[Potassium hydroxide 5 % solution in actinic keratosis : A novel therapeutic approach in the lesion-directed treatment]. / Kaliumhydroxid-5 %-Lösung bei aktinischer Keratose : Ein neuer Therapieansatz zur läsionsgerichteten Behandlung.

BACKGROUND: Actinic keratosis (AK) is an epithelial carcinoma in situ of the skin. There is a need for early treatment due to the risk of malignant transformation. In addition to being effective, the initial therapy in particular should be well tolerated and user-friendly. Potassium hydroxide (KOH) solution is already established as keratolytic treatment option for hyperkeratotic skin diseases such as mollusca contagiosa. MATERIALS AND METHODS: A prospective single-arm, multicentre medical device study (Treatment of AK with KOH, TAKKOH) was conducted to investigate the efficacy and safety of KOH 5% solution for the treatment of mild to moderate AK. Patients applied KOH solution twice daily for 14 days with a subsequent off-treatment phase of 14 days (≙ one treatment cycle) for a maximum of three treatment cycles or at least until treatment success was achieved. Treatment success, defined as complete remission (CR) of all AK lesions of a patient, was the primary objective. Secondary objectives included the evaluation of partial remission (PR), the number of AK lesions in remission, efficacy assessment by investigators and patients with a 6­point grading system and several safety parameters. RESULT: In all, 73 patients were enrolled in the study. CR was achieved in 54.9% of patients, whereas PR was observed in 64.8% with a 69.9% reduction in lesion numbers. With respect to safety, 46.6% of the patients experienced adverse events. Most of these events (82.6%) were adverse reactions comprising exclusively short-lived and mild local skin reactions. CONCLUSIONS: The study provides an indication of the efficacy and safety of KOH 5% solution for the lesion-directed topical therapy of AK.

Topical hydrocortisone 17-butyrate 21-propionate in the treatment of inflammatory skin diseases: pharmacological data, clinical efficacy, safety and calculation of the therapeutic index.

Hydrocortisone 17-butyrate 21-propionate (hydrocortisone buteprate, HBP) is a medium potent, non-halogenated double-ester of hydrocortisone with a favorable benefit/risk ratio for the treatment of inflammatory skin disorders. HBP is available as a 0.1% cream or ointment formulation. Good results were obtained with a once-daily topical treatment. HBP is characterized by a strong topical anti-inflammatory activity and weak systemic action. It is considered to have potency comparable to that of betamethasone 17-valerate (BV), but its systemic effects are less pronounced. HBP was shown to have a good efficacy in the treatment of various oozing and lichenified eczematous skin diseases including atopic dermatitis (AD) and in the treatment of psoriasis vulgaris. Even in very young children, HBP proved successful as an effective and safe drug. A therapeutic index of 2.0 can be attributed to this glucocorticoid. In this respect, there is no difference between topical HBP and other topical glucocorticoids with increased benefit/risk ratio, e.g. prednicarbate (PC), methylprednisolone aceponate (MPA) and mometasone furoate (MM).

[Frequent pathogen-induced diseases of the scalp]. / Häufige erregerbedingte Erkrankungen der Kopfhaut.

BACKGROUND: The scalp represents a special region for the manifestation of pathogen-induced diseases. OBJECTIVE: This article describes practice-relevant pathogen-induced skin diseases caused by bacteria, fungi, viruses and parasites. MATERIAL AND METHODS: Currently available publications were evaluated with special reference to therapeutic developments. RESULTS: Bacterial infections of the scalp must be treated consistently in the initial stages in order to avoid severe consequences. Skin diseases caused by fungi must be treated topically (e.g. neonatal cephalic pustulosis) or systemically and topically (e.g. tinea). Varicella zoster diseases in children and adults are treated differently. A safe and highly effective physically effective substance is now available for pediculosis capitis (head lice). CONCLUSION: Dermatologically relevant pathogen-induced diseases of the scalp can be well treated; however, tinea capitis still proves to be a special problem due to a lack of approved substances and long-term therapy.

Role of Staphylococcus aureus surface-associated proteins in the attachment to cultured HaCaT keratinocytes in a new adhesion assay.

Colonization of human skin with Staphylococcus aureus is a common feature in a variety of dermatologic diseases. In order to reproducibly investigate the adherence of Staphylococcus aureus to human epidermal cells, an in vitro assay was established using the biotin/streptavidine labeling system and the HaCaT cell line. This assay was used to define the role of several Staphylococcus aureus surface proteins with regard to their function in the staphylococcal adhesion process. Our studies included the standard laboratory strain Newman as well as its genetically constructed mutants DU5873, DU5852, DU5854, and DU5886 generated by allele replacement or transposon mutagenesis, which are deficient in the elaboration of staphylococcal protein A (spa), clumping factor (clfA), coagulase (coa), and the fibronectin-binding proteins A and B (fnbA/B), respectively. In comparison with strain Newman all mutants showed remarkably reduced adherence to the HaCaT keratinocyte cell line in our assay, yielding only between 43% and 60% of the adherence capacity of strain Newman after 60 min. Bacterial adherence could be re-established by introducing the cloned wild-type genes for the surface proteins on shuttle plasmids into the chromosomally defective mutants, thus suggesting a pathogenetic role of these proteins in the attachment of Staphylococcus aureus to human keratinocytes. Bacterial adherence was additionally enhanced by alkaline pH-values that are characteristic for skin conditions with epidermal barrier dysfunction. The use of Staphylococcus aureus mutant strains, deficient in the elaboration of defined proteins, allows specific investigation of colonization and virulence factors of this dermatologic relevant microorganism.

Two ceramide subfractions detectable in Cer(AS) position by HPTLC in skin surface lipids of non-lesional skin of atopic eczema.

The non-involved skin of atopic eczema (NEAE) is characterized by severe dryness and an impaired barrier function of the stratum corneum as indicated by an increased transepidermal water loss. Previous studies have demonstrated that this barrier impairment coincides with marked alterations in the amount and composition of stratum corneum ceramides. The aim of this study was to identify specific alterations in NEAE that may be used in the diagnosis of the atopic eczema. Using a classical procedure for high performance thin layer chromatography we could confirm earlier results: apart from Cer(EOH), which contains omega-hydroxy fatty acid (O) ester-linked to linoleic acid (E) and amide-linked to 6-hydroxy-4-sphingenine (H), the quantities of all ceramide fractions were significantly decreased. Furthermore, Cer(EOH)/Certotal was significantly increased, whereas the percentage of Cer(EOS), which contains sphingosine (S), and Cer(NP), which contains non-hydroxy fatty acid (N) amide-linked to phytosphingosine (P), were significantly decreased. Using a modified procedure for high performance thin layer chromatography we could demonstrate the formation of a double peak in the position of Cer(AS), which contains alpha-hydroxy fatty acid (A), in lipids of NEAE. The subfractions of the double peak comprised 15% and 12% of Certotal. MALDITOF mass spectrometry suggested that the double peak was formed by a homologous series of mono-hydroxylated and mono-unsaturated ceramides of different chain length, e.g., Cer(AS) subfractions containing either (C16,18) or (C22,24,26) alpha-hydroxy fatty acids. In contrast, in normal skin a single peak in Cer(AS) position, which comprised 22% of Certotal, was mainly formed by the long chain subfraction. In some cases this single peak displayed a small shoulder at its right flank, but never showed a clear peak separation when developed with NEAE samples. Furthermore, even in senile xerosis, or in either non-involved skin of psoriasis or seborrhoic eczema, only a single peak occurred in Cer(AS) position. Accordingly, the double peak might be specific for NEAE and turn out to be a marker for atopic eczema.

Effect of iron limitation on protein composition and ultrastructure of Haemophilus ducreyi.

Protein profiles of whole cells of Haemophilus ducreyi grown in the presence or absence of the iron chelator desferal, were compared by polyacrylamide gel electrophoresis. Each of four strains produced novel proteins in the range 43-160 kDa when cultured under conditions of reduced iron availability. At some sub-inhibitory concentrations, desferal produced enhanced growth, possibly due to it functioning as an exogenous siderophore. Organisms grown under conditions of reduced iron availability ultrastructurally showed also large periplasmic spaces between cytoplasm and outer membrane.

Palpable migratory arciform erythema. Clinical morphology, histopathology, immunohistochemistry, and response to treatment.

BACKGROUND: Palpable migratory arciform erythema is clinically characterized by sharply circumscribed, infiltrated erythematous patches that tend to spread irregularly, resulting in arciform morphologic features. The histopathologic features are characterized by a patchy inflammatory perivascular and periadnexal T-lymphocytic infiltrate throughout the dermis. The disease runs a chronic course and is rarely described in the literature. OBSERVATION: Three middle-aged patients of both sexes had palpable migratory arciform erythema with 1, several, or multiple lesions on the trunk. There was a dense perivascular and periadnexal, predominantly lymphocytic infiltrate of the reticular dermis without any interstitial distribution of inflammatory cells. Absence of mucin deposits and plasma cells was a striking feature. The immunohistochemical profile showed an infiltrate dominated by T cells of polyclonal origin. In addition, polyclonal B cells and histiocytes were present in small numbers. In all 3 cases, oral antibacterial treatment resulted in a complete (2 patients) or temporary (1 patient) resolution of skin lesions. CONCLUSIONS: Palpable migratory arciform erythema shows distinctive differences in clinical and pathological features and treatment in contrast to other diseases with cutaneous lymphocytic infiltrates, including lymphocytic infiltration of Jessner and Kanof. Therefore, it is likely a distinct disease entity.

Current antimicrobial susceptibility of cutaneous bacteria to first line antibiotics.

Antimicrobial susceptibility of common bacterial species occurring on human skin appears to be falling. Data for the antimicrobial susceptibility of major groups of bacteria isolated from human skin during routine cultures were complied and analysed over a period of 9 months. Routine diagnostics of specimens from skin lesions and normal human skin were analysed for the presence of specified groups of bacteria. The species were identified using standard methods. Anti-microbial susceptibility was determined using a broth microdilution system giving breakpoints, the Sensititre system. Of the 333 Staphylococcus aureus, 129 Streptococcaceae, 180 Enterobacteriaceae and 120 Pseudomonadaceae strains investigated more than 5% of Staphylococcus aureus strains were resistant to flucloxacillin and thus methicillin (MRSA). More than 25% of Staphylococcus aureus strains were resistant to tetracycline and erythromycin. Many MRSA strains were found multi-resistant. Gentamicin was active against a large majority of Enterobacteriaceae strains but many Pseudomonadaceae strains were resistant. Compared with previous corresponding surveys methicillin-resistant Staphylococcus aureus strains are clearly on the increase. To prevent a further increase of resistant strains a defined strategy for antibiotic use is needed in dermatology.

Optimal management of atopic dermatitis.

Optimal treatment of patients with atopic dermatitis requires the knowledge of its pathogenetic factors and the often time-consuming attention to the course of the disease in each individual patient. In the therapeutic attempt, altered skin barrier function, possible provocation factors and psychological matters have to be taken into account. Basic therapy should comprise optimal skin care and the strict avoidance of triggering factors if possible. During periods of acute exacerbation, topical glucocorticosteroids in combination with classic antihistamines with sedative effects are still the drugs of first choice and will result in the rapid relief of symptoms in most patients. UVA1 phototherapy has proven to be a glucocorticoid-equivalent alternative therapy for exacerbated atopic dermatitis. If superinfection with Staphylococcus aureus is evident, topical antiseptics are useful in treating localized lesions, while a general superinfected eczema should be treated with systemic staphylococcal-effective antibacterials. Cyclosporin or extracorporeal photochemotherapy are reserved for patients with very severe atopic dermatitis that is unresponsive to conventional treatment protocols. Promising future therapeutic approaches consist of an improvement in the antipruritic treatment options, the topical application of immunomodifying treatment modalities or phosphodiesterase inhibitors, and possibly Chinese herbal therapies and psychological intervention strategies.

Effects of Pityrosporum ovale on proliferation, immunoglobulin (IgA, G, M) synthesis and cytokine (IL-2, IL-10, IFN gamma) production of peripheral blood mononuclear cells from patients with seborrhoeic dermatitis.

The aetiology of seborrhoeic dermatitis (SD) is still unknown. An increased number of Pityrosposurm ovale in lesional skin of patients with SD has been suggested to play a crucial role in the pathogenesis of the disease since double-blind trials with antifungal drugs (e.g. ketoconazole) have shown that these agents result in a significantly reduced disease intensity. The frequent association of HIV infection and SD may be due to a suppressed cell-mediated immunity. In order to characterize the role of the humoral and cellular immune response in patients with SD the effects of a P. ovale extract on the proliferation of, and interleukin-2 (IL-2), IL-10 by an interferon-gamma (IFN gamma) production, and immunoglobulin (IgA, IgG, IgM) synthesis by peripheral blood mononuclear cells (PBMC) from patients with SD were studied in vitro. Healthy volunteers served as controls. PBMC from normal donors responded with a significantly increased proliferation to P. ovale antigen, whereas cells from patients with SD did not. Additionally, IL-2 and IFN gamma production by PBMC from patients with SD was markedly depressed compared with normal cells after stimulation with P. ovale. However, stimulation of PBMC from SD patients with P. ovale antigen induced significantly increased IL-10 synthesis. IgA, IgG and IgM synthesis was significantly increased in cultures of PBMC from patients with SD whether the cells were antigen-stimulated or not. Our results support the assumption that strong skin colonization with P. ovale in SD is due to an altered cellular immunity, which may be induced by increased IL-10 secretion.

Beta-adrenergic receptors in psoriasis: evidence for down-regulation in lesional skin.

Lesional psoriatic skin displays reduced responsiveness to beta-adrenergic stimulating agents. To elucidate whether the receptor protein itself is responsible for this, lesional and non-lesional psoriatic skin was investigated ex vivo for maximal beta-adrenergic binding density (Bmax) and beta-adrenergic binding affinity (KD). Epidermal crude membrane homogenates (ECMH) were prepared from split-thickness skin biopsies and saturated with the lipophilic beta-adrenergic antagonist (-)-125I-iodocyanopindolol (ICYP) as radioligand. Specific binding was saturable and Scatchard transformation of the binding data revealed a homogeneous class of beta-adrenergic receptors in all nine experiments. The maximal beta-adrenergic binding density was significantly less in lesional than in non-lesional psoriatic skin (Bmax = 49.7 +/- 7.2 fmol/mg protein vs. 67.1 +/- 2.2 fmol/mg protein, n = 9, P < 0.05). The binding affinity was similar in lesional and in non-lesional skin (KD = 9.0 +/- 1.5 pmol/l vs. 8.0 +/- 0.9 pmol/l). These results could at least partially explain the reduced responsiveness of the beta-adrenergic system in lesional psoriatic skin seen after stimulation with beta-adrenergic agonists.

Pathophysiological concept of Haemophilus ducreyi infection (chancroid)

Our knowledge concerning the pathogenesis of infection due to Haemophilus ducreyi is incomplete. In order to produce disease, H. ducreyi must presumably penetrate the skin of the external genitalia, colonize subcutaneous tissues, then produce tissue damage which results in ulcer formation. Penetration of the normal skin most likely occurs via minor abrasions. Adherence of H. ducreyi to different cell lines in vitro has been described, and might be mediated by adhesions such as pili or haemagglutinins. In addition, binding to extracellular matrix proteins has also been reported. Extracellular tissue-degrading enzymes were absent from broth culture supernatants of H. ducreyi. Such supernatants also failed to produce cytopathic effects with established or primary cell lines. Both live and heat-killed H. ducreyi organisms were able to produce lesions in a rabbit or a mouse model, although ulcer formation was dependent on viable H. ducreyi organisms in a recently introduced temperature-dependent rabbit model. With an excessive supply of iron, a more prolonged localized inflammatory disease effect was observed. Results derived from a subcutaneous chamber model demonstrated considerable changes in the expression of outer membrane proteins combined with antibody modulation during in vivo growth of H. ducreyi. These might be important factors for maintenance of infection in the human host particularly as these changes also occur in humans. Despite an increased knowledge of the pathogenesis of chancroid, important questions such as growth requirements, bubo-formation, role of cell-mediated immunity and ulcer formation are still unanswered. The application of molecular biological techniques in order to study these problems will be helpful.

The suppressive effect of serum samples from patients with chancroid on human mononuclear cells correlates with the clinical picture and is interleukin-2-dependent.

Plasma samples from patients with chancroid diagnosed both on clinical and microbiological grounds were assessed for their ability to inhibit mitogen-induced proliferation of human lymphocytes from healthy donors. All serum samples analysed suppressed phytohaemagglutinin A (PHA) blastogenic response. A significant difference in the observed extent was seen when serum samples from patients with and without associated lymphadenopathy were compared (P < 0.05). Using an interleukin-2 (IL-2)-dependent cell line it could be demonstrated that the addition of patients' plasma to cultured cells markedly depressed mitogen-induced IL-2 synthesis. Results presented suggest that cell-mediated mechanisms play a role in the pathogenesis of infection due to Haemophilus ducreyi.

Immunohistochemical investigations of genital ulcers caused by Haemophilus ducreyi.

To gain information on the specific composition of the inflammatory infiltrate of genital ulcers caused by Haemophilus ducreyi, biopsies of 6 genital ulcers which were diagnosed as chancroid on clinical and microbiological grounds were subjected to immunohistochemical investigations after conventional haematoxylineosin staining. A variety of antibodies reactive against B- and T-cells, plasma cells and granulocytes were used with each tissue sections. The lymphocytic infiltrate of chancroid ulcers consisted of both B- and T-lymphocytes and showed a cluster-like formation. B-lymphocytes were preferentially localized perivascularly in the middle layer, T-lymphocytes mainly in the deep layer of the inflamed oedematous tissue. Results stress the importance of both B- and T-cell mediated immune responses in Haemophilus ducreyi infection.

PIP: Chancroid, the most prevalent form of genital ulcer disease in developing countries, increases the risk of HIV transmission. Use of monoclonal antibodies against leukocyte differentiation antigens enabled analysis of the composition of the inflammatory infiltrate of genital ulcers. In this study, biopsies of six genital ulcers caused by Haemophilus ducreyi were examined immunohistochemically. In each case, staining revealed a superficial necrotic layer of polymorphonuclear leukocytes with fibrin and erythrocytes at the base of the ulcer, a middle layer of the edematous inflammatory dermis with prominent blood vessels and vascular thrombi, and a deep layer of an inflammatory infiltrate of plasma cells and lymphocytes. The lymphocytic infiltrate of chancroid ulcers consisted of both B- and T-lymphocytes and showed a cluster-like formation. B-lymphocytes were preferentially localized perivascularly in the middle layer, while T-lymphocytes tended to be located in the deep layer of the inflamed edematous tissue. These findings provide further evidence of the importance of the involvement of T-cells in the local immune clearance of H. ducreyi. Future studies should investigate lymphocyte secretions detected in genital ulcers caused by H. ducreyi to gain more information on the role of the cellular immune mechanisms in the disease.

Soluble interleukin-2 receptors in serum and urine of patients with chancroid and their response to therapy.

To investigate cell-mediated immune response in chancroid, soluble interleukin-2 receptor levels in serum and urine samples of healthy individuals and patients were measured by an enzyme-linked immunosorbent assay. Increased levels both in serum and in urine were observed in cases of Haemophilus ducreyi infection. In patients showing a prolonged incubation period, urine levels exceeded serum values. Therapy led to a reduction of elevated interleukin-2 receptor levels in serum and in urine.

Comparative investigation of human stratum corneum ceramides.

The stratum corneum (SC) requires ceramides, cholesterol, and fatty acids to provide the cutaneous permeability barrier. SC lipids can be analyzed by normal-phase high-performance thin-layer chromatography (HPTLC). However, without further analysis, some uncertainty remains about the molecular composition of lipids represented by every TLC band of an unknown sample. We therefore analyzed each ceramide band further by subjecting the isolated lipids to a direct coupling of reversed-phase high-performance liquid chromatography and electrospray ionization-mass spectrometry (HPLC/ESI-MS, or LC/MS). LC/MS analysis and ESI-MS/MS negative ion and collision-induced dissociation experiments revealed that ceramide band 4 contained not only N-(omega-OH-acyl)acyl-6-OH-sphingosine, Cer(EOH), but also N-(alpha-OH-acyl)-sphingosine. Band 5 exclusively contained N-acyl-6-OH-sphingosine. Our results demonstrate the benefit of LC/MS analysis for selective identification of human SC ceramides. Moreover, the combination of HPTLC for pre-separation and LC/MS for identification of lipids is an even more powerful tool for detailed ceramide analysis.

Mechanisms of skin adherence, penetration and tissue necrosis production by Haemophilus ducreyi, the causative agent of chancroid.

Haemophilus ducreyi (H. ducreyi) strains, representing both reference strains and low-passage isolates, were investigated in terms of surface structures and enzymatic equipment. The interaction of these factors with host tissue was analysed using new in vitro- and in vivo-models. By electron microscopy studies there was no evidence of an extracellular capsule or surface appendages such as pili or flagella. Interaction of all isolates tested with the lectin Phaseolus vulgaris suggests N-acetyl-D-glucosamine units as common structural features of H. ducreyi cell envelope polysaccharide. In attachment to epithelial cells more than one hemagglutinin might be implicated as different haemagglutination patterns could be observed whereby the activity was not heat-labile, but was abolished by formaldehyde. Hydrophobic interactions might be of importance as well as strains showed a wide range of reactions from hydrophobic to hydrophilic, low hydrophobicity being more marked with the older strains. No elaboration of degradative enzymes based on the measurement of enzymatic activity using insoluble dye-protein complexes could be detected in case of H. ducreyi, using Azocoll and Remazol Brilliantblue hide powder for detection of proteolytic activity and elastinorcein for detection of elastase activity. In vitro studies using human keratinocytes and Vero cells did not show any morphological changes when incubated with H. ducreyi culture filtrates. In vivo studies with a new mouse model for H. ducreyi infection could confirm the results of the in vitro studies. Mere contact to undamaged skin both of whole cell organisms, live or heat-killed, and of culture filtrates did not lead to any reaction or even damage of mouse skin. However, when the outer epidermal layer was overcome by intradermal injection of shaved mice ulcers developed. Tissue necrosis production was not bound to live organisms as dead ones showed the same effect. There is great evidence that this tissue necrosis is associated with H. ducreyi lipopolysaccharide (LPS) because intradermal injection of purified H. ducreyi LPS lead to the same reaction pattern. For the first time a cell mediated immune response could be demonstrated in case of H. ducreyi infection as different antigen preparations of H. ducreyi isolates induced proliferation of lymphocytes isolated from healthy unexposed individuals and from a chancroid-sensitized male. In the latter case measured cell responses were much stronger. The dose-dependent phenomenon was associated with interleukin-2 production. In summary, H. ducreyi isolates do not exhibit cytotoxic effects on the epithelial cells of the skin.(ABSTRACT TRUNCATED AT 400 WORDS)

Cutaneous peculiarities in blepharophimosis-ptosis-epicanthus inversus syndrome: report of a case.

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare inherited disorder with characteristic oculofacial affection of the eyelid region. Recent results of genetic analysis of the causative gene, as well as a hitherto unknown association with hormone-dependent endometrial carcinoma, motivated us to review this syndrome.

Gianotti-Crosti syndrome: clinical, serologic, and therapeutic data from nine children.

Gianotti-Crosti syndrome (GCS), a self-limiting papulovesicular acrodermatitis often associated with underlying viral infection, is mainly described in children. Nine children with GCS were evaluated with dermatologic examination and serologic tests for viral infections. Therapy was modified according to the subjective symptoms of patients, which included characteristic acrolocated papulovesicles, generalized skin eruption, and mild to severe pruritus. Results of serologic investigations revealed Epstein-Barr virus, Coxsackie A virus, parvovirus B19, and parainfluenza virus 1/2. In three children no underlying viral infection was found. Therapeutic interventions included topical clioquinol lotion 1 percent, topical application of corticosteroids, systemic antihistaminic therapy, and systemic methylprednisolone. Skin lesions resolved after 2 to 4 weeks in treated as well as in nontreated children. Although GCS in children often lacks close association with a causative viral infection, such severe infections as hepatitis B and human immunodeficiency virus must be considered. Whole-body involvement seems to correlate with severe pruritus and additional general symptoms requiring more intensive therapy.