Search

Data on primary prevention of zinc status and diabetes risk are sparse and inconsistent. Of note, the previous studies measured either dietary zinc intake with questionnaire or zinc status in serum or hair. Toenail zinc levels are reliable biomarkers of a relatively long-term exposure. A total of 3,960 American young adults, aged 20-32 years, free of diabetes at baseline in 1987 when toenail clippings were collected, were examined for incident diabetes through 2010. Toenail zinc levels were measured with an inductively-coupled-plasma mass spectroscopy method. Incident diabetes cases were identified by fasting or non-fasting plasma glucose levels, oral glucose tolerance tests, hemoglobin A1C levels, and/or antidiabetic medications. During the 23-year follow-up, 418 incident diabetes occurred. After adjusted for age, sex, ethnicity, study center, body mass index, education, smoking status, alcohol consumption, physical activity, family history of diabetes, homeostasis model assessment of insulin resistance, and other dietary and non-dietary potential confounders, the hazard ratio of incident diabetes comparing the highest to the lowest quartile of toenail zinc levels was 1.21 (95% CI: 0.90-1.63; Ptrend = 0.20). Findings from this study do not support the hypothesis that zinc status is inversely and longitudinally associated with the incidence of diabetes in American young adults.

The electrical properties of human nail plate are poorly characterized yet are a key determinate of the potential to treat nail diseases, such as onychomycosis, using iontophoresis. To address this deficiency, molar conductivities of 17 electrolytes comprising 12 ionic species were determined in hydrated human nail plate in vitro. Cation transport numbers across the nail for 11 of these electrolytes were determined by the electromotive force method. Effective ionic mobilities and diffusivities at infinite dilution for all ionic species were determined by regression analysis. The ratios of diffusivities in nail to those in solution were found to correlate inversely with the hydrodynamic radii of the ions according to a power law relationship having an exponent of -1.75 ± 0.27, a substantially steeper size dependence than observed for similar experiments in skin. Effective diffusivities of cations in nail were 3-fold higher than those of comparably sized anions. These results reflect the strong size and charge selectivity of the nail plate for ionic conduction and diffusion. The analysis implies that efficient transungual iontophoretic delivery of ionized drugs having radii upward of 5 Å (molecular weight, ca. ≥ 340 Da) will require chemical or mechanical alteration of the nail plate., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

To clarify the character of luliconazole nail solution we have developed, we investigated luliconazole distribution and antifungal activity in nail plate. An in vitro permeation study which measured luliconazole concentration of sliced nail in the transverse direction after treatment of luliconazole nail solution was conducted to investigate for concentration dependency and the influences of nail thickness and treatment duration. When 0.2, 1, 3, 5, and 7.5% luliconazole nail solutions were used, luliconazole was detected in the all the layers of nail and there was a concentration gradient from the dorsal side to deep nail layers. The luliconazole concentration was almost same after 14-day treatment with 5% luliconazole nail solution when using nails of different thicknesses. And we confirmed that concentration of luliconazole into the nail was increased depending on the treatment duration. In zone of inhibition test after 14-day treatment, 5% luliconazole nail solution showed statistically high formation rate of zones of inhibition compared to 8% ciclopirox nail lacquer. Above all, these data suggested that 5% luliconazole nail solution has the potential to show high therapeutic effect for onychomycosis.

Triphenyl phosphate (TPHP) is primarily used as either a flame retardant or plasticizer, and is listed as an ingredient in nail polishes. However, the concentration of TPHP in nail polish and the extent of human exposure following applications have not been previously studied. We measured TPHP in ten different nail polish samples purchased from department stores and pharmacies in 2013-2014. Concentrations up to 1.68% TPHP by weight were detected in eight samples, including two that did not list TPHP as an ingredient. Two cohorts (n=26 participants) were recruited to assess fingernail painting as a pathway of TPHP exposure. Participants provided urine samples before and after applying one brand of polish containing 0.97% TPHP by weight. Diphenyl phosphate (DPHP), a TPHP metabolite, was then measured in urine samples (n=411) and found to increase nearly seven-fold 10-14h after fingernail painting (p<0.001). To determine relative contributions of inhalation and dermal exposure, ten participants also painted their nails and painted synthetic nails adhered to gloves on two separate occasions, and collected urine for 24h following applications. Urinary DPHP was significantly diminished when wearing gloves, suggesting that the primary exposure route is dermal. Our results indicate that nail polish may be a significant source of short-term TPHP exposure and a source of chronic exposure for frequent users or those occupationally exposed., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The aim of this study was to use in vitro nail models to investigate the potential of a novel base formulation (Recura) containing either fluconazole or miconazole for the treatment of onychomycosis in comparison to two commercial comparators (Jublia and a Penlac generic). Initially, a modified Franz cell was used, where sections of human nail served as the barrier through which drug penetrated into an agar-filled chamber infected with dermatophytes. A second study was performed using a novel infected nail model where dermatophytes grew into human nail and adenosine triphosphate levels were used as biological marker for antimicrobial activity. The novel enhancing system Recura increased the permeation of both existing drugs through human nail sections mounted in a modified Franz cell. Furthermore, the infected nail model also confirmed that the system also enhanced the permeation through infected nail resulting in a decrease in adenosine triphosphate levels superior (P ≤ 0.05) to Penlac generic and equivalent (P > 0.05) to the commercial comparator Jublia. This study demonstrated that with the use of a novel permeation-enhancing formulation base, Recura enhances delivery of miconazole and fluconazole when applied ungually such that the efficacy was equivalent or superior to commercial comparators. Such a topically applied system has the possibility of overcoming the systemic side effects of antifungals when taken orally.

Two topical therapeutic agents were approved in Japan from 2015 to 2016, adding new options for onychomycosis therapy in the clinical field. In order to confirm the differences of formulation properties and nail pharmacokinetics between 5% luliconazole solution and 10% efinaconazole solution, drug concentration and antifungal activity in the nail were measured after topical treatment using human nail plates. In the in vitro permeation study, concentration of each drug was measured in the transversely sliced nail after single treatment with the two topical therapeutic agents. The results showed that concentration of luliconazole is higher than that of efinaconazole at all nail layers, differing by 1.7-8.4 times at each measurement point. Next, we examined antifungal activities of each drug in sliced nail after 14-day topical treatment. Mean rates of formation of inhibition zones for 5% luliconazole solution and 10% efinaconazole solution were 71.0% and 12.6%, respectively, and were statistically different. These results show that the two topical therapeutic agents have different properties, and suggest that 5% luliconazole solution has good nail permeation and retention characteristics. Moreover, luliconazole was found to retain enough antifungal activity in the nail plate against Trichophyton spp. after treatment with the topical agent.

Nail-Patella Syndrome (NPS) is a rare autosomal dominant condition comprising nail and skeletal anomalies. Skeletal features include dysplastic patellae and iliac horns, as well as scapula and elbow dysplasia. Nephropathy and glaucoma or intra-ocular hypertension can sometimes be present. NPS is due to variants affecting function in LMX1B, which encodes a LIM-homeodomain protein critical for limb, kidney and eye development. We describe the phenotype and the molecular data of 55 index patients and their 39 relatives presenting with typical NPS. We identified 38 different LMX1B anomalies, 19 of which were not reported before. In our series, 9% of families are not carriers of a LMX1B genomic alteration after extensive study of the coding and non-coding regions of the gene. One of the families showed no linkage to the LMX1B locus, raising the hypothesis of a genetic heterogeneity.

Introduction: Onychomycosis is a fungal nail infection that is difficult to treat due to poor accessibility of drugs into the nail plate. Although oral antifungals can reach the nail apparatus more readily, these therapies may not be suitable or desirable for some patients (e.g., multiple medications or immunocompromised). Efinaconazole 10% solution is a new topical antifungal recently approved and sold in Canada, the United States and Japan for the treatment of mild-to-moderate toenail onychomycosis. Efinaconazole has broad-spectrum antifungal activity against dermatophytes, nondermatophyte molds and yeasts, and high ungual penetration due to its low keratin binding properties., Areas Covered: The objective of this article is to summarize recent data regarding the efficacy, safety and pharmacokinetic properties of efinaconazole in the treatment of onychomycosis., Expert Opinion: Efinaconazole is a safe and effective treatment for onychomycosis that can be used in a wide range of patients due to its broad-spectrum antifungal activity and low rate of treatment-related adverse events. When incomplete response to oral therapy or devices (e.g. laser therapy) is encountered, efinaconazole could be used in combination to improve success rates. Alternatively, efinaconazole could be used as a 'closer' drug, in an effort to provide cure when the initial oral or device therapy has resulted in an incomplete response.

Background: Low selenium status in pregnancy has been associated with a number of adverse conditions. In nonpregnant populations, the selenium status or response to supplementation has been associated with polymorphisms in dimethylglycine dehydrogenase (DMGDH), selenoprotein P (SEPP1) and the glutathione peroxidases [cytosolic glutathione peroxidase (GPx1) and phospholipid glutathione peroxidase (GPx4)]., Objective: We hypothesized that, in pregnant women, these candidate polymorphisms would be associated with selenium status in early pregnancy, its longitudinal change, and the interindividual response to selenium supplementation at 60 μg/d., Design: With the use of stored samples and data from the United Kingdom Selenium in Pregnancy Intervention (SPRINT) study in 227 pregnant women, we carried out genetic-association studies, testing for associations between selenium status, its longitudinal change, and response to supplementation and common genetic variation in DMGDH (rs921943), SEPP1 (rs3877899 and rs7579), GPx1 (rs1050450) and GPx4 (rs713041). Selenium status was represented by the concentration of whole-blood selenium at 12 and 35 wk of gestation, the concentration of toenail selenium at 16 wk of gestation, and plasma glutathione peroxidase (GPx3) activity at 12 and 35 wk of gestation., Results: Our results showed that DMGDH rs921943 was significantly associated with the whole-blood selenium concentration at 12 wk of gestation (P = 0.032), which explained ≤2.0% of the variance. This association was replicated with the use of toenail selenium (P = 0.043). In unsupplemented women, SEPP1 rs3877899 was significantly associated with the percentage change in whole-blood selenium from 12 to 35 wk of gestation (P = 0.005), which explained 8% of the variance. In supplemented women, SEPP1 rs3877899 was significantly associated with the percentage change in GPx3 activity from 12 to 35 wk of gestation (P = 0.01), which explained 5.3% of the variance. Selenium status was not associated with GPx1, GPx4, or SEPP1 rs7579., Conclusions: In agreement with previous studies, we show that the genetic variant rs921943 in DMGDH is significantly associated with selenium status in United Kingdom pregnant women. Notably, our study shows that women who carry the SEPP1 rs3877899 A allele are better able to maintain selenium status during pregnancy, and their GPx3 activity increases more with supplementation, which suggests better protection from low selenium status. The SPRINT study was registered at www.isrctn.com as ISRCTN37927591.

Incorporation rates of the enantiomers of 3,4-methylenedioxymethamphetamine (MDMA) and its metabolite 3,4-methylenedioxyamphetamine (MDA) into hair and nails were investigated after controlled administration. Fifteen subjects without MDMA use received two doses of 125 mg of MDMA. Hair, nail scrapings, and nail clippings were collected 9-77 days after the last administration (median 20 days). Hair samples were analyzed in segments of 1- to 2-cm length. After chiral derivatization with N-(2,4-dinitro-5-fluorophenyl)-L-valinamide, MDMA and MDA diastereomers were analyzed by liquid chromatography-tandem mass spectrometry. Highest concentrations in hair segments corresponded to the time of MDMA intake. They ranged from 101 to 3200 pg/mg and 71 to 860 pg/mg for R- and S-MDMA, and from 3.2 to 116 pg/mg and 4.4 to 108 pg/mg for R- and S-MDA, respectively. MDMA and MDA concentrations in nail scrapings and clippings were significantly lower than in hair samples. There was no significant difference between enantiomeric ratios of R/S-MDMA and R/S-MDA in hair and nail samples (medians 2.2-2.4 for MDMA and 0.85-0.95 for MDA). Metabolite ratios of MDA to MDMA were in the same range in hair and nail samples (medians 0.044-0.055). Our study demonstrates that administration of two representative doses of MDMA was detected in the hair segments corresponding to the time of intake based on average hair growth rates. MDMA was detected in all nail samples regardless of time passed after intake. Comparable R/S ratios in hair and nail samples may indicate that incorporation mechanisms into both matrices are comparable.

Luliconazole (LLCZ), an imidazole derivative with a broad spectrum of potent antifungal activity especially for T. rubrum and T. mentagrophytes, is under development as a new drug for treatment of tinea unguium.　It is well known that curative effect of an antifungal agent in dermatophytosis is affected by the pharmacokinetics of an agent at the infection loci as well as its antifungal activity, but there is no report about the affinity of LLCZ to nail keratin. We studied LLCZ affinity to keratin powder prepared from healthy human nail and porcine hoof. The LLCZ adsorbed to keratin preparations was washed with phosphate buffer, and its concentration in the buffer supernatant was measured by HPLC. Antifungal titer of the supernatant was also biologically confirmed by disk diffusion assay. Adsorption rate of LLCZ was 80% or more, and LLCZ was gradually liberated into washing buffer. Cumulative liberation rate in 10 times repeated washing against initially adsorbed drug amount was 47.4% for keratin from human nail and was either 52.5% or 50.8% (depending on the LLCZ concentration) for keratin from porcine hoof. The supernatant showed antifungal potential to T. rubrum. These results indicate that LLCZ applied to the nail surface is fully adsorbed to nail keratin and gradually liberated from it. The nail keratin could function as drug reservoir to supply biologically active LLCZ to the nail tissue region of infection loci. The LLCZ delivered to the loci would exert its antifungal potential on tinea unguium. This study also suggests the versatility of porcine hoof powder as an alternative to human nail keratin preparation for non-clinical study.

Passive diffusion data for uncharged solutes in hydrated human nail plate are collected and compared to the predictions of two theories for diffusion of uncharged solutes in dense keratin matrices. Quantitative agreement between the experimental data and the theories examined is poor. Concerns with both the experiments and the theories are identified and discussed. It is evident from the analysis that magnitude of the experimental nail permeability data may be questioned, as may the extrapolation procedures used to estimate the properties of dense fiber arrays from more dilute systems. Despite these caveats, it can be inferred that the microstructure of the nail plate is more complex than that assumed in the described models. The influence of residual lipids is implicated. More rigorous experiments and theoretical analysis of mass transport in the nail plate system are warranted. Successful completion of these tasks could lead not only to better predictions of transungual drug delivery, but also to better models of skin permeability, if hydrated nail plate can indeed serve as a model for the corneocyte phase of (partially hydrated) stratum corneum.

This study demonstrates the potential of polymeric nanoparticles as drug reservoirs for sustained topical drug delivery into microneedle-treated human nail. Laser scanning confocal microscopy was used to image the delivery of a fluorescent model compound from nanoparticles into the nail. A label-free imaging technique, stimulated Raman scattering microscopy, was applied, in conjunction with two-photon fluorescence imaging, to probe the disposition of nanoparticles and an associated lipophilic 'active' in a microneedle-porated nail. The results provide clear evidence that the nanoparticles function as immobile reservoirs, sequestered on the nail surface and in the microneedle-generated pores, from which the active payload can be released and diffuse laterally into the nail over an extended period of time., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A rapid and simple analytical method for the quantification of uric acid (UA) in human fingernails by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection is described. UA was extracted from human fingernail samples at 90°C for 20min, then separated on an Inertsil ODS-2 column (250×4.6mm I.D., 5.0μm, GL Sciences) by isocratic elution using methanol: 74mM phosphate buffer (pH 2.2) 2:98 (v/v). An UV detector was used to monitor at 284nm. The results indicated that under optimized measurement conditions results were achieved within 8.0min, and a good linearity was achieved from the calibration curves (r(2)>0.9999) in the range of 1.0-10000ng; the limit of detection (S/N=3) was 2.0pg, the inter-day and intra-day assay precisions were all less than 0.46% and the mean recoveries (%) of the uric acid spiked in the human fingernail were 101.95%. The amounts of UA in the fingernails of healthy volunteers were determined., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The nail is a highly keratinized structure covering the tip of the digit, and considered to have several important functions in our daily life. In recent years, as biological aspects of the nail organ have been characterized, we realize that the nail unit and the hair follicle share various biological and immunological features. In particular, development and homeostasis of the nail unit also requires intimate epithelial-mesenchymal interactions that involve signaling pathways such as Wnt. There is also a striking immunological resemblance between both appendages, since the nail matrix, like the anagen hair bulb and the bulge, was shown to present unique characteristics of an immune privileged site. On the other hand, considerable progress in identifying nail stem cells has succeeded in locating putative stem cell niches in the nail unit. In this context, it is intriguing that nail stem cells residing in the nail matrix were recently shown to possess the ability to organize the process leading to digit regeneration. Further elucidation of signaling pathways governing epithelial-mesenchymal interactions in the nail unit seems to be a key to develop a novel therapeutic tool to treat amputees using nail epithelium. However, it is at least certain that the nail unit has a promising potential for the future of regenerative medicine. This review explores the biology of the nail organ by focusing on intriguing knowledge gained from recent studies., (Copyright © 2015 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Nail diseases are common, cause significant distress and treatments are far from successful. Our aim was to investigate the potential of UV-curable gels - currently used as cosmetics - as topical drug carriers for their treatment. These formulations have a long residence on the nail, which is expected to increase patient compliance and the success of topical therapy. The gels are composed of the diurethane dimethacrylate, ethyl methacrylate, 2-hydroxy-2-methylpropiophenone, an antifungal drug (amorolfine HCl or terbinafine HCl) and an organic liquid (ethanol or NMP) as drug solvent. Following its application to a substrate and exposure to a UVA lamp for 2 min, the gel polymerises and forms a smooth, glossy and amorphous film, with negligible levels of residual monomers. No drug-polymer interactions were found and drug loading did not affect the film's properties, such as thickness, crystallinity and transition temperatures. In contrast, the organic solvent did influence the film's properties; NMP-containing films had lower glass transition temperatures, adhesion and water resistance than ethanol-based ones. Water-resistance being a desired property, ethanol-based formulations were investigated further for stability, drug release and ungual permeation. The films were stable under accelerated stability testing conditions. Compared to terbinafine, amorolfine was released to a greater extent, had a higher ungual flux, but a lower concentration in the nailplate. However, both drugs were present at considerably high levels in the nail when their MICs are taken into account. We thus conclude that UV-curable gels are promising candidates as topical nail medicines., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Transungual nail penetrance has traditionally been considered to be the only route of delivery for topical antifungals in onychomycosis. Subungual penetrance may be an alternate route of delivery., Objective: To evaluate the ability of efinaconazole vehicle solution to reach the site of toenail onychomycosis through application to the hyponychium or hyponychium and dorsal nail surface, and assess the impact of the air gap between the nail plate and nail bed., Methods: Twenty-three participants with moderate to severe, mycologically-confirmed onychomycosis were enrolled (mean age, 48.5 years). Two separate applications of vehicle solution containing fluorescein for visualization were applied at the hyponychium or hyponychium and dorsal nail surface. Affected nails were later clipped to allow examination of the nail bed and further examination of the ventral surface of the nail. Spread of formulation was assessed under visible and UV light conditions by photographing target toenails after vehicle application and after nail clipping., Results: There was a positive correlation between the size of the air gap and degree of affected nail involvement (R2=0.064). Assessments under both visible and UV light indicated that the vehicle had spread to the site of infection, with deposition of fluorescein wherever vehicle had reached, irrespective of application methodology or size of air gap. Nail clippings also indicated absorption into the ventral surface of the nail plate., Limitations: The relative contributions of subungual versus transungual application of drug to the nail plate to the efficacy of efinaconazole topical solution, 10% in treating onychomycosis were not assessed., Conclusions: This study suggests that the low surface tension vehicle developed for efinaconazole topical solution, 10% can reach the site of infection by application to the hyponychium, dorsal or ventral nail surface and nail folds. This multidirectional approach to drug delivery at the site of fungal infection may contribute to the magnitude of efficacy seen in clinical trials.

Background: Onychomycosis is a common infection of the toenails that causes nail thickening and discoloration. The physical appearance of the infected nail can diminish self-image and negatively impact quality of life. Patients may use nail polish to mask the appearance of infected nails., Objective: To evaluate the in vitro nail penetration properties of tavaborole topical solution, 5%, through nail polish using ex vivo, non-diseased human fingernails., Methods: In study 1, tavaborole penetration was evaluated over 20 days of dosing using the Franz finite dose technique and modified Franz diffusion cells. Nails received either 1 coat of over-the-counter (OTC) typical polish or were left unpolished (controls). In study 2, tavaborole penetration was measured over 14 days of dosing using the finite dose technique and vertical diffusion cells. Nails were polished with either 4 coats or 1 coat of salon typical polish or with 2 coats or 1 coat of OTC typical polish, or they were left unpolished., Results: In study 1, the mean ± standard deviation (SD) cumulative tavaborole penetration at day 21 was numerically higher, though not statistically significant, through polished nails (3,526 ± 1,433 μg/cm(2))vs unpolished nails (2,661 ± 1,319 μg/cm(2)).In study 2, the mean cumulative tavaborole penetration was also numerically higher (statistical significance not assessed) through all nails that received polish vs unpolished nails. At day 15, mean ± SD cumulative tavaborole nail penetration was 1,179 ± 554 μg/cm(2) through 4 coats of salon typical polish, 1,227 ± 974 μg/cm(2) through 1 coat of salon typical polish, 1,493 ± 1,322 μg/cm(2) through 2 coats of OTC typical polish, 1,428 ± 841 μg/cm(2) through 1 coat of OTC typical polish, and 566 ± 318 μg/cm(2) through unpolished nails., Conclusion: Results from these in vitro studies demonstrated that tavaborole penetrated through human nails with up to 4 layers of nail polish.

An effective topical antifungal medication must penetrate through the nail plate at sufficient concentrations to eradicate the fungal infection. Tavaborole topical solution, 5% is a novel boron-based pharmaceutical approved for the treatment of toenail onychomycosis due to Trichophyton rubrum or T mentagrophytes. Four in vitro studies assessed the antifungal activity and nail penetration of tavaborole. In Study 1, tavaborole demonstrated minimum inhibitory concentration (MIC) values ranging from 0.25-2 μg/mL against all fungi tested; addition of 5% keratin powder did not affect the MIC against T rubrum. The minimum fungicidal concentration (MFC) values for tavaborole against T rubrum and T mentagrophytes were 8 and 16 μg/mL, respectively. In Study 2, tavaborole effectively penetrated through the nail plate; mean concentrations in the ventral/intermediate nail layer were significantly higher than ciclopirox at day 15. In Study 3, mean cumulative tavaborole penetration through ex vivo human nails was significantly higher than ciclopirox at day 15. In Study 4, tavaborole demonstrated superior nail penetration and fungicidal activity, as measured by zones of inhibition. These studies demonstrated the superior penetration of tavaborole through the nail plate vs ciclopirox. Tavaborole demonstrated robust antifungal activity, with low MIC and MFC values, even in the presence of keratin.

Purpose: Through the characterisation of the human onchomycotic nail plate this study aimed to inform the design of new topical ungual formulations., Methods: The mechanical properties of the human nail were characterised using a Lloyd tensile strength tester. The nail's density was determined via pycnometry and the nail's ultrastructure by electron microscopy. Raman spectroscopy analysed the keratin disulphide bonds within the nail and its permeability properties were assessed by quantifying water and rhodamine uptake., Results: Chronic in vivo nail plate infection increased human nailplate thickness (healthy 0.49 ± 0.15 mm; diseased 1.20 ± 0.67 mm), but reduced its tensile strength (healthy 63.7 ± 13.4 MPa; diseased 41.7 ± 5.0 MPa) and density (healthy 1.34 ± 0.01 g/cm(3); diseased 1.29 ± 0.00 g/cm(3)). Onchomycosis caused cell-cell separation, without disrupting the nail disulfide bonds or desmosomes. The diseased and healthy nails showed equivalent water uptake profiles, but the rhodamine penetration was 4-fold higher in the diseased nails using a PBS vehicle and 3 -fold higher in an ethanol/PBS vehicle., Conclusions: Onchomycotic nails presented a thicker but more porous barrier, and its eroded intracellular matrix rendered the tissue more permeable to topically applied chemicals when an aqueous vehicle was used.

Neoplasms originating from nail matrix keratinocytes are very rare. Onychomatricoma and onychocytic matricoma are benign tumors arising from nail matrix keratinocytes. Only one case of onychocytic carcinoma, the malignant counterpart of onychocytic matricoma, has been reported in the literature. Herein, we describe a case of invasive onychocytic carcinoma. Two biopsy specimens of the tumor, obtained at early and invasive stages, were examined histopathologically. The first biopsy specimen showed a retiform proliferation of eosinophilic and basophilic cells in the nail matrix. The second biopsy specimen showed a retiform basophilic cell proliferation with focal keratinization. Similar to normal nail matrix keratinocytes, the proliferating basophilic cells failed to express cytokeratin (CK)1, CK6 and CK10. Focal expression of hair-specific keratins, including K31, K85 and K86, was observed. On the basis of these findings, the tumor was identified as an invasive malignant tumor originating from nail matrix keratinocytes., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The cortisol level in fingernails may reflect the hormone's cumulative production over a long period, but the notions have not been fully established. In this study, we investigated the association of cortisol in fingernails with cortisol accumulation over a long period (hair cortisol) and over a relatively short period (salivary cortisol). In study 1, hair and fingernail samples were collected from 58 middle-aged and elderly men. The cortisol level in hair samples was moderately associated with the level in fingernail samples (r = 0.29, p < 0.05 and rs = 0.36, p < 0.01). In study 2, 37 workers provided 4 saliva samples over the course of one day (at awakening, 30 min after awakening, before lunch, and after work) and another set a month later. Further, the workers were asked to provide fingernail samples during a six-month period. We found that the cortisol level in saliva over the whole day (area under the curve for cortisol) was moderately associated with the cortisol level measured in fingernail samples that were collected 4 months (r = 0.43, p < 0.05 and rs = 0.50, p < 0.01) and 5 months later (r = 0.45, p < 0.05 and rs = 0.53, p < 0.01). These results indicated that the cortisol level in fingernail samples might retrospectively represent hormone production during a given period. The cortisol level in fingernail samples may be useful in the investigation of the link between psychosocial stress and health., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Although assessment of glycated nail proteins may be a useful marker for monitoring of diabetes, their nature and formation are still poorly understood. Besides a detailed anatomical analysis of keratin glycation, the usefulness of glycated nail protein assessment for monitoring diabetic complications was investigated., Methods: 216 patients (94 males, 122 females; mean age ± standard deviation: 75.0 ± 8.7 years) were enrolled. Glycation of nail and eye lens proteins was assessed using a photometric nitroblue tetrazolium-based assay. Following chromatographic separation of extracted nail proteins, binding and nonbinding fractions were analyzed using one-dimensional gel electrophoresis. Using a hand piece containing a latch-type-bur, a meticulous cutting of the nail plate into superficial and deep layers was performed, followed by a differential analysis of fructosamine., Results: Using SDS PAGE, four and two bands were identified among the nonglycated and glycated nail fraction respectively. Significantly lower fructosamine concentrations were found in the superficial nail layer (mean: 2.16 ± 1.37 μmol/g nails) in comparison with the deep layer (mean: 4.36 ± 2.55 μmol/g nails) (P<0.05). A significant higher amount of glycated eye lens proteins was found in diabetes mellitus patients (mean: 3.80 ± 1.57 μmol/g eye lens) in comparison with nondiabetics (mean: 3.35 ± 1.34 μmol/g eye lens) (P<0.05). A marked correlation was found between glycated nail and glycated eye lens proteins [y (glycated nail proteins) = 0.39 + 0.99 x (eye lens glycated proteins); r2 = 0.58, P<0.001]. The concentration of glycated eye lens proteins and the HbA1c level were found to be predictors of the concentration of glycated nail proteins., Conclusions: Glycation of nail proteins takes place in the deep layer of finger nails, which is in close contact with blood vessels and interstitial fluid. Glycation of nail proteins can be regarded as a representative marker for diabetic glycation-associated target organ damage.

The etiology of cancer is complex, and the disturbances in toxic and essential metals homeostasis are among many of the factors that lead to the development of malignancy. The aim of this study is to investigate the relationship between cancer risk and element status as well as cancer risk and external factors, such as diet, smoking and drinking habits, in order to support diagnosis of cancer. The samples of hair and nails obtained from patients with larynx cancer and healthy subjects were analyzed. Essential elements (Ca, Cr, Mg, Zn, Cu, Mn, and Fe), besides toxic metals (Cd, Co, and Pb), were determined using inductively coupled plasma atomic emission spectrometry (ICP-OES) and mass spectrometry (ICP-MS) techniques. The concentration of essential elements was from 1.5- (Zn) to 4.7-fold (Fe) higher in hair and from 2.4- to 3.3-fold higher in the nails of the control group compared to the patients, while the opposite trend was observed for the heavy metals. The differences between two groups in the level of metals (except for Zn) were statistically significant (p < 0.05). The association of cancer with metals and other factors was evaluated using various statistical methods, for which the best predictions were obtained using logistic regression, artificial neural networks and canonical discriminant analysis. The classifiers constructed using the data from a survey of diet and lifestyle, and analysis of elements in hair and nails, can be useful tools for estimating cancer risk and early screening of the disease.

The project was aimed at development of isotretinoin nail lacquer and assessment of its penetration efficiency across human nail plate. Preliminary studies (hydration enhancement factor and SEM) aided the selection of thioglycolic acid as permeation and eugenol was selected as local anesthetic in the formulation. The nail lacquer was optimized by 3(2) factorial design and a total of nine formulations were prepared and screened. In vitro adhesion and ex vivo permeation (cumulative drug permeation per unit area (CDP/A) = 6.61 ± 0.57 mg/cm(2)) across bovine hoof guided the selection of F3 as optimized formulation that was improvised. Viscosity adjustments to improve handling characteristics were affected by incorporation of ethyl cellulose (6%; F3M1) that scaled the viscosity to 312.681 cp and insignificantly (p > 0.05) affected CDP/A (6.32 ± 0.45 mg/cm(2)). In comparison to marketed preparation (Retino-A cream) F3M1 afforded two fold increase in CDP/A. The permeation characteristics were defined by Higuchi model (r(2) = 0.964) and flux value of 176 μg/cm(2)/h. Confocal laser scanning microscopy, after 72 h of nail lacquer application, revealed extensive distribution of the fluorescent tracer across the human nail plate in comparison to control that was confined to the top layer. Conclusively, an efficacious and stable nail lacquer of isotretinoin was developed for potential clinical topical use to target the drug to nail bed in treatment of nail psoriasis., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Epidemiologic studies, particularly randomized controlled trials, have shown a direct relation between dietary and environmental exposure to the metalloid selenium and risk of type 2 diabetes. We investigated the association between baseline toenail selenium levels and diabetes occurrence in a case-control study nested in ORDET, a population-based female cohort in Northern Italy. After a median follow-up of 16 years, we identified 226 cases of type 2 diabetes cases and 395 age-matched control women with available toenail samples at baseline. The multivariate odds ratios of diabetes in increasing a priori defined categories of toenail selenium exposure were 1.09 (95% confidence interval 0.61, 1.96), 0.71 (0.38, 1.34) and 1.14 (0.46, 2.80) compared with the lowest category. The results were not substantially altered when quartile distribution of toenail selenium in controls was used to define exposure categories. Spline regression analysis did not show homogeneous risk trends. Overall, we did not find an association between toenail selenium and subsequent development of diabetes. Since the diabetogenic activity of selenium is strongly supported by experimental studies and some observational investigations, our null results might be explained by the limitations of overall selenium toenail content to assess environmental exposure to selenium species of etiologic relevance in the study population., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Toenail is metabolic end product of the skin, which can provide information about heavy metal accumulation in human cells. Slow growth rates of toenail can represent heavy metal exposure from 2 to 12 months before the clipping. The toenail is a non-invasive biomarker that is easy to collect and store and is stable over time. In this systematic review, the suitability of toenail as a long-term biomarker was reviewed, along with the analysis and validation of toenail and confounders to heavy metal. This systematic review has included 30 articles chosen from a total of 132 articles searched from online electronic databases like Pubmed, Proquest, Science Direct, and SCOPUS. Keywords used in the search included "toenail", "biomarker", "heavy metal", and "drinking water". Heavy metal in toenail can be accurately analyzed using an ICP-MS instrument. The validation of toenail heavy metal concentration data is very crucial; however, the Certified Reference Material (CRM) for toenail is still unavailable. Usually, CRM for hair is used in toenail studies. Confounders that have major effects on heavy metal accumulation in toenail are dietary intake of food and supplement, smoking habit, and overall health condition. This review has identified the advantages and limitations of using toenail as a biomarker for long-term exposure, which can help future researchers design a study on heavy metal exposure using toenail.

Itraconazole (ITR) is a potent antifungal drug. However, poor aqueous solubility limits its permeation ability across the human nail plate. Therefore, in this project, ITR was converted to hydrochloride salt (ITR-HCl) to improve its solubility and to render it amenable to iontophoresis. ITR-HCl was characterized by spectroscopic methods and antifungal efficacy was evaluated in comparison to the base. In vitro and ex vivo transport studies (passive and iontophoresis) were carried out across the porcine hoof membrane and excised human cadaver toe using two different protocols; continuous delivery of drug for 24 h and pulsed delivery of drug for 3 days (8 h/day). The antifungal efficacy of ITR-HCL was comparable to ITR. Iontophoresis was found to be more effective than passive mode of delivery of ITR-HCL. In both iontophoresis as well as passive mode of delivery, the pulsed protocol resulted in more ungual and trans-ungual delivery of drug than continuous protocol. ITR-HCL could be delivered into and across the nail plate by iontophoresis. Human cadaver toe appears to be a good model to investigate the ungual delivery of drugs.

Objective: The main objective of this study is to develop a safer non-invasive treatment for nail infections since the current treatment regimen has drawbacks like, incidence of systemic side-effects and higher cost. Proposed topical treatment on the other hand can drastically improve the situation, hence highly desirable. This work was undertaken with a hypothesis to develop a transungual microemulsion gel for topical treatment of onychomycosis., Methods: Benzyl alcohol and isopropyl myristate were used as oil, Pluronic F68 as surfactant and ethanol as co surfactant, in double-distilled water and loading itraconazole as the model antifungal drug. Pseudo-ternary phase diagram was developed by titrating different ratios of total oil and water with total surfactant, and Km ratio was fixed at 1:1. Microemulsion formulations were prepared based on the phase diagram and incorporated in gels by adding Carbopol 934P. Nail permeation enhancers like urea and salicylic acid were used to increase drug permeation through the nail plate. Parameters like drug loading, clarity, particle size distribution, drug entrapment efficiency (DEE), drug release profile, release kinetics and nail uptake were checked for the evaluation of the formulations., Results: Complete release of drug from the formulation varied from 60 to 120 min. The optimized formulation had DEE of 92.75%, complete drug release in 60 min and highest nail uptake of 0.386%/mm(2) (39 µg of drug) with 5% urea as nail permeation enhancer., Conclusion: The formulation may prove beneficial in safer treatment of onychomycosis.

The main objective of the current work is to demonstrate the process of passive lateral diffusion in the human nail plate and its effect on the passive transungual permeation of antifungal drug ciclopirox olamine (CPO). A water soluble dye, methyl red sodium salt (MR) was used to visualize the process of lateral diffusion using a novel suspended nail experiment. The decline in concentration of CPO correlates with that of concentration of MR from the proximal to the distal end of the nail in suspended nail study. Three toenails each were trimmed to 5 mm × 5 mm (25 mm(2)), 7 mm × 7 mm (49 mm(2)), and 9 mm × 9 mm (81 mm(2)) to study the extent and effect of lateral diffusion of the CPO on its in vitro transungual permeation. The permeation flux of CPO decreased as the surface area of the toenail increased. There was a positive correlation between the concentrations of CPO and MR in the area of application and in the peripheral area of the toenails of the three surface areas, confirming the findings in the suspended nail experiment. Profound lateral diffusion of CPO was demonstrated and shown to reduce the in vitro passive transungual drug permeation and prolong the lag-time in human toenails. The study data implies that during passive in vitro transungual permeation experiments, the peripheral nail around the area of drug application has to be kept to a minimum, in order to get reliable data which mimics the in vivo situation.

Human populace of Assam, India repeatedly exposed to high concentration of iron in groundwater results in adverse health effects like hemochromatosis, liver cirrhosis and siderosis. In the present study, human hair and nail analysis were carried out to establish a possible relationship between iron toxicity and its deposition among the residents. Nail and hair iron concentrations ranged from 28.2 to 1046μgg(-1) (n=114) and 26.5-838 (n=108)μgg(-1) levels, respectively, among all the study participants. The iron content of the groundwater (421-5340μgL(-1)) (n=64) used for drinking purposes was positively correlated with both nail (r=0.788, p<0.0001) and hair (r=0.709, p<0.0001) iron concentrations. Age- and sex-matched controls corresponding to each group were selected from population residing in other parts of the country where groundwater does not have excess iron. All the study groups included population drinking iron-contaminated water above the WHO/BIS limit (>300µgL(-1)) for 5 years (Group 1), for more than 5-10 years (Group 2) and for more than 10 years (Group 3). Results suggested that the participants consuming groundwater exceeding the WHO limit of iron had significantly more iron accumulation than those using groundwater containing ≤300μgL(-1) iron (p<0.01). There was statistically higher concentration of iron in the nail samples than the hair samples in all the study groups (p<0.01). There was a positive correlation in iron concentration and the residence time of the participants (p<0.01). Iron levels in the male participants were significantly higher than the female participants in the present study (p<0.01). The current findings are sufficiently compelling to warrant more extensive study of iron exposure through drinking water and adverse effects to the human in the areas where iron concentration is high., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Onychomycosis is a very common nail disorder seen in dermatological practice. It is difficult to treat successfully for a multitude of reasons, and although topical antifungal therapy might be considered ideal for mild to moderate onychomycosis, efficacy has been limited by poor nail penetration of active ingredient through the nail plate into the nail bed and nail matrix to the site of infection. The intrinsic properties of an antifungal and its vehicle formulation are both considered important contributors to effective treatment. Here we review the formulation approach to efinaconazole topical solution, 10% an effective and well-tolerated treatment for onychomycosis. We demonstrate that the low surface tension formulation affords better penetration of efinaconazole through the nail plate, and also to the site of infection by spreading into the space between the nail and nail bed.

Objective: To evaluate the ability of efinaconazole vehicle to reach the site of toenail onychomycosis by spreading through the subungual space between the nail plate and nail bed. Lacquer-based vehicles are primarily limited to application on the nail plate and dependent on nail plate permeation., Methods: 11 patients (mean age 48.5 years) were entered with clinically determined onychomycosis. Presence of fungal infection was confirmed by KOH testing in eight patients. Two separate applications of vehicle (with fluorescein incorporated for better visualization) were applied at the hyponychium, avoiding application to the exterior nail plate surface. Affected nails were later clipped to allow examination of the nail bed and further examination of the underside of the nail. Spread of formulation was assessed under visible and UV light conditions by photographing target toenails after vehicle application, and after nail clipping., Results: Assessments under both visible and UV light indicated that the vehicle had spread into the subungual space, with deposition of flourescein wherever vehicle had reached, including in the nail bed. Nail clippings also indicated deposition to the underside of the nail plate., Limitations: The relative contributions of spreading into the subungual space, or permeation through the nail plate to the efficacy of efinaconazole topical solution, 10% in treating onychomycosis were not assessed., Conclusions: This study suggests that the vehicle developed for efinaconazole topical solution, 10%, when applied at the hyponychium, spreads into the subungual space between the nail plate and nail bed, reaching the site of infection.

Objectives: The aim of this study was to investigate the associations between plasma total antioxidant capacity (TAC) and anthropometric, biochemical, clinical, and dietary measurements in young and apparently healthy individuals., Methods: We evaluated 156 individuals (91 women and 65 men; ages 23.1 ± 3.5 y; body mass index 22 ± 2.9 kg/m(2)) for anthropometrics, biochemical markers, clinical, dietary, and some components of the antioxidant defense system, including the plasma TAC. Statistical analyses were performed to detect differences between individuals with TAC higher and lower than the mean value and to screen the associations between TAC and variables of interest. A linear regression model was fitted to identify TAC predictors., Results: Daily caloric intake and macronutrient consumption were lower in individuals who exhibited the highest TAC values (P < 0.05). Linear regression analysis showed that daily calories and carbohydrate intake was a possible negative TAC predictor (P < 0.05). Nevertheless, there was no difference in the values of oxidized low-density lipoprotein in the individuals separated by means of TAC. In contrast, individuals whose plasma TAC values were above the mean showed higher low-density lipoprotein cholesterol concentrations, total cholesterol/high-density lipoprotein cholesterol values, and selenium in nails (P < 0.05)., Conclusions: In physiological conditions, the caloric intake level seems to be an important factor to act in the modulation of plasma TAC, before establishing anthropometric impairments of body or metabolic composition, or both. Additionally, the plasma TAC increase may be able to act as a compensatory mechanism., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Fast and precise retrospective dosimetry is crucial in making decisions about medical procedures and safety measures in radiation accidents. Electron paramagnetic resonance (EPR) spectroscopy has a potential as one of available biodosimetry methods for use in victims of such incidents. In this study, authors present the findings on EPR dosimetry in fingernails. Authors describe changes of EPR signals in unirradiated and irradiated nails in time after cutting and the effect of water on the mechanically induced and radiation-induced EPR signals measured ex vivo in the fingernails. The effect of dose on amplitude of the EPR signal was measured in nails that were soaked for 10 min in water after their irradiation. The obtained dose-response curves, which reflect changes in concentration of the radiation-induced RIS5 radicals, reach their maximum for doses of 40-60 Gy., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Effective transungual delivery of topical antifungal agents in onychomycosis has been hampered by poor nail permeation. To be effective they must have antifungal efficacy, and effectively permeate through the dense keratinized nail plate to the site of infection in the nail bed and nail matrix. The therapeutic efficacy of efinaconazole topical solution, 10% has been established in two phase 3 clinical trials in distal lateral subungual onychomycosis., Objective: To investigate the transungual delivery of efinaconazole in onychomycosis patients and its fungicidal activity in the toenail., Methods: Concentrations of efinaconazole were determined as part of a multi-center, open label study in forty onychomycosis patients following repeated application of efinaconazole topical solution, 5% and 10% to the toenails over 28 days, with a 2-week follow-up. Fungicidal activity against T. rubrum in the ventral layer of human nails was determined using an in vitro human nail infection model (ChubTur®)., Results: Efinaconazole concentrations in the nail were four orders of magnitude higher than MIC values of efinaconazole against dermatophytes. Further, nail drug concentrations were not influenced by the presence of disease or nail thickness, and maintained at high antifungal levels post-treatment. Efinaconazole was effective in reducing fungal viability, suggesting that sufficient amounts of efinaconazole were being delivered into the ventral layer of the nail plate.
, Conclusions: Effective transungual delivery of efinaconazole was demonstrated. The high efinaconazole concentrations in patient toenails and fungicidal activity in vitro potentially contribute to the clinical efficacy reported in phase 3 studies.

S100 fused-type proteins (SFTPs) such as filaggrin, trichohyalin, and cornulin are differentially expressed in cornifying keratinocytes of the epidermis and various skin appendages. To determine evolutionarily conserved, and thus presumably important, features of SFTPs, we characterized nonmammalian SFTPs and compared their amino acid sequences and expression patterns with those of mammalian SFTPs. We identified an ortholog of cornulin and a previously unknown SFTP, termed scaffoldin, in reptiles and birds, whereas filaggrin was confined to mammals. In contrast to mammalian SFTPs, both cornulin and scaffoldin of the chicken are expressed in the embryonic periderm. However, scaffoldin resembles mammalian trichohyalin with regard to its expression in the filiform papillae of the tongue and in the epithelium underneath the forming tips of the claws. Furthermore, scaffoldin is expressed in the epithelial sheath around growing feathers, reminiscent of trichohyalin expression in the inner root sheath of hair. The results of this study show that SFTP-positive epithelia function as scaffolds for the growth of diverse skin appendages such as claws, nails, hair, and feathers, indicating a common evolutionary origin.

Asthma is a multifactorial disease and its severity varies with the inflammatory status of the patient. It has been hypothesized that deficiency of trace elements has an important role in the etiology of asthma. The aim of the study was to evaluate the concentration of trace elements in nails of adolescents with different degrees of airway inflammation. We assessed the prevalence of active and severe asthma in adolescents (n = 106) through the ISAAC questionnaire. Subjects were allocated into two different groups according to the value of fraction exhaled nitric oxide (FeNO) measured. Also, nail specimens were collected in order to determine the concentration of accumulated trace elements (Cu, Zn, Mn, Se) by ICP-MS. It was performed Student's t test to evaluate statistical differences between inflammatory groups considering normally distributed data. On the other hand, when data presented non-normal distribution, Mann-Whitney U test was utilized. Spearman coefficients were calculated to investigate correlations between FeNO and mineral concentrations. Exhaled NO was increased in male subjects. We found association between active asthma and elevated exhaled NO. There was no significant difference in Cu (4.40 vs. 4.52), Zn (84.66 vs. 79.48), Mn (0.59 vs. 0.76), and Se (0.18 vs. 0.19) concentrations (μg/g) among distinct FeNO groups as well as was not observed correlation between exhaled NO levels and any element. Deficiency of trace elements in nails were not associated with increased FeNO.

Background: Sertoli-Leydig cell tumor (SLCT) is a rare sex-cord tumor that usually occurs unilaterally and accounts for < 0.5% of all ovarian tumors. SLCT is uncommon in post-menopausal women, with the average age of diagnosis being 25 years., Case: We present a case of a 63-year-old post-menopausal woman presenting with progressive hirsutism, and male-pattern baldness. Unusual nail changes were also observed., Methods: Hormonal profile of the patient revealed increased testosterone and estradiol levels, and a 3.5 cm left ovarian mass. The patient was evaluated and was not found to be anemic or iron-deficient. Intraoperative frozen section assessment during laparoscopic exploration revealed SLCT, which was confirmed subsequently by histopathological and immunohistochemical (IHC) examination. Nail bed tissues were collected from normal females and evaluated by IHC for the presence of androgen receptors (AR)., Results: The patient had an excellent postoperative course and all her testosterone-related manifestations were reversed within one year of surgery. Following surgery, the patient's unique nail abnormalities also resolved gradually. The IHC evaluation also confirmed the presence of AR in nail bed tissues of females., Conclusion: SLCT, albeit rare, should be considered in post-menopausal women presenting with virilization and elevated androgen levels. Unusual nail signs may develop in response to increased androgen levels in these patients.

Onychomycosis is a common fungal nail disease that is difficult to treat topically due to the deep location of the infection under the densely keratinized nail plate. Keratin affinity of topical drugs is an important physicochemical property impacting therapeutic efficacy. To be effective, topical drugs must penetrate the nail bed and retain their antifungal activity within the nail matrix, both of which are adversely affected by keratin binding. We investigated these properties for efinaconazole, a new topical antifungal for onychomycosis, compared with those of the existing topical drugs ciclopirox and amorolfine. The efinaconazole free-drug concentration in keratin suspensions was 14.3%, significantly higher than the concentrations of ciclopirox and amorolfine, which were 0.7% and 1.9%, respectively (P < 0.001). Efinaconazole was released from keratin at a higher proportion than in the reference drugs, with about half of the remaining keratin-bound efinaconazole removed after washing. In single-dose in vitro studies, efinaconazole penetrated full-thickness human nails into the receptor phase and also inhibited the growth of Trichophyton rubrum under the nail. In the presence of keratin, efinaconazole exhibited fungicidal activity against Trichophyton mentagrophytes comparable to that of amorolfine and superior to that of ciclopirox. In a guinea pig onychomycosis model with T. mentagrophytes infection, an efinaconazole solution significantly decreased nail fungal burden compared to that of ciclopirox and amorolfine lacquers (P < 0.01). These results suggest that the high nail permeability of efinaconazole and its potent fungicidal activity in the presence of keratin are related to its low keratin affinity, which may contribute to its efficacy in onychomycosis., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Introduction: Onychomycosis causes approximately one-half of all nail disorders and its prevalence has been steadily increasing. It is difficult to treat, partly due to the subungual location and the inability of both oral and topical antifungals to reach the site of infection. Published cure rates with oral drugs are < 50% and even lower with topical drugs. Pathogenic factors include the diversity of fungal organisms and the difficulty of drugs penetrating the nail plate. Tavaborole is a broad-spectrum oxaborole antifungal agent with low molecular weight, permitting optimal nail plate penetration. In vitro and ex vivo studies have demonstrated the superior nail-penetrating properties of tavaborole compared to existing topical antifungal medications approved for the treatment of onychomycosis., Areas Covered: The clinical characteristics and prevalence of onychomycosis, currently available treatments, and the chemistry, safety and pharmacokinetic properties of tavaborole for the treatment of onychomycosis., Expert Opinion: Tavaborole is a novel, topical antifungal pharmaceutical agent pending FDA approval for the treatment of toenail onychomycosis due to dermatophytes. Efficacy has been demonstrated by a clinical development program including in vitro data and two large Phase III trials that enrolled ∼ 1200 patients. When approved, tavaborole topical solution, 5% may become a safe and effective option for the treatment of onychomycosis.

The availability of high-quality germline DNA is an important prerequisite for a variety of genetic analyses. We have shown previously that fingernail clippings provide an optimal source of autologous, constitutional DNA for PCR-based applications. However, most existing protocols for nucleic acid purification from nails do not provide sufficiently high yields of pure and intact DNA for more demanding downstream analyses such as next generation sequencing (NGS). We have extensively tested and systematically modified a number of different protocols for DNA purification from nail material to optimize the yield and quality. The integrity of DNA was determined by PCR amplification of short (<300 bp), mid-range (>400 bp), and long-range (>2 kb) sequences using different target genes. Among the methods tested, the Prepfiler Forensic DNA Extraction kit was identified as the most appropriate approach to isolation of high-quality DNA from nail clippings. A standardized input of 20 mg nail material (1 to 10 pieces of fingernail clippings) yielded a mean of 1 μg DNA (range, 0.5 to 2.3 μg). Subsequent PCR-analysis revealed efficient amplifiability of short and mid-range targets in 93% and 90%, and long-range fragments in 60% of the samples tested. The adequacy for next generation sequencing applications was demonstrated by successful high-resolution HLA-typing in ten transplant recipients. Hence, the protocol presented facilitates the exploitation of fingernail material even for demanding genomic analyses both in research and diagnostics., (Copyright © 2014 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Context: Onychomycosis is a common fungal infection of the nail plate and bed that affects up to 14% of the population and can have a substantial impact on the quality of life of those affected., Objective: This study compared the onychopharmacokinetics, nail absorption, nail distribution, and nail penetration of [(14)C]-ciclopirox dissolved in novel lipid diffusion enhancers with that of a commercial ciclopirox nail lacquer using the in vitro finite dose model., Materials and Methods: The penetration rate of ciclopirox was determined by applying doses of topical formulation twice daily to human nail plates for 11 d. Drug absorption was then measured by monitoring its rate of appearance in each nail layer and in the cotton pad/nail supporting bed., Results: After a multiple day treatment, cumulative concentrations of ciclopirox formulated with lipid enhancers in the deep nail layer and the nail bed were significantly greater than cumulative concentrations of the commercial ciclopirox lacquer (p < 0.001) as well as several orders of magnitude greater than the minimal inhibitory concentration (MIC) deemed necessary to inhibit the growth of the causative dermatophyte species., Conclusion: When formulated with lipid enhancers, the amount of ciclopirox in the ventral/intermediate layer and supporting bed dramatically exceed the inhibitory concentration of ciclopirox for the most common onychomycosis organisms. These results suggest that topical ciclopirox with lipid enhancers has the potential to be an effective topical treatment for onychomycosis, and the lipidic pathway of the nail can be utilized as a means of effective transungual delivery.

Until very recently, analysis of bone biopsies by means of the method of electron paramagnetic resonance (EPR) collected after surgery or amputation has been considered as the sole reliable method for radiation dose assessment in hands and feet. EPR measurements in finger- and toenail have been considered for accident dosimetry for a long time. Human nails are very attractive biophysical materials because they are easy to collect and pertinent to whole body irradiation. Information on the existence of a radiation-induced signal in human nails has been reported almost 25 years ago. However, no practical application of EPR dosimetry on nails is known to date because, from an EPR perspective, nails represent a very complex material. In addition to the radiation-induced signal (RIS), parasitic and intense signals are induced by the mechanical stress caused when collecting nail samples (mechanically induced signals-MIS). Moreover, it has been demonstrated that the RIS stability is strongly influenced not only by temperature but also by humidity. Most studies of human nails were carried out using conventional X-band microwave band (9 GHz). Higher frequency Q-band (37 GHz) provides higher spectral resolution which allows obtaining more detailed information on the nature of different radicals in human nails. Here, we present for the first time a complete description of the different EPR signals identified in nails including parasitic, intrinsic and RIS. EPR in both X- and Q-bands was used. Four different MIS signals and five different signals specific to irradiation with ionizing radiation have been identified. The most important outcome of this work is the identification of a stable RIS component. In contrast with other identified (unstable) RIS components, this component is thermally and time stable and not affected by the physical contact of fingernails with water. A detailed description of this signal is provided here. The discovery of stable radiation-induced radical(s) associated with the RIS component mentioned opens a way for broad application of EPR dosimetry in human nails. Consequently, several recent dosimetry assessments of real accident cases have been performed based on the described measurements and analyses of this component.

The penetration behavior into human nails and animal hoof membranes of a novel antifungal agent (EV-086K) for the treatment of onychomycosis was investigated in this study. The new drug provides a high lipophilicity which is adverse for penetration into nails. Therefore, four different formulations were developed, with particular focus on a colloidal carrier system (CCS) due to its penetration enhancing properties. On the one hand, ex vivo penetration experiments on human nails were performed. Afterwards the human nail plates were cut by cryomicrotome in order to quantify the drug concentration in the dorsal, intermediate and ventral nail layer using high-performance liquid chromatography (HPLC) with UV detection. On the other hand, equine and bovine hoof membranes were used to determine the in vitro penetration of the drug into the acceptor compartment of an online diffusion cell coupled with Fourier transform infrared attenuated total reflectance (FTIR-ATR) spectroscopy. In combination, both results should exhibit a correlation between the EV-086K penetration behavior in human nail plates and animal hoof membranes. The investigations showed that the developed CCS could increase drug delivery through the human nail most compared to other formulations (nail lacquer, solution and hydrogel). Using animal hooves in the online diffusion cell, we were able to calculate pharmacokinetic data of the penetration process, especially diffusion and permeability coefficients. Finally, a qualitative correlation between the penetration results of human nails and equine hooves was established., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Pure hair and nail ectodermal dysplasia (PHNED) comprises a heterogeneous group of rare heritable disorders characterized by brittle hair, hypotrichosis, onychodystrophy and micronychia. Autosomal recessive (AR) PHNED has previously been associated with mutations in either KRT85 or HOXC13 on chromosome 12p11.1-q14.3. We investigated a consanguineous Pakistani family with AR PHNED linked to the keratin gene cluster on 12p11.1 but without detectable mutations in KRT85 and HOXC13. Whole exome sequencing of affected individuals revealed homozygosity for a rare c.821T>C variant (p.Phe274Ser) in the KRT74 gene that segregates AR PHNED in the family. The transition alters the highly conserved Phe274 residue in the coil 1B domain required for long-range dimerization of keratins, suggesting that the mutation compromises the stability of intermediate filaments. Immunohistochemical (IHC) analyses confirmed a strong keratin-74 expression in the nail matrix, the nail bed and the hyponychium of mouse distal digits, as well as in normal human hair follicles. Furthermore, hair follicles and epidermis of an affected family member stained negative for Keratin-74 suggesting a loss of function mechanism mediated by the Phe274Ser substitution. Our observations show for the first time that homozygosity for a KRT74 missense variant may be associated with AR PHNED. Heterozygous KRT74 mutations have previously been associated with autosomal dominant woolly hair/hypotrichosis simplex (ADWH). Thus, our findings expand the phenotypic spectrum associated with KRT74 mutations and imply that a subtype of AR PHNED is allelic with ADWH.