Fas‐ligand staining in non‐drug‐ and drug‐induced maculopapular rashes

Background: Morphologically and histopathologically, drug‐ and non‐drug‐induced maculopapular rashes can be almost indistinguishable. It has been postulated that Fas‐ligand (Fas‐L) is involved in the pathogenesis of drug rashes but not in the genesis of rashes, such as viral exanthems, that are not induced by medications. Aim: This study sought to determine if epidermal Fas‐L is a distinguishing feature in the pathology of drug and non‐drug maculopapular rashes. Methods: Archived skin biopsies of patients with a confirmed diagnosis of drug or non‐drug maculopapular rashes (n = 10 each) and positive and negative controls were retrieved for immunohistochemical staining for Fas‐L. The proportion of Fas‐L‐positive skin biopsies were compared. The presence of tissue eosinophilia was also evaluated. Results: Ten percent of non‐drug‐induced rashes were Fas‐L positive compared to 50% of drug rashes (p = 0.05). Twenty percent of non‐drug exanthems had moderate tissue eosinophilia, while 60% from drug rashes had moderate to dense tissue eosinophilia (p = 0.17). Conclusion: There is a trend toward Fas‐L being more prevalent in the epidermis of drug maculopapular rashes, although this did not reach statistical significance. This is possibly because of the small sample size. Wang ECE, Lee JSS, Tan AWH, Tang MBY. Fas‐ligand staining in non‐drug‐ and drug‐induced maculopapular rashes.     

The risks of do‐it‐yourself and over‐the‐counter devices for tattoo removal

The tattoo removal market has boomed over the years following the increased prevalence of tattooed individuals around the world. Surgery and laser are currently the gold standards for tattoo removal. However, both of them have drawbacks. Surgery is better suited for small tattoos in areas of adequate skin laxity but leave a scar, while laser removal is a long and painful procedure, with no guarantee of a complete efficacy. Both are expensive procedures, and not all individuals are ready to fund them privately. Consequently, some individuals are in the search of faster, easier, and cheaper procedures that can be performed either by themselves or by laypeople. The unregulated market of internet provides a favorable ground for many websites to offer various tattoo removal methods. Besides, some tattooists and other non‐medical laypeople have started to get interested by such a growing market, especially as some laser devices manufactured in Asia are now available at competitive prices, and due to weaknesses in the EU legislation regarding the use of lasers for cosmetic procedures by non‐medical laypeople. We review here different do‐it‐yourself and over‐the‐counter tattoo removal methods. We discuss the potential risks for tattooed individuals and stress the importance of a better regulation of such a market.     

In vitro and in vivo evidence of tyrosinase inhibitory activity of a synthesized (Z)‐5‐(3‐hydroxy‐4‐methoxybenzylidene)‐2‐thioxothiazolidin‐4‐one (5‐HMT)

Tyrosinase is a key enzyme that catalyses the initial rate‐limiting steps of melanin synthesis. Due to its critical role in melanogenesis, various attempts were made to find potent tyrosinase inhibitors although many were not safe and effective in vivo. We evaluated tyrosinase inhibitory activity of six compounds. Among them, (Z)‐5‐(3‐hydroxy‐4‐methoxybenzylidene)‐2‐thioxothiazolidin‐4‐one (5‐HMT) had the greatest inhibitory effect and potency as the IC₅₀ value of 5‐HMT was lower than that of kojic acid, widely‐known tyrosinase inhibitor. Based on in silico docking simulation, 5‐HMT had a greater binding affinity than kojic acid with a different binding conformation in the tyrosinase catalytic site. Furthermore, its skin depigmentation effect was confirmed in vivo as 5‐HMT topical treatment significantly reduced UVB‐induced melanogenesis in HRM2 hairless mice. In conclusion, our study demonstrated that 5‐HMT has a greater binding affinity and inhibitory effect on tyrosinase and may be a potential candidate for a therapeutic agent for preventing melanogenesis.     

Increased expression of IL‐33 in rosacea skin and UVB‐irradiated and LL‐37‐treated HaCaT cells

Rosacea is one of the most common dermatoses of adults. Although the detailed pathophysiology remains unknown, it is thought that rosacea is caused by a consistently aberrant, innate immune response, and that LL‐37 plays an important role. However, involvement of the inflammatory cytokine IL‐33 has not yet been studied. We explored the role played by IL‐33 in the pathophysiology of rosacea. First, we immunohistochemically evaluated the expression of IL‐33 and its receptor (ST2) in rosacea skin. Second, we exposed HaCaT cells to ultraviolet B (UVB) irradiation in the presence or absence of LL‐37 and measured the expression of proinflammatory cytokines including IL‐33. We also analysed VEGF (vascular endothelial growth factor) mRNA expression and protein release after costimulation of HaCaT cells by LL‐37 and IL‐33. Immunohistochemically, IL‐33 expression was enhanced in the skin of rosacea patients, especially with erythematotelangiectatic subtype. In vitro, UVB and LL‐37 synergistically increased mRNAs expression of proinflammatory cytokines, especially IL‐33 and IL‐1β. IL‐33 protein release was also synergistically increased by LL‐37 and UVB treatment. LL‐37 and IL‐33 stimulated VEGF mRNA expression and VEGF release from HaCaT cells. Our findings suggest that rosacea skin with abundant LL‐37 may robustly produce and release IL‐33 when exposed to UV radiation. IL‐33 may participate in the angiogenesis and vasodilation of rosacea skin by enhancing VEGF release.     

Side‐by‐side comparison of photodynamic therapy and pulsed‐dye laser treatment of port‐wine stain birthmarks

Background Pulsed‐dye laser (PDL)‐mediated photothermolysis is the current standard treatment for port‐wine stain (PWS) birthmarks. Vascular‐targeted photodynamic therapy (PDT) might be an alternative for the treatment of PWS. Objectives To compare clinical outcomes of PDT and PDL treatment of PWS. Methods Two adjacent flat areas of PWS lesions were selected from each of 15 patients (two male and 13 female; age 11–36 years) and randomly assigned to either single‐session PDL or PDT. PDL was delivered using a 585‐nm pulsed laser. PDT was carried out with a combination of haematoporphyrin monomethyl ether (HMME) and a low‐power copper vapour laser (510·6 and 578·2 nm). Clinical outcomes were evaluated colorimetrically and visually during follow‐up. Results A total of nine red PWS lesions and six purple PWS lesions were treated. For red PWS, colorimetric assessment showed that the blanching rates of PDL and PDT at 2 months ranged from ?11% to 24% and 22% to 55%, respectively. For purple PWS, blanching rates of PDL and PDT ranged from 8% to 33% and 30% to 45%, respectively. Overall, there was a significant difference between the blanching effect of single‐session PDL treatment and a single‐session PDT treatment. Conclusions This side‐by‐side comparison demonstrates that PDT is at least as effective as PDL and, in some cases, superior. The true value of PDT for the treatment of PWS deserves further investigation.     

Utilization of matrix‐assisted laser desorption and ionization time‐of‐flight mass spectrometry for identification of infantile seborrheic dermatitis‐causing Malassezia and incidence of culture‐based cutaneous Malassezia microbiota of 1‐month‐old infants

Matrix‐assisted laser desorption and ionization time‐of‐flight mass spectrometry (MALDI‐TOF‐MS) has been utilized for identification of various microorganisms. Malassezia species, including Malassezia restricta, which is associated with seborrheic dermatitis, has been difficult to identify by traditional means. This study was performed to develop a system for identification of Malassezia species with MALDI‐TOF‐MS and to investigate the incidence and variety of cutaneous Malassezia microbiota of 1‐month‐old infants using this technique. A Malassezia species‐specific MALDI‐TOF‐MS database was developed from eight standard strains, and the availability of this system was assessed using 54 clinical strains isolated from the skin of 1‐month‐old infants. Clinical isolates were cultured initially on CHROMagar Malassezia growth medium, and the 28S ribosomal DNA (D1/D2) sequence was analyzed for confirmatory identification. Using this database, we detected and analyzed Malassezia species in 68% and 44% of infants with and without infantile seborrheic dermatitis, respectively. The results of MALDI‐TOF‐MS analysis were consistent with those of rDNA sequencing identification (100% accuracy rate). To our knowledge, this is the first report of a MALDI‐TOF‐MS database for major skin pathogenic Malassezia species. This system is an easy, rapid and reliable method for identification of Malassezia.     

Induction of eosinophil‐ and Th2‐attracting epidermal chemokines and cutaneous late‐phase reaction in tape‐stripped skin

Abstract: Skin barrier damage induces various harmful or even protective reactions in the skin, as represented by enhancement of keratinocyte cytokine production. To investigate whether acute removal of stratum corneum modulates the production of chemokines by epidermal cells, we treated ears of BALB/c and C57BL/6 mice by tape‐stripping, or acetone‐rubbing as a control of acute barrier disruption procedure. There was no difference between the tape‐stripped and acetone‐rubbed skin sites in the increased and recovered levels of transepidermal water loss. The mRNA expression levels of all the chemokines tested, including Th1 chemokines (CXCL10, CXCL9 and CXCL11), Th2 chemokines (CCL17 and CCL22) and eosinophil chemoattractant (CCL5), were higher in the epidermal cells from BALB/c than in those of C57BL/6 mice. In particular, CCL17, CCL22 and CCL5 were remarkably elevated in BALB/c mice and augmented by tape‐stripping more markedly than acetone‐rubbing, whereas Th1 chemokines were enhanced by acetone‐rubbing more remarkably. Tape‐stripping induced dermal infiltration of eosinophils in BALB/c but not C57BL/6 mice. In a contact hypersensitivity model, where BALB/c mice were sensitized on the abdomen and challenged on the ears with fluorescein isothiocyanate, mice exhibited higher ear swelling responses at the late‐phase as well as delayed‐type reactions, when challenged via the tape‐stripped skin. The challenge via tape‐stripped skin augmented the expression of IL‐4 and CCR4 in the skin homogenated samples, indicating infiltration of Th2 cells. These findings suggest that acute barrier removal induces the expression of Th2 and eosinophil chemokines by epidermal cells and easily evokes the late phase reaction upon challenge with antigen.     

Obesity exacerbates imiquimod‐induced psoriasis‐like epidermal hyperplasia and interleukin‐17 and interleukin‐22 production in mice

Psoriasis is a chronic inflammatory skin disorder that is accompanied by an imbalance between the proliferation and differentiation of keratinocytes. A number of studies have suggested an association between obesity and severe psoriasis; however, it remains to be clarified whether obesity exacerbates psoriasis. To address this unsolved question, we induced psoriasiform dermatitis in mouse models for obesity. We found that obesity exaggerated the severity of psoriasiform dermatitis induced by topical application of the Toll‐like receptor (TLR) 7 agonist, imiquimod. Ear swelling and epidermal hyperplasia were more prominent in the obese mice than in the control mice. When compared to imiquimod‐treated control mice, imiquimod‐treated obese mice expressed higher levels of psoriasis mediators, interleukin‐17A (IL‐17A) and IL‐22 in the skin. Food intake restriction partially abrogated enhanced ear swelling and cytokine overproduction in obese mice. Furthermore, the obesity environment and imiquimod treatment synergistically induced an IL‐17A downstream molecule, regenerating islet‐derived 3γ (Reg3γ), which is a critical molecule for psoriatic epidermal hyperplasia. Palmitic acid, one of the fatty acids released by subcutaneous adipocytes, increased the expression of REG3A (a human homologue of mouse Reg3γ) in both the HaCaT keratinocyte cell line and normal human keratinocytes. Taken together, these results strongly suggest that obesity exacerbates psoriasiform dermatitis in mice by upregulating IL‐17A, IL‐22 and Reg3γ.     

Reduction in the appearance of facial hyperpigmentation by topical N‐undecyl‐10‐enoyl‐l‐phenylalanine and its combination with niacinamide

Objectives N‐undecyl‐10‐enoyl‐l ‐phenylalanine (Sepiwhite^®, N‐undecylenoyl phenylalanine), a reported alpha‐melanocyte‐stimulating hormone (MSH) receptor antagonist, has been observed to reduce melanin production in cultured melanocytes. In other testing, niacinamide has been found to inhibit melanosome transfer in cultured cells and to reduce the appearance of hyperpigmented spots in clinical studies. Since these two agents function by different mechanisms, we conducted two studies to determine if their combination is more effective than niacinamide alone in reducing facial hyperpigmentation. Methods  Two double‐blind, 10‐week (2‐week washout + 8‐week treatment), left‐right randomized, split‐face clinical studies were conducted. In one, two groups of Japanese women applied one of two pairs of test emulsion formulations: a vehicle control and a 5% niacinamide formulation (n= 40), or a 5% niacinamide and a 5% niacinamide plus 1%N‐undecylenoyl phenylalanine formulation (n = 40). Each formulation was applied to the randomly assigned side of the face. In the second study, Caucasian women applied one of three emulsions: vehicle control, 5% niacinamide formulation, or combination 5% niacinamide plus 1%N‐undecylenoyl‐phenylalanine formulation to the randomly assigned side of the face (n = ～60 treatment sites per formulation). In both studies, hyperpigmented spots were evaluated at weeks 4 and 8 by quantitative image analysis. Results  In both studies, the combination formulation was significantly more effective than the vehicle and the 5% niacinamide formulation in reducing the appearance of hyperpigmentation after 8 weeks. Conclusions  The combination of 5% niacinamide and 1%N‐undecylenoyl phenylalanine is an effective anti‐aging technology for use on facial skin.     

Photo‐induced graft‐versus‐host disease

Overlap chronic graft‐versus‐host disease (GVHD) associates both features of acute and chronic GVHD. Trigger factors for chronic GVHD are unclear. We describe two patients who received allogenic haematopoietic stem‐cell transplantation, and who later developed overlap chronic GVHD after sun exposure. Available data from in vivo investigations suggest ultraviolet B radiation (UVB) has a beneficial effect on acute and chronic GVHD. The role of sun irradiation as a trigger for isomorphic cutaneous GVHD has been rarely reported in the literature. Herein, we demonstrate for the first time, using repetitive broadband phototesting, that UVB triggers chronic GVHD.     

Connexin‐26‐Mutation bei „Keratitis‐Ichthyosis‐Deafness”‐Syndrom (KID‐Syndrom)

Background: Keratitis‐ichthyosis‐deafness syndrome (KID syndrome) is an extremely rare disorder. Inheritance is autosomal dominant but many cases occur sporadically following a spontaneous mutation. The cause of KID syndrome are missense mutations of the gene GJB2, encoding connexin 26. Patients and Methods: We clinically studied two cases of KID syndrome and extracted genomic DNA from peripheral blood. Results: The patients showed different heterozygous mutations of the connexin 26 gene and had quite different clinical courses. Conclusions: Both patients showed heterozygous mutations of the connexin 26 gene; a different Cx26 dominant mutation can cause a very different clinical course.     

UVB‐ and NGF‐induced cutaneous sensitization in humans selectively augments cowhage‐ and histamine‐induced pain and evokes mechanical hyperknesis

Exaggerated itch responses to pruritic chemical provocations and mechanical stimuli are evident in patients with chronic itch, for example, in atopic dermatitis. Currently used human models of itch do not account for such itch sensitization features, and the mechanisms underlying clinical itch sensitization are unknown. This study utilized two established human models of cutaneous nociceptive sensitization to explore how pre‐established inflammatory hyperalgesia (ultraviolet‐B‐irradiation; “UVB”) and non‐inflammatory neurotrophic pain sensitization (nerve growth factor; “NGF”) alter sensitivity to chemical and mechanically evoked itch. Twenty healthy volunteers participated in the UVB experiment. Six volar forearm areas (2 cm diameter) were UVB irradiated with ≤2 × minimal erythemal dose, and two non‐irradiated areas were used as controls. Sixteen healthy volunteers participated in the NGF experiment and had 2 μg intradermally injected (4 × 50 μL in 2 cm diameter areas) into both volar forearms. Isotonic saline was applied as control. Pain sensitivity measurements (mechanical and heat pain thresholds) were conducted to validate the models. Subsequently, itch was evoked using histamine and cowhage spicules in the sensitized skin areas, and itch/pain was rated using visual analogue scales. Mechanical hyperknesis (increased itch to punctuate stimuli) was probed with von Frey filaments before/after each itch provocation. Both UVB‐ and NGF models induced robust primary mechanical hyperalgesia (P < .01) and hyperknesis (P < .05). Neither of the models augmented itch in response to chemical itch provocations but significant increases specifically for pain ratings were observed for both histamine and cowhage (P < .05). This suggests that these models are of limited value as proxies for itch sensitization to pruritogens observed, e.g., in inflammatory dermatoses.