Hand eczema in children referred for patch testing: North American Contact Dermatitis Group Data, 2000-2016.

BACKGROUND: Little is known about the aetiologies and relevant allergens in paediatric patients with hand eczema (HE). OBJECTIVES: To characterize the aetiologies and determine the proportion of positive and currently relevant allergens in children/adolescents (age < 18 years) with HE referred for patch testing. METHODS: A retrospective analysis (2000-2016) of North American Contact Dermatitis Group data was performed. RESULTS: Of 1634 paediatric patients, 237 (14·5%) had involvement of the hands. Final physician diagnoses included allergic contact dermatitis (49·4%), atopic dermatitis (37·1%) and irritant contact dermatitis (16·9%). In multivariable logistic regression models, employment was the only association with increased odds of any HE or primary HE. Children with HE vs. those without HE had similar proportions of positive patch tests (56·1% vs. 61·7%; χ2 -test, P = 0·11). The five most common currently relevant allergens were nickel, methylisothiazolinone, propylene glycol, decyl glucoside and lanolin. In multivariable logistic regression models of the top 20 relevant allergens, HE was associated with significantly higher odds of currently relevant reactions to lanolin, quaternium-15, Compositae mix, thiuram mix, 2-mercaptobenzathiazole and colophony. The allergens with the highest mean significance-prevalence index number were methylisothiazolinone, carba mix, thiuram mix, nickel and methylchloroisothiazolinone/methylisothiazolinone. CONCLUSIONS: Children with HE who were referred for patch testing had a high proportion of positive patch tests, which was similar to the proportion found in children without HE. Children with HE had a distinct and fairly narrow profile of currently relevant allergens.

Patch testing discordance alert: false-negative findings with rubber additives and fragrances.

From July 1996 through June 1998, the North American Contact Dermatitis Group evaluated 318 patients for suspected contact dermatitis by patch testing simultaneously with Finn Chambers and the T.R.U.E. Test allergen system. Discrepancies between the two systems were found in some of the results, particularly with fragrance and rubber allergens. These results suggest that positive reactions to fragrance, thiuram, and carba mix allergens may be missed if the T.R.U.E. Test is used alone.

A preliminary report of the occupation of patients evaluated in patch test clinics.

BACKGROUND: The interplay between the occupational environment and worker's skin can result in contact dermatitis of both irritant and allergic types. Other forms of dermatitis can also be influenced by occupational exposures. OBJECTIVE: The aim of this study is to compare the occupations and allergens of occupational contact dermatitis cases with nonoccupational contact dermatitis cases. METHODS: Diagnostic patch testing with allergens of the North American Contact Dermatitis Group and occupational coding by the National Institute for Occupational Safety and Health methods. RESULTS: Of 2,889 patients referred for evaluation of contact dermatitis, 839 patients (29%) were found to have occupational contact dermatitis. Of the 839 cases deemed occupational, 455 cases (54%) were primarily allergic in nature and 270 cases (32%) were primarily irritant in nature. The remaining 14% were diagnoses other than contact dermatitis, aggravated by work. The occupation most commonly found to have allergic contact dermatitis was nursing. Allergens strongly associated with occupational exposure were thiuram, carbamates, epoxy, and ethylenediamine. CONCLUSION: Some contact allergens are more commonly associated with occupational contact dermatitis. Nursing and nursing support are occupations most likely to be overrepresented in contact dermatitis clinics.

Photoprotective effect of black tea extracts against UVB-induced phototoxicity in skin.

In previous studies, we showed that green tea and black tea extracts and their major polyphenolic constituents protect against UVB light-induced carcinogenesis in murine skin. All of these studies required chronic administration of tea extracts or specific constituents either topically or orally. However, it is not known whether acute or subchronic administration of black tea extracts or constituents can ameliorate UVB-induced early effects in skin. In the present study, cultured keratinocytes and mouse and human skin were employed to assess the effect of both oral and topical administration of standardized black tea extract (SBTE) and its two major polyphenolic subfractions namely BTF1 and BTF2 against UVB-induced photodamage. In SKH-1 hairless mice, topical application of SBTE (0.2 mg/cm2) prior to UVB exposure (180 mJ/cm2) resulted in 40% reduced incidence and 64% reduced severity of erythema and 50% reduction in skinfold thickness by day 6 when compared to nontreated UVB-exposed animals. The SBTE was also effective in protecting against UVB-induced erythema in human volunteers. Administration of SBTE 5 min after UVB irradiation was similarly effective in reducing UVB-induced inflammation in both murine and human skin. The major polyphenolic subfractions, BTF1 and BTF2, were also effective in protecting in mouse skin. The SBTE subfractions inhibited UVB-induced tyrosine phosphorylation of epidermal growth factor receptor (EGFR). The UVB irradiation of human epidermoid carcinoma cells resulted in 3.3-fold induction of tyrosine phosphorylation of EGFR. Pretreatment with BTF1 and BTF2 reduced tyrosine phosphorylation of EGFR by 53% and 31%, respectively. The UVB-mediated enhanced expression of the early response genes, c-fos and c-jun in human epidermal keratinocytes was reduced in a dose-dependent manner by SBTE. Topical application of SBTE was also effective in reducing accumulation of c-fos and p53 proteins by 82% and 78%, respectively, in UVB-exposed mouse skin. These data provide evidence that constituents of black tea can abrogate UVB-induced erythema and associated early events in murine and human skin.

Haplotype analysis of families with erythropoietic protoporphyria and novel mutations of the ferrochelatase gene.

Ferrochelatase, the enzyme that catalyzes the terminal step in the heme biosynthetic pathway, is the site of the defect in the human inherited disease erythropoietic protoporphyria. Molecular genetic studies have shown that the majority of erythropoietic protoporphyria cases are transmitted in dominant fashion and that mutations underlying erythropoietic protoporphyria are heterogeneous. We performed haplotype analysis of American families that shared recurrent ferrochelatase gene mutations yet had forbearers from several European countries. This was to gain insight into whether these mutations represent mutational hotspots at the ferrochelatase gene, or propagation of ancestral alleles bearing the mutations. Two recurrent mutations were found to occur on distinctive chromosome 18 haplotypes, consistent with being hotspot mutations. On the other hand, we found three sets of two unrelated families that shared the same haplotypes bearing these mutations, which could reflect geographic dispersion of ancestral mutant alleles. In addition, we report novel mutations associated with erythropoietic protoporphyria: g(+ 1)-->t transversion of the exon 4 donor site, g(+ 1)-->a transition of the exon 6 donor site, and t(+ 2)-->a substitution at the exon 9 donor site; these mutations are predicted to cause splicing defects of the associated exons. We also identified a g(+ 5)-->a transition of the exon 1 donor site in four unrelated families with erythropoietic protoporphyria, and a G(- 1)-->A substitution at the exon 9 donor site in an additional family. The probability that these sequence changes are normal polymorphisms was virtually excluded (p < 0.0001) by their absence in 120 ferrochelatase alleles from 30 normal subjects and 30 individuals with manifested erythropoietic protoporphyria with or without a known mutation.

North American Contact Dermatitis Group patch test results for the detection of delayed-type hypersensitivity to topical allergens.

BACKGROUND: Allergic contact dermatitis is a significant cause of cutaneous disease affecting many individuals. Patch testing, when used properly, often provides support for the diagnosis of allergic contact dermatitis. OBJECTIVE: This article reports patch testing results from July 1, 1994, to June 30, 1996, by the North American Contact Dermatitis Group (NACDG). METHODS: Patients evaluated in our patch test clinics were tested with the same screening series of allergens by the use of a standardized patch testing technique. The data from these patients were recorded on a standard computer entry form and analyzed. RESULTS: Forty-nine allergens were tested on 3120 patients. Budesonide was added to the series in July 1995 and tested on 1678 patients. Of these patients, 66.5% had positive allergic patch test reactions, and 57% had at least one allergic reaction that was felt to be clinically relevant to the present or past dermatitis. The 20 screening allergens commercially available to United States dermatologists in the Allergen Patch Test Kit, accounted for only 54.1% of the patients with positive allergic reactions. The additional 30 allergens on the NACDG screening series accounted for 47% of patients with positive allergic reactions. Had the Allergen Patch Test Kit alone been used, 12.4% of all patients tested may have had their disease misclassified as a nonallergic disorder, and an additional 34.4% of all tested patients would not have had their allergies fully defined. Among those patients with positive responses to the supplemental allergens, 81% of the responses were of present or past relevance. The 12 most frequent contact allergens were nickel sulfate, fragrance mix, thimerosal, quaternium-15, neomycin sulfate, formaldehyde, bacitracin, thiuram mix, balsam of Peru, cobalt chloride, para-phenylenediamine, and carba mix. The present relevance varied with the specific allergen from 10.7% (thimerosal) to 85.7% (quaternium-15). Among newer allergens, methyldibromoglutaronitrile/phenoxyethanol (cosmetic preservative) caused positive allergic reactions in 2% of the patients; tixocortol-21-pivalate and budesonide (corticosteroids), in 2.0% and 1.1% of the patients, respectively; and ethylene urea/melamine formaldehyde mix (textile resin), in 5% of the patients. CONCLUSION: The usefulness of patch testing is enhanced with the number of allergens tested, because allergens not found on the commercially available screening series in the United States frequently give relevant allergic reactions.

Photosensitivity in the pediatric patient.

Photosensitivity in the pediatric patient is caused by a diverse group of disorders. It may indicate a serious underlying systemic disease such as lupus erythematosus or dermatomyositis, or be an early symptom of a rare group of genetic disorders that includes the porphyrias, xeroderma pigmentosum, Cockayne syndrome, Bloom syndrome, and Rothmund-Thomson syndrome. Idiopathic disorders and ultraviolet light-induced reactions to topical or systemic agents may also cause photosensitivity in children. Early recognition and prompt diagnosis may prevent complications associated with prolonged unprotected exposure to sunlight and permit recognition of families at risk for rare heritable disorders associated with photosensitivity.

Ultraviolet radiation B induces differentiation and protein kinase C in normal human epidermal keratinocytes.

Mid-wave ultraviolet radiation (UVB, 280-320 nm) is highly efficient at inducing erythema, pyrimidine dimers in DNA, oncogene expression and initiation of cutaneous tumors. These UVB-induced responses of epidermal cells have been correlated with the direct effects of UVB on DNA. However, UVB has also been shown to have biologic effects at the cellular level that appear to mimic some of the membrane-associated effects produced by phorbol ester tumor promoters such as 12-O-tetradecanoyl phorbol-13-acetate (TPA). For example, we have previously shown that both UVB irradiation and TPA treatment are followed by release of arachidonic acid and a rapid, dose-dependent inhibition of epidermal growth factor (EGF) binding. TPA generates cellular responses through activation of a phospholipid-dependent, calcium-sensitive protein kinase, protein kinase C (PKC). The primary goal of the studies described here was to compare the cellular effects of TPA with those of UVB with special regard to PKC and keratinocyte growth control, using normal human epidermal keratinocytes. The results obtained showed that both TPA and UVB radiation induced differentiation in normal human keratinocytes. UVB radiation, however, increased both cytosolic and membrane-associated levels of PKC, in contrast to TPA, which increased PKC primarily in the membrane fraction. PKC is probably not the initial chromophore or target molecule of UVB, but because activation of PKC has been shown to be essential for keratinocyte differentiation, differentiation induced by UVB may be caused by activation of PKC by UVB-induced release of diacylglycerol or arachidonic acid.

Arachidonic acid release: an in vitro alternative for dermal irritancy testing.

Validated in vitro alternatives are being utilized extensively for mutagenicity and ocular irritancy testing. However, validation of alternative assays for dermal irritancy is progressing more slowly. As the irritant response in human skin is mediated, at least in part, by eicosanoids derived from arachidonic acid, the effect of relatively pure anionic surfactants (AS, n=8) and surfactant-containing finished products (FP, n=25) on the release of [3H]arachidonic acid from a prelabelled murine fibroblast cell line (C3H-10T1/2 cells) in vitro was examined. Test substances were administered at various non-lethal concentrations, in triplicate, to 12- and 24-well plates containing preconfluent monolayers (80-90% confluence) of C3H-10T1/2 cells. Because it is impossible to test all concentrations of each test substance in a single assay, statistical techniques were developed to 'standardize' in vitro assay results. In each assay, radiolabel release due to a positive control was also measured, using 0.04, 0.05 and 0.06 mM concentrations of sodium dodecyl sulfate (SDS). Test substance releases were then transformed into 'SDS equivalent' responses, significantly reducing both inter- and intra-assay variability. A straight line was fitted to the test substance responses and compared with that for SDS to calculate the relative potency in vitro for individual AS and FP. Relative potencies correlated with in vivo responses, that is primary dermal irritation indices obtained in rabbits, with Spearman p=0.408 (P<0.03) for 32 tested agents, and p=0.976 (P<0.001) for the eight AS. Exclusion of extremely alkaline or acidic FP (pH>11 or <2, n=4) and those which were insoluble in the aqueous cell culture media at the 1% stock dilution (n=5), improved the overall in vivo-in vitro correlation significantly (p=0.683, P<0.001, n=23) and produced a significant correlation for FP alone (p=0.539, P<0.05, n=15). These results suggest that release of [3H]arachidonic acid from cultured skin cells represents a novel, mechanistically based in vitro screen for dermal irritancy testing.

Activated ras genes occur in human actinic keratoses, premalignant precursors to squamous cell carcinomas.

UNLABELLED: BACKGROUND/DESIGN: The clonal theory of cancer predicts that transformed cells within a given tumor are derived from a single initiated precursor. Advancement of this precursor through various stages of tumor development occurs with the further accumulation of selective genetic and epigenetic lesions. Mammalian ras genes are important constituents of mitogenic signaling pathways, and when activated, they contribute to deregulated cellular growth. Activated ras genes play important roles in the development of certain skin tumors. Studies on a number of animal tumor model systems have shown that ras gene activation can be an early and perhaps initial event in the development of skin tumors. Activated ras genes are also found in a significant percentage of somatic human squamous cell carcinomas. To gain retrospective insight into the stages at which activated ras genes contribute to squamous cell carcinoma development, we investigated their incidence in actinic keratoses, premalignant precursors to squamous cell carcinomas. Using a nonradioactive polymerase chain reaction-based method developed in our laboratory, we examined a panel of 19 actinic keratoses and 33 squamous cell carcinomas for activated ras genes. RESULTS: DNA analysis revealed ras gene mutations in three (16%) of 19 actinic keratoses and in four (12%) of 33 squamous cell carcinomas. Activating mutations occurred at codon 12 of the K-ras gene, and codons 12, 13, and 61 of the H-ras gene. All positive actinic keratoses and squamous cell carcinomas occurred in sun-exposed regions. CONCLUSIONS: Activated ras genes can play important roles during early stages of squamous cell carcinoma development. Aberrant repair of UV-induced pyrimidine dimers is a likely cause of this activation.

Polycyclic aromatic hydrocarbon-DNA and protein adducts in coal tar treated patients and controls and their relationship to glutathione S-transferase genotype.

Coal tar treated psoriasis patients were used as a model population to evaluate a panel of immunoassays for monitoring exposure to benzo[a]pyrene (BP) and related polycyclic aromatic hydrocarbons (PAH). The assays included measurement of PAH diol epoxide-DNA adducts in white blood cells by competitive enzyme-linked immunosorbent assay (ELISA) with fluorescence endpoint detection, PAH-albumin adducts by competitive ELISA with color endpoint detection and serum levels of antibodies recognizing BP diol epoxide-DNA adducts by noncompetitive color ELISA. PAH-DNA adducts by ELISA were elevated in patients (mean 6.77 +/- 12.05/10(8)) compared to controls (4.90 +/- 8.81/10(8), p = 0.12). There was no difference in PAH-albumin adducts between patients (mean 0.61 +/- 0.31 fmol/micrograms) and controls (0.63 +/- 0.30 fmol/micrograms). Glutathione S-transferase M1 genotype was also determined but no relationship was found between presence of the gene and either DNA or protein adduct levels. About 30% of both patients and controls had measurable titer of antibodies recognizing BPDE-I-DNA adducts. Measurement of white blood cell DNA adducts by ELISA was the most sensitive method for detecting PAH exposure in coal tar-treated psoriasis patients.

Effect of benzoyl peroxide on protein kinase C in cultured human epidermal keratinocytes.

Benzoyl peroxide (BzPO) has been the most widely used topical agent for acne since the 1960s. This is true despite numerous reports that BzPO can enhance the development of carcinomas from murine epidermal papillomas. Because activation of protein kinase C (PKC) is considered to mediate cellular responses to other epidermal tumor promotors, we wished to investigate the relationship between BzPO and PKC in cultured human epidermal keratinocytes (NHEK). We assayed (a) direct effects of BzPO on PKC activity in a cell-free system using semipurified human keratinocyte PKC, (b) BzPO effects on the subcellular distribution of PKC, and (c) BzPO modulation of NHEK proliferation and phorbol ester-induced differentiation. NHEK maintained in serum-free media (0.15 mM Ca2+) were treated with concentrations of BzPO in acetone from 100 nM to 500 microM, with concentrations of acetone not exceeding 0.1%. No short-term translocation of PKC from cytosol to membrane was observed at any BzPO concentration. BzPO did not downregulate subcellular levels of PKC activity after 24 h of exposure. BzPO did not significantly antagonize phorbol ester-induced inhibition of proliferation or differentiation but did weakly antagonize Ca(2+)-induced differentiation. Consistent with a PKC-mediated mechanism for Ca(2+)-induced differentiation, BzPO inhibited both human and murine PKC in a cell-free system. These results suggest that BzPO does not promote malignant conversion through a PKC-dependent mechanism, and in fact, inhibits PKC activity in vitro.

Photodamage, photoaging and photoprotection of the skin.

Overexposure to ultraviolet and visible radiation causes sunburn. Aspirin and other nonsteroidal anti-inflammatory drugs, cool baths and topical steroids offer only mild relief. Long-term sun exposure causes chronic inflammatory skin changes. Photodamage, rather than the normal aging process, may account for 90 percent of age-associated cosmetic skin problems. Physicians should stress to their patients that all ultraviolet exposure (including sun beds and tanning salons) causes skin damage. Regular sunscreen use during childhood and adolescence may result in an 80 percent reduction in the lifetime incidence of ultraviolet-induced skin damage, including nonmelanoma skin cancers.

Clinical manifestations of photosensitivity in patients with human immunodeficiency virus infection.

A number of light-induced pathologic changes in the skin of individuals with HIV infection have been reported in the dermatologic literature. The relationship between HIV and one of these more well-defined types of photosensitivity, PCT, while still uncertain seems definable and related to an infectious origin. The relationship of retrovirus infection and photosensitivities that are of idiopathic origin in HIV-infected individuals, as well as non-infected individuals, is much more conjectural. The association seems, however, to be more frequent than co-incidental, and the link probably resides in the realm of altered immune modulation. Since individuals with HIV frequently require phototherapy, such light-induced problems are likely to become more common. It is important that the dermatologist recognize these relationships.