than that of the marketed product. The nPE formulae present a very promising option as they showed optimum physicochemical characterization with high antifungal activity and high drug uptake as well as good nail hydration effect.

We evaluated a hydroalcoholic extract of Sapindus saponaria L. pericarps (ETHOSS), as a candidate to a topical antifungal medicine for onychomycosis. ETHOSS was produced by extracting the crushed fruits in ethanol. The saponin contents were identified and characterized by electrospray ionization mass spectrometry. We measured the in vitro antifungal activity against three dermatophyte fungi, isolated from onychomycosis: Trichophyton rubrum , T. mentagrophytes, and T. interdigitale , using broth microdilution tests. The minimum fungicide concentration of ETHOSS ranged from 195.31 to 781.25 μg/mL. The cytotoxicity of the crude extract was tested on the HeLa cell line, and its ability to permeate into healthy human nails by photoacoustic spectroscopy and Fourier transformation infrared spectrometer (FTIR) spectroscopy by attenuated total reflection. Besides its strong antifungal activity, ETHOSS showed low cytotoxicity in human cells. It was able to permeate and reach the full thickness of the nail in one hour, without the aid of facilitating vehicles, and remained there for at least 24 h. These results suggest that ETHOSS has great potential for treating onychomycosis.

Background: Onychomycosis is by far the most common finger or toe nail fungal infectious disease caused by dermatophytes, non-dermatophytic molds or yeast. It accounts for 50% of the total nail disorders, and affects patients physically, socially, and psychologically and can seriously influence their quality of life., Objectives: Oral antifungals are routinely used to treat the nail fungal disease; however oral therapy is associated with severe side effects and longer treatment times. In recent years, drug delivery directly into the nail or nail bed has gained attention and various topical products have been tested that can cure the disease when applied topically or transungually. Nevertheless, drug penetration into and through the nail is not straightforward and requires chemicals to improve its permeability or by applying physical stress to promote drug penetration into and through the nail. This lucid review presents an overview of various causes of onychomycosis, current therapeutic approaches, and efforts aimed at increasing the permeability of nails through various strategies such as chemical, physical and mechanical methods for permeation enhancement., Conclusion: Various strategies have been proposed for the treatment of onychomycosis, however, much research into a more precise and effective therapy is still required., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Vertebrate Hox genes are critical for the establishment of structures during the development of the main body axis. Subsequently, they play important roles either in organizing secondary axial structures such as the appendages, or during homeostasis in postnatal stages and adulthood. Here, we set up to analyze their elusive function in the ectodermal compartment, using the mouse limb bud as a model. We report that the HoxC gene cluster was co-opted to be transcribed in the distal limb ectoderm, where it is activated following the rule of temporal colinearity. These ectodermal cells subsequently produce various keratinized organs such as nails or claws. Accordingly, deletion of the HoxC cluster led to mice lacking nails (anonychia), a condition stronger than the previously reported loss of function of Hoxc13 , which is the causative gene of the ectodermal dysplasia 9 (ECTD9) in human patients. We further identified two mammalian-specific ectodermal enhancers located upstream of the HoxC gene cluster, which together regulate Hoxc gene expression in the hair and nail ectodermal organs. Deletion of these regulatory elements alone or in combination revealed a strong quantitative component in the regulation of Hoxc genes in the ectoderm, suggesting that these two enhancers may have evolved along with the mammalian taxon to provide the level of HOXC proteins necessary for the full development of hair and nail., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Urate in the fingernails of gout patients and healthy volunteers was successfully detected by high-performance liquid chromatography (HPLC) with ultraviolet (UV) in our previous research. This study aimed to further investigate whether nail urate could be a proxy for the burden of monosodium urate (MSU) crystals deposits in gout. To this end, we conducted a study in two parts. Firstly, we successfully detected urate in the nail by HPLC-UV and evaluated nail urate concentrations in control subjects and patients with gout. As expected, we found that levels of nail urate were significantly higher in patients with gout than in healthy controls, and the nail urate level was significantly correlated with the volume of MSU crystals deposits measured by dual-energy CT (DECT). Secondly, we found that nail urate can reflect changes in urate levels in the body during urate lowering therapy through a 3-month follow-up study. Our results provide the possibility of quantification of urate in human fingernails as a non-invasive alternative for assessing MSU crystals deposits in gout.

Naftifine is used to treat fungal skin infections as it inhibits dermatophytes, which are the cause of onychomycosis. However, naftifine's ability to permeate the human nail barrier has not been investigated, thus, the antimycotic potential is not clearly established. This work aims to evaluate the effect of penetration enhancing factors on the accumulation of naftifine hydrochloride through human nail clippings. Naftifine polymeric nail lacquers with Eudragit RL100 were developed as a suitable delivery system. Low penetration of naftifine into nail has been determined as less than 10% of applied drug dose accumulated in the nail layers. Incorporation of thioglycolic acid into formulations resulted in increased accumulation of antifungal agent in the nail layers by 100% compared with a control group. Salicylic acid did not effect naftifine accumulation in the human nail. The permeation of naftifine through the nail increased by threefold when the thioglycolic acid-containing formulation was applied and the nail was pretreated with a fractional CO 2 laser. Structural changes of the nail barrier, induced by fractional CO 2 laser, were visualized by microscopy. The results suggest, that naftifine nail penetration could be significantly increased when physical and chemical enhancing factors are applied.

The extraction of cortisol from fingernails represents a recent advancement in the retrospective, long-term assessment of hypothalamic-pituitaryadrenal (HPA) axis activity: Fingernail cortisol has the potential to overcome some of the major disadvantages of established HPA axis markers. However, the introduction of any novel methodology also raises certain caveats. This review provides a comprehensive summary of the current state of research on fingernail cortisol. It identifies a number of strengths of his novel methodology (e.g., its high feasibility), while also pointing out open questions which currently challenge the interpretability of fingernail findings, in particular regarding the time period of cortisol secretion reflected in fingernail samples, as well as regarding potential determinants or confounders of fingernail cortisol (e.g. sociodemographic, lifestyle, or health characteristics). Clarification of these issues in the context of further methodological studies is necessary to validate the use of fingernail cortisol as a retrospective marker of HPA axis activity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Onychomycosis is one of the most prevalent and severe nail fungal infections, which is affecting a wide population across the globe. It leads to variations like nail thickening, disintegration and hardening. Oral and topical drug delivery systems are the most desirable in treating onychomycosis, but the efficacy of the results is low, resulting in a relapse rate of 25-30%. Due to systemic toxicity and various other disadvantages associated with oral therapy like gastrointestinal, hepatotoxicity, topical therapy is commonly used. Topical therapy improves patient compliance and reduces the cost of treatment. However, due to poor penetration of topical therapy across the nail plate, research is focused on different chemical, mechanical and physical methods to improve drug delivery. Penetration enhancers like Thioglycolic acid, Hydroxypropyl-β-cyclodextrin (HP-β-CD), Sodium lauryl sulfate (SLS), carbocysteine, N-acetylcysteine etc. have shown results enhancing the drug penetration across the nail plate. Results with physical techniques such as iontophoresis, laser and Photodynamic therapy are quite promising, but the long-term suitability of these devices is in need to be determined. In this article, a brief analysis of the treatment procedures, factors affecting drug permeation across nail plate, chemical, mechanical and physical devices used to increase the drug delivery through nails for the onychomycosis management has been achieved., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Background: Pachyonychia congenita (PC) is a rare autosomal dominant disorder of keratinization mediated by genetic mutations in KRT6A, KRT6B, KRT6C, KRT16, or KRT17. While nail dystrophy in PC has a significant impact on quality of life, the histopathological features of the nail plate in PC have not been previously reported. We report the histopathological features of nail plates provided by 19 patients with genetically confirmed PC., Methods: Nineteen patients with genetically confirmed PC provided a total of 56 nail plates for histopathologic examination. The nail plates were examined for the presence of hyphae, yeast, bacteria, neutrophils, parakeratosis, plasma globules, and hemorrhage. Specimens with onychomycosis (three patients) were excluded from the analysis., Results: No specific histopathological feature was identified in PC nails. Parakeratosis and plasma globules were the most prominent features in both clinically affected and unaffected PC nails. There was a significant association between clinical dystrophy of all 20 nails and KRT6A mutations, and a lack of dystrophy of all 20 nails in KRT6B mutations., Conclusions: Parakeratosis and plasma globules in the absence of other inflammatory disorders should raise PC in the histopathologic differential diagnosis. The presence of onychomycosis in a nail plate does not exclude a diagnosis of PC., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Onychomycosis, or fungal nail infection, is a common fungal infection largely caused by dermatophyte fungi, such as Trichophyton rubrum or Trichophyton mentagrophytes, which affects a significant number of people. Treatment is either through oral antifungal medicines, which are efficacious but have significant safety concerns, or with topical antifungal treatments that require long treatment regimens and have only limited efficacy. Thus, an efficacious topical therapy remains an unmet medical need. Among the barriers to topical delivery through the nail are the physico-chemical properties of the antifungal drugs. Here, we explore the ability of a range of antifungal compounds with different hydrophilicities to penetrate the nail. Human nail discs were clamped within static diffusion (Franz) cells and dosed with equimolar concentrations of antifungal drugs. Using LC-MS/MS we quantified the amount of drug that passed through the nail disc and that which remained associated with the nail. Our data identified increased drug flux through the nail for the more hydrophilic compounds (caffeine as a hydrophilic control and fluconazole, with LogP -0.07 and 0.5, respectively), while less hydrophilic efinaconazole, amorolfine and terbinafine (LogP 2.7, 5.6 and 5.9 respectively) had much lower flux through the nail. On the other hand, hydrophilicity alone did not account for the amount of drug associated with/bound to the nail itself. While there are other factors that are likely to combine to dictate nail penetration, this work supports earlier studies that implicate compound hydrophilicity as a critical factor for nail penetration., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: Heather Davies-Strickleton, Julie Cook, Christine Ridden, David Edwards, John Ridden and David Cook are employees of Blueberry Therapeutics Ltd. Sally Hannam, Alan Gibbs and Rhys Bennett are employees of Alderley Analytical Ltd. All research was funded by Blueberry Therapeutics Ltd. Data collection was performed by Alderley Analytical Ltd., who were recruited by Blueberry Therapeutics Ltd. for this service. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Onychomycosis is a progressive fungal infection of the nails that involves the deeper nail layer and nail bed. It is important to maintain sufficient drug concentration in the diseased tissues after topical application. In this study, a stable topical delivery system for efinaconazole (EFN) was designed to enhance absorption potential through the skin and nail plate by incorporating ethanol, diethylene glycol monoethyl ether (Transcutol P) and isopropyl myristate, and cyclomethicone into the topical solution as a delivery vehicle, permeation enhancers, and a wetting agent, respectively. In addition, the stability of EFN in the formulation was significantly improved by adding butylated hydroxytoluene, diethylenetriamine pentaacetic acid, and citric acid as an antioxidant, chelating agent, and pH-adjusting agent, respectively, without discoloration. The optimum EFN formulation (EFN-K) showed 1.46-fold greater human skin permeation than that of the reference control (commercial 10% EFN topical solution). Furthermore, after a 24-hour incubation, the amount of infiltrated EFN from EFN-K in the human nail plate was 4.11-fold greater than that of the reference control, resulting in an 89.7% increase in nail flux at 7 days after treatment. EFN-K significantly accelerated structural recovery of the keratin layer in a Trichophyton mentagrophytes -infected guinea pig onychomycosis model, decreasing the mean viable fungal cell count by 54.3% compared to the vehicle-treated group after once-daily treatment for 4 weeks. Thus, the accelerated skin and nail penetration effect of EFN-K is expected to achieve good patient compliance, and improve the complete cure rate of onychomycosis.

Background: Onychomycosis is an opportunistic fungal infection often infecting people with compromised immune system. Currently available treatment interventions such as physical, surgical, and chemical-based approaches are successful in treating the condition, however, are painful and nonpatient complaint. Moreover, dermal creams with antifungal agents do not penetrate nail plate as required; hence, there is a necessity of developing a novel formulation with enhanced penetration., Aims: The aim of the present research work was to develop ketoconazole microemulsion-loaded hydrogel formulation containing nigella oil as permeation enhancer for the treatment of onychomycosis., Methods: Screening of oils, surfactants, and cosurfactants were done based on solubility studies followed by the construction of pseudo-ternary phase diagrams with 2% ketoconazole. The microemulsion was characterized for globule size, zeta potential, viscosity, and thermodynamic stability. Ex-vivo studies were carried out using Franz diffusion cells using porcine skin membrane. The antifungal activity of microemulsion-loaded hydrogel was evaluated using cup plate method using Candida albicans and Aspergillus niger., Results: The optimized microemulsion had a composition of 54.97% Capryol:Nigella (2:1), 36.07% Transcutol:Propylene glycol (2:1), and 7.13% water and was later incorporated into polymeric gel base. The microemulsion-loaded hydrogel exhibited a 10 hours sustained release profile as compared to the marketed cream and an enhanced activity against marketed ketoconazole cream and compared with marketed ketoconazole formulation., Conclusion: The thermodynamic stability, sustained drug release with greater permeation, and enhanced activity due to the presence of nigella oil in microemulsion-loaded hydrogel warrant its application as an excellent vehicle for treating fungal infections., (© 2019 Wiley Periodicals, Inc.)

Urine, hair and nail samples were collected from a population of both sex aged from 40 to 87 years in Niška Banja (227 km south of Belgrade, Serbia) with a high level of natural radioactivity (HLNRA). To assess and monitor the public exposure, urine samples for each subject (24 h period) were collected and concentration of uranium (U) was analysed using alpha-particle spectrometry. Human hair and nails considered as bio-indicators of the public exposure to radionuclides over a long period of months or even years and concentration of U was determined using inductively coupled plasma-mass spectrometry. The mean concentrations of U in urine, hair and nail were 123 ng/L, 17 ng/g and 8 ng/g, respectively. There was a large variation and may be due to geological origin., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Onychomycosis is a nail fungal infection, mostly caused by dermatophytes. The treatment efficacy is impaired by difficulties of reaching effective drug levels at the site of infection; frequent relapses occur after cessation of antifungal therapy. The aim of the study was to compare two commercial products containing ciclopirox or efinaconazole for antimycotic activity and antifungal drug resistance. A study of permeation and penetration through bovine hoof membranes, as a nail model, was performed to evaluate the antimycotic activity of permeates against clinical isolates of selected fungi, and the frequency of spontaneous in vitro Trichophyton rubrum -resistant strains was assessed by broth microdilution assays. The results suggest that ciclopirox creates a depot in the nail, leading to a gradual release of the drug over time with action on both the nail plate and bed. Conversely, efinaconazole, mildly interacting with nail keratin, mainly exerts its antifungal activity in the nail bed. However, in the case of T. rubrum , the antifungal activities of the drugs in the nail plate seem comparable. Finally, efinaconazole showed a potential for induction of resistance in T. rubrum , which may limit its efficacy over time. Ciclopirox did not show any potential to induce resistance in T. rubrum and appears endowed with a more complete activity than efinaconazole in the management of onychomycosis as the nail keratin is a substrate for the growth of fungal cells, and the availability of drug in large concentration just in the nail bed may not be sufficient to guarantee the complete eradication of pathogens., (Copyright © 2019 Monti et al.)

Onychomycosis is a chronic fungal infection of the nail that is recalcitrant to treatment. It is unclear why normally effective antifungal therapy results in low cure rates. Evidence suggests that there may be a plethora of reasons that include the limited immune presence in the nail, reduced circulation, presence of commensal microbes, and fungal influence on immune signaling. Therefore, treatment should be designed to address these possibilities and work synergistically with both the innate and adaptive immune responses.

Incontinentia Pigmenti (IP; MIM 308300) is an X-linked dominant genodermatosis caused by pathogenic variant in IKBKG. The phenotype in adults is poorly described compared to that in children. Questionnaire survey of 99 affected women showed an age at diagnosis from newborn to 41 years, with 53 diagnosed by 6 months of age and 30 as adults. Stage I, II, and III lesions persisted in 16%, 17%, and 71%, respectively, of those who had ever had them. IP is allelic to two forms of ectodermal dysplasia. Many survey respondents reported hypohidrosis and/or heat intolerance and most had Stage IV findings. This suggests that "Stage IV" may be congenitally dysplastic skin that becomes more noticeable with maturity. Fifty-one had dentures or implants with 26 having more invasive jaw or dental surgery. Half had wiry or uncombable hair. Seventy-three reported abnormal nails with 27 having long-term problems. Cataracts and retinal detachment were the reported causes of vision loss. Four had microphthalmia. Respondents without genetic confirmation of IP volunteered information suggesting more involved phenotype or possibly misassigned diagnosis. Ascertainment bias likely accounts for the low prevalence of neurocognitive problems in the respondents., (© 2019 Wiley Periodicals, Inc.)

Backgrounds: We previously demonstrated the presence of onychodermis below nail matrix and nail bed. Because nail matrix is a producer of nail plate, we hypothesized that onychodermis below nail matrix could be the nail counterpart of follicular dermal papilla. In this study, we sought to further characterize histologic, histochemical, and immunohistochemical features of nail matrix onychodermis., Methods and Results: Hematoxylin and eosin slides of 10 polydactyly nail units and 10 nail matrix biopsies from children and adults were reviewed. In polydactyly nail units, the onychodermis beneath nail matrix was characterized by onychofibroblasts showing abundant cytoplasm, and this area was slightly separated from the undersurface of the nail matrix. Nail matrix biopsy specimens also showed similar histology in the nail matrix onychodermis. Alcian blue stain demonstrated mucin deposition in onychofibroblasts within the nail matrix onychodermis. Immunohistochemically, elastin was rarely expressed in the nail matrix onychodermis while it was strongly expressed in the dermis of other areas of polydactyly nail units. Elastin was not expressed in follicular dermal papilla of terminal hair follicles of the scalp., Conclusion: Our findings demonstrate the presence and localization of nail matrix onychodermis (onychomatricodermis). Our study also demonstrates similar elastin expression patterns in the onychomatricodermis and follicular dermal papilla., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Immunohistochemical (IHC) stains that distinguish benign, pigmented nail lesions from malignancy are needed. Candidate markers of malignant transformation include p16, HMB45, and Ki-67, with p16 being of particular interest. There is limited knowledge about the spectrum of p16 expression in pigmented lesions, especially junctional melanocytic proliferations of the nail. The objective of this study was to determine if any of these markers demonstrate diagnostic utility in distinguishing between benign activation of junctional melanocytes (BAM) and melanoma in situ (MIS) of the nail unit., Methods: In this retrospective study, ten cases of BAM and eight cases of MIS were identified. Archival slides available for review included H&E (hematoxylin and eosin), Fontana-Masson, and MelanA (Mart1) IHC slides. IHC studies for p16, HMB45, and dual-color Ki-67/MelanA (Mart1) were then performed., Results: None of the tested IHC stains distinguished BAM from MIS. p16 IHC expression was uniformly negative with the exception of two cases of MIS. HMB45 was positive in all BAM and MIS cases. Ki-67/MelanA showed positive Ki-67 staining of MelanA-positive melanocytes in two cases of MIS, and all other cases of MIS and BAM were negative for Ki-67. The two positive p16 and two positive Ki-67/MelanA cases were non-overlapping., Conclusion: p16, HMB45, and Ki-67/MelanA IHC studies show no apparent utility in distinguishing BAM from MIS in the nail unit., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Identification of onychomycosis is mainly based on clinical diagnosis with auxiliary diagnostic methods such as potassium hydroxide (KOH) microscopy, periodic acid-Schiff staining or fungal culture. However, each method is limited by its sensitivity and specificity., Aim: To develop a new test method using the common fungal end product, ergosterol, and investigate if it can be used as a new diagnostic tool., Methods: We collected consecutive data from 20 participants with nail problems. Following clinical diagnosis, samples were taken for KOH microscopy and for mass spectrometry (MS) to check for the presence of ergosterol., Results: Of the 20 cases collected, 7 were positive for fungal infection by MS. Four of these were already suspected to have onychomycosis, whereas one of the remaining three subjects was presumed to have dry nail and the other two to have onycholysis. The MS test seemed to be better at detecting combinations of nail conditions. Conversely, of the five patients clinically diagnosed as having onychomycosis, four had a positive MS result, whereas the fifth had negative results on both KOH and MS. Two other participants had a positive KOH test and were also found to have positive MS results., Conclusion: Detection of the presence of ergosterol by MS seems to be a useful tool for confirming onychomycosis. However, further studies are needed to verify the sensitivity and specificity of this MS method., (© 2019 British Association of Dermatologists.)