The presence of benzophenone in sunscreens and cosmetics containing the organic UV filter octocrylene: A laboratory study.

BACKGROUND: The reason why patients photosensitized to the drug ketoprofen (KP) may develop severe photoallergic skin reactions to octocrylene (OCT), an organic ultraviolet filter in sunscreens and cosmetics, remains largely unknown. OCT can be synthesized by using unsubstituted benzophenone (BP), a possible human carcinogen. OBJECTIVES: To verify if, and to what extent, BP residues are present in OCT-containing consumer products. METHODS: The raw material of OCT and 39 skincare products, of which 28 contain OCT, were chemically analysed for the presence of BP by means of liquid chromatography. RESULTS: In the OCT raw material and in all 28 OCT-containing products the presence of BP could be demonstrated, mostly in concentrations above 10 ppm (0.001%), whereas a majority of OCT-free products (8/11, 73%) did not contain BP. Moreover, BP concentrations significantly increased, in a time- and temperature-dependent manner, likely due to the additional degradation of OCT. CONCLUSIONS: Photoallergic contact dermatitis from OCT in patients photosensitized to KP might rely on residual BP impurities. Toxicological and ecological studies that evaluate the safety of OCT might also need to consider the concomitant presence of BP.

A Cell Fate Switch in the Caenorhabditis elegans Seam Cell Lineage Occurs Through Modulation of the Wnt Asymmetry Pathway in Response to Temperature Increase.

Populations often display consistent developmental phenotypes across individuals despite inevitable biological stochasticity. Nevertheless, developmental robustness has limits, and systems can fail upon change in the environment or the genetic background. We use here the seam cells, a population of epidermal stem cells in Caenorhabditis elegans, to study the influence of temperature change and genetic variation on cell fate. Seam cell development has mostly been studied so far in the laboratory reference strain (N2), grown at 20° temperature. We demonstrate that an increase in culture temperature to 25° introduces variability in the wild-type seam cell lineage, with a proportion of animals showing an increase in seam cell number. We map this increase to lineage-specific symmetrization events of normally asymmetric cell divisions at the fourth larval stage, leading to the retention of seam cell fate in both daughter cells. Using genetics and single-molecule imaging, we demonstrate that this symmetrization occurs via changes in the Wnt asymmetry pathway, leading to aberrant Wnt target activation in anterior cell daughters. We find that intrinsic differences in the Wnt asymmetry pathway already exist between seam cells at 20° and this may sensitize cells toward a cell fate switch at increased temperature. Finally, we demonstrate that wild isolates of C. elegans display variation in seam cell sensitivity to increased culture temperature, although their average seam cell number is comparable at 20°. Our results highlight how temperature can modulate cell fate decisions in an invertebrate model of stem cell patterning.

Varicella-Zoster Virus ORF9p Binding to Cellular Adaptor Protein Complex 1 Is Important for Viral Infectivity.

ORF9p (homologous to herpes simplex virus 1 [HSV-1] VP22) is a varicella-zoster virus (VZV) tegument protein essential for viral replication. Even though its precise functions are far from being fully described, a role in the secondary envelopment of the virus has long been suggested. We performed a yeast two-hybrid screen to identify cellular proteins interacting with ORF9p that might be important for this function. We found 31 ORF9p interaction partners, among which was AP1M1, the µ subunit of the adaptor protein complex 1 (AP-1). AP-1 is a heterotetramer involved in intracellular vesicle-mediated transport and regulates the shuttling of cargo proteins between endosomes and the trans-Golgi network via clathrin-coated vesicles. We confirmed that AP-1 interacts with ORF9p in infected cells and mapped potential interaction motifs within ORF9p. We generated VZV mutants in which each of these motifs was individually impaired and identified leucine 231 in ORF9p to be critical for the interaction with AP-1. Disrupting ORF9p binding to AP-1 by mutating leucine 231 to alanine in ORF9p strongly impaired viral growth, most likely by preventing efficient secondary envelopment of the virus. Leucine 231 is part of a dileucine motif conserved among alphaherpesviruses, and we showed that VP22 of Marek's disease virus and HSV-2 also interacts with AP-1. This indicates that the function of this interaction in secondary envelopment might be conserved as well.IMPORTANCE Herpesviruses are responsible for infections that, especially in immunocompromised patients, can lead to severe complications, including neurological symptoms and strokes. The constant emergence of viral strains resistant to classical antivirals (mainly acyclovir and its derivatives) pleads for the identification of new targets for future antiviral treatments. Cellular adaptor protein (AP) complexes have been implicated in the correct addressing of herpesvirus glycoproteins in infected cells, and the discovery that a major constituent of the varicella-zoster virus tegument interacts with AP-1 reveals a previously unsuspected role of this tegument protein. Unraveling the complex mechanisms leading to virion production will certainly be an important step in the discovery of future therapeutic targets.

Increased herpes zoster risk associated with poor HLA-A immediate early 62 protein (IE62) affinity.

Around 30% of individuals will develop herpes zoster (HZ), caused by the varicella zoster virus (VZV), during their life. While several risk factors for HZ, such as immunosuppressive therapy, are well known, the genetic and molecular components that determine the risk of otherwise healthy individuals to develop HZ are still poorly understood. We created a computational model for the Human Leukocyte Antigen (HLA-A, -B, and -C) presentation capacity of peptides derived from the VZV Immediate Early 62 (IE62) protein. This model could then be applied to a HZ cohort with known HLA molecules. We found that HLA-A molecules with poor VZV IE62 presentation capabilities were more common in a cohort of 50 individuals with a history of HZ compared to a nationwide control group, which equated to a HZ risk increase of 60%. This tendency was most pronounced for cases of HZ at a young age, where other risk factors are less prevalent. These findings provide new molecular insights into the development of HZ and reveal a genetic predisposition in those individuals most at risk to develop HZ.

Inverse Association Between Atopy and Melanoma: A Case-control Study.

Heightened cutaneous immune surveillance in atopic patients may inhibit development of melanoma. The aim of this study was to analyse the association between atopy and melanoma (development and outcome). A total of 188 cases of melanoma and 596 healthy controls were interviewed by telephone with a standardized questionnaire on atopic, demographic and melanoma characteristics. Cases were matched with controls on important confounders (age, sex, sunburn sensitivity, hair colour, number of moles, sunburn as juvenile, ever solarium, familial melanoma). Melanoma outcome data (disease relapse and death) within cases were retrieved. Analysis showed a general inverse association between atopy and melanoma development, but this was statistically significant only for a history of personal atopy (odds ratio 0.53, 95% confidence interval: 0.30-0.96, p-value = 0.04). Among melanoma patients, atopy did not affect survival or progression. In conclusion, this study suggests an inverse association between a history of atopy and melanoma development, but not with disease progression.

Mepacrine as successful monotherapy for refractory Jessner-Kanof disease: still an important drug in the dermatologic armamentarium.

INTRODUCTION: Jessner-Kanof disease (JKD), a lymphocytic infiltration of the skin, can be difficult to treat. Mepacrine (quinacrine), an anti-malarial less available in Belgium, may be beneficial. PATIENTS AND METHODS: Two female patients with biopsy-proven and therapy-resistant JKD, not responding to topical and systemic corticosteroids, (hydroxy-)chloroquine and/or dapsone, were treated with mepacrine 100 mg daily. RESULTS: In both patients an amelioration was observed during the first month of treatment, and clinical remission was obtained by the fourth month, without any side-effects. In both cases, the dose could be tapered to three times weekly. DISCUSSION: JKD is strongly related to lupus erythematosus (tumidus), and although spontaneous remissions may occur, it is notoriously difficult to treat. Mepacrine may be initiated as an add-on therapy to (hydroxy-)chloroquine, but also as monotherapy. A dose of 100 mg a day, tapered to weekly doses once remission is obtained, seems feasible. Except for (mild) yellow skin discoloration, the drug has few side-effects, and offers the advantage of not displaying retinal toxicity. CONCLUSION: Mepacrine is still a useful and safe drug for treating cutaneous lupus erythematosus and related skin conditions, such as refractory JKD in particular. Its future availability, also in Belgium, is therefore important.

Efficacy, tolerability and safety of switching from etanercept to infliximab for the treatment of moderate-to-severe psoriasis: A multicenter, open-label trial (TANGO).

Biologic anti-tumor necrosis factor-α (anti-TNF-α) therapies have revolutionized the management of psoriasis. However, despite similar mechanisms of action, inter-patient variability in the clinical responses to therapy remain unexplained. Possible differences between agents include stability or bioavailability and anti-drug antibody development, and patient factors such as compliance may play a role. As a result, it is not uncommon for physicians to switch a patient from one anti-TNF-α agent to another when initial response is inadequate. This multicenter, single-arm, observational, Phase IV study assessed the efficacy and safety of infliximab therapy in patients with moderate-to-severe psoriasis who had not responded to 24 weeks' etanercept treatment. Drug efficacy was assessed using specific psoriasis indexes; health-related quality of life (HRQoL) was measured using the Dermatology Life Quality Index and the Skindex-29. A total of 48 patients were screened, 38 were treated with infliximab and 31 completed the study. Of these, 71% achieved Psoriasis Area and Severity Index 75 after 10 weeks, and improvement in HRQoL was documented. The results of this study showed that patients with moderate-to-severe psoriasis could be successfully switched from etanercept to infliximab, with improvements in both clinical parameter and HRQoL.

Selective use of sequential digital dermoscopy imaging allows a cost reduction in the melanoma detection process: a belgian study of patients with a single or a small number of atypical nevi.

BACKGROUND: Dermoscopy is a technique which improves melanoma detection. Optical dermoscopy uses a handheld optical device to observe the skin lesions without recording the images. Sequential digital dermoscopy imaging (SDDI) allows storage of the pictures and their comparison over time. Few studies have compared optical dermoscopy and SDDI from an economic perspective. OBJECTIVE: The present observational study focused on patients with one-to-three atypical melanocytic lesions, i.e. lesions considered as suspicious by optical dermoscopy. It aimed to calculate the "extra-costs" related to the process of melanoma detection. These extra-costs were defined as the costs of excision and pathology of benign lesions and/or the costs of follow-up by SDDI. The objective was to compare these extra-costs when using optical dermoscopy exclusively versus optical dermoscopy with selective use of SDDI. METHODS: In a first group of patients, dermatologists were adequately trained in optical dermoscopy but worked without access to SDDI. They excised all suspicious lesions to rule out melanoma. In a second group, the dermatologists were trained in optical and digital dermoscopy. They had the opportunity of choosing between immediate excision or follow-up by SDDI (with delayed excision if significant change was observed). The comparison of extra-costs in both groups was made possible by a decision tree model and by the division of the extra-costs by the number of melanomas diagnosed in each group. Belgian official tariffs and charges were used. RESULTS: The extra-costs in the first and in the second group were respectively €1,613 and €1,052 per melanoma excised. The difference was statistically significant. CONCLUSIONS: Using the Belgian official tariffs and charges, we demonstrated that the selective use of SDDI for patients with one-to-three atypical melanocytic lesions resulted in a significant cost reduction.

Polymorphic light eruption may be associated with cigarette smoking and alcohol consumption.

BACKGROUND: Although the genetic influence on polymorphic light eruption (PLE) is well established, the role of lifestyle factors is less well defined. METHODS: A retrospective case-control study was conducted that included 74 PLE patients and 102 controls. Each participant was interviewed about demographic, disease and lifestyle characteristics such as smoking, alcohol consumption and use of medications. Multivariate logistic regression models were used to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Compared with the controls, patients with PLE were significantly more likely to be younger females (P<0.05). Univariate analysis did not show a significant association between any of the smoking-related questions and PLE. However, after adjusting for gender and drinking alcohol, patients with PLE were significantly more likely to smoke 15 cigarettes or more daily [adjusted OR=4.06 (95% CI=1.19, 13.80) compared with 0 daily cigarettes] than controls. Participants who consumed six or more drinks a week were less likely to have PLE [adjusted OR=0.24 (95% CI=0.07, 0.80)]. In contrast, women who used oral anticonceptives for a longer period were four-fold more likely to have PLE [adjusted OR=4.74 (95% CI=1.33, 16.86)]. CONCLUSION: Several lifestyle factors may be associated with PLE, but further studies are warranted to confirm these retrospective findings.

Peroxisome proliferator-activated receptors in squamous cell carcinoma and its precursors.

BACKGROUND: Peroxisome proliferator-activated receptors (PPARs) mediate several functions that are of interest in carcinogenesis. Although PPARalpha, PPARbeta, and PPARgamma are expressed in multiple human, their expression has not been investigated in non-melanoma skin cancer. METHODS: We performed a retrospective paired immunohistochemical analysis of normal skin, actinic keratosis (AK), and squamous cell carcinoma (SCC) among 35 individuals. Specimens were considered PPAR immunoreactive when 1% or more of the tumor cells showed clear evidence of immunostaining. Cyclooxygenase-2 (COX-2) expression, the fraction of proliferating endothelial cells, and microvessel density were also evaluated in these samples. RESULTS: PPARalpha immunoreactivity was significantly less likely to occur in SCC and AK than in normal skin of each individual. In contrast to PPARalpha, PPARbeta appeared to be upregulated in (pre)malignant skin lesions. For each individual, the likelihood that normal skin, AK, or SCC was immunoreactive against PPARgamma was comparable. COX-2 immunopositivity was significantly associated with PPARbeta and PPARgamma immunoreactivity. No statistical differences were noted for the angiogenesis parameters and PPARalpha, PPARbeta, or PPARgamma expression, except that the microvessel density was significantly higher among PPARbeta-immunoreactive SCCs compared to that among immunonegative SCCs. CONCLUSION: Although further research is warranted, these results suggest that PPAR ligands such as fibrates and thiazolidinediones may have chemoprophylactic properties in skin carcinogenesis.

A phase II multicenter clinical trial of systemic bexarotene in psoriasis.

BACKGROUND: Bexarotene, a novel and unique synthetic P, RXR-selective retinoid, is available as a treatment for cutaneous T-cell lymphoma. In psoriasis, a common retinoid-sensitive disease, no data are available on bexarotene treatment. OBJECTIVE: In this phase II study we investigated the safety, tolerability, and effectiveness of bexarotene in psoriasis at doses of 0.5 to 3.0 mg/kg/day. METHODS: Fifty patients with moderate to severe plaque-type psoriasis were treated with bexarotene in 4 sequential dose-defined panels of 12-13 patients at doses of 1.0, 2.0, 0.5, and 3.0 mg/kg/day for 12-24 weeks. Patients were monitored for safety and clinical efficacy. RESULTS: No serious adverse events related to the drug occurred. Bexarotene was well tolerated in most patients. Most frequently observed adverse events related to bexarotene were hypertriglyceridaemia (56%) and a decrease in free T4 serum levels (54%). Significant improvement of psoriasis after bexarotene at all doses was confirmed by a modified psoriasis area and severity index (mPASI), plaque elevation (PEL), and physician's global assessment (PGA). Overall response rates (> or =50% improvement) for mPASI, PEL, and PGA were 22%, 52%, and 36%, respectively. No significant dose-response effect was established for these parameters. CONCLUSION: The present study indicates an anti-psoriatic effect of bexarotene. Further studies are necessary to assess the optimal dose and the potential for bexarotene as a new therapy for psoriasis.

Pyoderma gangrenosum: a challenging complication of bilateral mastopexy.

A case of pyoderma gangrenosum progressively developing after bilateral mastopexy at the surgical site is described. The described case was successfully treated with corticosteroids, the application of the dermal regeneration template Integra and autologous skin grafts. This approach was able to save the patient's life and to generate a high-quality aesthetical outcome. The article reported the case, reviewed the literature of pyoderma gangrenosum related to mastopexy or augmentation mammoplasty and discussed the use of a dermal regeneration template to optimise aesthetical results after reconstructive surgery.