Prenatal Treatment of X-Linked Hypohidrotic Ectodermal Dysplasia using Recombinant Ectodysplasin in a Canine Model.

X-linked hypohidrotic ectodermal dysplasia (XLHED) is caused by defects in the EDA gene that inactivate the function of ectodysplasin A1 (EDA1). This leads to abnormal development of eccrine glands, hair follicles, and teeth, and to frequent respiratory infections. Previous studies in the naturally occurring dog model demonstrated partial prevention of the XLHED phenotype by postnatal administration of recombinant EDA1. The results suggested that a single or two temporally spaced injections of EDI200 prenatally might improve the clinical outcome in the dog model. Fetuses received ultrasound-guided EDI200 intra-amniotically at gestational days 32 and 45, or 45 or 55 alone (of a 65-day pregnancy). Growth rates, lacrimation, hair growth, meibomian glands, sweating, dentition, and mucociliary clearance were compared in treated and untreated XLHED-affected dogs, and in heterozygous and wild-type control dogs. Improved phenotypic outcomes were noted in the earlier and more frequently treated animals. All animals treated prenatally showed positive responses compared with untreated dogs with XLHED, most notably in the transfer of moisture through paw pads, suggesting improved onset of sweating ability and restored meibomian gland development. These results exemplify the feasibility of ultrasound-guided intra-amniotic injections for the treatment of developmental disorders, with improved formation of specific EDA1-dependent structures in dogs with XLHED.

Cellular and Metabolic Basis for the Ichthyotic Phenotype in NIPAL4 (Ichthyin)-Deficient Canines.

Mutations in several lipid synthetic enzymes that block fatty acid and ceramide production produce autosomal recessive congenital ichthyoses (ARCIs) and associated abnormalities in permeability barrier homeostasis. However, the basis for the phenotype in patients with NIPAL4 (ichthyin) mutations (among the most prevalent ARCIs) remains unknown. Barrier function was abnormal in an index patient and in canines with homozygous NIPAL4 mutations, attributable to extensive membrane stripping, likely from detergent effects of nonesterified free fatty acid. Cytotoxicity compromised not only lamellar body secretion but also formation of the corneocyte lipid envelope (CLE) and attenuation of the cornified envelope (CE), consistent with a previously unrecognized, scaffold function of the CLE. Together, these abnormalities result in failure to form normal lamellar bilayers, accounting for the permeability barrier abnormality and clinical phenotype in NIPA-like domain-containing 4 (NIPAL4) deficiency. Thus, NIPAL4 deficiency represents another lipid synthetic ARCI that converges on the CLE (and CE), compromising their putative scaffold function. However, the clinical phenotype only partially improved after normalization of CLE and CE structure with topical ω-O-acylceramide because of ongoing accumulation of toxic metabolites, further evidence that proximal, cytotoxic metabolites contribute to disease pathogenesis.

DFD-01 Reduces Transepidermal Water Loss and Improves Skin Hydration and Flexibility.

INTRODUCTION: In plaque psoriasis, the benefit of topical steroids is well established. The vehicle formulation of topical steroids may also provide benefit in addition to the effects of the steroid itself. DFD-01 (betamethasone dipropionate spray, 0.05%) is a formulation composed of a topical steroid in an emollient-like vehicle that enhances penetration to the target site of inflammation in the skin. The aim of this study was to assess the effect of DFD-01 and its vehicle on skin hydration and barrier function in compromised skin and to evaluate its effect on flexibility in healthy skin. METHODS: Eighteen healthy white volunteers were enrolled in each of two studies. In Study 1, dry shaving of volar forearms created a compromised skin barrier, through which transepidermal water loss (TEWL) was measured using an evaporimeter. Capacitance, a measure of epidermal hydration, was also measured at baseline and at 1, 2 and 4 h after application of DFD-01 or its vehicle formulation. In Study 2, intact skin flexibility was tested with a cutometer before and at 1, 2 and 4 h after application of DFD-01 or vehicle. RESULTS: In Study 1, both DFD-01 and its vehicle were effective at reducing TEWL through the compromised stratum corneum. Capacitance measurements confirmed this finding; razor-chafed skin treated with either DFD-01 or vehicle exhibited levels of skin hydration similar to unshaved control skin. Study 2 found softening and greater flexibility of normal skin treated with either DFD-01 or vehicle compared with nontreated control skin samples. CONCLUSIONS: These tests suggest that the DFD-01 formulation and its vehicle are each effective at retaining moisture within a damaged skin barrier and for softening and increasing the flexibility of intact skin. FUNDING: Dr. Reddy's Laboratories.

Measuring niacin-associated skin toxicity (NASTy) stigmata along with symptoms to aid development of niacin mimetics.

Though cardioprotective, niacin monotherapy is limited by unpleasant cutaneous symptoms mimicking dermatitis: niacin-associated skin toxicity (NASTy). Niacin is prototypical of several emerging drugs suffering off-target rubefacient properties whereby agonizing the GPR109A receptor on cutaneous immune cells provokes vasodilation, prompting skin plethora and rubor, as well as dolor, tumor, and calor, and systemically, heat loss, frigor, chills, and rigors. Typically, NASTy effects are described by subjective patient-reported perception, at best semi-quantitative and bias-prone. Conversely, objective, quantitative, and unbiased methods measuring NASTy stigmata would facilitate research to abolish them, motivating development of several objective methods. In early drug development, such methods might better predict clinical tolerability in larger clinical trials. Measuring cutaneous stigmata may also aid investigations of vasospastic, ischemic, and inflammatory skin conditions. We present methods to measure NASTy physical stigmata to facilitate research into novel niacin mimetics/analogs, detailing characteristics of each technique following niacin, and how NASTy stigmata relate to symptom perception. We gave niacin orally and measured rubor by colorimetry and white-light spectroscopy, plethora by laser Doppler flowmetry, and calor/frigor by thermometry. Surprisingly, each stigma's abruptness predicted symptom perception, whereas peak intensity did not. These methods are adaptable to study other rubefacient drugs or dermatologic and vascular disorders.

Randomized comparison of a silicone tape and a paper tape for gentleness in healthy children.

PURPOSE: To compare the relative gentleness of a silicone tape to a paper tape in healthy infants and children. DESIGN: A randomized, grader-blinded, comparative study. SUBJECTS AND SETTING: The sample group comprised 24 healthy infants and children 9.1 to 46.7 months of age (mean ± SEM, 34.0 ± 2.21). The study was conducted at a dermatological research facility (cyberDERM, Inc) located in Broomall, Pennsylvania. All volunteers were recruited from the surrounding community. METHODS: Tapes measuring 1 × 1.5 inches were randomly applied to the left and right intrascapular regions of the upper back. Tapes were removed in a standardized fashion after 24 hours. The primary study outcome, gentleness, was based on visual assessments of skin damage, discomfort, and quantification of keratin removal. Four-point scales were used to assess skin damage, and a 10-point Faces, Legs, Activity, Cry, and Consolability instrument was used to assess discomfort. Secondary assessments included hair removal, tape edge-lift assessments, and parent preference for either tape. RESULTS: There was a significantly lower mean ± SEM erythema response for the silicone tape (0.93 ± 0.14 vs 1.35 ± 0.11, P = .0129) than for the paper tape. No measurable epidermal stripping occurred with the silicone tape compared to a mean ± SEM response of 0.29 ± 0.11 for the paper tape (P = .0039). Discomfort was significantly lower (P = .0002) for the silicone tape as compared to the paper tape (Faces, Legs, Activity, Cry, and Consolability score mean difference from baseline 0.5 vs 3.3, P = .0002). Keratin removal was significantly less with the silicone as compared to paper tape (8.7 ± 0.5 µg/mL vs 15.2 ± 1.3 µg/mL, P < .0001). Few hairs were removed with either tape. There was significantly less (P < .0001) edge-lift with the paper tape than the silicone tape; no statistically significant differences in parent preferences for silicone versus paper tapes were measured (P = .3359). CONCLUSIONS: Gentleness assessments favored the silicone tape compared to a paper tape and warrant further clinical investigation in the neonatal intensive care unit.

A randomized and controlled comparison of gentleness of 2 medical adhesive tapes in healthy human subjects.

PURPOSE: To compare gentleness of a silicone tape to a paper tape and to an untreated control. DESIGN: Controlled, randomized, grader-blinded cohort trial. SUBJECTS AND SETTING: The sample group comprised 28 healthy volunteers aged 55 years and older (median age = 63 years) with a Fitzpatrick Skin Type of I, II, or III. All volunteers were recruited from the greater Philadelphia area and the study was conducted at a dermatological research facility specializing in noninvasive instrumental measurements. METHODS: Tapes were applied and removed daily (excluding weekends) to 2 of 3 sites on the left and right volar forearms over an 11-day period. The center site on each forearm was left untreated and tapes were randomized to the proximal and distal sites. The primary assessment was transepidermal water loss (TEWL); secondary assessments included erythema/edema, denudation/skin-stripping, and subject self-evaluations. Study personnel conducting the primary and secondary assessments were not involved with treatments to maintain the blinded nature of the study. The identity of the 2 tapes was not revealed to the subjects until after conclusion of the study. RESULTS: On day 11 the mean TEWL value for the paper tape was significantly higher than that for both the untreated control and silicone tape (P < .001). End-of-study mean TEWL values were 2.65 ± 0.68 g/mh for the silicone tape, 6.85 ± 4.97 g/mh for the paper tape, and 3.73 ± 1.19 g/mh for the untreated control. At all assessments, the silicone tape exhibited net changes from baseline that were significantly less than the paper tape (P < .05 day 1, P < .001 days 4, 7, and 11) and similar for the untreated control. Only at days 4 (P < .01) and 11 (P < .001) was the paper tape significantly higher than that for the untreated control. Throughout the study, both tapes exhibited mean TEWL values within the range of normal intact forearm skin, indicating that both tapes were gentle. No differences in erythema/edema scores occurred but the silicone tape resulted in lower denudation/skin-stripping scores than the paper tape at days 4 to 11 (P < .0001). Self-assessment of pain at removal was low for both tapes but significantly lower for the silicone tape (days 1-7, P = .02; day 11, P = .009). Forty-four percent of participants expressed a preference for the silicone tape as compared to the paper tape (19%), with 37% stating no preference. CONCLUSIONS: Based on TEWL assessment of disruption of the stratum corneum water barrier, the silicone tape proved gentler to the skin than the paper tape. After 9 applications and removals over 11 days of study, the silicone tape was similar to the untreated control, whereas the paper tape exhibited significantly higher mean TEWL values than both the untreated control and the silicone tape. Expert grader assessments corroborate these findings. These data indicate that the silicone tape may provide additional gentleness when it is clinically needed.

Comparison of two preoperative skin antiseptic preparations and resultant surgical incise drape adhesion to skin in healthy volunteers.

BACKGROUND: Adhesion of incise drapes is important at the wound edge, where the skin and drapes are contiguous with the wound. Separation of incise drapes from the skin has been reported to be associated with a sixfold increase in the infection rate compared with surgical procedures in which the drape did not lift off. The present study sought to determine whether the choice of preoperative skin preparation affects the adhesion of various incise drapes. METHODS: Following randomization, the backs of twenty-two healthy volunteers were prepared with two skin preparations, 3M DuraPrep Surgical Solution Patient Preoperative Skin Preparation or ChloraPrep with Tint (Scrub Teal) Patient Preoperative Skin Preparation, according to the label directions. Sample strips (12.7 × 76.2 mm) of three different drapes were applied to the prepared areas and were covered with gauze soaked with saline solution for thirty minutes to simulate a fluid challenge. Drape samples were mechanically removed with use of a peel tester based on an international standard for testing peel adhesion of pressure-sensitive tape. Adverse events were monitored and the skin condition was observed. The primary outcome was drape adhesion, measured as the peel strength in units of gram-force. Outcomes were assessed according to drape type and skin preparation with use of mixed-model analysis of variance. RESULTS: Skin prepared with DuraPrep solution had significantly greater drape adhesion (mean peel strength, 181 gf) compared with skin prepared with ChloraPrep (79 gf, p < 0.001). Although maintaining good adhesion is important, an incise drape that has excessive adhesion may cause skin irritation. Regardless of the skin preparation used, the skin reaction at the application site ranged from none to moderate erythema, and in no instance constituted an adverse event that required treatment. CONCLUSIONS: The data suggest that the type of skin preparation affects drape adhesion. For surgical procedures in which incise drapes are used, choosing a skin preparation that enhances drape adhesion may minimize drape lifting and the potential for wound contamination.

Genetic Ancestry, Skin Reflectance and Pigmentation Genotypes in Association with Serum Vitamin D Metabolite Balance.

BACKGROUND: Lower serum vitamin D (25(OH)D) among individuals with African ancestry is attributed primarily to skin pigmentation. However, the influence of genetic polymorphisms controlling for skin melanin content has not been investigated. Therefore, we investigated differences in non-summer serum vitamin D metabolites according to self-reported race, genetic ancestry, skin reflectance and key pigmentation genes (SLC45A2 and SLC24A5). MATERIALS AND METHODS: Healthy individuals reporting at least half African American or half European American heritage were frequency matched to one another on age (+/- 2 years) and sex. 176 autosomal ancestry informative markers were used to estimate genetic ancestry. Melanin index was measured by reflectance spectrometry. Serum vitamin D metabolites (25(OH)D3, 25(OH)D 2 and 24,25(OH)2D3) were determined by high performance liquid chromatography (HPLC) tandem mass spectrometry. Percent 24,25(OH)2D3 was calculated as a percent of the parent metabolite (25(OH)D3). Stepwise and backward selection regression models were used to identify leading covariates. RESULTS: Fifty African Americans and 50 European Americans participated in the study. Compared with SLC24A5 111Thr homozygotes, individuals with the SLC24A5 111Thr/Ala and 111Ala/Ala genotypes had respectively lower levels of 25(OH)D3 (23.0 and 23.8 nmol/L lower, p-dominant=0.007), and percent 24,25(OH)2D3 (4.1 and 5.2 percent lower, p-dominant=0.003), controlling for tanning bed use, vitamin D/fish oil supplement intake, race/ethnicity, and genetic ancestry. Results were similar with melanin index adjustment, and were not confounded by glucocorticoid, oral contraceptive, or statin use. CONCLUSIONS: The SLC24A5 111Ala allele was associated with lower serum vitamin 25(OH)D3 and lower percent 24,25(OH)2D3, independently from melanin index and West African genetic ancestry.

Reduction in facial photodamage by a topical growth factor product.

A topical gel containing a proprietary mixture of over 110 growth factors, cytokines, and soluble matrix proteins secreted by human dermal fibroblasts was evaluated for safety and efficacy in the treatment of mild to severe facial photodamage. In a double-blind study, 60 subjects were randomly assigned to receive either active gel or the vehicle and applied twice daily for 6 months along with a moisturizing cleanser and sunscreen. Efficacy (profilometry, photography, and clinical assessment) and safety (adverse event reporting) measures were evaluated at 0, 3, and 6 months. Treatment with the active gel for 3 months produced greater reduction in fine lines and wrinkles than the vehicle treatment as measured by objective and subjective assessment techniques. The results were either statistically significant (P < or = .05) or trending towards statistical significance (P < or = .1). This study demonstrates that addition of a topical formulation of growth factors and cytokines to a basic skin care regimen reduces the signs of photoaging.

Preliminary studies on the relationship among peel force, quantitative measures of skin damage and subjective discomfort.

BACKGROUND/AIMS: The ability to anticipate skin damage and subject/patient discomfort due to the removal of adhesive materials without human testing is currently limited. While standardized laboratory methods have been developed, their ability to model and predict the interaction with relevant living substrate is imperfect. The aim of this study was to assess the adhesion of various materials as a function of time using the abdomen as the body site, and determine if a relationship existed with skin damage and subject discomfort. METHODS: Strips of six different materials used in medical devices and known to have different adhesive properties in the laboratory setting were tested in this study. The strips were adhered to the abdomens of normal volunteer subjects for varying periods of time. Peel force was measured under conditions developed to lessen the influence of skin elasticity. Disturbance of the skin barrier was assessed by measuring transepidermal water loss; erythema by reflectance L*a*b* measurements; skin cells removal by quantitation of dyed cells adhering to the test strips; and discomfort using subject self-assessment. RESULTS: When measured at times from 30 min to 72 h after application, the peel force was highest for materials at 30 min. The peel force for one of the six materials, designated F, was clearly higher than the others at time points from 30 min to 48 h after application. Interestingly, this material caused less disruption to the skin barrier and was reported to cause less discomfort. CONCLUSIONS: In this system, there was not a correspondence between adhesion as measured by peel force and skin damage or self-report of discomfort. Further investigations will be required to establish the predictive value of other biophysical measurements and discomfort.

Assessment of diaper-clogging potential of petrolatum moisture barriers.

Petrolatum-based ointments often are used to treat and prevent incontinence dermatitis. However, anecdotal reports indicate that petrolatum ointments may affect the absorbency of disposable briefs also commonly used in incontinence management. To examine whether petrolatum ointments clog a commonly used absorbent brief, a randomized, balanced-block design study was conducted in a controlled laboratory setting to compare the brief-clogging potential of three petrolatum ointments to a non-alcohol barrier film. Test products were applied to 6-cm x 6-cm test sites on the volar forearms of 16 volunteers. Pre-weighed mini briefs were applied to the test sites in a manner that simulates normal brief wear. After 5 minutes of wear, the mini briefs were weighed to determine percent of product transfer from skin to mini brief. The mini briefs then were reapplied to the same test sites and a synthetic urine solution was introduced between the skin and the mini brief. Mini briefs subsequently were removed to determine fluid uptake by weight. Results indicate significant differences between the four test products (P < 0.01) both in percent transfer and in mini brief fluid absorption. From 59% to 69% of the petrolatum-based products transferred from the skin to the mini briefs and a 54% to 90% reduction in fluid uptake was noted, as determined by weight. The non-alcohol barrier film did not transfer to the mini brief and fluid uptake was minimally affected. Further study in the clinical and practice settings to determine the effect and consequences of barrier product transfer on absorbent garments is warranted.