Quo vadis dermatology: a scenario for the future.
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Cosmetic Techniques↗
Biomedical subjects
Klaus Wolff
Publications and source records attributed to Klaus Wolff.
Paraneoplastic pemphigus in association with hepatocellular carcinoma.
Paraneoplastic pemphigus (PNP) is an autoimmune mucocutaneous blistering disease associated with neoplasms, most frequently of the lymphoproliferative type. Rare PNP cases related to nonhematological solid tumors have been reported. The patient in this report presented with severe mucocutaneous involvement of PNP associated with hepatocellular carcinoma. Histopathology showed vacuolar interface dermatitis with keratinocyte necrosis and intraepidermal acantholysis. Direct immunofluorescence exhibited deposition of intercellular IgG and complement and granular complement at the dermoepidermal junction. Indirect immunofluorescence testing showed a typical intercellular staining on monkey esophagus and rat bladder epithelium. Immunoprecipitation showed characteristic target antigens of 250, 210, and 190 kDa molecular weights. This patient met all diagnostic criteria for paraneoplastic pemphigus and is, to our knowledge, the first report of a case associated with hepatocellular carcinoma.
Aged↗
Validity of an unsupervised self-administered questionnaire for self-assessment of melanoma risk.
Mass screening for cutaneous melanoma is impracticable because of its low yield and high costs. The validity of self-selection of high-risk individuals through self-assessment of melanoma risk factors is not known. The aim of this study was to assess the validity of an unsupervised self-administered questionnaire for the self-assessment of melanoma risk. In a case-control study, melanoma cases (n = 202) and controls (n = 202) matched for age and gender filled in a questionnaire about melanoma risk factors. After filling in the questionnaire, all participants were interviewed and examined by a dermatologist in order to compare self-assessment with physician-assessment. The number of naevi, skin phototype and ultraviolet damage to the skin were identified as independent risk factors for melanoma on both self-assessment and physician-assessment. Receiver operating characteristics analysis showed no statistically significant difference between the accuracy of the self-assessment-based model and the model based on physician-assessment. While excluding 90% of the controls, the self-assessment-based high-risk group included 39% (95% confidence interval 31-48%) of the melanoma patients and the physician-assessment-based high-risk group included 42% (95% confidence interval 33-52%) of the melanoma patients. In conclusion, an unsupervised self-administered questionnaire is, to some extent, useful for the identification of individuals at high risk for melanoma. The moderate accuracy of self-assessment and physician-assessment to identify individuals at high risk for melanoma is a limitation for the practicability of targeted melanoma screening in general.
Case-Control Studies↗
Pharmacokinetics of pimecrolimus, a novel nonsteroid anti-inflammatory drug, after single and multiple oral administration.
OBJECTIVE: To investigate the pharmacokinetics and tolerability of the new nonsteroid anti-inflammatory pimecrolimus (SDZ ASM 981, Elidel) after oral administration. DESIGN: A single-dose, randomised, double-blind, placebo-controlled, dose-rising, parallel-group study in healthy male volunteers, and a multiple-dose, randomised, double-blind, placebo-controlled, dose-rising study in patients with psoriasis. SETTING: One centre in France (single-dose study) and one centre in Austria (multiple-dose study). METHODS: The first study investigated the pharmacokinetics and tolerability of ascending single oral doses of pimecrolimus (5-60mg). The 60mg dose was repeated in the same subjects after a fat-rich breakfast. The second study investigated the pharmacokinetics, tolerability, safety and efficacy of rising oral doses administered once daily (5-20mg) or twice daily (20 and 30mg) for 28 days. Only the pharmacokinetic, safety and tolerability data of this study are presented. OUTCOME MEASURES AND RESULTS: Oral administration of pimecrolimus was well tolerated up to the highest dose (60mg). Pimecrolimus was rapidly absorbed (time to maximum blood concentration 0.7-2 hours). A high-fat meal before drug administration delayed the time to peak concentration. Blood concentrations appear to have a long-terminal half-life (30-40 hours after a single dose in fasted subjects, 50-100 hours after the final dose on day 28 in psoriasis patients). After multiple doses, steady state was attained after 6-13 days. Maximum blood concentrations (C(max)) and exposure (area under the concentration-time curve; AUC) were broadly dose proportional. At the highest dose administered in the multiple-dose study (30mg twice daily), a C(max ) of 54.7 microg/L was measured and an AUC(24) of 589.8 microg.h/L was calculated at steady state (day 13). CONCLUSION: The results support further evaluation of the therapeutic potential of oral pimecrolimus for the treatment of inflammatory diseases.
Administration, Oral↗
Fibroblast growth factor-2 induces Lef/Tcf-dependent transcription in human endothelial cells.
Lef/Tcf proteins belong to a family of architectural transcription factors that control developmental processes and play an important role in oncogenesis. Classical activators of Lef/Tcf-dependent transcription comprise the Wnt family of proteins, which translocate beta-catenin into the nucleus and allow the formation of transactivation-competent Lef/Tcf-beta-catenin complexes. Here we show that in human endothelial cells fibroblast growth factor-2 (FGF-2) reduces GSK-3 activity and augments nuclear levels of beta-catenin. FGF-2 induced Lef/Tcf-dependent transcription of a cyclin D1-luciferase construct. Gel shift assays revealed binding of Tcf-4 as the only Lef/Tcf family member and of beta-catenin to the Lef/Tcf site in the cyclin D1 promoter. Cotransfection with a dominant negative Tcf-4 construct inhibited the FGF-2-induced cyclin D1 promoter activity. Overexpression of an uninhibitable GSK-3beta mutant resulted in partial inhibition of FGF-2-mediated cyclin D1 induction. The importance for cyclin D1 in FGF-2-induced angiogenesis in vivo is shown in cyclin D1(-/-) mice, where FGF-2-induced new vessel formation was significantly reduced compared with FGF-2-induced angiogenesis in cyclin D1(+/+) mice. In conclusion, FGF-2 is a novel modulator of Lef/Tcf-beta-catenin signaling in endothelial cells, suggesting that angiogenic properties of FGF-2 are at least in part mediated by Lef/Tcf-beta-catenin activation.
Cell Nucleus↗
Endovascular stent grafting versus open surgical operation in patients with infrarenal aortic aneurysms: a propensity score-adjusted analysis.
BACKGROUND: Although transfemoral endovascular aneurysm management (TEAM) of infrarenal abdominal aortic aneurysms (AAA) is widely performed, open graft replacement is still considered the standard of care. The aim of this study was to investigate whether clear indications for TEAM can be established in patients with significant comorbidities without investigating differences in relative procedure efficacy or durability. METHODS AND RESULTS: A propensity score-based analysis of 454 consecutive patients treated electively for AAA from January 1995 through December 2000 was performed. Of those 454 patients, 248 received open surgery and 206 received TEAM. In-hospital mortality rates (MRs) were compared. After adjusting for propensity scores, a Cox proportional hazard model (COX) was employed to test the influence of the respective treatment on postoperative 900-day survival estimates (SEs). Several potential preoperative risk factors were used as covariates. The MR of all patients was 3.7%. Explorative analysis demonstrated that patients treated by TEAM presented with significantly more risk factors. In American Society of Anesthesiologists class IV patients, a significant difference in MR was detected (4.7% for TEAM versus 19.2% for open surgery; P<0.02). After adjusting for the propensity to receive TEAM or open surgery, a regression analysis of survival based on COX revealed predictive influences of impaired kidney (P<0.047) or pulmonary function (P<0.001), increased age (P<0.05), and selection of treatment modality (P<0.002) on SE. CONCLUSIONS: TEAM represents a less invasive procedure for AAA therapy in patients with significant preoperative risk factors. Especially in geriatric patients with multiple morbidities, TEAM offers a method of therapy with acceptable MRs and SEs, making active treatment possible in otherwise incurable patients.
Adult↗
Bcl-X(L) is a chemoresistance factor in human melanoma cells that can be inhibited by antisense therapy.
Malignant melanoma is a tumor that responds poorly to a variety of apoptosis-inducing treatment modalities, such as chemotherapy. The expression of genes that regulate apoptotic cell death plays an important role in determining the sensitivity of tumor cells to chemotherapeutic intervention. Bcl-x(L) is an antiapoptotic member of the Bcl-2 family and is universally expressed in human melanoma. To evaluate the Bcl-x(L) protein as a potential therapeutic target in melanoma, the influence of Bcl-x(L) expression levels on the chemoresistance of human melanoma cells was investigated. Overexpression of Bcl-x(L) in stably transfected human melanoma Mel Juso cells significantly reduced sensitivity to cisplatin-induced apoptosis (p < or = 0.05). In a parallel approach, reduction of Bcl-x(L) protein by specific AS oligonucleotide (ISIS 16009) treatment enhanced the chemosensitivity of Mel Juso cells by 62% compared to cells treated with MM control oligonucleotide (ISIS 16967) as well as chemotherapy-induced apoptosis. These data suggest that Bcl-x(L) is an important factor contributing to the chemoresistance of human melanoma. Reduction of Bcl-x(L) expression by AS oligonucleotides provides a rational and promising approach that may help to overcome chemoresistance in this malignancy.
Antineoplastic Agents↗
Dimethylfumarate inhibits TNF-induced nuclear entry of NF-kappa B/p65 in human endothelial cells.
Fumaric acid esters, mainly dimethylfumarate (DMF), have been successfully used to treat psoriasis. Based on previous observations that DMF inhibited expression of several TNF-induced genes in endothelial cells, we wished to explore the molecular basis of DMF function in greater detail. In first experiments we analyzed DMF effects on tissue factor expression in human endothelial cells in culture, because tissue factor is expressed by two independent sets of transcription factors, by NF-kappa B via TNF and by early gene response-1 transcription factor via vascular endothelial growth factor (VEGF). We show that DMF inhibits TNF-induced tissue factor mRNA and protein expression as well as TNF-induced DNA binding of NF-kappa B proteins, but not VEGF-induced tissue factor protein, mRNA expression, or VEGF-induced early gene response-1 transcription factor/DNA binding. To determine where DMF interferes with the TNF/NF-kappa B signaling cascade, we next analyzed DMF effects on I kappa B and on the subcellular distribution of NF-kappa B. DMF does not inhibit TNF-induced I kappa B alpha phosphorylation and I kappa B degradation; thus, NF-kappa B is properly released from I kappa B complexes even in the presence of DMF. Importantly, DMF inhibits the TNF-induced nuclear entry of NF-kappa B proteins, and this effect appears selective for NF-kappa B after the release from I kappa B, because the constitutive shuttling of inactive NF-kappa B/I kappa B complexes into and out from the nucleus is not blocked by DMF. Moreover, DMF does not block NF-kappa B/DNA binding. In conclusion, DMF appears to selectively prevent the nuclear entry of activated NF-kappa B, and this may be the basis of its beneficial effect in psoriasis.
Active Transport, Cell Nucleus↗
Why is epiluminescence microscopy important?
The new morphological information provided by epiluminescence microscopy (ELM) requires a fresh approach to the analysis of pigmented lesions. It necessitates a learning process that pertains to the recognition of hitherto unknown morphological features and is based on the discrimination of these features and their combination into two different patterns. ELM has been shown to improve the sensitivity and specificity of the diagnosis of melanoma and other pigmented lesions by 25-30%. Digitized ELM (DELM) provides an unlimited capacity for data storage and retrieval. It is a computerized imaging method, objective and noninvasive; it provides objective evidence of lesional changes on follow-up; documents growth and any changes in the structure and shape of lesions; and thus helps in decisions on whether to excise them or not. It provides for quality control by means of the aforementioned documentation, which may also serve as back-up in the case of medico-legal problems. In addition, the spectrum is widened by the dimension of teledermatology and cybernet computer-assisted diagnosis, which holds great promise for the future. ELM and DELM are thus the most important single development of the past three decades in the early diagnosis of melanoma.
Humans↗
Organotypic keratinocyte coculture using normal human serum: an immunomorphological study at light and electron microscopic levels.
Organotypic human skin equivalents of keratinocytes and fibroblasts embedded in collagen matrix have been the subject of studies dealing with various culture conditions. Development of standardized living skin equivalents using defined culture media containing respective supplements can provide important instruments of investigation in skin biology. In addition, tissue engineering has created human skin substitutes for treatment of acute and chronic wounds. In our study, we generate a modified organotypic human skin equivalent using normal human serum instead of fetal calf serum (FCS). This living skin equivalent shows regular stratification of the epidermis and the dermal-epidermal junction zone at the light and electron microscopic level after 1 and 3 weeks of coculture. Indirect immunofluorescence reveals regular expression of differentiation antigens and the major structural proteins collagen IV, laminin 5 and the integrin chains alpha 6 and beta 4 at the dermo-epidermal junction zone. Immunoelectron microscopy demonstrates expression of collagen IV, alpha 6 and beta 4 integrin after 1 and 3 weeks of coculture. This organotypic skin model could be the basis for autologous skin grafting for acute or chronic wounds using autologous serum as well as patients' keratinocytes and fibroblasts, thus minimizing the risk of transmitting infectious agents.
Animals↗
Selection of mimotopes of the cell surface adhesion molecule Mel-CAM from a random pVIII-28aa phage peptide library.
The cell surface adhesion molecule Mel-CAM is highly expressed in advanced primary and metastatic melanoma. Mel-CAM was first described as an integral membrane glycoprotein of malignant melanoma cells. The murine monoclonal antibody MAd18-5D7 recognizes an epitope of the extracellular domain of Mel-CAM and is able to enhance Mel-CAM mediated adhesion of melanoma cells in aggregation assays. For the characterization of peptides that antigenically mimic surface-exposed areas of Mel-CAM we screened a newly constructed random pVIII-28aa bacteriophage peptide library against MAd18-5D7. After three panning rounds a population of phages binding to MAd18-5D7 was enriched. Peptides expressed on the surface of these phages were then tested for their specificity for the antibody's antigen binding site. DNA sequences coding for two specific peptide ligands were determined. One of the deduced amino acid sequences showed similarity to a portion of the sequence of the third immunoglobulin-like extracellular domain of Mel-CAM. Both peptides blocked the interaction of MAd18-5D7 with Mel-CAM present in a MelJuSo melanoma cell line lysate. Phage displayed as well as synthetic peptides inhibited in a dose-dependent manner the binding of MAd18-5D7 to recombinant Mel-CAM in enzyme-linked immunosorbent assay experiments. No such inhibition was observed using a panel of other anti-Mel-CAM antibodies. Our results clearly indicate that these 28mer peptides are structural equivalents of the MAd18-5D7 epitope of Mel-CAM and that they will be useful tools for further in vitro and in vivo studies of Mel-CAM mediated cell-cell interaction.
Amino Acid Sequence↗
Pimecrolimus identifies a common genomic anti-inflammatory profile, is clinically highly effective in psoriasis and is well tolerated.
The ascomycin macrolactam pimecrolimus is a novel inflammatory cytokine release inhibitor that so far has not been administered systemically to humans. In this phase I/II randomized double-blind, placebo-controlled, multiple rising dose proof of concept study psoriasis patients were treated with oral pimecrolimus or placebo. Gene profiling identified a common genomic profile with a downregulation of genes associated with inflammation but no changes in gene expression linked to drug-related side-effects. A steady state of pimecrolimus was reached after 5-10 d, Cmax, and area under the curve (0-24) was 54.5 ng per ml and 589.9 ng h per ml, respectively, at steady state at the highest dose. There was clear clinical efficacy in patients receiving 20 mg pimecrolimus twice daily and 30 mg twice daily with a reduction of Psoriasis Area and Severity Index by 60% and 75%, respectively. Histopatho logically and immunopathologically there was a reversion of the psoriatic phenotype towards normal. There were no notable clinical, laboratory, kidney function, or immunologic side-effects. We conclude that pimecrolimus taken orally is highly effective in a concentration-dependent manner in patients with psoriasis and on a short-term basis it is well tolerated and this is confirmed by its pharmacogenomic profile. The latter also indicates that pimecrolimus should be equally effective in other inflammatory skin diseases.
Adult↗
FcgammaRIII expression on cultured human keratinocytes and upregulation by interferon-gamma.
Keratinocytes of human epidermis are actively involved in inflammatory and autoimmune reactions of the skin and interact with resident or infiltrating immunocompetent cells via cytokines, chemokines, and intercellular adhesion mechanisms. Most immunocompetent cells have been reported to express Fcgamma receptors (FcgammaR), which are important for immunoregulatory functions. In this study we investigate FcgammaRIII expression on cultured human keratinocytes and upregulation by interferon-gamma. By real-time polymerase chain reaction, we show basal mRNA expression of both subclasses FcgammaRIIIA and FcgammaRIIIB, but after interferon-gamma treatment mRNA of FcgammaRIIIA and FcgammaRIIIB is increased 4.4 and 6.5 times, respectively. FcgammaRIII protein expression and its increase after interferon-gamma treatment were shown on cultured human keratinocytes by indirect immunofluorescence. In immunoblotting experiments, a bonified anti-CD16 antibody revealed reactivity to a polypeptide of 50-65 kDa on lysates of treated and untreated keratinocytes. In summary, we demonstrate expression of mRNA specific for the FcgammaRIIIA and FcgammaRIIIB subclasses and their upregulation by interferon-gamma on human keratinocytes in vitro, and confirm FcgammaRIII protein expression by indirect immunofluorescence and by immunoblotting experiments.
Adult↗
Treatment of cutaneous mastocytosis.
Therapy of cutaneous mastocytosis is directed towards skin and systemic symptoms due to mediator release and targeted on skin lesions. Symptomatic therapy of cutaneous mastocytosis involves agents that inhibit the release of mediators or antagonize H1 and H2 receptors such as antihistamines ketodifen and Aspirin. Disodium cromoglycate has no effect of the cutaneous symptoms of cutaneous mastocytosis. Skin-targeted therapies that lead to a resolution of the lesions of cutaneous mastocytosis are psoralen-photochemotherapy and topical corticosteroid therapy either by occlusion or intralesional injection for a limited number of lesions. There is no treatment that permanently cures cutaneous mastocytosis and patient selection will therefore have to be made on the basis of the clinical manifestations, onset of disease, the probability of spontaneous involution and the severity of cutaneous and systemic symptoms.
Humans↗