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Objective: To assess glycation of nail proteins as a tool in the diagnosis of diabetes., Methods: Glycation of nail proteins was assessed using a modified photometric nitroblue tetrazolium-based assay, which provides information about average glucose values of the last 6-9 months. Analysis is possible on 10 mg of nail clippings with a within-run coefficient of variation (CV) of 11%. The analyte is extremely stable. The reference range for glycated nail protein (0.55-3.60 μmol/g nail) increases upon ageing., Results: In diabetics (n = 112), values for glycated nail protein are significantly higher (median: 4.07 μmol/g nail, IQR: 2.37-6.89 μmol/g nail, P < 0.0001) than in non-diabetics (n = 116). ROC analysis shows an AUC of 0.848 (specificity 93.1%; sensitivity 68.9%)., Conclusion: This affordable method is a simple alternative for diagnosing diabetes in remote areas as the pre-analytical phase (including all processes from the time a laboratory request is made by a physician until the sample is ready for testing) is extremely robust., (© 2013 John Wiley & Sons Ltd.)

We have recently developed target-specific derivatization methods for determining the metabolites in human nails. The nails can be used to obtain physiologic information and may serve as noninvasive biosamples for the diagnosis of chronic disease. Certain endogenous biogenic D,L-amino acids, polyamines, and advanced glycation end-products (AGEs) have been detected in human nails. By identifying biological trace components in human samples, we tested the possibility of using these new methods to diagnose chronic disease, i.e., diabetes and lung cancer. When comparing the index from diabetic patients to that from healthy volunteers, there was no significant difference in the content of L-amino acids, methylglyoxal, and glyoxal in the nails. However, a statistically significant correlation was observed between the D/L-amino acid concentration ratios (Ala, Val, Ile, Leu; p<0.01), and 3-deoxyglucosone concentrations (p<0.001). Additionally, in the lung cancer patient group, as compared with healthy volunteers, the concentrations of spermine showed a statistically significant (p<0.05) correlation. This review describes our current target-specific derivatization UPLC-ESI-MS methods for the determination of metabolites and related compounds, e.g., D,L-amino acids, polyamines, and AGEs, in human nails. Advanced applications of human nails as new, noninvasively obtained biosamples for the diagnosis of chronic disease are also described.

Novel multifunctional photosensitizers (MFPSs), 5,10,15-tris(4-N-methylpyridinium)-20-(4-phenylthio)-[21H,23H]-porphine trichloride (PORTH) and 5,10,15-tris(4-N-methylpyridinium)-20-(4-(butyramido-methylcysteinyl)-hydroxyphenyl)-[21H,23H]-porphine trichloride (PORTHE), derived from 5,10,15-Tris(4-methylpyridinium)-20-phenyl-[21H,23H]-porphine trichloride (Sylsens B) and designed for treatment of onychomycosis were characterized and their functionality evaluated. MFPSs should function as nail penetration enhancer and as photosensitizer for photodynamic treatment (PDT) of onychomycosis. Spectrophotometry was used to characterize MFPSs with and without 532 nm continuous-wave 5 mW cm(-2) laser light (± argon/mannitol/NaN3 ). Nail penetration enhancement was screened (pH 5, pH 8) using water uptake in nails and fluorescence microscopy. PDT efficacy was tested (pH 5, ± argon/mannitol/NaN3 ) in vitro with Trichophyton mentagrophytus microconida (532 nm, 5 mW cm(-2) ). A light-dependent absorbance decrease and fluorescence increase were found, PORTH being less photostable. Argon and mannitol increased PORTH and PORTHE photostability; NaN3 had no effect. PDT (0.6 J cm(-2) , 2 μm) showed 4.6 log kill for PORTH, 4.4 for Sylsens B and 3.2 for PORTHE (4.1 for 10 μm). Argon increased PORTHE, but decreased PORTH PDT efficacy; NaN3 increased PDT effect of both MFPSs whereas mannitol increased PDT effect of PORTHE only. Similar penetration enhancement effects were observed for PORTH (pH 5 and 8) and PORTHE (pH 8). PORTHE is more photostable, effective under low oxygen conditions and thus realistic candidate for onychomycosis PDT., (© 2013 The American Society of Photobiology.)

Background: Numerous studies have suggested that selenium deficiency may be associated with an increased risk for several types of cancer, but few have focused on thyroid cancer., Materials and Methods: We examined the association between post-diagnostic fingernail selenium levels and differentiated thyroid cancer risk in a French Polynesian matched case-control study. Conditional logistic regression models were used to estimate odds ratios and 95% confidence intervals., Results: The median selenium concentration among controls was 0.76 μg/g. Significantly, we found no association between fingernail selenium levels and thyroid cancer risk after conditioning on year of birth and sex and additionally adjusting for date of birth (highest versus lowest quartile: odds-ratio=1.12, 95% confidence interval: 0.66-1.90; p-trend=0.30). After additional adjustment for other covariates, this association remained non-significant (p-trend=0.60). When restricting the analysis to thyroid cancer of 10 mm or more, selenium in nails was non-significantly positively linked to thyroid cancer risk (p-trend=0.09). Although no significant interaction was evidenced between iodine in nails and selenium in nails effect (p=0.70), a non-significant (p-trend =0.10) positive association between selenium and thyroid cancer risk was seen in patients with less than 3 ppm of iodine in nails. The highest fingernail selenium concentration in French Polynesia was in the Marquises Islands (M=0.87 μg/g) and in the Tuamotu-Gambier Archipelago (M=0.86 μg/g)., Conclusions: Our results do not support, among individuals with sufficient levels of selenium, that greater long-term exposure to selenium may reduce thyroid cancer risk. Because these findings are based on post-diagnostic measures, studies with prediagnostic selenium are needed for corroboration.

β-catenin plays an important role in hair morphogenesis. Previously, the nuclear and cytoplasmic localizations of β-catenin were identified in hair-matrix cells. To evaluate β-catenin expression in the nail matrix, we obtained human nail units. Immunohistochemistry for β-catenin was used to evaluate sections of normal nail units and of sections from a single case of onychomatricoma. In the nail unit, β-catenin was expressed in the nucleus and cytoplasm of the suprabasal nail-matrix cells. Of the other epithelial-cell types, only the cell membrane was β-catenin-positive. In the nail tissue from the onychomatricoma case, β-catenin was expressed in the nucleus and cytoplasm of the upper epithelial layers. Our result suggests that β-catenin plays an important role in nail formation. In addition, β-catenin expression in onychomatricoma supports the presence of nail-matrix cells in this condition. To our knowledge, this is the first report of β-catenin expression in the nucleus and cytoplasm of the nail matrix., (© 2013 British Association of Dermatologists.)

Onychomycosis, a common fungal infection of the nail, can have a substantial impact on quality of life. The success of topical therapy for onychomycosis depends on effective penetration, which can be enhanced using an appropriate delivery method. This study evaluated the effectiveness of a novel topical lacquer on enhancing [(14)C]-ketoconazole penetration by comparing nail absorption, nail distribution, and nail penetration of [(14)C]-ketoconazole dissolved in the novel lacquer versus a commercial ketoconazole cream. Using the in vitro finite dose model, the formulations were applied daily to human nail plates for 7 days. Drug absorption was measured by monitoring rate of appearance in each nail layer and the supporting bed. After the multiple day treatment, cumulative concentrations of ketoconazole formulated in novel lacquer in the deep nail layer and the nail bed were significantly greater than cumulative concentrations of commercial ketoconazole (p<0.05), as well as several orders of magnitude greater than the minimal inhibitory concentration (MIC) deemed necessary to inhibit the growth of causative dermatophytic and yeast species. These results suggest that this novel ketoconazole lacquer has the potential to be an effective topical treatment for onychomycosis., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Limited data exist on the contribution of dietary sources of arsenic to an individual's total exposure, particularly in populations with exposure via drinking water. Here, the association between diet and toenail arsenic concentrations (a long-term biomarker of exposure) was evaluated for individuals with measured household tap water arsenic. Foods known to be high in arsenic, including rice and seafood, were of particular interest., Methods: Associations between toenail arsenic and consumption of 120 individual diet items were quantified using general linear models that also accounted for household tap water arsenic and potentially confounding factors (e.g., age, caloric intake, sex, smoking) (n = 852). As part of the analysis, we assessed whether associations between log-transformed toenail arsenic and each diet item differed between subjects with household drinking water arsenic concentrations <1 μg/L versus ≥1 μg/L., Results: As expected, toenail arsenic concentrations increased with household water arsenic concentrations. Among the foods known to be high in arsenic, no clear relationship between toenail arsenic and rice consumption was detected, but there was a positive association with consumption of dark meat fish, a category that includes tuna steaks, mackerel, salmon, sardines, bluefish, and swordfish. Positive associations between toenail arsenic and consumption of white wine, beer, and Brussels sprouts were also observed; these and most other associations were not modified by exposure via water. However, consumption of two foods cooked in water, beans/lentils and cooked oatmeal, was more strongly related to toenail arsenic among those with arsenic-containing drinking water (≥1 μg/L)., Conclusions: This study suggests that diet can be an important contributor to total arsenic exposure in U.S. populations regardless of arsenic concentrations in drinking water. Thus, dietary exposure to arsenic in the US warrants consideration as a potential health risk.

Arsenic (As) distribution in nail clippings from three healthy human subjects was investigated using the microbeam experimental setup of the hard x-ray micro-analysis (HXMA) beamline from the Canadian Light Source (CLS) synchrotron. A pair of toenail and fingernail clippings was collected from each of three subjects (one contributed two fingernail clippings). The fingernail and toenail clippings were embedded in polyester resin and cut in cross-sectional slices with an average thickness of 270 µm. Nine nail clipping cross sections were analyzed from the three subjects. The same method was used to produce five cross sections of nail phantom clippings with concentrations of As ranging from 0 to 20 µg g−1, in increments of 5 µg g−1. These samples were used to produce a calibration line for the As Kα peak. The energy of the x-ray beam was set at 13 keV for optimal excitation of As and the beam size was 28 × 10 µm2. Each sample was analyzed using a point-by-point scanning technique in a 45° beam-sample and 90° beam-detector geometry. The dwelling time was set at 30 s for the human nail clippings and 20 s for the nail phantom clippings, using a step size of 50 µm in both the horizontal and vertical directions for all samples. As concentration for each point was calculated based on the calibration line parameters and the fitted amplitude of the observed As Kα peak. As concentration maps were produced for each nail clipping cross section. The maps show that small regions (<0.1 mm2) with higher As concentrations (>1 µg g−1) are located predominantly in the ventral and dorsal layers of the nail. The results are in agreement with findings reported in a recent study and can be linked to nail histology and keratin structure.

This study determined the onychopharmacokinetics, nail absorption, distribution, and penetration of [¹⁴C]-terbinafine HCl in a new topical formulation into/through the human finger nail using the in vitro finite dose model. This study determined the penetration rate of terbinafine HCl from multiple doses of topical formulation applied daily for 14 days. Results showed that the total dose recovery (mass balance) was almost 100%. The concentration of terbinafine HCl in the deeper nail plate (ventral/intermediate layers) and the cotton-pad nail bed samples after the 14-day treatment were 613 ± 145 and (±S.D.) and 27 ± 1.2 µg/cm³ (or 1.9 ± 0.6 µg/cm³ daily) on average, respectively. In comparison with nail concentration data from the literature for other topical terbinatine formulations, our results show that higher amounts of terbinafine HCl reached the deep nail plate and/or the nail bed after a 14-day topical treatment with this topical formulation in vitro.

Purpose: To investigate whether permeation enhancement techniques affect the nail plate., Methods: Infrared and impedance spectroscopies examined the effects of hydration, iontophoresis and N-acetyl-L-cysteine on the human nail., Results: While significant shifts to higher wavenumbers were observed for the symmetric and asymmetric -CH2 stretching vibrations these changes were essentially the same for the three treatments suggesting they were principally due to hydration alone. Spectral changes associated with amide bonds from nail protein were particularly evident post-treatment with N-acetyl-L-cysteine. The alternating current conductivity and permittivity of the nail, particularly at low frequencies, increased with hydration. Iontophoresis increased the low frequency ac conductivity of the nail but had less effect on the nail capacitance/permittivity. Further, the effects seemed to return gradually to baseline after termination of current passage. Treatment with N-acetyl-L-cysteine produced a greater perturbation, leading to increased low-frequency conductivity and a shift of the frequency-dependent conductivity region to a higher frequency., Conclusions: Overall, the effects of iontophoresis on infrared and impedance spectroscopic profiles of the nail were attributable simply to increased hydration and similar to those observed after skin iontophoresis. In contrast, both spectroscopy techniques indicated that N-acetyl-L-cysteine disrupted nail structure in line with the enhancer's known effect on keratin.

Millions of people suffer from superficial infections caused by dermatophytes. Intriguingly, these filamentous fungi exclusively infect keratin-rich host structures such as hair, nails, and skin. Keratin is a hard, compact protein, and its utilization by dermatophytes for growth has long been discussed as a major virulence attribute. Here, we provide strong support for the hypothesis that keratin degradation is facilitated by the secretion of the reducing agent sulfite, which can cleave keratin-stabilizing cystine bonds. We discovered that sulfite is produced by dermatophytes from environmental cysteine, which at elevated concentrations is toxic for microbes and humans. We found that sulfite formation from cysteine relies on the key enzyme cysteine dioxygenase Cdo1. Sulfite secretion is supported by the sulfite efflux pump Ssu1. Targeted mutagenesis proved that dermatophyte mutants in either Cdo1 or Ssu1 were highly growth-sensitive to cysteine, and mutants in Ssu1 were specifically sensitive to sulfite. Most notably, dermatophyte mutants in Cdo1 and Ssu1 were specifically growth-defective on hair and nails. As keratin is rich in cysteine, our identified mechanism of cysteine conversion and sulfite efflux supports both cysteine and sulfite tolerance per se and progression of keratin degradation. These in vitro findings have implications for dermatophyte infection pathogenesis.

Onychomycosis is associated with the cutaneous fungal infection of the nail and the nail folds (skin surrounding the nail). It is therefore important to target drug delivery into the nail folds along with nail plate and the nail bed. Systematic and strategic selection of the penetration enhancers specific for the skin and the nail is discussed. Twelve penetration enhancers were screened for their ability to improve solubility, in vitro nail penetration, in vitro skin permeation, and in vitro skin penetration of the antifungal drug ciclopirox olamine. In contrast to transdermal drug delivery, the main selection criteria for skin penetration enhancer in topical drug delivery were increased drug accumulation in the epidermis and minimal permeation across the skin. Thiourea improved the solubility and nail penetration of ciclopirox olamine. It also showed enhancement in the transungual diffusion of the drug. Propylene glycol showed a 12-fold increase in solubility and 3-fold increase in epidermal accumulation of ciclopirox olamine, while minimizing the transdermal movement of the drug. Thiourea was the selected nail permeation enhancer and propylene glycol was the selected skin penetration enhancer of ciclopirox olamine. A combination of the selected enhancers was also explored for its effect on drug delivery to the nail and nail folds. The enhancer combination reduced the penetration of ciclopirox in the skin and also the permeation through the nail. The proposed preformulation strategy helps to select appropriate enhancers for optimum topical delivery and paves way towards an efficient topical formulation for passive transungual drug delivery.

Background: Recently, an intriguing concept was introduced into the literature that defines the area underlying the nail bed as a specific mesenchymal substructure unique to the nail organ. It has been termed onychodermis. The onychodermis expresses CD10 with remarkable specificity. Herein, we compare adult and fetal human hair follicles with fetal nail organs in an attempt to draw analogies for the mesenchyme associated with both adnexal structures., Methods: We examined immunohistochemically samples from adult and fetal hair follicles for the expression of CD10, CD34 and the mesenchymal stem cell marker nestin and compared the antigen profile with that of the fetal nail organ., Results: The CD10-positive/CD34-negative onychodermis is prominently visible at the end of the second trimester. A corresponding follicular structure was not identified, either in the adult or in the developing hair follicle. Nestin staining does not define the onychodermis., Conclusions: The concept of the onychodermis is equally valid in the developing nail organ where it is also defined by its expression for CD10. Its function may be related to the anchorage of the overlying nail bed but may also involve a more dynamic role in the induction of hard keratins in the latter, contributing to the formation of the nail plate., (Copyright © 2013 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.)

Use of dietary supplements in the U.S. has increased steadily over the last 25 years. While misformulation is uncommon, the consequences can be serious. A March 2008 voluntary market recall removed supplement products responsible for the most serious selenium toxicity outbreak that has occurred in the U.S. We quantified selenium concentrations in the misformulated supplement products, measured the temporal response in the nail biologic monitor, and associated exposure to self-reported selenosis symptoms. Subjects recruited through state health departments and referrals provided samples of the misformulated supplement products, exposure information, monthly toenail and or fingernail clippings or onycholysitic nail fragments, and listed their newly onset adverse health effects attributed to selenium toxicity. Ninety-seven subjects enrolled and submitted at least one test sample. Peak selenium concentrations (up to 18.3 and 44.1 μg/g for toenails and fingernails, respectively) were measured. Multiple samples (52 total) of all six recalled supplement lots were analyzed ranging from 22,300 to 32,200 μg selenium per daily dose. Average consumption was 30.9 ± 13.9 doses; 73 subjects provided follow-up data on selenosis symptoms at 2.50 ± 0.14 years. Nail samples accurately reflect exposure in this selenium toxicity outbreak, which resulted in long-term/permanent adverse health effects.

Terbinafine hydrochloride (TBF-HCl) is an active substance that is using for treatment of onychomycosis. Onychomycosis is a fungal infection which is the most common disease of nail plate. The nail plate is a barrier which prevents effective topical treatment of ungual disorders. In this study, TBF-HCl loaded liposome and ethosome formulations and also gel form of these formulations were prepared. The formulations were characterized and in vitro and ex vivo release studies were performed. Nail characterization studies were also performed to examine the effect of formulations and experimental conditions on nail surface. As a result, all formulations can serve as efficient formulations for ungual application of TBF-HCl. By the way, the results of the accumulation studies suggested that liposome poloxamer gel formulation could be promising system for ungual drug delivery due to the better accumulation and easier application of the formulation., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Because of the disadvantages of invasive sampling, it is desirable to explore non-invasive matrices for human biomonitoring of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA). The aim of this study was to evaluate the application of nail, hair and urine for human biomonitoring of PFOS and PFOA. The concentrations of PFOS and PFOA in matched nail, hair, urine and serum samples collected from 64 donors were measured. The chemicals of interest were detected with high detection frequency in these matrices (90%-100%) except for PFOA in urine samples (56%). Generally, the gender influences on the levels of PFOS and PFOA in these non-invasive matrices were in agreement with that in serum. For PFOS, the coefficients of Spearman correlation between serum samples and nail, hair and urine samples were 0.786 (p<0.001), 0.545 (p<0.001) and 0.302 (p<0.05), respectively. For PFOA, the correlation was only observed between nail samples and serum samples with a correlation coefficient of 0.299 (p<0.05). The results suggested that nail has more potential than hair and urine to be applied in human biomonitoring for PFOS and PFOA in general populations., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: In a previous study a new hydrosoluble nail lacquer (P-3051) containing 8% ciclopirox (CPX) showed higher nail penetration compared to a water-insoluble 5% amorolfine (MRF) lacquer. To our knowledge, in vivo human data on a similar topic are not available., Objectives: To compare fingernail penetration of P-3051 with that of MRF reference in humans and to evaluate their predicted efficacy against Trichophyton rubrum and Candida parapsilosis., Methods: Single centre, randomized, multiple dose, open label, within subjects study. Test and reference were self-applied to all fingernails of either hand for 28 days. At baseline and after 15 and 25 days, the nail free edge was collected for analysis. Efficiency coefficients were calculated for T. rubrum and C. parapsilosis as ratios of nail concentration/minimum inhibitory concentration. The coefficients were classified as very high, high or poor., Results: Nail concentrations after 15 days were 2.82 ± 0.58 μg/mg for CPX and 0.64 ± 0.11 μg/mg for MRF. At day 25 there was a non-significant decline (1.85 ± 0.31 μg/mg, P = 0.077) for CPX and a highly significant (0.13 ± 0.03 μg/mg, P = 0.0002) 80% decline for MRF. Efficiency coefficients were very high/high in all subjects treated with P-3051 against both T. rubrum and C. parapsilosis; they were significantly lower for MRF reference against both pathogens at both observation points., Conclusions: P-3051 exhibited better penetration and higher predicted efficacy after in vivo multiple application to human fingernails when compared to MRF reference. These in vivo data are in good agreement with our previous in vitro study., (© 2012 The Authors. Journal of the European Academy of Dermatology and Venereology © 2012 European Academy of Dermatology and Venereology.)

Purpose: To estimate the in vitro ungual penetration depth of sodium fluorescein and nile blue chloride by laser scanning confocal microscopy., Methods: The depth, uniformity and pathways of penetration of both markers into human nail during passive and iontophoretic experiments were investigated. The penetration of sodium fluorescein into the dorsal, ventral and intermediate layers of the nail was also studied. Transversal images were used to estimate directly the relative penetration of the markers with respect to the complete thickness of the nail. "Exposed layer" images allowed estimating the depth of penetration by taking xy-plans, starting by the exposed layer, and following the z axis into the nail., Results: The fluorescent markers penetrated 7-12% of the nail thickness. Iontophoresis increased penetration of both markers compared to passive diffusion. However, ungual penetration was not modified by the intensity of current applied. Penetration into the dorsal, ventral, and intermediate nail layers was similar. The method developed allowed inter- and intra- nail variability to be accounted for., Conclusions: Iontophoresis enhanced moderately the penetration of the two markers into the nail plate as compared to passive diffusion. The confocal images suggested the transcellular pathway to be predominant during both passive and iontophoretic experiments.

It is established that the most informative blood biochemical indicators of destructive process in patients with onycholysis are to be considered concentration of oxiproline in blood. The changing of ratio of fractions oxiproline, balance between concentration of enzymes of antioxidant defense and metalloproteinase and concentration of hemoglobin in blood make it possible to diagnose the mixed type of hypoxemia which is a possible cause of destruction of kerato-hyaline tissue in patients with onycholysis.

Between October 1994 and October 1995, the number of birth defects per 1,000 live births in Al Basrah Maternity Hospital was 1.37. In 2003, the number of birth defects in Al Basrah Maternity Hospital was 23 per 1,000 live births. Within less than a decade, the occurrence of congenital birth defects increased by an astonishing 17-fold in the same hospital. A yearly account of the occurrence and types of birth defects, between 2003 and 2011, in Al Basrah Maternity Hospital, was reported. Metal levels in hair, toenail, and tooth samples of residents of Al Basrah were also provided. The enamel portion of the deciduous tooth from a child with birth defects from Al Basrah (4.19 μg/g) had nearly three times higher lead than the whole teeth of children living in unimpacted areas. Lead was 1.4 times higher in the tooth enamel of parents of children with birth defects (2,497 ± 1,400 μg/g, mean ± SD) compared to parents of normal children (1,826 ± 1,819 μg/g). Our data suggested that birth defects in the Iraqi cities of Al Basrah (in the south of Iraq) and Fallujah (in central Iraq) are mainly folate-dependent. This knowledge offers possible treatment options and remediation plans for at-risk Iraqi populations.

Drug delivery by topical route for the treatment of onychomycosis, a nail fungal infection, is challenging due to the unique barrier properties of the nail plate which imparts high resistance to the passage of antifungal drugs. Permeation enhancers are used in transungual formulations to improve the drug flux across the nail plate. Selection of the effective permeation enhancer among the available large pool of permeation enhancers is a difficult task. Screening the large number of permeation enhancers using conventional Franz diffusion cells is laborious and expensive. The objective of present study was to evolve a simple, accurate and rapid method for screening of transungual drug permeation enhancers based on the principle of hydration of nail plate. The permeation enhancer which affects the structural or physicochemical properties of nail plate would also affect their hydration capacity. Two screening procedures namely primary and secondary screenings were evolved wherein hydration and uptake of ciclopirox olamine by nail plates were measured. Hydration enhancement factor, HEF(24) and drug uptake enhancement factor, UEF(24) were determined for screening of 23 typical permeation enhancers. The Pearson's correlation coefficient between HEF(24) and UEF(24) was determined. A good agreement between the HEF(24) and UEF(24) data proved the validity of the proposed nail plate hydration model as a screening technique for permeation enhancers., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Introduction: Current topical treatments for onychomycosis are unsatisfactory. New topical agents that offer efficacy without the potential adverse effects of oral antifungal therapy would benefit patients with this condition and encourage a greater treatment rate., Areas Covered: Currently available topical therapies are reviewed, and new approaches for enhancing delivery of the established antifungal terbinafine through the nail are summarized. We focus on the use of ultra-deformable lipid vesicles to facilitate delivery of terbinafine to the nail and surrounding tissue. TDT 067 (terbinafine in Transfersome) is the only such therapy in development for onychomycosis, and we review published preclinical and clinical studies on this formulation., Expert Opinion: TDT 067 offers the use of new technology to deliver an established antifungal, terbinafine. Preclinical data suggest that the Transfersome accelerates entry of terbinafine released from TDT 067 into fungi and potentiates its antifungal effects, resulting in enhanced activity, compared with conventional terbinafine. This translated into high rates of mycological cure and evidence of clinical effect in a study of TDT 067 administered twice daily for 12 weeks in patients with onychomycosis. An ongoing Phase-III trial involving more than 700 patients treated for 48 weeks is investigating the efficacy and safety of TDT 067.

Previous studies have suggested that the electron paramagnetic resonance in fingernails can be used for radiation dosimetry purposes. Use of fingernails as an emergency dosimeter has benefits of easy, noninvasive sampling and fast dose measurements (∼10 min) potentially in field conditions and almost immediately after an exposure event. This study represents the next step in the development of EPR fingernail dosimetry; e.g., evaluation of the stability of the radiation-induced signal (RIS) at different storage and irradiation conditions. RIS fading during storage in both stressed (untreated) and unstressed (soaked in water) samples (n = 20) was studied at two temperature conditions: freezing (temp ≈ -20°C) and room temperature (20-24°C). Fingernail samples with the same clipping size and number and irradiated to 15 and 20 Gy were measured for over 200 d. Those irradiated to 100 and 200 Gy were measured for 114 d. The other group of samples irradiated to 1, 3, 8, and 20 Gy was followed for 25 mo of storage time. This study demonstrated that all samples that were kept at low freezing temperatures showed a stable RIS with no significant fading. All samples that were kept at room temperatures showed an initial fading of the signal with a slow rise of the EPR signal after irradiation with time to a saturation level. Obtained results allow making recommendations on the appropriate storage conditions of fingernails for EPR dosimetry use.

Topical therapy is desirable in treatment of nail diseases like onychomycosis (fungal infection of nail) and psoriasis. The topical treatment avoids the adverse effects associated with systemic therapy, thereby enhancing the patient compliance and reducing the treatment cost. However the effectiveness of the topical therapies has been limited due to the poor permeability of the nail plate to topically applied therapeutic agents. Research over the past one decade has been focused on improving the transungual permeability by means of chemical treatment, penetration enhancers, mechanical and physical methods. The present review is an attempt to discuss the different physical and chemical methods employed to increase the permeability of the nail plate. Minimally invasive electrically mediated techniques such as iontophoresis have gained success in facilitating the transungual delivery of actives. In addition drug transport across the nail plate has been improved by filing the dorsal surface of the nail plate prior to application of topical formulation. But attempts to improve the trans-nail permeation using transdermal chemical enhancers have failed so far. Attempts are on to search suitable physical enhancement techniques and chemical transungual enhancers in view to maximize the drug delivery across the nail plate.

Aims: Due to its limited availability there has been very little research on the mesenchyme of the nail unit. Recently, we discovered specialized mesenchymal cells beneath the nail matrix and proposed to call them onychofibroblasts. The purpose of this study was to further delineate more precisely by histology and immunohistochemistry the specialized nail mesenchyme., Methods and Results: Thirty supernumerary digits were obtained during operations to correct polydactyly. Longitudinal and transverse sections were obtained from formalin-fixed paraffin-embedded blocks. In sections stained with haematoxylin and eosin, a mesenchymal area that showed much more cellularity and less eosinophilic, loose connective tissue was identified beneath the nail matrix and nail bed. Using Alcian blue staining, mucin was detected in this mesenchymal area below the nail matrix and nail bed. Immnunohistochemically, CD10 and versican were expressed strongly in the mesenchyme containing onychofibroblasts under the nail matrix and nail bed., Conclusions: These results demonstrate the presence and localization of a specialized nail mesenchyme containing onychofibroblasts in a well-defined area beneath the nail matrix and nail bed. Thus, we propose the term onychodermis for this specialized nail mesenchyme that is histologically and immunohistochemically distinct from the dermis of other parts of the nail unit., (© 2012 Blackwell Publishing Ltd.)

The main objective of the present study was to investigate the plausibility of iontophoretic delivery of drugs to the nail matrix via proximal nail fold. The in vitro drug transport studies were performed in Franz diffusion cells across folded epidermis, which is used as a model for the proximal nail fold. The amount of drug transported into the receiver compartment following iontophoresis for 3 h at 0.5 mA/cm(2) was 150-fold higher than the control (0.008 ± 0.002 μg/cm(2)). The amount of drug present in the skin after iontophoresis (0.45 ± 0.12 μg/mg) was approximately fivefold higher as compared with that of the control (0.08 ± 0.01 μg/mg). Iontophoresis of terbinafine across the proximal nail fold was assessed using excised cadaver toe model as well. A custom-designed foam-pad-type patch system was used for iontophoresis in cadaver toes. The amount of the drug delivered into the nail matrix following iontophoresis for 3 h was significantly higher than the minimum inhibition concentration of terbinafine. However, on the contrary, passive delivery for about 24 h did not result in any detectable drug levels in the nail matrix. Iontophoresis across the proximal nail fold could be developed as a potential method to target drugs to nail matrix., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: AEC (ankyloblepharon-ectodermal defects-clefting) syndrome is an autosomal dominant ectodermal dysplasia disorder caused by mutations in the transcription factor p63. Clinically, the skin is dry and often fragile; other features can include partial eyelid fusion (ankyloblepharon), hypodontia, orofacial clefting, sparse hair or alopecia, and nail dystrophy., Objectives: To investigate how p63 gene mutations affect gene and protein expression in AEC syndrome skin., Methods: We performed microarray analysis on samples of intact and eroded AEC syndrome skin compared with control skin. Changes were verified by quantitative real-time reverse transcription-polymerase chain reaction and, for basal keratinocyte-associated genes, by immunohistochemistry and analysis of microdissected skin., Results: We identified significant upregulation of six genes and downregulation of 69 genes in AEC syndrome skin, with the main changes in genes implicated in epidermal adhesion, skin barrier formation and hair follicle biology. There was reduced expression of genes encoding the basement membrane proteins FRAS1 and collagen VII, as well as the skin barrier-associated small proline-rich proteins 1A and 4, late cornified envelope protein 5A, hornerin, and lipid transporters including ALOX15B. Reduced expression of the hair-associated keratins 25, 27, 31, 33B, 34, 35, 81 and 85 was also noted. We also confirmed similar alterations in gene expression for 26 of the 75 genes in eroded AEC scalp skin., Conclusions: This study identifies specific changes in skin structural biology and signalling pathways that result from mutant p63 and provides new molecular insight into the AEC syndrome phenotype., (© 2012 The Authors. BJD © 2012 British Association of Dermatologists.)

Even though the systemic antibiotic therapy is usually applied after prosthetic infections surgical treatments, it is unable to reach the infection site in sufficient concentrations to eradicate bacteria. Delivering antibiotics locally with the use of custom made device (spacer or nail coating) might eradicate or reduce the infection and the risk of recolonization, providing a very high concentration of antibiotic. PMMA-based (Mendec Spine) composites with BaSO(4) were enriched with β-tricalcium phosphate (Porosectan-TCP) or only a slightly higher BaSO(4) concentration (Porosectan-BaSO(4)) to obtain higher porosity. The aim of the study was to evaluate: (i) drug absorption capability and drug release kinetics in vitro soaking them with a combined solution of gentamicin and vancomycin, (ii) their in vitro and in vivo biocompatibility, and finally, (iii) they were tested preliminarily in an experimental model of bone infection. The simultaneous presence of β-TCP and BaSO(4) resulted in the formation of a texture of interconnecting channels with different diameters, from a few microns to several hundred microns, which totally filled the material. The porosity, determined by microcomputed tomography, was significantly higher in both tested plain composites (Porosectan-TCP: +17.3%; Porosectan-BaSO(4): +7.5%) in comparison to control composite material (Mendec Spine). The kinetics of antibiotic release from composites was rapid and complete, producing high drug concentrations for a short period of time. Both composites showed a good level of biocompatibility. The osteomyelitic model confirmed that both composites, soaked in antibiotic solution, were able to cure bone infection. These composites could be useful for preparing devices for prosthetic joint infections treatment also allowing the use of antibiotics solution at required concentrations.

Arsenic (As) is a ubiquitous element. The current WHO guideline for As in drinking water is 10 μg/L. Furthermore, about 130 million people have only access to drinking water containing more than 10 g As/L. Although numerous studies have shown the related adverse effects of As, sensitive appropriate biomarkers are still required for studies of environmental epidemiology. A review of the literature has shown that various biomarkers are used for such research. Their limits and advantages are highlighted in this paper: (i) the detection of As or its derivatives in the blood is an indication of the dose ingested but it is not evidence of chronic intoxication. (ii) The detection of As in urine is an indispensible procedure because it is a good marker for internal dose. It has been demonstrated to correlate well for a number of chronic effects related to As levels in drinking water. However confounding factors must be taken into account to avoid misinterpretation and this may require As speciation. (iii) As in the hair and nails reflects the level of long term exposure but it is difficult to relate the level with the dose ingested. (iv) Some studies showed a correlation between urinary As and urinary and blood porphyrins. However, it is difficult to use only porphyrins as a biomarker in a population survey carried out without doing further studies. (v) Genotoxic effects are based on the characterization of these potential effects. Most studies have detected increases in DNA damage, sister chromatid exchange, micronuclei or chromosomal aberrations in populations exposed to As in drinking water. Micronuclei assay is the technique of choice to follow these populations, because it is sensitive and easy to use. To conclude, whatever epidemiological studies are, the urinary and toenail biomarkers are useful to provide indications of internal dose. Moreover, micronuclei assay can be complementary use as biomarker of early effects., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: A girl suffering from a rare syndrome of unknown aetiology, termed hypercalprotectinaemia, was evaluated for tissue zinc status, because calprotectin is a protein which chelates Zn at multiple binding-sites, which might have affected the distribution of Zn in her body., Methods: Measurement of serum, urine, hair and nail zinc (Zn) concentration, complemented with measurement of total Zn in ultrafiltrates of plasma., Results: Her serum Zn concentration was 105-133 μmol/L. Zn levels in her hair (102 μg/g), nail (90 μg/g) and urine (3-12 μmol/L; 20-80 μg/dL) were all at the lower end of the reference intervals described in the sparse literature. Zn concentrations in ultrafiltrates of plasma were below the detection limit (<100 nmol/L). Thus, the elevated serum Zn did not translate into a similarly increased level of Zn in any of the tissues tested, nor in free Zn concentrations. Instead it appeared to be a result of Zn being chelated to binder proteins, most probably calprotectin., Conclusion: Her grossly elevated serum calprotectin concentration is probably able to raise circulating total Zn concentrations without raising ionized concentrations, but this Zn remains confined to the circulating blood as well as to excreted body fluids, particularly faeces.

Trace element concentrations in body tissues of healthy centenarians have not been widely analyzed, yet they can be used as reference data leading to improved assessment of the aging process and monitoring of the micronutrient status of this age group. The present study sought to assess trace element concentrations and behaviors in the fingernails of healthy Chinese centenarians. The effects of gender on element concentrations, which also play an important role in determining the lifespan, were also investigated. Trace elements (Ba, Cd, Co, Cr, Cu, Fe, Li, Mn, Mo, Ni, Pb, Se, Sr, and Zn) in the fingernails of 78 healthy Chinese centenarians were determined by inductively coupled plasma mass spectrometry. The overall reference values obtained in milligram per kilogram are as follows: Ba, 5.10; Cd, 0.031; Co, 0.101; Cr, 0.82; Cu, 3.71; Fe, 154.35; Li, 0.31; Mn, 3.09; Mo, 0.040; Ni, 0.95; Pb, 1.86; Se, 0.44; Sr, 6.20; and Zn, 147.96. Data analysis showed that only Cr and Se concentrations show a normal distribution, and no significant difference between male and female groups was found for any element except Cr. Result also revealed that sufficient Se, Co, and Zn as well as lower or lack of exposure to Cr contribute positively to the lifespan of centenarians. The results suggest that regulating in vivo contents of trace elements, especially Se, Co, and Zn, is reasonable to intervene with geriatric diseases.

Occupational exposure to welding fumes (WF) is thought to cause Parkinson's disease (PD)-like neurological dysfunction. An apprehension that WF may accelerate the onset of PD also exists. Identifying reliable biomarkers of exposure and neurotoxicity are therefore critical for biomonitoring and neurological risk characterization of WF exposure. Manganese (Mn) in welding consumables is considered the causative factor for the neurological deficits seen in welders. Hence, we sought to determine if Mn accumulation in blood or nail clippings can be a marker for adverse exposure and neurotoxicity. To model this, rats were exposed by intratracheal instillation to dissolved or suspended fume components collected from gas metal arc-mild steel (GMA-MS) or manual metal arc-hard surfacing (MMA-HS) welding. Trace element analysis revealed selective Mn accumulation in dopaminergic brain areas, striatum (STR) and midbrain (MB), following exposure to the two fumes. This caused dopaminergic abnormality as evidenced by loss of striatal tyrosine hydroxylase (Th; 25-32% decrease) and Parkinson disease (autosomal recessive, early onset) 7 (Park7; 25-46% decrease) proteins. While blood Mn was not detectable, Mn levels in nails strongly correlated with the pattern of Mn accumulation in the striatum (R(2)=0.9386) and midbrain (R(2)=0.9332). Exposure to manganese chloride (MnCl(2)) caused similar Mn accumulation in STR, MB and nail. Our findings suggest that nail Mn has the potential to be a sensitive and reliable biomarker for long-term Mn exposure and associated neurotoxicity. The non-invasive means by which nail clippings can be collected, stored, and transported with relative ease, make it an attractive surrogate for biomonitoring WF exposures in occupational settings., (Published by Elsevier Ireland Ltd.)

Introduction: Topical drug delivery to treat nail diseases such as onychomycosis and psoriasis is receiving increasing attention. Topical nail delivery is challenged by the complicated structure of the nail and the low permeability of most drugs across the nail plate. Considerable effort has been directed at developing methods to promote drug permeation across the nail plate. Iontophoresis efficiently enhances molecular transport across the skin and the eye and is now being tested for its potential in ungual delivery., Areas Covered: This review covers the basic mechanisms of transport (electro-osmosis and -migration) and their relative contribution to nail iontophoresis as well as the key factors governing nail permselectivity and ionic transport numbers. Methodological issues concerning research in this area are summarized. The data available in vivo on nail iontophoresis of terbinafine specifically are reviewed in separate sections., Expert Opinion: Our understanding of nail iontophoresis has improved considerably since 2007; most decisively, the feasibility of nail iontophoresis in vivo has been clearly demonstrated. Future work is required to establish the adequate implementation of the technique so that its clinical efficacy to treat onychomycosis and nail psoriasis can be unequivocally determined.

Mining activities may affect the health of miners and communities living near mining sites, and these health effects may persist even when the mine is abandoned. During mining processes various toxic wastes are produced and released into the surrounding environment, resulting in contamination of air, drinking water, rivers, plants, and soils. In a geochemical sampling campaign undertaken in the Panasqueira Mine area of central Portugal, an anomalous distribution of several metals and arsenic (As) was identified in various environmental media. Several potentially harmful elements, including As, cadmium (Cd), chromium (Cr), manganese (Mn), nickel (Ni), lead (Pb), and selenium (Se), were quantified in blood, urine, hair, and nails (toe and finger) from a group of individuals living near the Panasqueira Mine who were environmentally and occupationally exposed. A group with similar demographic characteristics without known exposure to mining activities was also compared. Genotoxicity was evaluated by means of T-cell receptor (TCR) mutation assay, and percentages of different lymphocyte subsets were selected as immunotoxicity biomarkers. Inductively coupled plasma-mass spectrometry (ICP-MS) and inductively coupled plasma-atomic emission spectrometry (ICP-AES) analysis showed elevated levels of As, Cd, Cr, Mn, and Pb in all biological samples taken from populations living close to the mine compared to controls. Genotoxic and immunotoxic differences were also observed. The results provide evidence of an elevated potential risk to the health of populations, with environmental and occupational exposures resulting from mining activities. Further, the results emphasize the need to implement preventive measures, remediation, and rehabilitation plans for the region.

Heavy metals, particularly cadmium, lead, and arsenic, constitute a significant potential threat to human health. This study was conducted to determine the levels of cadmium, lead, and arsenic in nail samples from farmers at Muda Agricultural Development Authority (MADA), Kedah, Malaysia, and evaluate factors that can contribute to their accumulations. A total of 116 farmers participated in this study. Inductively coupled plasma mass spectrometry (ICP-MS) was used to analyze concentration of heavy metals in the nail samples and questionnaires were given to participants to get demographic, health status, and their agricultural activities data. In this paper, the level of heavy metals was within the normal range and varies according to demographic factors. We found that there were significant correlations between working period with level of lead and arsenic (r=0.315 and r=0.242, resp., P<0.01) and age with lead level (r=0.175, P<0.05). Our findings suggested that agricultural activities could contribute to the accumulation of heavy metals in farmers. Hence, the control of environmental levels of and human exposure to these metals to prevent adverse health effects is still an important public health issue.

Background: Arsenic, cadmium, mercury, and lead are associated with cardiovascular disease in epidemiologic research. These associations may be mediated by direct effects of the metals on blood pressure (BP) elevation. Manganese is associated with cardiovascular dysfunction and hypotension in occupational cohorts., Objectives: We hypothesized that chronic arsenic, cadmium, mercury, and lead exposures elevate BP and that manganese lowers BP., Methods: We conducted a cross-sectional analysis of associations between toenail metals and BP among older men from the Normative Aging Study (n = 639), using linear regression and adjusting for potential confounders., Results: An interquartile range increase in toenail arsenic was associated with higher systolic BP [0.93 mmHg; 95% confidence interval (CI): 0.25, 1.62] and pulse pressure (0.76 mmHg; 95% CI: 0.22, 1.30). Positive associations between arsenic and BP and negative associations between manganese and BP were strengthened in models adjusted for other toenail metals., Conclusions: Our findings suggest associations between BP and arsenic and manganese. This may be of public health importance because of prevalence of both metal exposure and cardiovascular disease. Results should be interpreted cautiously given potential limitations of toenails as biomarkers of metal exposure.

This work aimed to (a) characterize the microstructure and porosity of human nail and bovine hoof by mercury intrusion porosimetry and SEM image analysis, (b) study the effects of hydration and of N-acetyl-l-cysteine treatment on the microstructure of both membranes, and (c) determine whether the microstructural modifications were associated with changes in drug penetration measured by standard diffusion studies. Bovine hoof surface is more porous than nail surface although there were no differences between the mean surface pore sizes. Hydration and N-acetyl-l-cysteine increased the roughness and apparent surface porosity, and the porosity determined by mercury intrusion porosimetry of both membranes. Pore-Cor™ was used to generate tridimensional structures having percolation characteristics comparable to nail and hooves. The modeled structures were horizontally banded having an inner less-porous area which disappeared upon treatment. Treatment increased the predicted permeability of the simulated structures. Triamcinolone permeation increased significantly for hooves treated N-acetyl-l-cysteine, i.e., the membranes for which microstructural and permeability changes were the largest. Thus, microstructural changes determined via mercury intrusion porosimetry and subsequently modeled by Pore-Cor™ were related to drug diffusion. Further refinement of the technique will allow fast screening of penetration enhancers to be used in ungual drug delivery., (Copyright © 2011 Elsevier B.V. All rights reserved.)

A novel ultrasound-mediated drug delivery system has been developed for treatment of a nail fungal disorder (onychomycosis) by improving delivery to the nail bed using ultrasound to increase the permeability of the nail. The slip-in device consists of ultrasound transducers and drug delivery compartments above each toenail. The device is connected to a computer, where a software interface allows users to select their preferred course of treatment. In in vitro testing, canine nails were exposed to 3 energy levels (acoustic power of 1.2 W and exposure durations of 30, 60, and 120 seconds). A stereo -microscope was used to determine how much of a drug-mimicking compound was delivered through the nail layers by measuring brightness on the cross section of each nail tested at each condition, where brightness level decreases coincide with increases in permeability. Each of the 3 energy levels tested showed statistical significance when compared to the control (P < .05) with a permeability factor of 1.3 after 30 seconds of exposure, 1.3 after 60 seconds, and 1.5 after 120 seconds, where a permeability factor of 1 shows no increase in permeability. Current treatments for onychomycosis include systemic, topical, and surgical. Even when used all together, these treatments typically take a long time to result in nail healing, thus making this ultrasound-mediated device a promising alternative.

The resolution of free DL-amino acids in human nail was carried out by combination of the R(-)-4-(3-isothiocyanatopyrrolidin-1-yl)-7-(N,N-dimethylaminosulfonyl)-2,1,3-benzoxadiazole [R(-)-DBD-PyNCS] derivatives and UPLC-ESI-TOF-MS. The reaction of the reagent with amino acids effectively proceeds at 55 °C for 20 min in the presence of 1% triethylamine (TEA) to produce the corresponding diastereomers. Each pair of the resulting derivatives was efficiently separated by a gradient program (a mixture of H(2)O and CH(3)CN containing 0.1% formic acid (HCOOH) or 5 mM CH(3)COONH(4) and CH(3)CN) using a reversed-phase ACQUITY UPLC™ BEH C(18) (1.7 μm, 100 mm × 2.1 mm i.d.) column and sensitively detected by TOF-MS. The detection limits (S/N=3) of the TOF-MS were 1.0-750 fmol, respectively. A good linearity was achieved from the calibration curves, which was obtained by plotting the peak area ratios of the analytes relative to the internal standard (IS), i.e., 6-aminohexanoic acid, versus the injected amounts of each amino acid (r(2)>0.996), and the intra-day and inter-day assay precisions were less than 8.93%. The derivatives of the free DL-amino acids in human nail were successfully identified by the proposed procedure. As we know, for the first time, these five kinds of D-amino acids, which were D-Ala, D-Val, D-Pro, D-Ile and D-Leu, were found from human nail samples. Fifteen kinds of L-amino acids were also recognized from human nails. Using these methods, the amounts of DL-amino acids in the nails of healthy volunteers and diabetic patients were determined. When comparing the index from diabetic patients to those from healthy volunteers, there is no significant difference in the content of the L-amino acids in the nails. However, a statistically significant (P<0.01) correlation was observed between the D/L-amino acid concentration ratios (Ala, Val, Ile, Leu). Therefore, because the proposed method provides a good mass accuracy and the trace detection of the DL-amino acids in human nails, this analytical technique could be a noninvasive technique to assist in the diagnosis and assessment of disease activity in diabetic patients., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The effects of organic solvent systems on nail hydration and permeability have not been well studied. The objectives of the present study were to investigate the effects of binary aqueous organic solvent systems of ethanol (EtOH), propylene glycol (PPG), and polyethylene glycol 400 (PEG) on the barrier properties of nail plates. (3) H-water, (14) C-urea, and (14) C-tetraethylammonium ions were the probes in the nail uptake and transport experiments to study the effect(s) of organic solvents on nail hydration and permeability. Gravimetric studies were also performed as a secondary method to study nail hydration and the reversibility of the nail after organic solvent treatments. Both ungual uptake and transport were directly related to the concentration of the organic solvent in the binary systems. Partitioning of the probes into and transport across the nail decreased with an increase in the organic solvent concentration. These changes corresponded to the changes in solution viscosity and the barrier properties of the nail. In general, the effects for PPG and PEG were more pronounced than those for EtOH. Practically, these results suggest that organic solvents in formulations can increase nail barrier resistivity., (Copyright © 2011 Wiley-Liss, Inc.)

Extensive human exposure to perfluoroalkyl compounds (PFAA) together with their persistence and various toxicities have arisen increasing concern. A noninvasive method would improve exposure assessment for large population, especially the children susceptible to contaminants. The aim of the study was to assess the use of PFAA measurements in human nails as a biomarker of exposure to PFAAs. Fingernail, toenail, and blood samples were collected from 28 volunteers. The PFAA concentrations were determined by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Six PFAA were detected in nails, with perfluorooctane sulfonate (PFOS) being the compound with the highest median concentration (33.5 and 26.1 ng/g in fingernail and toenail, respectively). Followed was perfluorononanoate (PFNA), with the median concentrations of 20.4 and 16.8 ng/g, respectively, in fingernail and toenail. Other PFAA detected were perfluorooctanoate (PFOA), perfluorodecanoate (PFDA), perfluorododecanoate (PFDoA), and perfluorotetradecanoate (PFTA), with median levels ranging between 0.19 and 8.94 ng/g. PFOS and PFNA concentrations in fingernail significantly correlated with those in serum. Fingernail PFOS and PFNA levels were 2.8 and 24.4 times, respectively, higher than the serum levels. The accumulation of PFAA in nails, together with its advantages in noninvasive sampling and ability of reflecting long-term exposure, made nails PFAA an attractive biomarker of exposure.

The limited source of human nail plate for studying drug permeation inspired us to develop a nail plate model made of human hair keratin. The manufacturing process consisted of keratin extraction, dialysis, molding, solvent evaporation, and curing, producing a water-resistant film. The permeability of the film was examined using three markers: sodium fluorescein, rhodamine B, and fluorescein isothiocyanate-dextran as water-soluble, lipid-soluble, and large molecule models, respectively. Bovine hoof was used for comparison. First investigation showed that keratin films (thickness 120 μm) resembled hooves (thickness 100 μm) except that these films were more permeable to rhodamine B compared with hooves (1.8-fold, p<0.01). Subsequent investigations using ungual penetration enhancers (urea, thioglycolic acid, and papain) showed that keratin films were generally more susceptible than hooves. This study revealed that the produced keratin film offers a possibility as a human nail plate substitute. However, inclusion of the penetration enhancer must be carefully interpreted., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The risks and benefits of using mercury (Hg) in dental amalgam have long been debated. This study was designed to estimate Hg body burden and its association with dental amalgam fillings in 182 children (ages: 5-15 years) living in Taif City. Hg was measured in urine (UHg), hair (HHg) and toenails (NHg) by the Atomic Absorption Spectrophotometer with Vapor Generator Accessory system. Urinary Hg levels were calculated as both micrograms per gram creatinine (μg/g creatinine) and micrograms per liter (μg/L). We found that children with amalgam fillings (N=106) had significantly higher UHg-C levels than children without (N=76), with means of 3.763 μg/g creatinine versus 3.457 μg/g creatinine, respectively (P=0.019). The results were similar for UHg (P=0.01). A similar pattern was also seen for HHg, with means of 0.614 μg/g (N=97) for children with amalgam versus 0.242 μg/g (N=74) for those without amalgam fillings (P=0). Although the mean NHg was higher in children without amalgam (0.222 μg/g, N=61) versus those with (0.163 μg/g, N=101), the relationship was not significant (P=0.069). After adjusting for many confounders, the multiple logistic regression model revealed that the levels of UHg-C and HHg were 2.047 and 5.396 times higher, respectively, in children with dental amalgam compared to those without (P<0.01). In contrast, a significant inverse relationship was seen between NHg levels and dental amalgam fillings (P=0.003). Despite the controversy surrounding the health impact of dental amalgam, this study showed some evidence that amalgam-associated Hg exposure might be related with symptoms of oral health, such as aphthous ulcer, white patches, and a burning-mouth sensation. Further studies are needed to reproduce these findings. The present study showed that significant numbers of children with or without amalgam had Hg levels exceeding the acceptable reference limits. The detrimental neurobehavioral and/or nephrotoxic effects of such an increased Hg on children should be a cause of concern, and further investigation is warranted. Our results are alarming and indicate an urgent need for biomonitoring and assessment of exposure. Changes in dental practices involving amalgam, especially for children, are highly recommended in order to avoid unnecessary exposure to Hg., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Topical therapy has recently been proposed for treating onychomycosis and other nail disturbances. However, the clinical outcome may be limited by the difficulty of active ingredients effectively penetrating the nail plate. Bovine hoof membranes have been widely used to predict in vitro efficacy of drug products in nail diseases. Many studies have compared bovine hooves with human healthy nails, considering the difference between healthy and unhealthy nails to be negligible., Objectives: To validate bovine hoof slices as a model for human unhealthy nails by investigating the transungual permeation/retention of ciclopirox (CPX) through bovine hoof slices and excised infected human toenails after application of a new film-forming formulation (P-3051). To investigate the ability of CPX to achieve fungicidal concentrations in and through infected toenails., Methods: A new experimental technique based on a permeation unit allowed analysis by high-performance liquid chromatography of the amounts of CPX permeating through and retained in the membranes. The efficacy index was evaluated as follows: amount of permeated CPX/Trichophyton rubrum minimum inhibiting concentration., Results: Extrapolated CPX flux through bovine hoof slices was about 14-fold higher than through infected human toenails, the difference being mainly due to the fourfold higher thickness of the toenails. In toenails, the CPX efficacy index for T. rubrum was positive (>1·0) soon after P-3051 application., Conclusions: This study confirms the validity of bovine hoof slices as a model for infected human nails, and suggests a substantial equivalence between the two models. Following P-3051 application, CPX reaches fungicidal concentrations in and through human infected toenails., (© 2011 The Authors. BJD © 2011 British Association of Dermatologists 2011.)

Easily accessible biomarkers for fetal stress biology are lacking. We here explore whether quantification of major fetal steroids, dehydroepiandrosterone (DHEA) or DHEA sulfate (DHEAS), with liquid chromatography/tandem mass spectrometry in infant nails is a tool to assess fetal stress biology in response to maternal stressful life events during pregnancy. Sufficient nail (≥ 1 mg) was available from 80 infants (93% of those providing samples). The concentration of DHEA, but not DHEAS, was increased in infants of mothers with stressful life events during pregnancy (DHEA: F₁,₄₁=6.105, P=0.018; DHEAS: F₁,₇₇=0.767, P=0.384). DHEA concentrations were not related to maternal stress before pregnancy (F₁,₄₁=0.010, P=0.922). Infant nail DHEA may be a fetal biological correlate of intrauterine exposure to maternal stress. The method promises the first non-invasive retrospective biomarker for intrauterine stress biology, opening new ways for research and clinical applications in fetal medicine, endocrinology, obstetrics, gynecology, and for understanding the developmental origins of health and disease., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Autism is a complex disorder which is heterogeneous in nature with varying degrees of severity for which no specific biological marker has been identified. Several studies are focused on the hair and nail protein pattern as a means to identify specific markers for the diagnosis of many childhood disorders like mental retardation, dyslexia, trichorrhexis nodosa, trichothiodystrophy, etc. The present study is one such approach in investigating the electrophoretic pattern of proteins in hard keratins and their percentage of nitration since nitric oxide production and nitration of tyrosine residues in proteins of autistic children are the emerging topic of research., Methods: We extracted and quantified the proteins from hair and nail samples of autistic children with different grades of severity, [low functioning autism (LFA), medium functioning autism (MFA), and high functioning autism (HFA)] and also from age- and sex-matched normal children. Protein pattern was evaluated by one-dimensional SDS-PAGE and the separated proteins were made to cross react with anti-nitro tyrosine antibody by Western blot analysis. Blood levels of TBARS, NO, GSH, vitamins A and C, SOD and GPx were also determined., Results: In the autistic groups, decreased concentration of protein in both hair and nail samples was observed. The SDS-PAGE analysis revealed that there was a significant decrease in both high and low sulfur proteins in the hair and nail extracts of autistic children and the Western blot analysis showed increased percentage of nitration of low sulfur proteins in autistic children when compared with normal children. Decreased levels of enzymatic and non-enzymatic antioxidants and increased concentration of TBARS and NO were also observed in the blood of autistic children. The LFA group showed more significant alteration (p<0.001) in the concentration of proteins (in hair and nail) and percentage of nitration when compared with HFA and controls., Conclusion: Lower protein content and higher percentage of nitration in hair and nail of autistic children correlated with their degrees of severity., (Copyright © 2011 Elsevier B.V. All rights reserved.)

In the frozen longitudinal section of the nail unit, CD10 was previously found in nail mesenchymal cells beneath nail matrix, and we proposed calling the nail mesenchymal cells onychofibroblasts. In this study, to further characterize nail mesenchyme containing onychofibroblasts, we examined the expression of several mesenchymal markers immunohistochemically in transverse paraffin sections of the nail unit. CD10 was strongly expressed in the nail mesenchyme containing onychofibroblasts beneath the nail matrix. However, CD10 was not observed in dermal fibroblasts and surrounding extracellular matrix of the lateral nail fold (LNF), except around blood vessels and eccrine structures. In addition, versican was expressed diffusely in the nail mesenchyme containing onychofibroblasts in contrast to the dermis of LNF. Fibrillin, which is a major component of elastic fiber in the dermis, was expressed very weakly on the nail mesenchyme below the nail matrix but was expressed strongly in the dermis of LNF. These findings support the existence of specialized nail mesenchyme containing onychofibroblasts that is distinguished from the dermis of LNF.

Background: Despite oxidized low density lipoprotein (ox-LDL) plays important roles in the pro-inflammatory and atherosclerotic processes, the relationships with metabolic and oxidative stress biomarkers have been only scarcely investigated in young adult people. Thus, the aim of this study was to assess plasma ox-LDL concentrations and the potential association with oxidative stress markers as well as with anthropometric and metabolic features in healthy young adults., Methods: This study enrolled 160 healthy subjects (92 women/68 men; 23±4 y; 22.0±2.9 kg/m2). Anthropometry, body composition, blood pressure, lifestyle features, biochemical data, and oxidative stress markers were assessed with validated tools. Selenium, copper, and zinc nail concentrations were measured by atomic absorption spectrophotometry., Results: Total cholesterol (TC), LDL-c and uric acid concentrations, TC-to-HDL-c ratio, and glutathione peroxidase (GPx) activity were positive predictors of ox-LDL concentrations, while nail selenium level (NSL) was a negative predictor, independently of gender, age, smoking status, physical activity. Those individuals included in the highest tertile of GPx activity (≥611 nmol/[mL/min]) and of NSL (≥430 ng/g of nail) had higher and lower ox-LDL concentrations, respectively, independently of the same covariates plus truncal fat or body mass index, and total cholesterol or LDL-c concentrations., Conclusions: Ox-LDL concentrations were significantly associated with lipid biomarkers, GPx activity, uric acid concentration, and NSL, independently of different assayed covariates, in young healthy adults. These findings jointly suggest the early and complex relationship between lipid profile and redox status balance.