Roland Kaufmann

Psoriasis: a possible risk factor for development of coronary artery calcification.

Background  Psoriasis is a chronic inflammatory skin disorder affecting about 2% of white‐skinned individuals. Epidemiological data on the prevalence and degree of coronary artery calcification (CAC) as an indicator for cardiovascular diseases in patients with psoriasis are contradictory.

Pulsed erbium:YAG laser ablation in cutaneous surgery

Among the various pulsed midinfrared‐lasers studied in skin surgery the 2.94 μm Erbium: YAG laser has been shown to combine most efficacious ablation with least thermal damage due to its unique absorption characteristics in tissue water.

Adverse reactions to local anesthetics: Analysis of 197 cases

BACKGROUND Adverse drug reactions to local anesthetics are frequently reported. However, little is known about the underlying mechanisms. Therefore we investigated 177 patients with a history of 197 events after application of these drugs. METHODS The diagnostic approach included prick and intracutaneous tests, provocative challenge tests with causative and unrelated local anesthetics, and in selected cases, radioimmunoassays to detect specific IgE. In addition, tests were performed with preservatives, including sodium metabisulfite and parahydroxybenzoic acid ester. RESULTS Results of prick and intracutaneous tests with local anesthetics were all negative. Only three patients reacted after subcutaneous challenge with the causative drug (local anesthetics of the amide type). Although one patient showed a delayed-type response to mepivacaine, two patients had immediate-type reactions to articaine and lidocaine. However, in both cases no specific IgE could be detected. In five patients with positive skin test reactions to preservatives, challenge test results remained negative. CONCLUSION Two immediate-type reactions were not IgE-mediated. In only one of 197 reported adverse reactions were we able to prove delayed-type allergic response. Therefore true allergic reactions caused by local anesthetics are extremely rare.

Endothelial P-Selectin as a Target of Heparin Action in Experimental Melanoma Lung Metastasis

Spontaneous and experimental metastasis can be effectively inhibited by the widely used anticoagulant heparin in different tumor models. At the cellular level, many of the antimetastatic effects of heparin in vivo are due to its action on P-selectin-mediated binding. Whereas previous attention has focused on P-selectin-dependent tumor-cell-platelet interactions in blood-borne metastasis, we sought to address the potential contribution of endothelial P-selectin expression to adhesive events between the microvasculature and melanoma cells in vivo. Transplantation of bone marrow from P-selectin-deficient into wild-type mice conveyed inhibition of ex-perimental melanoma metastasis. However, the extent to which bone marrow-conferred lack of platelet P-selectin expression attenuated melanoma lung metastasis was significantly less than that seen in P-selectin-deficient mice, suggesting that endothelial P-selectin expression may additionally contribute to formation of hematogenous metastases. This assumption was supported by our intravital microscopy studies, in which a significant proportion of melanoma cells were capable of directly interacting with postcapillary venules of the murine ear in a P-selectin-dependent manner. Heparin not only inhibits P-selectin-mediated melanoma cell rolling but also attenuates melanoma metastasis formation in vivo, further supporting the concept that endothelial P-selectin expression may represent an additional target of heparin action in experimental melanoma lung metastasis.

A New Calcipotriol/Betamethasone Dipropionate Formulation (DaivobetTM) Is an Effective Once-Daily Treatment for Psoriasis vulgaris

Background: Topical corticosteroids and calcipotriol have been used separately for many years to treat psoriasis. A new combination ointment has been formulated, which contains both calcipotriol and the corticosteroid betamethasone dipropionate. Objective: To compare the combination ointment with betamethasone dipropionate ointment, calcipotriol ointment and ointment vehicle in patients with psoriasis vulgaris. Methods: 1,603 patients were randomised to one of the 4 double-blind treatments used once daily for 4 weeks. Results: Themean percentage change in the PASI at the end of treatment was –71.3 (combination), –57.2 (betamethasone), –46.1 (calcipotriol) and –22.7 (vehicle). The mean difference of combination minus betamethasone was –14.2 (95% CI: –17.6 to –10.8, p < 0.001), of combination minus calcipotriol –25.3 (95% CI: –28.7 to –21.9, p < 0.001) and of combination minus vehicle –48.3 (95% CI: –53.2 to –43.4, p < 0.001). 6.0% of patients (combination) reported local adverse reactions compared to 4.9% (betamethasone), 11.4% (calcipotriol) and 13.6% (vehicle). Conclusion: Calcipotriol/betamethasone dipropionate combination ointment used once daily is well tolerated and more effective than either active constituent used alone.

Expression of polo-like kinase (PLK1) in thin melanomas: a novel marker of metastatic disease

Background: The maximum thickness of a primary malignant melanoma as measured by Breslows method is currently the most important prognostic factor. However, some thin melanomas (≤ 0.75 mm), which should have an excellent prognosis according to Breslow, can be lethal due to their ability to metastasize.

Proteasome inhibition reduces superantigen-mediated T cell activation and the severity of psoriasis in a SCID-hu model.

There is increasing evidence that bacterial superantigens contribute to inflammation and T cell responses in psoriasis. Psoriatic inflammation entails a complex series of inductive and effector processes that require the regulated expression of various proinflammatory genes, many of which require NF-kappa B for maximal trans-activation. PS-519 is a potent and selective proteasome inhibitor based upon the naturally occurring compound lactacystin, which inhibits NF-kappa B activation by blocking the degradation of its inhibitory protein I kappa B. We report that proteasome inhibition by PS-519 reduces superantigen-mediated T cell-activation in vitro and in vivo. Proliferation was inhibited along with the expression of very early (CD69), early (CD25), and late T cell (HLA-DR) activation molecules. Moreover, expression of E-selectin ligands relevant to dermal T cell homing was reduced, as was E-selectin binding in vitro. Finally, PS-519 proved to be therapeutically effective in a SCID-hu xenogeneic psoriasis transplantation model. We conclude that inhibition of the proteasome, e.g., by PS-519, is a promising means to treat T cell-mediated disorders such as psoriasis.

Efomycine M, a new specific inhibitor of selectin, impairs leukocyte adhesion and alleviates cutaneous inflammation

Specific interference with molecular mechanisms guiding tissue localization of leukocytes may be of great utility for selective immunosuppressive therapies. We have discovered and characterized efomycines, a new family of selective small-molecule inhibitors of selectin functions. Members of this family significantly inhibited leukocyte adhesion in vitro. Efomycine M, which was nontoxic and showed the most selective inhibitory effects on selectin-mediated leukocyte-endothelial adhesion in vitro, significantly diminished rolling in mouse ear venules in vivo as seen by intravital microscopy. In addition, efomycine M alleviated cutaneous inflammation in two complementary mouse models of psoriasis, one of the most common chronic inflammatory skin disorders. Molecular modeling demonstrated a spatial conformation of efomycines mimicking naturally occurring selectin ligands. Efomycine M might be efficacious in the treatment of human inflammatory disorders through a similar mechanism.

Redox-modulated pathways in inflammatory skin diseases

Inflammatory skin diseases account for a large proportion of all skin disorders and constitute a major health problem worldwide. Contact dermatitis, atopic dermatitis, and psoriasis represent the most prevalent inflammatory skin disorders and share a common efferent T-lymphocyte mediated response. Oxidative stress and inflammation have recently been linked to cutaneous damage in T-lymphocyte mediated skin diseases, particularly in contact dermatitis. Insights into the pathophysiology responsible for contact dermatitis can be used to better understand the mechanism of other T-lymphocyte mediated inflammatory skin diseases, and may help to develop novel therapeutic approaches. This review focuses on redox sensitive events in the inflammatory scenario of contact dermatitis, which comprise for example, several kinases, transcription factors, cytokines, adhesion molecules, dendritic cell surface markers, the T-lymphocyte receptor, and the cutaneous lymphocyte-associated antigen (CLA). In vitro and animal studies clearly point to a central role of several distinct but interconnected redox-sensitive pathways in the pathogenesis of contact dermatitis. However, clinical evidence that modulation of the skins redox state can be used therapeutically to modulate the inflammatory response in contact dermatitis is presently not convincing. The rational for this discrepancy seems to be multi-faceted and complex and will be discussed.

Multicentre intraindividual randomized trial of topical methyl aminolaevulinate–photodynamic therapy vs. cryotherapy for multiple actinic keratoses on the extremities

Background Methyl aminolaevulinate–photodynamic therapy (MAL‐PDT) is an effective treatment in facial/scalp actinic keratosis (AK).