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.

Inhibition of MMPs Cat G and downregulates the signaling of TGF-ß/Smad in chronic photodamaged human fibroblasts.

OBJECTIVE: To understand the action of Cathepsin G (Cat G) and matrix metalloproteases (MMPs) on the ß/Smad pathway of transforming growth factor ß (TGF-ß) in chronically photodamaged human fibroblasts. Cat G plays a significant role in the process of skin photoaging and in collagen synthesis and degradation which is induced by UV irradiation it could interact with TGF-ß/Smad signaling. No available studies have thoroughly explored its molecular mechanisms of photoaging regulation. PATIENTS AND METHODS: Fibroblasts were divided into 4 groups: (1) control, (2) UVA irradiation of 25 J/cm2, (3) UVA irradiation of 25 J/cm2 + MMPs inhibitor, and (4) 25 J/cm2 UVA irradiation + Cat G inhibitor. All treatments were repeated daily for 21 days. Western blot and ELISA was employed to detect Protein levels for Cat G, MMPs, and several smads. RESULTS: Compared to UVA-irradiated cells, the addition of MMPs inhibitor downregulated the expression of smad2, smad3, and smad4 as well as TGF-ß. The addition of Cat G inhibitor downregulated the expression of smad2, smad3, and smad4 as well as TGF-ß. These data suggest that TGF-ß/Smad signaling was decreased by inhibition of MMPs and Cat G decreased in chronically human fibroblasts which are photo-damaged. CONCLUSIONS: These results may help expand our knowledge of mechanisms mediating photoaging and is possibly instrumental to the exploration of novel anti-photoaging treatments.

The three moments of skin cream application: an evidence-based proposal for use of skin creams in the prevention of irritant contact dermatitis in the workplace.

Contact dermatitis is one of the most common occupational diseases, with serious impact on quality of life, lost days at work and a condition that may be chronically relapsing. Regular prophylactic skin cream application is widely acknowledged to be an effective prevention strategy against occupational contact dermatitis; however, compliance rates remain low. To present a simple programme for skin cream application in the workplace with focus on implementation to drive down the rate of occupational irritant contact dermatitis, an expert panel of eight international dermatologists combined personal experience with extensive literature review. The recommendations are based on clinical experience as supported by evidence-based data from interventional studies. The authors identified three moments for skin cream application in the work place: (i) before starting a work period; (ii) after washing hands; and (iii) after work. Affecting behaviour change requires systematic communications, monitoring and reporting, which is proposed through Kotter's principles of organizational change management. Measurement tools are provided in the appendix. Interventional data based on application of this proposal is required to demonstrate its effectiveness.

Effect of ultrasound and heat on percutaneous absorption of l-ascorbic acid: human in vitro studies on Franz cell and Petri dish systems.

OBJECTIVE: Percutaneous absorption of l-ascorbic acid (LAA) is limited due to its high hydrophilicity and low stability. Here, we investigated the effect of post-dosing sonophoresis (329 kHz, 20 mW cm-2 ) and heat (36°C) on transdermal delivery of LAA. METHODS: Ultrasound/heat, heat and control treatments were applied on skin surface for 2 and 5 min after topical application of C14-labelled LAA aqueous solution. After 15 min post-exposure, radioactivity was measured in tape-striped stratum corneum (TS-SC), epidermis, dermis and receptor fluid. As Franz diffusion cell model may have different acoustic response than in vivo human tissues, a novel Petri dish model was developed and compared with Franz cell model on the effects of ultrasound/heat treatment on the skin permeability. RESULTS: Five-min ultrasound/heat treatment significantly accelerated skin absorption/penetration of LAA; 2-min treatment showed no enhancement effect on Franz diffusion cell model at the end of experiment. The use of Petri dish model significantly increased LAA concentrations in epidermis after 5 min of ultrasound/heat treatment, compared to the results of Franz cell model. CONCLUSION: Combination of ultrasound (329 kHz, 20 mW cm-2 ) and heat (36°C) significantly enhanced LAA transdermal penetration, when the time of treatment was sufficient (5 min). As Petri dish model was designed to simulate acoustic respond of dense human tissue to ultrasound, the difference between Franz cell and Petri dish models suggests that the enhancement effect of ultrasound/heat on skin penetration in vivo may be greater than that determined on in vitro Franz cell model.

Qualitative vs. quantitative atopic dermatitis criteria - in historical and present perspectives.

This review summarizes historical aspects, clinical expression and pathophysiology leading to coining of the terms atopy and atopic dermatitis, current diagnostic criteria and further explore the possibility of developing quantitative diagnostic criteria of atopic dermatitis (AD) based on the importance of atopic features - subjective, objective, and those derived from laboratory tests - the new partly promising AD biomarkers. 'Atopy', introduced in 1923, denoted 'the sense of a strange disease without a precise place in the body'. A decade later, Sulzberger and Hill, first defined 'atopic dermatitis'. The pioneering well-recognized criteria, 'Hanifin & Rajka' (Acta Derm Venereol, 92, 1980, 44), were developed empirically on 'clinical experience' and expert consensus. As opposed to the widely used, rather anamnestic 'UK Criteria' (1994), they have few formal validation studies, but appear to well embrace various atopic phenotypes. Pruritus, xerosis, typical morphology/distribution of dermatitis and tendency to a relapsing/chronic course are common basic features in AD criteria, whereas skin sensitivity, heredity and various ill-defined atopic stigmata also seem to comprise the atopic phenomenon. Specific pheno- and endotypes are now emerging potentially enabling us to better classify patients with AD, but the influence of these on the diagnosis of AD is so far unclear. Few diagnostic models use quantitative scoring systems to establish AD cases from normal population, which, however, may be useful to better study and manage this disease. Long-term prospective observational studies, from which few are available at this point, along with interventional studies, are a perquisite and will provide the best option to improve our understanding of its complex characteristics and etiology.

Pitfalls in clinical trials reveal need for well tolerated, more effective depigmenting agents.

OBJECTIVE: Examine clinical trials performed for depigmenting agents in order to determine the most effective and well-tolerated depigmenting agent. METHODS: We searched clinical trials, published and unpublished, performed for hydroquinone, ascorbic acid, azelaic acid, retinol and niacinamide in the period 2009 till present. Studies were examined based on participant information, design, duration, intervention, outcome measurements and statistical significance. RESULTS: Sixty-one studies were examined, 40 published and 21 unpublished. Design, outcome measures and intervention showed sources of bias were not avoided. Only 30% of published trials were double-blind, 27% used a placebo and 80% used subjective measurements for their results. Unpublished trials follow similar outcomes, however, did not provide any significant results. CONCLUSION: Based on these results, we are unable to recommend a safer, more effective depigmenting agent. Lack of thorough trials limits us from accepting depigmenting agent full evaluation. To accept a depigmenting agent, its duration must test for long-term safety, clinical trial must be double-blind and comparative, use participants of the correct skin type and measure outcomes objectively. In addition, lack of results for parallel unpublished studies leaves room for discussion. Efforts toward creating more effective formulations are welcomed.

Measurement, analysis and prediction of topical UV filter bioavailability.

The aim of the present study was to objectively quantify and predict bioavailability of three sunscreen agents (i.e., benzophenone-3, 2-ethylhexylsalicylate, and 2 ethylhexyl-4-methoxycinnamate) in epidermis treated by petrolatum and emulsion-based formulations for 7 and 30min on four human volunteers. Profiles of sunscreen agents through stratum corneum (SC), derived from the assessment of chemical amounts in SC layers collected by successive adhesive tape-stripping, were successfully fitted to Fick's second law of diffusion. Therefore, permeability coefficients of sunscreen agents were found lower with petrolatum than with emulsion based formulations confirming the crucial role of vehicle in topical delivery. Furthermore, the robustness of that methodology was confirmed by the linear relationship between the chemical absorption measured after 30min and that predicted from the 7-min exposure experiment. Interestingly, in this dermatopharmacokinetic method, the deconvolution of permeability coefficients in their respective partition coefficients and absorption constants allowed a better understanding of vehicle effects upon topical bioavailability mechanisms and bioequivalence of skin products.

Nail apparatus melanoma: is trauma a coincidence? Is this peculiar tumor a real acral melanoma?

Nail Apparatus Melanoma (NAM) is rare, particularly in Caucasians. Understanding its pathogenesis and collecting epidemiologic data may be difficult due to its location and the exiguity of the case series of this cancer. Cutaneous melanoma has been thought related to UV radiation, and NAM is considered an acral variant of melanoma, even if the nail presents a specific anatomy. Little is reported about pathogenesis, except reports suggesting traumatic injuries as a causal factor. UV exposure is debated in nail melanoma because of its structure. The nail is, in fact, a unique structure with sun-exposed and non exposed melanocytes. NAM arises from the nail melanocytes, located in the nail matrix, which is the germinative part of the nail and composed of a proximal and distal portion. The proximal nail matrix lays under the proximal nail fold that covers it and is non-sun exposed, while the distant nail matrix, clinically visible as the lunula, is sun-exposed, though lying underneath the nail plate. According to these anatomical data, NAM is a distinct melanoma type, and studies need to classify it as acral melanoma or as a particular type of melanoma with its own pathogenesis and prognostic criteria. This study investigates potential risk factors of NAM, emphasizing (i) trauma and (ii) UV exposure among our NAM patients.

Skin benefits with a novel emollient-treated menstrual pad.

Manufacturers of consumer products consistently seek to improve marketed products in terms of both safety and efficacy. The desire for continued improvement is seen even in well-established products such as catamenial products which have existed in some form for thousands of years. A recent innovation in the design of menstrual pads is the addition of a surface finish of emollient for the purpose of increasing comfort during wear. The present paper presents different evaluations of such an emollient-treated menstrual pad with a novel absorbent core. These investigations demonstrated product tolerability, defined the optimal formulation and concentration of the emollient-containing finish, and demonstrated successful transfer of the emollient to the relevant skin surface. In addition, enhancement of skin moisturization, associated with exposure to the emollient-treated pad, was demonstrated by several technologies: assessment of skin moisturization by Corneometer®, skin friction testing, and skin capacitance.

Age-related percutaneous penetration part 2: effect of age on dermatopharmacokinetics and overview of transdermal products.

Transdermal drug delivery allows for a constant rate of drug administration and prolonged action, which can be beneficial to elderly patients who are often polymedicated. Several studies have compared dermatopharmacokinetics in the young and elderly with conflicting results. Despite the potential limitations of age-related changes in skin factors and cutaneous metabolism, marketed transdermal products generally do not report age-related differences in pharmacokinetics. This overview discusses the current data, summarizes marketed product findings and highlights the importance of further studies to evaluate age-related dermatopharmacokinetics.

Age-related percutaneous penetration part 1: skin factors.

Changes in the skin that occur in the elderly may put them at increased risk for altered percutaneous penetration from pharmacotherapy along with potential adverse effects. Skin factors that may have a role in age-related percutaneous penetration include blood flow, pH, skin thickness, hair and pore density, and the content and structure of proteins, glycosaminoglycans (GAGs), water, and lipids. Each factor is examined as a function of increasing age along with its potential impact on percutaneous penetration. Additionally, topical drugs that successfully overcome the barrier function of the skin can still fall victim to cutaneous metabolism, thereby producing metabolites that may have increased or decreased activity. This overview discusses the current data and highlights the importance of further studies to evaluate the impact of skin factors in age-related percutaneous penetration.

Evaluation of incidental thyroid nodules in patients with primary melanoma.

AIM: Literature data have suggested an increase of incidental thyroid nodules in patients with malignancies, including melanoma. METHODS: The ultrasound findings of 168 consecutive melanoma patients were revisited in order to evaluate the presence of incidental thyroid nodules and the results were compared with clinical features, Breslow thickness and the rate of malignancy of incidental thyroid nodules. RESULTS: We observed that: 1) incidental thyroid nodules are more frequent in patients affected by melanoma (60.6%) than in the healthy population; 2) no statistically significant difference were found in thyroid involvement on the basis of gender and age; 3) incidental thyroid nodules frequency is increased in patients with thinner melanoma and this increase is more evident if we consider melanoma in situ and female patients; 4) it was not detected malignant incidental thyroid nodules. CONCLUSION: The data revealed a high frequency of incidental thyroid nodules in patients with melanoma, suggesting that it is necessary to study this association in a larger group of patients, also including age/gender matched controls.

Allergic contact dermatitis: epidemiology, molecular mechanisms, in vitro methods and regulatory aspects. Current knowledge assembled at an international workshop at BfR, Germany.

Contact allergies are complex diseases, and one of the important challenges for public health and immunology. The German 'Federal Institute for Risk Assessment' hosted an 'International Workshop on Contact Dermatitis'. The scope of the workshop was to discuss new discoveries and developments in the field of contact dermatitis. This included the epidemiology and molecular biology of contact allergy, as well as the development of new in vitro methods. Furthermore, it considered regulatory aspects aiming to reduce exposure to contact sensitisers. An estimated 15-20% of the general population suffers from contact allergy. Workplace exposure, age, sex, use of consumer products and genetic predispositions were identified as the most important risk factors. Research highlights included: advances in understanding of immune responses to contact sensitisers, the importance of autoxidation or enzyme-mediated oxidation for the activation of chemicals, the mechanisms through which hapten-protein conjugates are formed and the development of novel in vitro strategies for the identification of skin-sensitising chemicals. Dendritic cell cultures and structure-activity relationships are being developed to identify potential contact allergens. However, the local lymph node assay (LLNA) presently remains the validated method of choice for hazard identification and characterisation. At the workshop the use of the LLNA for regulatory purposes and for quantitative risk assessment was also discussed.

Pragmatic approach to the clinical work-up of patients with putative allergic disease to metallic orthopaedic implants before and after surgery.

Allergic complications following insertion of metallic orthopaedic implants include allergic dermatitis reactions but also extracutaneous complications. As metal-allergic patients and/or surgeons may ask dermatologists and allergologists for advice prior to planned orthopaedic implant surgery, and as surgeons may refer patients with complications following total joint arthroplasty for diagnostic work-up, there is a continuous need for updated guidelines. This review presents published evidence for patch testing prior to surgery and proposes tentative diagnostic criteria which clinicians can rely on in the work-up of patients with putative allergic complications following surgery. Few studies have investigated whether subjects with metal contact allergy have increased risk of developing complications following orthopaedic implant insertion. Metal allergy might in a minority increase the risk of complications caused by a delayed-type hypersensitivity reaction. At present, we do not know how to identify the subgroups of metal contact allergic patients with a potentially increased risk of complications following insertion of a metal implant. We recommend that clinicians should refrain from routine patch testing prior to surgery unless the patient has already had implant surgery with complications suspected to be allergic or has a history of clinical metal intolerance of sufficient magnitude to be of concern to the patient or a health provider. The clinical work-up of a patient suspected of having an allergic reaction to a metal implant should include patch testing and possibly in vitro testing. We propose diagnostic criteria for allergic dermatitis reactions as well as noneczematous complications caused by metal implants.

Transdermal estradiol and testosterone transfer in man: existence, models, and strategies for prevention.

BACKGROUND: Transdermal hormone application allows delivery of a clinically relevant hormone dose often with fewer systemic side effects than oral formulations. However, transdermal hormone transfer from a dosed individual to naïve interpersonal contact occurs and may cause significant hormone imbalance and adverse effects. METHODS: We reviewed PubMed, Medline, and Scopus articles from the years 1950 to 2010 for articles related to transdermal hormone transfer in the setting of in vivo and in vitro human and animal models. We used the following key words: transfer, transdermal, absorption, cutaneous, hormone, estradiol, and testosterone. Unpublished trials were reviewed on the US Food and Drug Administration (FDA) website for product approval. RESULTS: Data reflecting in vivo transfer of transdermal estradiol and testosterone in man is available from case reports, clinical trials, and FDA product information. While results clearly show that transfer can occur, methods for measuring the effect are not standardized and are thus difficult to compare among positive and negative studies. No in vitro human studies or animal models have been developed to specifically examine transfer potential of transdermal estradiol or testosterone. CONCLUSION: It is necessary to consider the mechanism behind transdermal hormone transfer and consider ways to enhance clinical benefits to the dosed individual while minimizing transfer to a naïve interpersonal contact. A detailed discussion of trial comparisons and future optimization methods may help enhance our understanding of the potential for transdermal hormone transfer and encourage development of newer formulations and/or application methods to minimize its occurrence.

Modest but increased penetration through damaged skin: an overview of the in vivo human model.

BACKGROUND/AIM: Quantifying percutaneous penetration of topical drugs as well as those compounds relevant to occupational exposure is important for assessing their delivery, efficacy and toxicology. Methods for assessing penetration are established for intact skin; however, what may be equally relevant is how much penetration occurs through damaged skin. METHODS: The Embase database was accessed online in March 2009 in search of human in vivo studies measuring penetration through damaged or diseased skin. RESULTS: Few studies have measured penetration through damaged human skin in vivo. A majority demonstrate a modest enhancement in penetration, with the exception of microdialysis studies that show a significant enhancement. The enhancement generally favored hydrophilic molecules over lipophilic molecules. CONCLUSIONS: Damaged or diseased skin may display a modest increase in penetration compared to intact skin, which is dependent on the method of measurement; however, additional studies with consistent methods are needed to fully elucidate how much penetration occurs through the many types and degrees of damaged skin.