Michael G. Wilkerson

Nanoparticles: small and mighty

The properties of engineered nanomaterials and nanoparticles such as zinc oxide and titanium dioxide may differ substantially from naturally occurring materials and particles. Nanoparticles have unique physical properties making them ideal for use in various skin care products currently on the market. Nano‐preparations are currently under investigation as novel treatments of acne vulgaris, recurrent condyloma accuminata, atopic dermatitis, hyperpigmented skin lesions, and other non‐dermatologic diseases. Because of their increased surface area, nanoparticles have increased reactivity and a small size allowing for enhanced mobility through the human body and environment. As their use becomes more prevalent, nanoparticles are being scrutinized for their safety and long‐term effects. This review discusses the benefits of nanoparticles in dermatological therapies and skin care products as well as potential disadvantages and possible mechanisms of toxicity.

Red lunulae revisited: A clinical and histopathologic examination

Red lunulae are associated with rheumatoid arthritis, systemic lupus erythematosus, alopecia areata, cardiac failure, hepatic cirrhosis, lymphogranuloma venereum, psoriasis, carbon monoxide poisoning, twenty-nail dystrophy, and reticulosarcoma. We examined four patients with red lunulae. Three had chronic obstructive pulmonary disease. Two of these three were alcohol abusers and were without any of the conditions previously associated with red lunulae. Two of the four also had palmar erythema. Histopathologic examination of the red lunula in one of the four cases did not show signs of neovascularization. We report our findings in these patients, which suggest that red lunulae result from increased arteriolar blood flow, a vasodilatory capacitance phenomenon, or changes in the optical properties of the overlying nail so that normal blood vessels become more apparent.

Squaric acid and esters: Analysis for contaminants and stability in solvents

Two squaric acid diesters, squaric acid diethyl ester (SADEE) and squaric acid dibutyl ester (SADBE), have been suggested as replacements for 2,4-dinitrochlorobenzene in the treatment of alopecia areata and alopecia totalis. We synthesized these squaric acid diesters and examined them for the presence of carcinogenic contaminants, hexachlorobutadiene and tetrachloro-2-cyclobutene-1-one, by gas chromatography-mass spectrometry (GC-MS). The stability of SADBE to hydrolysis by water in acetone, butanol, isopropanol, and absorbent ointment with and without molecular sieves was examined. The stability of SADEE in ethanol and acetone, with and without molecular sieves, was also studied. Hydrolysis products were detected by their formation of a colored complex with ferric chloride. This complex absorbs in the visual range at 480 nm, thus affording a convenient method for determination of the concentration of free squaric acid in a solution. No contaminants were found by positive or negative ion detection in our GC-MS system. At the end of 3 weeks the extent of hydrolysis was greater in alcohols than in acetone when 10 and 100 molar excess of water were added to the solutions. In the presence of molecular sieves, hydrolysis was reduced even at 100 molar excess of added water in alcohol ar acetone. However, under storage conditions without sieves, acetone solutions and alcohol solutions were equally stable over a period of 2 months. Molecular sieves reduce hydrolysis of squarate esters in the presence of a large molar excess of water, regardless of solvent.

Chronic exposure to nanosized, anatase titanium dioxide is not cyto- or genotoxic to Chinese hamster ovary cells

Titanium dioxide nanoparticles (nano‐TiO2) are widely used in cosmetics, skin care products, paints, and water treatment processes. Disagreement remains regarding the safety of nano‐TiO2, and little epidemiological data is available to provide needed resolution. Most studies have examined effects using acute exposure experiments with relatively few studies using a chronic exposure design. We examined cyto‐ and genotoxicity in CHO‐K1 cells following 60 days of continuous exposure to defined levels of nano‐TiO2 (0, 10, 20, or 40 μg/ml). Oxidative stress increased in a concentration‐dependent manner in short‐ (2 days) and long‐term cultures, but long‐term cultures had lower levels of oxidative stress. The primary reactive oxygen species appeared to be superoxide, and ROS indicators were lowered with the addition of superoxide dismutase (SOD). No cyto‐ or genotoxic effects were apparent using the XTT, trypan‐blue exclusion, and colony‐forming assays for viability and the Comet and Hprt gene mutation assays for genotoxicity. Nano‐TiO2 increased the percentage of cells in the G2/M phase of the cell cycle, but this effect did not appear to influence cell viability or cell division. Cellular Ti content was dose‐dependent, but chronically exposed cells had lower amounts than acutely exposed cells. CHO cells appear to adapt to chronic exposure to nano‐TiO2 and detoxify excess ROS possibly through upregulation of SOD in addition to reducing particle uptake. Environ. Mol. Mutagen. 2011.

Lichenoid histopathologic changes in patients with clinical diagnoses of exfoliative dermatitis

Among 30 patients who received a clinical diagnosis of exfoliative dermatitis and were hiopsied between 1982 and 1990, nine showed microscopic features of lichenoid dermatitis. Clinical information was available in eight of these cases. Possible etiologic factors included lymphoma, herpes simplex infection, connective tissue disease, and (in five cases) reactions to drugs. In each instance, microscopic features included a superficial perivascular lymphocytic infiltrate involving the dermal-epidermal interface, vacuolar alteration of the basilar layer, and individually necrotic keratinocytes at all levels of the epidermis. Such microscopic changes are not usually described in connection with exfoliative dermatitis, with the possible exception of those cases related to lichen planus or lupus erythematosus. Disseminated lichenoid drug eruption is one possible interpretation of the drug-induced cases. Erythema multiforme is another condition that has similar microscopic features and has been associated with drugs (many of which also cause exfoliative dermatitis), infectious agents, neoplasms, and connective tissue diseases. Lichenoid dermatitis can become generalized and clinically mimic an exfoliative dermatitis. Many, but not all, of these eruptions may be triggered by drugs.

Contaminants of dinitrochlorobenzene

DNCB (2,4-dinitrochlorobenzene) is used in the treatment of alopecia areata, recalcitrant verrucae, and for evaluating immunocompromised patients. Currently, there is no pharmaceutical grade of DNCB available for clinical use. Recently, no nitrochlorobenzene contamination was found with the use of positive ion detection gas chromatography--mass spectrometry. We examined six commercial sources of DNCB, with the use of negative ion detection gas chromatography--mass spectrometry, for volatile impurities such as nitrochlorobenzene which might remain from the manufacturing process. The use of negative ion detection increases the sensitivity of this technic to benzene rings substituted with electron withdrawing groups like the nitrochlorobenzenes. We found that all sources of DNCB contain various combinations of nitrochlorobenzene, dinitrobenzene, nitrodichlorobenzene, and other isomers of DNCB. Nitrochlorobenzene has been shown to be mutagenic in the Ames test and carcinogenic in animal studies. The presence of nitrochlorobenzene and other contaminants in commercial grades of DNCB raises questions about the continued clinical application of this agent.

Role of oligomers in the amyloidogenesis of primary cutaneous amyloidosis

BACKGROUND Primary cutaneous amyloidosis (PCA) describes a heterogeneous group of cutaneous diseases characterized by amyloid deposition; this may manifest as macules, papules, or nodules, depending on the subtype involved. To date, relatively little is known about the process of amyloidogenesis in the skin; however, investigators recently have identified small amyloid species, known as oligomers, which give rise to large amyloid fibrillar aggregates. OBJECTIVE The purpose of the current study was to identify small oligomers in patients with PCA using novel immunohistochemical techniques and to examine our findings in light of previous hypotheses of amyloid formation in these diseases. METHODS Six cases of PCA were analyzed using Congo red, thioflavin S, and hematoxylin-eosin. We also analyzed these samples with the novel oligomer-specific conformational antibody I-11 to detect the small, misfolded protein oligomers. Semiquantitative analysis was performed on these samples to grade the amount of amyloid aggregates and oligomers detected in the skin samples with light and polarized microscopy. RESULTS In the cases examined, we detected intracellular oligomers in the basal cell layer of the epidermis and the surrounding cells in the dermis. We also were able to detect large aggregates of amyloid in our samples and to correlate the relationship of oligomers to amyloid aggregates in accordance with previous studies on cutaneous amyloidosis and other amyloid-related diseases. LIMITATIONS Small sample size is a limitation. CONCLUSIONS PCA is an amyloid-related disease that likely follows a similar mechanism as other more intensively studied amyloid diseases.

Trichodysplasia spinulosa: A rare complication of immunosuppression

Trichodysplasia spinulosa (TS) is a recently described rare disease of immunosuppressed patients characterized by folliculocentric papules and keratin spicules. The condition is highly associated with the TS-associated polyomavirus (TSPyV); however, the causal mechanism remains undiscovered. Currently, there is a dearth of case reports on this condition, and treatment for TS is not well established. We report a case of TS that successfully responded to reduction of immunosuppression.

Transitional cell neoplasm of the nasolacrimal duct associated with human papillomavirus type 11

Background: Tumors of the lacrimal sac are rare but noteworthy because of their significant potential to become malignant or life‐threatening if treatment is delayed. Dermatologists may be the first to encounter such neoplasms.

Exacerbation of bullous pemphigoid after hand, foot, and mouth disease treated with rituximab.

Bullous pemphigoid (BP) is a chronic autoinflammatory, blistering disease typically affecting the elderly. It is the most common disorder within the pemphigoid group and represents the most frequent autoimmune blistering disease in general.1, 2 The etiopathogenesis involves the induction of an inflammatory cascade that is hypothesized to include many triggering factors, one of which includes infections.2 Here we present a man with a history of stable BP and subsequent severe flaring of his disease after contracting hand, foot, and mouth disease (HFMD). We also discuss rituximab as an adequate therapy in treating refractory BP.