Reversible cellular damage by dimethyl sulfoxide reflected by release of marker enzymes for intracellular fractions

Summary Irritative human skin reactions were induced by dimethyl sulfoxide (DMSO). Suction blisters were raised on these areas within 1.5 h after their induction, and simultaneously on normal skin. The activities of marker enzymes for subcellular fractions in the suction blisters were determined.In suction blisters raised on the DMSO induced wheals significantly higher values of the cytosol enzyme lactate dehydrogenase and also some higher values of the lysosomal marker -mannosidase were found than in blisters produced on normal skin. Membrane-bound marker enzymes for subcellular fractions were not elevated.Since the skin is macroscopically completely normal 24 h after application of DMSO, our results indicate that the induction of a certain membrane damage with release of intracellular enzymes does not necessarily lead to cellular necrosis.     

Cellular events leading to blister formation in bullous pemphigoid

Cellular events occurring in eight patients with bullous pemphigoid were studied by light and electron microscopy. Sections (0.5 μm) of large surface area, overlapping blisters and surrounding skin, were examined and correlated ultrastructural studies were performed on selected areas. The peroxidase contained in granules of neutrophils, cosinophils and young macrophages was visualized by incubation with diaminobenzidine and hydrogen peroxide. This cytochemical reaction was used as a marker to study the release of granule enzymes from these inflammatory cells. The release of such enzymes from eosinophils and occasionally from macrophages on the epidermal basement membrane (more precisely in the lamina lucida) was demonstrated in the skin surrounding the blisters in four patients. The release of these enzymes was also observed in the floor of the blisters in all eight patients. It is well known that these granules contain several protcolytic enzymes. These observations are therefore consistent with the proposal that proteolytic enzymes of eosinophils play a pathogenic role during the initial stages of blister formation in bullous pemphigoid.     

Calcium entry into keratinocytes induces exocytosis of lysosomes

During the final steps of epidermal differentiation, extracellular calcium ions enter keratinocytes and induce transglutaminase activity and cornified envelope formation. In other cell types, entry of calcium mediated by ionophores has been reported to induce exocytosis of lysosomes. In this study, we investigated whether lysosomes of keratinocytes might exhibit a similar behaviour. Ionomycin treatment induced cornified envelope formation in keratinocytes, but also morphological changes including plasma membrane blebbing, although no immediate alteration in cell viability could be detected. The activity of the soluble lysosomal enzymes cathepsin C and -galactosidase in the culture medium was increased upon ionomycin treatment. Cell leakage did not seem to be responsible for this phenomenon, as suggested by measurements of the cytosolic enzymes adenylate kinase and dipeptidylpeptidase III in the culture medium. Metabolic labelling followed by immunoprecipitation showed that ionomycin induced release of cathepsin D into the culture medium. Simultaneously, lysosome-associated membrane proteins (Lamps) 1 and 2 were detected at the cell surface of ionomycin-treated keratinocytes by biochemical and morphological approaches. These results suggest that upon ionomycin treatment, calcium entry stimulates exocytosis of lysosomes in keratinocytes.Abbreviations AK Adenylate kinase - BSA Bovine serum albumin - DMSO Dimethylsulphoxide - DPPIII Dipeptidylpeptidase III - DTT Dithiothreitol - EDTA Ethylene diaminotetraacetic acid - EGTA Ethylene glycol-O,O-bis(2-aminoethyl)-N,N,N,N-tetraacetic acid - LDH Lactate dehydrogenase - PBS Phosphate-buffered saline - SDS Sodium dodecylsulphate     

The antiproteolytic compound α 2 in human skin

Summary Monoclonal antibodies recognizing the antiproteolytic compound ₂-macroglobulin (MG) were used for immunohistological studies on normal human skin. MG-specific immunoreactivity was found to be localized to the papillary dermis and to be concentrated in the region of the epidermodermal junction. In view of these findings and the possible involvement of proteolytic enzymes and their inhibitors in blister formation, we asked whether MG occurs in the fluid of experimentally induced blisters. MG was identified (by western-blotting) and quantified (by a monoclonal antibody based enzyme immunoassay) in the fluid of experimentally induced suction blisters. Taken together, MG is present in such blister fluid in concentrations 6 times lower than in serum, but still in an antiproteolytic range. These findings allow suggestion of a possible role for the antiproteolytic compound MG in blister formation.     

Lichen planus pemphigoides: report of two cases

Case 1 A 73‐year‐old woman with a 5‐month history of widespread lichenoid eruption developed disseminated blisters. She had insulin‐dependent diabetes mellitus and renal tuberculosis treated with isoniazide (300 mg/day), rifampin (600 mg/day), ethambutol (1.5 g/day) and pyrazinamide (2 g/day) following right nephrectomy. Antituberculous therapy which had been begun 2 months before the onset of lichenoid eruption was stopped by the patient following the appearence of blisters. Examination revealed lichenoid plaques on the face, neck, trunk and extremities and tense bullae on the neck and extremities ( Fig. 1a ). The bullae were either on lichenoid plaques or normal appearing skin. Some of the blisters were hemorrhagic. Two skin biopsies were performed. The first biopsy from a blister with a lichenoid base on the arm, showed typical changes of lichen planus (LP) with subepidermal cleft formation. The second biopsy from a blister on normal appearing skin on the trunk showed subepidermal bulla with perivascular inflammatory cell infiltrate of eosinophils and lymphocytes. Direct immunofluorescence (DIF) of perilesional skin showed linear deposition of IgG and C3 along basal membrane zone (BMZ). Direct immunofluorescence on salt‐split skin revealed epidermal binding of immunoreactants. Indirect immunofluorescence showed a circulating IgG autoantibody binding to the BMZ at a titre of 1/200. Immunoblot analysis of her serum recognized minor 180 Kd BP antigen. An initial trial of dapsone (100 mg/day) for 2 weeks was not effective. She was then treated with oral methylprednisolone (32 mg/day), which induced rapid improvement in her skin lesions ( Fig. 1b ). After 2 months of treatment, corticosteroid was stopped and the patient stayed in remission for 1 year till she died due to myocard infarction.

Figure 1 Open in figure viewer PowerPoint (a) Lichenoid papules and hemorrhagic blisters on the face and the neck. (b) After 2 months of oral methylprednisolone therapy     

Very late antigen (VLA) expression in various forms of epidermolysis bullosa simplex

Summary The very late antigen (VLA) glycoproteins are a family of adhesion membrane receptors involved in cell-cell and cell-matrix interactions. In order to investigate the expression of these molecules in inherited epidermolysis bullosa (EB), we studied the reactivity of monoclonal antibodies directed against VLA-1, -2, -3, -4, -5, and -6, and VLA receptors in skin sections from patients affected by several types of EB simplex (EBs) using indirect immunofluorescence. Skin samples were obtained from six patients with generalized type (Koebner), one patient with localized type (Weber-Cockayne) and one patient with Dowling-Meara EBs type and also from two normal controls. No significant modification of the expression of these adhesion receptors was observed. Anti-VLA-2 and anti-VLA-3 stained the whole cytoplasmic membrane of basal keratinocytes and allowed the detection of focal areas of cytolysis in unblistered skin from the Koebner and Dowling-Meara type. In Koebner type blisters anti-VLA-3 stained the cell remnants at the roof of the blister with a linear staining along the epidermal basement membrane on the dermal side. In Dowling-Meara type blisters anti-VLA-3 also stained cell remnants at the bottom of the cavity. Anti-VLA-6 stained the bottom of the blister cavity with the same distribution of bullous pemphigoid serum but with a stronger and more constant reactivity. Our data show that anti-VLA-3 and anti-VLA-6 can usefully be utilized in diagnostic immunomapping studies of EBs.     

Erythrodermic bullous pemphigoid

Case 1 An 87‐year‐old man, with a 2‐year history of a generalized exfoliative erythroderma involving approximately 90% of the body, presented with an onset of tense blisters symmetrically distributed on most of his body. Clinical examination revealed generalized erythema, edema, moderate lichenification, and scaling, with several tense and grouped blisters on the hypocondrium, buttocks, left knee, and back of the left hand ( Fig. 1 ). A biopsy specimen, taken from lesional erythematous skin, revealed a dermal–epidermal separation with a mixed inflammatory infiltrate containing numerous eosinophils. Direct immunofluorescence of perilesional skin on the abdomen demonstrated linear deposition of immunoglobulin G (IgG) and C3 at the basement membrane zone (BMZ) ( Fig. 2 ). Indirect immunofluorescence demonstrated serum IgG antibodies directed against BMZ antigens at a titer of 1 : 20. Utilizing salt‐split human skin as a substrate, serum revealed the presence of IgG antibodies that bound to the epidermal side at a titer of 1 : 80. Blotting studies demonstrated circulating IgG antibodies which bound to the 180 kDa bullous pemphigoid (BP) antigen ( Fig. 3 ). Human leukocyte antigen (HLA) typing revealed A3, B41, Cw2, DR4, DR11, DRw53, and DQ3.

Figure 1 Open in figure viewer PowerPoint Several small, tense, grouped blisters associated with diffuse erythema and moderate lichenification and scaling localized on the anterior surface of the trunk     

新生儿线状IgA大疱性皮病

患儿男, 生后10 d, 因皮肤红斑、水疱6 d就诊入院。皮肤科检查:全身皮肤散在或融合分布红斑, 在正常皮肤或红斑基础上可见大小不等的紧张性水疱, 部分水疱破溃、糜烂;口腔黏膜可见血疱、红色糜烂面。组织病理检查示表皮下水疱, 疱内可见中性粒细胞及少量嗜酸性粒细胞。直接免疫荧光检查显示:沿基底膜带有均质型线状IgA和颗粒状C3沉积, IgG阴性。诊断:新生儿线状IgA大疱性皮病。给予营养支持、防感染等综合治疗后, 皮肤红斑、水疱消退, 黏膜损害减轻出院。患儿出院后16个月电话随访, 一般情况良好, 皮肤黏膜皮损消退、愈合, 无新发皮疹, 生长发育正常。     

Cytokines and glucocorticoids differentially regulate APN/CD13 and DPPIV/CD26 enzyme activities in cultured human dermal fibroblasts

Cultured human dermal fibroblasts coexpress two cell surface ectopeptidases, aminopeptidase N (APN/CD13) and dipeptidyl peptidase IV (DPPIV/CD26). These enzymes catalyze the removal of a single amino acid or a dipeptide from the N-termini of oligopeptides, respectively. They are also localized in a differential pattern in normal, non-sun-exposed, adult skin, a finding that supports the supposition that these enzymes might have different functions in the skin, but relatively little is known about their functions in the skin. A better understanding of how the activities of these enzymes are regulated should increase our understanding of their functions in the skin. APN/CD13 was routinely expressed at higher levels on cultured fibroblasts than was DPPIV/CD26. Treatment of cultured fibroblasts with specific factors differentially modulated the activities of these enzymes. APN/CD13 was significantly upregulated by treatment with interleukin-4 (IL-4), interferon (IFN), and the glucocorticoids dexamethasone and hydrocortisone. In contrast, the regulation of DPPIV/CD26 activity was found to be different and more complex. This enzyme was consistently upregulated by IL-1 and IL-1, but consistently downregulated by glucocorticoids, tumor necrosis factor (TNF) and transforming growth factor ₁ (TGF₁). Thus, although these two enzymes are expressed on the same populations of cultured cells, their activities are differentially regulated. This finding, along with their differential distribution in normal skin, suggests that APN/CD13 and DPPIV/CD26 have different functions in the skin.     

Decreased specific anti-elastase activity in the uninvolved skin of patients with psoriasis

Summary Inhibitory activities against elastase, chymotrypsin and trypsin were studied in the fluid from experimentally developed suction blisters in the uninvolved skin of patients with psoriasis. These activities determined by spectrophotometry of specific synthetic low molecular weight substrates were compared with respective antiproteinase activities in sera of 32 patients with psoriatic lesions, ten patients in remission, and ten healthy volunteers. A marked reduction (29.2%) in the specific elastase inhibitory activity of blister fluid was found in patients with psoriasis when compared with normal subjects (p<0.05), since neither chymotrypsin nor trypsin inhibitory activities were altered. This reduction was despite about a 30% increase in the elastase inhibitory activity in the sera of these patients, which was related presumably to their increased activity of ₁-proteinase inhibitor, the main serum antiserine proteinase inhibitor. A decreased blister fluidserum elastase inhibition ratio was shown in a large majority of patients with psoriasis, even in symptomless patients. The deficiency in specific elastase inhibitory activity of suction blister fluid was predominantly associated with early onset of psoriasis, guttate lesions and inactive lesions, skin involvement less than 20% of body surface, duration of relapse shorter than 2 months, and frequent relapses. These data indicate that the uninvolved skin of patients with psoriasis contains low concentrations of specific elastase tissue inhibitor, which deficiency might result in an excessive in vivo hydrolytic activity of neutrophil elastase released from migrating cells in the psoriatic skin.     

Epidermolytic hyperkeratosis

A 2-year-old boy reported with complaints of spontaneous, recurrent, excessive blisters, accompanied by redness and scaling, since birth. The blisters ruptured after a couple of hours, leaving behind raw, exuding, denuded areas, which healed by hyperpigmentation. No scarring was observed. Such episodes were quite regular in infancy. Subsequently, there was a perceptible decline in these episodes with the growth of the child. In addition, the child had multiple, warty scales located in the groin, axillae, and neck. Examination of the skin surface revealed ruptured bullae of varying size. On removal of the roof of a bulla, raw, exuding, erythematous, eroded areas were exposed ( Fig. 1 ). Hyperpigmentation at the healing site was prominent. The lesions were located over the extremities and trunk. In addition, hyperkeratotic warty eruptions confined to the neck, axillae, and groin were also identified ( Figs 2 and 3 ). Palmoplantar keratosis and a single palmar crease on both hands were other interesting associations. ^{1 , 2} Hematoxylin and eosin stained sections of the skin showed marked hyperkeratosis, hypergranulosis, and vacuolar degeneration of the stratum spinosum. In the dermis, there was a lymphohistiocytic infiltrate ( Fig. 4 ). ³ Karyotype analysis was normal. The blisters were snipped and the erosions were treated with local application of liquor aluminum acetate 1%. Amoxycillin and clavulanic acid suspension (Augmentin) was administered at a dosage of 125 mg twice daily until the lesions healed.

Figure 1 Open in figure viewer PowerPoint Raw, exuding erythematous areas     

The lazaroid tirilazad is a new inhibitor of direct and indirect UVA-induced lipid peroxidation in human dermal fibroblasts

Lipid peroxidation caused by oxidative stress within the tissue leads to destruction and dysfunction of cellular membranes. Human dermal fibroblasts in the skin are subject to constant photooxidative stress caused mainly by deeply penetrating UVA irradiation. Therefore, the membrane damage caused by this photooxidative stress may be a major promoter of photoaging and photocarcinogenic processes initiated and promoted by long-term UVA exposure of the skin. The oxidative destruction is counterbalanced by a complex network of enzymatic and nonenzymatic antioxidants creating the skins line of defence against UVA-induced reactive oxygen species. The lazaroid tirilazad represents a new synthetic group of antioxidants with structural molecular similarity to glucocorticosteroids. We investigated the antioxidative capacity of tirilazad by determining its effects on the levels of malondialdehyde (MDA), as a marker of lipid peroxidation, induced directly or indirectly by UVA in human dermal fibroblasts. In a time- and dose-dependent kinetic, we demonstrated that fibroblasts incubated with tirilazad are well protected against subsequent UVA irradiation and show no increase in MDA levels similar to the unirradiated controls. This was also observed when lipid peroxidation was caused chemically by incubation of human dermal fibroblasts with 200 M Fe³⁺-citrate and 1 mM ascorbyl phosphate as a model of indirect UVA-induced skin damage. Lysates of fibroblasts treated this way showed a tenfold increase in MDA levels, whereas preincubation with tirilazad resulted in a significantly lower increase in MDA levels. Furthermore, in a comparison with the well-established radical scavenger Trolox, an -tocopherol analogue, tirilazad offered better protection to the membranes. Our results demonstrate for the first time that the lazaroid tirilazad is an effective inhibitor of direct and indirect UVA-induced increases in MDA as a marker of lipid peroxidation in human dermal fibroblasts.     

Changes in Transepidermal Water Loss and Skin Hydration according to Expression of Aquaporin-3 in Psoriasis

Background

Aquaporins (AQPs) are a family of water transporting proteins present in many mammalian epithelial and endothelial cell types. Among the AQPs, AQP3 is known to be a water/glycerol transporter expressed in human skin.

Objective

The relationship between the expression level of AQP3 and transpidermal water loss (TEWL) in the lesional and peri-lesional skin of psoriasis-affected patients, and skin hydration in the lesional and peri-lesional skin of psoriasis patients, was investigated.

Methods

The expression of AQP3 in psoriasis-affected and healthy control skin was determined using immunohistochemical and immunofluroscence staining. TEWL and skin hydration were measured using a Tewameter® TM210 (Courage & Khazaka, Cologne, Germany) and a Corneometer® CM 820 (Courage & Khazaka), respectively.

Results

AQP3 was mainly expressed in the plasma membrane of stratum corneum and the stratum spinosum in normal epidermis. Unlike the normal epidermis, AQP3 showed decreased expression in the lesional and peri-lesional epidermis of psoriasis. TEWL was increased, and skin hydration was decreased, in the lesional and peri-lesional skin of psoriasis patients, compared with the healthy control sample.

Conclusion

Although various factors contribute to reduced skin hydration in the lesional and peri-lesional skin of psoriasis, AQP3 appears to be a key factor in the skin dehydration of psoriasis-affected skin.     

Papular perniosis mimicking erythema multiforme: the first case report in Thailand

A healthy 23‐year‐old man of Thai descent presented with skin lesions on the acral part of the feet, which developed after exposure to an Australian winter with an average temperature of 5 °C. Immediately after the exposure, the patient developed mild anesthesia around the toes which was accentuated after a bath. During the exposure, warm winter clothes, including boots and socks, were worn. Several hours later, a few itchy bumps were noted bilaterally on the fifth toes. The patient then cleansed and immersed his feet in an over‐the‐counter antiseptic preparation. By the next day, the lesions had enlarged and formed blisters filled with clear fluid. The lesions gradually progressed to cover the dorsal part of the feet within the next few days. He applied an over‐the‐counter antibacterial/antifungal cream to the lesions for 3 days without any improvement. Five days later the lesions became purplish red. Itching was the only symptom experienced. The patient was a nonsmoker who was in good health and denied a history of skin diseases, herpes simplex viral infection, or any intake of oral medication. Physical examination, performed in Thailand, revealed symmetrically distributed, discrete, purplish papules, some with dusky red centers, on the dorsal surfaces of all toes without blisters or erosion ( Fig. 1 ). No lesions were detected on the plantar surfaces of the feet, the legs, hands, or elsewhere on the body. Complete blood cell count, erythrocyte sedimentation rate (ESR), venereal disease research laboratory (VDRL) test, cryoglobulin, hepatitis B surface antigen (HBsAg), and anti‐hepatitis core immunoglobulin M (anti‐HBC IgM) were within normal limits or negative.

Figure 1 Open in figure viewer PowerPoint Erythema multiforme‐like lesions on the acral part of the feet     

Evaluation of the in vitro skin permeation of antiviral drugs from penciclovir 1% cream and acyclovir 5% cream used to treat herpes simplex virus infection

Background

Herpes simplex virus infection (HSV) is a common and ubiquitous infection of the skin which causes mucocutaneous lesions called cold sores (herpes labialis) or fever blisters. It is estimated that approximately 80% of the population worldwide are carriers of the Herpes simplex virus, approximately 40% suffer from recurrent recurrent infections. This study evaluates the in vitro skin permeation and penetration of penciclovir and acyclovir from commercialized creams for the treatment of herpes labialis (cold sores), using non viable excised human abdominal skin samples, which were exposed to 5 mg/cm² of acyclovir 5% cream or penciclovir 1% cream.

Methods

After 24 h of cream application, excess cream was washed off and layers of stratum corneum were removed by successive tape stripping. Amounts of active ingredients having penetrated through the skin were measured, as well as the amounts in the washed-off cream, in skin strips and creams remaining in the skin. Molecular modelling was used to evaluate physico-chemical differences between the drugs. Western blot analysis enabled to determine whether the marker of basal cells keratin 5 could be detected in the various tape strips.

Results

Application of penciclovir 1% cream yielded higher concentration of drug in the deeper layers of the epidermis as well as a higher drug flux through the skin. Molecular modelling showed two higher hydrophobic moieties for acyclovir. Presence of the basal cell marker keratin 5 was underscored in the deeper tape strips from the skin, giving evidence that both drugs can reach their target cells.

Conclusion

Penciclovir 1% cream has the tendency to facilitate the diffusion of the drug through the stratum corneum into the deeper epidermis layers, in which it could reach the target basal cells at effective therapeutical concentration. The small difference in the surface properties between both molecules might also contribute to favour the passage of penciclovir through the epidermis into the deeper basal cells.     

Changes of the activities of enzymes involved in prostaglandin synthesis in rat skin during development and aging

Summary The developmental changes of enzymes involved in prostaglandin (PG) synthesis were investigated in rat skin from birth to 1.5 years old. In all stages of development, the activities of PG-synthesizing enzymes were found in 100,000xg supernatants of homogenates of rat skin, and PGD₂ was the major PG among those formed from PGH₂ in the presence of 1 m glutathione (GSH). The PGD synthetase activity in rat skin at birth was 2.14 nmol/min per mg protein, increasing to the highest level (3.69 nmol/min per mg protein) at 3 weeks after birth and then gradually decreasing up to 1.5 years old. The activities of PGE₂ and PGF₂ synthetases in rat skin were almost unchanged during development and aging. In contrast, the activity of GSH-S-transferase was at its lowest level at birth and gradually increased, reaching a plateau at 3 weeks after birth and remaining relatively constant during the development. The increase of PGD synthetase activity in 3-week-old rats was mainly due to the increase of specific activity of PGD synthetase in the epidermis, which was separated from the dermis by heat treatment (55° C, 30s). Immunohis-tochemical study, using (rat spleen PGD synthetase)-specific antibody, revealed that the number of immunopositive cells, which were identified as Langerhans cells, increased in the epidermis in 3-week-old rats. These results suggest that a change of PGD₂ synthetase activity during aging of the skin is closely related to the development of ATPase⁺ Langerhans cells in the epidermis.     

Amyloidosis cutis dyschromica in two female siblings: cases report

Background

Cutaneous amyloidosis has been classified into primary cutaneous amyloidosis (PCA, OMIM #105250), secondary cutaneous amyloidosis and systemic cutaneous amyloidosis. PCA is the deposition of amyloid in previously apparent normal skin without systemic involvement. Amyloidosis cutis dyschromica (ACD) is a rare distinct type of PCA. Here, the unique clinical and histological findings of two Chinese female siblings with ACD were described.

Cases presentations

Patient 1 was a 34-year-old female, presented with mildly pruritic, diffuse mottled hyperpigmentation and hypopigmentation. The lesions involved all over the body since she was 10 years old. There were a few itchy blisters appearing on her arms, lower legs and truck, especially on the sun-exposed areas in summer. Some hypopigmented macules presented with slight atrophy. Patient 2 was 39-year-old, the elder sister of patient 1. She had similar skin lesions since the same age as the former. The atrophy and blisters on the skin of the patient with amyloidosis cutis dyschromica have not been described in previous literature. Histological examinations of the skin biopsies taken from both patients revealed amyloid deposits in the whole papillary dermis. Depending on the histological assessment, the two cases were diagnosed as amyloidosis cutis dyschromica.

Conclusion

The two cases suggest that the atrophy and blisters may be the uncommon manifestations of amyloidosis cutis dyschromica. It alerts clinicians to consider the possibility of ACD when meeting patients with cutaneous dyschromia. Skin biopsy is essential and family consultation of genetic investigation is very important in such cases.     

How do keratinizing disorders and blistering disorders overlap?

Inherited keratinizing disorders are caused by mutations in the genes encoding cornified cell envelope proteins, enzymes and their inhibitors, adhesion molecules, cytoskeletal proteins and others in the epidermis. These molecules are known to regulate differentiation, proliferation and cell adhesions. Intriguingly, some keratinizing disorders show blistering skin lesions, while some inherited blistering disorders show abnormal keratinization. Therefore, hereditary keratinizing and blistering diseases are closely related and show overlapping genetic backgrounds. In this review, we overviewed keratinizing and blistering disorders in terms of overlapping of the two disease groups. Gene mutations in desmosomal components cause striate keratoderma, Naxos disease, epidermolytic palmoplantar keratoderma and plakophilin deficiency, which first show skin fragility and blisters and later hyperkeratosis. Gene mutations in hemidesmosomal components cause various forms of epidermolysis bullosa, some of which show hyperkeratosis on the nails, palms and soles, in addition to blister formation. Diseases with gene mutations in calcium pump proteins are Darier disease and Hailey–Hailey disease, which show clinicopathological overlaps and develop both keratinizing and blistering skin lesions. Finally, gene mutations in epidermal keratins cause epidermolysis bullosa simplex, epidermolytic ichthyosis, superficial epidermolytic ichthyosis, epidermolytic palmoplantar keratoderma and pachyonychia congenita/focal palmoplantar keratoderma, which show thickening of the palms and soles with underlying blister formation. In general, responsible proteins for diseases developing both keratinizing and blistering conditions are adhesion molecules, calcium pump proteins and keratins, but not connexins, cornified cell envelop proteins, enzymes or inhibitors. It is still unknown how particular keratinizing diseases develop blisters and vice versa.     

The use of dihydroxyacetone for photoprotection in variegate porphyria

A 33-year-old woman presented with complaints of facial scarring, blisters on the dorsal hands, skin fragility, and increased hair growth on the temples. She reported that these “scratch marks” had appeared spontaneously for 3 years. She was otherwise healthy and not on any medication. On examination, the patient had several 3–4-mm erythematous papules, some with depressed centers, on the dorsal aspects of the hands ( Fig. 1 ) and the face, but no observable milia. In the perioral region, there were numerous depressed pock-like scars. There was no obvious hypertrichosis.

Figure 1 Open in figure viewer PowerPoint Erythematous papules with depressed centers on the dorsal hand     

Toxic epidermal necrolysis complicated by multiple intestinal ulcers

On 11 November 2001, a 30‐year‐old woman was treated by an emergency doctor for cold symptoms, including pyrexia and pain in the pharynx. She was prescribed norfloxacin (NFLX), acetaminophen, and tranexamic acid, as well as additional supporting medicines that she chose not to use. On the following day, the patient went to the outpatient unit of the department of internal medicine of a general hospital; she was admitted because of continuing fever. She was prescribed a combination medication for Bifidus bacillus containing mefenamic acid and aluminum hydroxide gel/magnesium hydroxide, as well as NFLX and teprenone, but erosions of her face appeared on 15 November, followed by erosions of the trunk on 17 November. She was suffering from inflammation and blisters over her whole body. She was diagnosed with toxic epidermal necrolysis (TEN) by the department of dermatology of the same hospital. The patient underwent steroid pulse therapy for 3 days from 17 November, which was not effective, and was transferred to our hospital on 22 November. In the initial examination, the patient's body was almost entirely covered with blisters, including her face, trunk, and both arms. Erosions were also present in her mouth, on the conjunctivae of both eyelids, and on her vulva (see Fig. 1 ). In addition, we recognized false membrane formation on the eyelid conjunctivae in both corneas. Abrasions covered 61% of the patient's body.

Figure 1 Open in figure viewer PowerPoint The patient's body was almost entirely covered with blisters, including her face (a), trunk (b), and both arms (c). Erosions were also present in her mouth, on the conjunctivae of both eyelids, and on her vulva