[Aged skin and skin care]. / Altershaut und Hautpflege.

BACKGROUND: Aged skin is the sum of chronological und UV-induced aging. Light-exposed skin is unattractive, with irregular pigmentation, roughness und scaliness. The skin is often dry and itches. METHODS: The present paper provides an overview of diseases of aging skin and describes how to prevent or reduce disease by prophylactic and therapeutic skin care. RESULTS: Aged skin can develop into several skin diseases, e.g., different types of eczema and skin cancer. In the body folds we often find an irritant contact eczema caused by friction from skin to skin, sweating, and urinary and fecal incontinence. In the bedridden, bed sores can also develop. Furthermore, there is a delay in wound healing owing to old age. Use of adequate creams and ointments is very helpful in preventing and improving most skin diseases of mature skin. However, the knowledge of aged people and healthcare professionals about the importance of skin care is low. Older people are often unable to care for their skin because they are lacking the physical and mental ability. CONCLUSION: Healthcare professionals are not sufficiently trained about the value of proper skin care. Adequate studies on the role of skin care and selection of the correct preparation in various aged-related diseases are lacking.

Oral intake of specific bioactive collagen peptides reduces skin wrinkles and increases dermal matrix synthesis.

Dietary consumption of food supplements has been found to modulate skin functions and can therefore be useful in the treatment of skin aging. However, there is only a limited number of clinical studies supporting these claims. In this double-blind, placebo-controlled study, the effectiveness of the specific bioactive collagen peptide (BCP) VERISOL® on eye wrinkle formation and stimulation of procollagen I, elastin and fibrillin biosynthesis in the skin was assessed. A hundred and fourteen women aged 45-65 years were randomized to receive 2.5 g of BCP or placebo, once daily for 8 weeks, with 57 subjects being allocated to each treatment group. Skin wrinkles were objectively measured in all subjects, before starting the treatment, after 4 and 8 weeks as well as 4 weeks after the last intake (4-week regression phase). A subgroup was established for suction blister biopsies analyzing procollagen I, elastin and fibrillin at the beginning of the treatment and after 8 weeks of intake. The ingestion of the specific BCP used in this study promoted a statistically significant reduction of eye wrinkle volume (p < 0.05) in comparison to the placebo group after 4 and 8 weeks (20%) of intake. Moreover a positive long-lasting effect was observed 4 weeks after the last BCP administration (p < 0.05). Additionally, after 8 weeks of intake a statistically significantly higher content of procollagen type I (65%) and elastin (18%) in the BCP-treated volunteers compared to the placebo-treated patients was detected. For fibrillin, a 6% increase could be determined after BCP treatment compared to the placebo, but this effect failed to reach the level of statistical significance. In conclusion, our findings demonstrate that the oral intake of specific bioactive collagen peptides (Verisol®) reduced skin wrinkles and had positive effects on dermal matrix synthesis.

Oral supplementation of specific collagen peptides has beneficial effects on human skin physiology: a double-blind, placebo-controlled study.

Various dietary supplements are claimed to have cutaneous anti-aging properties; however, there are a limited number of research studies supporting these claims. The objective of this research was to study the effectiveness of collagen hydrolysate (CH) composed of specific collagen peptides on skin biophysical parameters related to cutaneous aging. In this double-blind, placebo-controlled trial, 69 women aged 35-55 years were randomized to receive 2.5 g or 5.0 g of CH or placebo once daily for 8 weeks, with 23 subjects being allocated to each treatment group. Skin elasticity, skin moisture, transepidermal water loss and skin roughness were objectively measured before the first oral product application (t0) and after 4 (t1) and 8 weeks (t2) of regular intake. Skin elasticity (primary interest) was also assessed at follow-up 4 weeks after the last intake of CH (t3, 4-week regression phase). At the end of the study, skin elasticity in both CH dosage groups showed a statistically significant improvement in comparison to placebo. After 4 weeks of follow-up treatment, a statistically significantly higher skin elasticity level was determined in elderly women. With regard to skin moisture and skin evaporation, a positive influence of CH treatment could be observed in a subgroup analysis, but data failed to reach a level of statistical significance. No side effects were noted throughout the study.

[Diaper dermatitis]. / Windeldermatitis.

Diaper dermatitis is one of the most common skin diseases during infancy and childhood. It is a type of irritant contact eczema resulting from a complex interaction between urine and feces under occlusive conditions in combination with the hyperhydration of the stratum corneum, pressure and friction under the diaper. These conditions pave the way for Candida albicans infection, which is often associated with diaper dermatitis. The anogenital region can be involved by a variety of dermatoses, so a precise skin examination, detailed history and sometimes histologic examination are needed for a precise diagnosis. Therapeutically, frequent diaper changes and adequate skin care are most important.

Malignant melanoma and Wiedemann-Beckwith syndrome in childhood.

Patients with Wiedemann-Beckwith syndrome (WBS, MIM 130650), a congenital overgrowth syndrome, have a known increased tumor risk especially for embryonic tumors. WBS belongs to the "imprinting" syndromes caused by overexpression of IGF2 and/or loss of CDKN1C on chromosome 11p15.5. A 13-year-old boy with WBS developed a spitzoid malignant melanoma (Clark level V, Breslow index 4.8 mm) on the right cheek. Genetic analyses of the patient's blood showed hypermethylation at the H19 locus on chromosome 11p. The (epi)genetic changes of the WBS locus might have played a role in the pathogenesis of melanoma development.

[Rational treatment of first-degree burns]. / Rationale Behandlung von Patienten mit Verbrennungen 1. Grades.

First-degree burns are the most common type of burn, but are often inadequately treated. The methods of treatment and the course of healing are poorly documented owing to the fact that first-degree burns are generally not considered to be a serious injury. First-degree burns can be caused by thermal injury or UV irradiation (sunburn). The pathophysiology and the therapeutic approach are similar, although the damage follows a different time course for each injury--immediate damage after contact with hot objects, liquids or fire, delayed damage after sun exposure. After initial cooling with water, aqueous emulsions with small amounts of well-tolerated lipids (O/W emulsions) are best suited for treating first-degree burns or sunburn. Water evaporates producing cooling and reducing inflammation; the lipids accelerate the repair of the damaged skin barrier and reduce drying. Foam sprays and lotions are ideal because they are easy and painless to apply. The use of topical corticosteroids is not recommended, as superiority to the vehicle has not been shown.

Intraoral lesions associated with sebaceous nevus syndrome.

The sebaceous nevus syndrome describes the rare association of a sebaceous nevus with systemic features such as mental retardation, seizures and colobomas (among others). It is thought to be a cutaneous mosaic inherited as a paradominant trait. Three cases are provided illustrating the intraoral manifestations of the syndrome. The first histological comparison of contiguous mucosal and cutaneous lesions is provided. We also describe the possible association of SFM syndrome with a benign fibrous histiocytic lesion of the mandible. This and other mandibular tumors associated with the sebaceous nevus syndrome may have significant implications for patients. Awareness of the potential presence or development of significant intraoral lesions in association with the sebaceous nevus syndrome is important for those involved in the care of patients with this syndrome.

Matrix metalloproteinase 19 processes the laminin 5 gamma 2 chain and induces epithelial cell migration.

In this study we analyzed the proteolytic activity of MMP-19 and its impact on keratinocyte migration. In the HaCaT keratinocyte cell line overexpressing wild-type MMP-19 (HaCaT-WT), transmigration through fibrin and type IV collagen matrices was significantly increased compared to cells harboring a catalytically inactive mutant (HaCaT-EA). Studying the expression of MMP-19 in early stages of squamous cell cancer (SCC), we found co-localization of MMP-19 and laminin 5 at the invading tumor front but not in suprabasal epidermis of the tumor. Examination of laminin 5 processing revealed increased processing of the gamma2 chain in the medium and matrix of HaCaT-WT cells and degradation by recombinant human MMP-19 to 105-kDa and 80-kDa fragments. Parental HaCaT grown on the matrix of HaCaT-WT and HaCaT-EA cells displayed differential tyrosine phosphorylation. Using integrin blocking and stimulating antibodies we could attribute these differences to a shift from beta4-integrin-dependent signaling on the HaCaT-EA matrix toward alpha3-integrin-dependent signaling on the HaCaT-WT matrix. As a consequence, parental HaCaT showed increased migration on the matrix of HaCaT-WT cells. These data suggest that the MMP-19-dependent processing of the gamma2 chains leads to the integrin switch favoring epithelial migration and that MMP-19 actively participates in the early stages of SCC invasion.

Toxicological evaluation of nitrosamines in condoms.

Volatile N-nitrosamines have been found in rubber products including gloves, balloons, toys, baby bottle teats, soothers, and condoms. N-Nitrosamines are potent carcinogens, and therefore, European legislation has limited the release of N-nitrosamines and N-nitrosatable compounds in teats and soothers to 0.01-0.1 mg/kg rubber, respectively. Previously, endogenous nitrosamine formation in the vagina has been suggested as a cause of cervical cancer. It was speculated that exogenous N-nitrosamines and N-nitrosatable compounds from condoms may also lead to genital cancer. Therefore, we reviewed the literature and calculated the risk for the induction of tumors by nitrosamines from condoms. In vitro Biaudet et al. (1997) found up to 88 ng nitrosatable compounds migrating from condoms to cervical mucous within 24 hrs. During sexual intercourse about 0.6 ng may migrate in the female genital mucous membranes because of the short contact to the condom, e.g. 10 min. Comparable amounts of nitrosamines may also migrate in the penile skin. Estimating 1500 contacts to condoms during lifetime (50 condoms/year for 30 years) this may result in the adsorption of up to 0.9 microgram nitrosamines in total. Animal studies in Syrian hamsters showed the induction of local and/or systemic tumors, in particular liver tumors, after topical application of nitrosamines to the skin or mucous membrane at a total dose of about 1 g. This dose exceeds the dose to be expected from contact with condoms by more than 1 million. Also, epidemiological studies do not support a role for condoms in the induction of cancer. The incidence of cervical cancer and liver tumors is high in developing countries, where condoms are seldom used. In addition, humans are regularly exposed to nitrosamines from food and tobacco smoke at a dose which is 1,000 to 10,000 fold higher than expected from condom use. In summary, the risk for the induction of tumors from nitrosamines in condoms is very low.

Impaired cutaneous permeability barrier function, skin hydration, and sphingomyelinase activity in keratin 10 deficient mice.

Point mutations in the suprabasal cytokeratins 1 (K1) or 10 (K10) in humans have been shown to be the cause of the congenital ichthyosis epidermolytic hyperkeratosis. Recently, a K10 deficient mouse model was established serving as a model for epidermolytic hyperkeratosis. Homozygotes suffered from severe skin fragility and died shortly after birth. Heterozygotes developed hyperkeratosis with age. To see whether phenotypic abnormalities in the mouse model were associated with changes in skin barrier function and skin water content we studied basal transepidermal water loss and capacity for barrier repair after experimental barrier disruption as well as stratum corneum hydration. Also, we determined the activities of acid and neutral sphingomyelinase key enzymes of the tumor necrosis factor and interleukin-1 signal transduction pathways generating the ceramides most important for epidermal permeability barrier homeostasis. Neonatal homozygotes showed an 8-fold increase in basal transepidermal water loss compared with wild type controls. Adult heterozygotes exhibited delayed barrier repair after experimental barrier disruption. Stratum corneum hydration was reduced in homozygous and heterozygous mice. Acid sphingomyelinase activity, which is localized in the epidermal lamellar bodies and generates ceramides for extracellular lipid lamellae in the stratum corneum permeability barrier, was reduced in homozygous as well as heterozygous animals. Neutral sphingomyelinase activity, which has a different location and generates ceramides involved in cell signaling, was increased. The reduction in acid sphingomyelinase activity may explain the recently described decreased ratio of ceramides to total lipids in K10 deficient mice. In summary, our results demonstrate the crucial role of the keratin filament for permeability barrier function and stratum corneum hydration.

Iontophoresis of nickel elicits a delayed cutaneous response in sensitized individuals that is similar to an allergic patch test reaction.

Wearing of patch test chambers for 1-2 days is uncomfortable for patients. Allergen application by iontophoresis avoids this, but it is unknown so far whether iontophoresis itself interferes with the delayed immune response. We compared the effects occurring 48 h after iontophoresis with distilled water, 0.9% NaCl, and 0.01 M NiSO4 in normal volunteers and in nickel-sensitized patients (total n=36). Visual assessment was performed and transepidermal water loss (TEWL), stratum corneum hydration, cutaneous blood flow, and immunohistopathology were determined. After iontophoresis with nickel sulfate, only individuals sensitized to nickel reacted with a positive clinical response, increase in cutaneous blood flow, decline in epidermal CD-1a-positive cells, increase in epidermal proliferation (Ki-67-positive cells), pronounced infiltration of cells positive for CD4, CD11, or CLA, and cellular activation (expression of ICAM1, HLA-DR). Iontophoresis with distilled water or saline did not result in such reactions in volunteers with or without nickel sensitization, and the latter also tolerated nickel iontophoresis without significant skin reactions. We conclude that the delayed cutaneous response to nickel induced via iontophoresis is specific and similar to a positive patch test reaction. Iontophoresis may therefore be considered as an alternative to patch testing.

Roles for tumor necrosis factor receptor p55 and sphingomyelinase in repairing the cutaneous permeability barrier.

Epidermal TNF expression increases in response to cutaneous permeability barrier disruption and wound healing. TNF signaling is mediated by acid and neutral sphingomyelinases (A- and N-SMase), which generate ceramide, an important regulator of proliferation, differentiation, and apoptosis. In the epidermis, ceramide is known to be an integral part of the extracellular stratum corneum (SC) lipid bilayers that constitute the permeability barrier of the skin. We show here that topical application of TNF after experimental injury to the SC of hairless mice (hr(-/-)) enhances barrier repair. In TNF receptor p55-deficient (TNF-R55-deficient) mice (hr(+/+)), cutaneous barrier repair was delayed compared with wild-type (hr(+/+)) or TNF-R75-deficient (hr(+/+)) animals. After barrier disruption in hairless (hr(-/-)) and wild-type (hr(+/+)), but not in TNF-R55-deficient (hr(+/+)) mice, the enzymatic activities of both A-SMase and N-SMase were significantly enhanced. Stimulation of SMase activities was accompanied by an increase in C(24)-ceramide levels. Most A-SMase activity in hairless mice (hr(-/-)) was found in the outer epidermal cell layers and colocalized in the lamellar bodies with A-SMase and sphingomyelin. Reduction of epidermal A-SMase activity by the inhibitor imipramine resulted in delayed permeability barrier repair after SC injury. Together, these results suggest that TNF-R55 signaling pathways contribute to cutaneous permeability barrier repair through SMase-mediated generation of ceramide.

Impaired neutral sphingomyelinase activation and cutaneous barrier repair in FAN-deficient mice.

The WD-40 repeat protein FAN binds to a distinct domain of the p55 receptor for tumor necrosis factor (TNF) and signals the activation of neutral sphingomyelinase (N-SMase). To analyze the physiological role of FAN in vivo, we generated FAN-deficient mice by targeted gene disruption. Mice lacking a functional FAN protein do not show any overt phenotypic abnormalities; in particular, the architecture and cellular composition of lymphoid organs appeared to be unaltered. An essential role of FAN in the TNF-induced activation of N-SMase was demonstrated using thymocytes from FAN knockout mice. Activation of extracellular signal-regulated kinases in response to TNF treatment, however, was not impaired by the absence of the FAN protein. FAN-deficient mice show delayed kinetics of recovery after cutaneous barrier disruption suggesting a physiological role of FAN in epidermal barrier repair. Although FAN exhibits striking structural homologies with the CHS/Beige proteins, FAN-deficient mice did not reproduce the phenotype of beige mice.

Expression of epidermal keratins and the cornified envelope protein involucrin is influenced by permeability barrier disruption.

In previous studies we have shown that experimental permeability barrier disruption leads to an increase in epidermal lipid and DNA synthesis. Here we investigate whether barrier disruption also influences keratins and cornified envelope proteins as major structural keratinocyte proteins. Cutaneous barrier disruption was achieved in hairless mouse skin by treatments with acetone +/- occlusion, sodium dodecyl sulfate, or tape-stripping. As a chronic model for barrier disruption, we used essential fatty acid deficient mice. Epidermal keratins were determined by one- and two-dimensional gel electrophoresis, immunoblots, and anti-keratin antibodies in biopsy samples. In addition, the expression of the cornified envelope proteins loricrin and involucrin after barrier disruption was determined by specific antibodies in human skin. Acute as well as chronic barrier disruption resulted in the induction of the expression of keratins K6, K16, and K17. Occlusion after acute disruption led to a slight reduction of keratin K6 and K16 expression. Expression of basal keratins K5 and K14 was reduced after both methods of barrier disruption. Suprabasal keratin K10 expression was increased after acute barrier disruption and K1 as well as K10 expression was increased after chronic barrier disruption. Loricrin expression in mouse and in human skin was unchanged after barrier disruption. In contrast, involucrin expression, which was restricted to the granular and upper spinous layers in normal human skin, showed an extension to the lower spinous layers 24 h after acetone treatment. In summary, our results document that acute or chronic barrier disruption leads to expression of keratins K6, K16, and K17 and to a premature expression of involucrin. We suggest that the coordinated regulation of lipid, DNA, keratin, and involucrin synthesis is critical for epidermal permeability barrier function.

Effects of xerosis and ageing on epidermal proliferation and differentiation.

The hallmarks of dry skin (xerosis) are scaliness and loss of elasticity. Decreased hydration and a disturbed lipid content of the stratum corneum are also well-known features. The frequency of dry skin increases with ageing. The aim of this study was to examine if these known features of dry skin are related to changes in epidermal proliferation and differentiation. In addition, age-related changes in normal and in dry skin were examined: 62 volunteers were divided by clinical grading and biophysical measurements into groups with young/normal, young/dry, aged/normal and aged/dry skin. Biopsy samples from the lower legs (most severe dryness) were examined by two-dimensional gel electrophoresis and by immunohistochemistry for epidermal proliferation, epidermal keratins and cornified envelope proteins. There was a slight increase in proliferation in both groups with dry skin compared with normal skin of the corresponding age. In aged/normal compared with young/normal skin there was a significant decrease in proliferation. However, epidermal proliferation was the same in aged/dry skin as in young/normal skin. For epidermal differentiation, an age-independent decrease of keratins K1 and K10 and an associated increase in the basal keratins K5 and K14 was detected in dry skin. There was also an age-independent premature expression of the cornified envelope protein involucrin. In contrast, loricrin expression was not influenced by dry skin conditions. In summary, epidermal proliferation was significantly decreased in aged/normal compared with young/normal skin. Dry skin showed significant changes in the epidermal expression of basal and differentiation-related keratins, and a premature expression of involucrin irrespective of age.

Short- and long-term effectiveness of oral and bath PUVA therapy in urticaria pigmentosa and systemic mastocytosis.

BACKGROUND: Previous studies have shown that oral PUVA is effective in urticaria pigmentosa. Long-term results, however, are unknown. OBJECTIVE: We studied the long-term effectiveness of oral PUVA treatment in urticaria pigmentosa as well as in systemic mastocytosis. In addition, the success of bath PUVA was examined in these diseases. METHODS: Twenty patients with urticaria pigmentosa and systemic mastocytosis treated by oral PUVA were examined retrospectively for a time period of up to 18 years. We studied the duration of improvement and correlated these results with the total PUVA dose, the skin type and the age of onset. Four patients were treated by bath PUVA therapy. RESULTS: In oral PUVA therapy an improvement was seen in 14 out of 20 patients (70%). There was no difference in the response rate between urticaria pigmentosa and systemic mastocytosis and there was no correlation with the total PUVA dosage. The duration of the treatment's success ranged from a few weeks to more than 10 years. 25% of the patients showed an improvement for more than 5 years. Patients with onset during childhood and early adolescence and patients with skin types I and II responded favourably to the treatment. Bath PUVA therapy was without effect in our 4 patients. CONCLUSION: Oral PUVA is very effective for the long-term treatment of urticaria pigmentosa as well as systemic mastocytosis.

Integrity of the permeability barrier regulates epidermal Langerhans cell density.

Previous studies have shown that barrier requirements regulate epidermal liquid and DNA synthesis. In the present study, we examined the possibility that the integrity of the permeability barrier influences epidermal Langerhans cells involved with the immune response. Barrier disruption was achieved by treatment of human skin with acetone, sodium dodecylsulphate (SDS), or tape stripping, until a 10-20-fold increase in transepidermal water loss was achieved. Serial biopsies were performed 6-168 h after treatment, and Langerhans cells were complexed with anti-CD1a (Leu6) or S-100 antibodies, and visualized with an immunoperoxidase technique. Acetone treatment resulted in an increase in epidermal Langerhans cell density, reaching a maximum of 94% over control (P < 0.01) by 24 and 48 h post-treatment. Following SDS treatment or tape stripping, epidermal Langerhans cell density was increased by 100 and 175% (P < 0.01), respectively. There was a linear correlation between the degree of barrier disruption and the increase in epidermal Langerhans cell density. Studies with the Ki-S3 proliferation-associated nuclear antigen revealed a two- to threefold increase in epidermal proliferation after barrier disruption. The time curves of the increase in Langerhans cell density and the increase in epidermal proliferation were similar, suggesting that there was a coordinate regulation. In contrast with our previous studies employing patch test reactions to allergens or irritants, disruption of barrier function neither resulted in an increased dermal Langerhans cell density, nor influenced T lymphocytes (CD3+, Leu4+), macrophages (KiM8+), ICAM-1 or ELAM-1 expression in the skin. In addition, barrier disruption did not result in either dermal inflammation or epidermal spongiosis. In summary, these findings support our hypothesis that the permeability barrier influences epidermal Langerhans cell density, which is involved in maintaining an immunological barrier.

[Von Recklinghausen neurofibromatosis and dermal melanocytic nevi]. / Neurofibromatose von Recklinghausen und dermale melanozytäre Nävi.

Neurofibromas, café au lait macules and freckles in the axillary or inguinal regions are common manifestations of von Recklinghausen's neurofibromatosis (NF-1). Less known is the simultaneous appearance of dermal melanocytic naevi. We describe the case of a 21-year-old Vietnamese woman who showed generalized, multiple neurofibromas, a solitary plexiform neurofibroma in the left gluteal region and Lisch nodules. In addition, there were several large grey-blue macules histologically characterized by fusiform pigment-bearing cells in the dermis, which we diagnosed as persistent aberrant mongolian spots. In the right zygomatic region she presented a grey-blue, hair-bearing macule, which we saw as a variant of Ota's naevus. A genetic background for this coincidence of a systemic with a local phakomatosis can be supposed, as both Schwann's cells and melanocytes are derived from the neural crest. Such pathologic rearrangement in the embryogenesis of the cellular elements could be important for the pathogenesis of NF-1 and dermal melanocytic nevi.