Coxsackievirus A10 impairs nail regeneration and induces onychomadesis by mimicking DKK1 to attenuate Wnt signaling.

Coxsackievirus A10 (CV-A10) infection, a prominent cause of childhood hand-foot-and-mouth disease (HFMD), frequently manifests with the intriguing phenomenon of onychomadesis, characterized by nail shedding. However, the underlying mechanism is elusive. Here, we found that CV-A10 infection in mice could suppress Wnt/ß-catenin signaling by restraining LDL receptor-related protein 6 (LRP6) phosphorylation and ß-catenin accumulation and lead to onychomadesis. Mechanistically, CV-A10 mimics Dickkopf-related protein 1 (DKK1) to interact with Kringle-containing transmembrane protein 1 (KRM1), the CV-A10 cellular receptor. We further found that Wnt agonist (GSK3ß inhibitor) CHIR99021 can restore nail stem cell differentiation and protect against nail shedding. These findings provide novel insights into the pathogenesis of CV-A10 and related viruses in onychomadesis and guide prognosis assessment and clinical treatment of the disease.

Patient Recovery from COVID-19 Infections: Follow-Up of Hair, Nail, and Cutaneous Manifestations.

BACKGROUND: COVID-19 is a pandemic disease worldwide. Although cutaneous manifestations may present in affected patients, there have been limited studies on the cutaneous findings and hair and nail abnormalities after discharge. OBJECTIVE: To establish the cutaneous manifestations, hair and scalp disorders, and nail abnormalities in patients who recovered from COVID-19 infections. METHODS: A retrospective chart review and telephone interviews were conducted to determine the cutaneous manifestations, hair and scalp disorders, and nail abnormalities of patients aged over 18 years who were diagnosed with COVID-19 infections at Siriraj Hospital, Bangkok, Thailand, between January and June 2020. RESULTS: Ninety-three patients with prior COVID-19 infections participated in the study. The COVID-19 severity had been mild for most (71%). Cutaneous manifestations were reported in 8 patients (8.6%), with the common skin conditions being maculopapular rash and urticaria. The onsets of the skin conditions were before admission (1%), during admission (4.3%), and after discharge (3.2%). Increased hair shedding was also reported in 22 patients (23.7%), with a female predominance. Three patients were affected during admission, while the others were affected after discharge. The patients with moderate, severe, and critical COVID-19 infections experienced significantly more hair shedding than those with asymptomatic and mild diseases. Only 2 patients with mild COVID-19 disease reported nail abnormalities (chromonychia and brittle nails). CONCLUSIONS: Cutaneous manifestations, hair disorders, and nail abnormalities can occur in patients with COVID-19 after their discharge from hospital. Patients should therefore be followed up in anticipation of dermatological problems.

Assessment of the nail penetration of antifungal agents, with different physico-chemical properties.

Onychomycosis, or fungal nail infection, is a common fungal infection largely caused by dermatophyte fungi, such as Trichophyton rubrum or Trichophyton mentagrophytes, which affects a significant number of people. Treatment is either through oral antifungal medicines, which are efficacious but have significant safety concerns, or with topical antifungal treatments that require long treatment regimens and have only limited efficacy. Thus, an efficacious topical therapy remains an unmet medical need. Among the barriers to topical delivery through the nail are the physico-chemical properties of the antifungal drugs. Here, we explore the ability of a range of antifungal compounds with different hydrophilicities to penetrate the nail. Human nail discs were clamped within static diffusion (Franz) cells and dosed with equimolar concentrations of antifungal drugs. Using LC-MS/MS we quantified the amount of drug that passed through the nail disc and that which remained associated with the nail. Our data identified increased drug flux through the nail for the more hydrophilic compounds (caffeine as a hydrophilic control and fluconazole, with LogP -0.07 and 0.5, respectively), while less hydrophilic efinaconazole, amorolfine and terbinafine (LogP 2.7, 5.6 and 5.9 respectively) had much lower flux through the nail. On the other hand, hydrophilicity alone did not account for the amount of drug associated with/bound to the nail itself. While there are other factors that are likely to combine to dictate nail penetration, this work supports earlier studies that implicate compound hydrophilicity as a critical factor for nail penetration.

Acquired Leukonychia of the Distal Nail Plate: A Morphologic and Proteomic Analysis.

Leukonychia, or whitening of the nail plate, is a common disease that was first described in 1919. Leukonychia is classified as acquired or congenital and may be due to abnormality of the nail bed (pseudoleukonychia) or nail plate (true leukonychia). The distal whitened area of the nail plate was clipped from a 31-year-old woman with striated leukonychia and a 32-year-old man and 34-year-old woman with punctate leukonychia. Routine hematoxylin and eosin staining of all clipped samples was performed. A piece of nail with leukonychia and a normal nail from case 2 were sent to the Mayo Clinic for mass spectrometric analysis. On hematoxylin and eosin examination, all leukonychia samples showed odd-appearing eosinophilic linear parakeratinization in the mid-segment of the nail plate. Mass spectrometric analysis of case 2 revealed serum proteins (albumin, serotransferrin IgG, gamma chain, IgG lambda chain, and haptoglobulin) and hair proteins that were not found in the keratin content of the normal nail (keratin type Ha1 and cuticular keratin Ha4). This is the first description of odd-appearing linear parakeratosis and the first proteomic analysis showing abnormal protein content in acquired leukonychia.

Cyclophosphamide-induced melanonychia in a patient with steroid dependent nephrotic syndrome: A rare presentation.

Melanonychia is described as a brown to black pigmentation of nail, due to stimulation and hyperplasia of nail matrix. Various systemic disorders, trauma, inflammatory disorders, fungal infections, drugs, benign melanocytic hyperplasia, etc., are responsible for this condition, and most of them are benign. A number of chemotherapeutic agents can cause melanonychia. Cases of cyclophosphamide-induced melanonychia are not frequent. We report a 38-year-old female, a known case of steroid dependent nephrotic syndrome, who developed melanonychia on starting treatment with cyclophosphamide. It is a benign condition, which resolves on discontinuation of the drug.

Perianal and perineal keratoacanthoma: Two cases demonstrating histologic similarity to subungual keratoacanthoma.

Perianal keratoacanthomas are rare, with 10 cases reported to date. Perineal keratoacanthoma has not previously been described. In this report, we describe two cases of keratoacanthoma, one perianal and one perineal. Both lesions show prominent dyskeratotic keratinocytes, with striking and curious histologic resemblance to subungual keratoacanthoma.

The nail as an investigative tool in medicine: What a dermatologist ought to know.

The nail is an important skin appendage, but not many dermatologists are aware of the importance it receives outside our specialty. This article focuses on the nail in non-dermatological contexts. The nail is a keratinized matrix capable of continuous growth with the ability to incorporate various compounds within its structure. Therefore it can be used to monitor long-term consumption of drugs. It is also an excellent source of germ-line DNA for genetic analyses. With an increased undrstanding of nail physiology, there is now a better understanding of its connection to various pathologies as well. Nails, being peripherally placed, are easy to sample without significant discomfort to the patient, making them a valuable diagnostic tool. For this narrative review, we carried out a PubMed search using the key words "nail clipping," "nail DNA," "nail diabetes mellitus;" "nail clipping oncology," and "nail forensics". Retrieved articles were searched for information pertaining to non-dermatologic uses of nail for evaluation, which is presented in a narrative fashion. It is clear from recent literature that the nail is not just an inert skin appendage, but a dynamic window into the ever-changing metabolic and genetic milieu. We highlight the numerous roles of nail specimens, as well as point towards future research needed therein.

Diagnosis of nail psoriasis: evaluation of nail-derived microRNAs as potential novel biomarkers.

BACKGROUND: MicroRNA levels in sera or hair may potentially be useful biomarkers for various diseases. The diagnosis of nail diseases is sometimes difficult, and nail psoriasis without skin lesions is indistinguishable from nail changes caused by other diseases. OBJECTIVES: We evaluated nail microRNA levels as biomarkers for the diagnosis of psoriasis patients. MATERIALS & METHODS: MicroRNA levels were examined in psoriasis patients with (11 patients) and without (six patients) nail changes. Normal control nails were collected from 17 healthy subjects. Eight patients with other diseases who also had nail changes were also included as disease controls. RESULTS: Microarray, real-time PCR, and in situ hybridisation indicated that the expression levels of nail miR-4454 were decreased in psoriasis patients with nail changes, compared to those patients with other diseases involving nail change, or healthy subjects. The miR-4454 levels in nails showed a significant inverse correlation with the Nail Psoriasis Severity Index (NAPSI) score, suggesting that nail miR-4454 levels reflect nail condition. CONCLUSION: The levels of microRNAs in nails may be suitable biomarkers for diagnosis or evaluation of disease activity of psoriasis.

Efinaconazole 10% and Tavaborole 5% Penetrate Across Poly-ureaurethane 16%: Results of In Vitro Release Testing and Clinical Implications of Onychodystrophy in Onychomycosis.

BACKGROUND: Poly-ureaurethane has been previously described for the management of dry, brittle, and in general, dystrophic nails. The polymer yields a waterproof, breathable barrier to protect the nail plate and prevent further damage to the nail, while regulating transonychial water loss (TOWL). Because nail dystrophy and dessication are contributing factors to onychomycosis, a barrier that protects the nail but also allows a topical antifungal to permeate its shield is potentially an advantageous combination. Oral antifungals such as terbinafine, itraconazole, and fluconazole, as well as the newer topical antifungals efinaconazole and tavaborole (although formulated to penetrate the nail unit and work with the porosity and inherent electrical charge of the nail plate), do not take into account nail damage that has been created from years of harboring a dermatophyte infection. Up to 50% of cases presumed to be onychomycosis are in fact onychodystrophy without fungal infection, and laboratory testing for fungus should be obtained prior to initiating antifungal treatment. Whether a nail has onychomycosis, or onychodystrophy due to other causes, barrier function and structural integrity are compromised in diseased nails, and should be addressed. A poly-ureaurethane barrier that protects against wetting/drying, fungal reservoirs, and microtrauma, followed by the addition of oral or topical antifungals after laboratory fungal confirmation may optimize outcomes in the treatment of onychomycosis.
OBJECTIVE: The purpose of this work was to determine through in vitro release testing (IVRT) whether poly-ureaurethane 16% allows for penetration of efinaconazole 10% or tavaborole 5%. Results could spur subsequent clinical studies which would have implications for the addition of an antifungal based on fungal confirmation, after addresssing the underlying nail dystrophy primarily.
METHODS: A vertical diffusion cell system was used to evaluate the ability of efinaconazole 10% and tavaborole 5% to penetrate across poly-ureaurethane 16%. The diffusion cells had a 1.0 cm2 surface area and approximately 8 mL receptor volume. Poly-ureaurethane 16% was applied to a 0.45 μm nylon membrane and allowed to dry before use. Efinaconazole 10% or tavaborole 5% was then applied to the poly-ureaurethane 16% coated membrane, and samples were pulled from the receptor chamber at various times. Reverse phase chromatography was then used to assess the penetration of each active ingredient across the membrane.
RESULTS: The flux and permeability of efinaconazole or tavaborole across poly-ureaurethane 16% were determined from efinaconazole 10% or tavaborole 5%, respectively. The flux and permeability of efinaconazole were determined to be 503.9 +/- 31.9 μg/cm2/hr and 14.0 +/- 0.9 nm/sec. The flux and permeability of tavaborole were determined to be 755.5 +/- 290.4 μg/cm2/hr and 42.0 +/- 16.1 nm/sec.
CONCLUSION: In addition to the treatment of onychoschizia, onychorrhexis, and other signs of severe dessication of the nail plate, a barrier that regulates TOWL should be considered in the management onychomycosis to address barrier dysfunction and to promote stabilization of the damaged nail. Previously published flux values across the nail are reported to be 1.4 μg/cm2/day for efinaconazole and 204 μg/cm2/day for tavaborole. These values are substantially lower than the herein determined flux for both molecules across poly-ureaurethane 16%. A comparison of the data suggests that poly-ureaurethane 16%, if used prior to efinaconazole or tavaborole, would not limit the ability of either active ingredient to access the nail, and therefore, would be unlikely to reduce their antifungal effect. Onychodystrophy is inherent in, and often precedes onychomycosis, and consideration should be given for initiation of treatment in the same sequence: stabilizing and protecting the nail plate barrier primarily, and subsequently adding oral or topical antifungals after laboratory confirmation. Future clinical studies will be needed to determine combination efficacy for in vivo use.

J Drugs Dermatol. 2016;15(9):1116-1120.

Nail disorders in older people, and aspects of their pharmaceutical treatment.

The aim of this paper was to explore how aging influences the nail unit, its disorders and its response to treatment, and to identify some of the age-related gaps in the ungual drug delivery literature. Aging causes obvious changes to the nail, some of which are inherently due to old age, while others are due to diseases/conditions which become more prevalent as we age. Alterations in the nail plate's colour, contour, thickness, fragility, surface features, cell size, chemical composition and growth rate are some of the changes, with toenails and fingernails showing different effects. With respect to disease, the incidence of onychomycosis - the most common nail disorder - is considerably higher in older people. Similarly, brittle nails become more common as we age. In contrast, the literature about aging and the incidence of nail psoriasis is inconclusive, although, it is clear that as one gets older, the negative impact of nail psoriasis on one's quality of life decreases. Pharmaceutical treatment of the diseases comprises local and systemic therapies, sometimes in combination. Systemic therapies have the inherent disadvantages of adverse systemic effects, drug interactions and the need for monitoring, disadvantages which are especially problematic for older people who are more likely to suffer from co-morbidities and be on other medications. Topical therapy avoids such disadvantages. However, the success rates of commercially available preparations are low, and older people may need help with their application. It is also proposed that regular inspection and grooming of nails should become part of routine care of older people, as these would provide opportunities to identify and treat any problems at an earlier stage.

Application of Hansen Solubility Parameters to predict drug-nail interactions, which can assist the design of nail medicines.

We hypothesised that Hansen Solubility Parameters (HSPs) can be used to predict drug-nail affinities. Our aims were to: (i) determine the HSPs (δD, δP, δH) of the nail plate, the hoof membrane (a model for the nail plate), and of the drugs terbinafine HCl, amorolfine HCl, ciclopirox olamine and efinaconazole, by measuring their swelling/solubility in organic liquids, (ii) predict nail-drug interactions by comparing drug and nail HSPs, and (iii) evaluate the accuracy of these predictions using literature reports of experimentally-determined affinities of these drugs for keratin, the main constituent of the nail plate and hoof. Many solvents caused no change in the mass of nail plates, a few solvents deswelled the nail, while others swelled the nail to varying extents. Fingernail and toenail HSPs were almost the same, while hoof HSPs were similar, except for a slightly lower δP. High nail-terbinafine HCl, nail-amorolfine HCl and nail-ciclopirox olamine affinities, and low nail-efinaconazole affinities were then predicted, and found to accurately match experimental reports of these drugs' affinities to keratin. We therefore propose that drug and nail Hansen Solubility Parameters may be used to predict drug-nail interactions, and that these results can assist in the design of drugs for the treatment of nail diseases, such as onychomycosis and psoriasis. To our knowledge, this is the first report of the application of HSPs in ungual research.

Size and Charge Dependence of Ion Transport in Human Nail Plate.

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.

Subungual leiomyoma in the left thumb of a 16-year-old female.

Cutaneous leiomyomata, which are benign smooth muscle neoplasms, commonly present as dermal-based nodules or papules with smooth borders and firm consistency. Digital, particularly subungual leiomyomata are quite rare. A 16-year-old female presented to nail clinic complaining of discoloration of the lunula of the left thumbnail for 2.5 months. On initial examination, a pink longitudinal band was present in the center of the nail plate, with yellow discoloration and distal onycholysis. The patient had only mild tenderness with firm palpation, and did not recall trauma of the area. A nail matrix biopsy was performed to determine the etiology of the lesion. Microscopic examination demonstrated a well-demarcated dermal-based spindle-cell fascicular proliferation. Bland cells exhibited eosinophilic cytoplasm and elongate nuclei with blunt ends and minimal cytologic atypia. Prominent nucleoli, mitoses or necrosis were not appreciated. Immunohistochemical stains for smooth muscle actin and caldesmon highlighted the cells. Contrarily, S-100, epithelial membrane antigen, p63, factor XIIIa, CD34, CD68 and p75 were all negative. Ki-67 showed a low proliferative index. The immunoprofile combined with the morphologic features were interpreted as subungual leiomyoma. Subungual leiomyoma is a very rare diagnosis. We seek to bring awareness and expedite the diagnosis in patients with this lesion.

Invasive onychocytic carcinoma.

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.