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Dimethyl fumarate (DMF) promotes an IL-17Alow IFN-γlow IL-4+ CD4+ T cell phenotype. Adoptive transfer of in vitro DMF-treated myelin peptide-reactive IL-17Alow IFN-γlow IL-4+ CD4+ T cells prior to immunization for EAE reduces the severity of encephalomyelitis. This beneficial effect of transferred DMF-treated CD4+ T cells requires an early in vivo recall.

Autoimmune diseases are characterized by dendritic cell (DC)-driven activation of pro-inflammatory T cell responses. Therapeutic options for these severe diseases comprise small molecules such as dimethyl fumarate, or "gasotransmitters" such as CO. Herein we describe the synthesis of bifunctional enzyme-triggered CO-releasing molecules (ET-CORMs) that allow the simultaneous intracellular release of both CO and methyl fumarate. Using bone-marrow-derived DCs the impressive therapeutic potential of these methyl fumarate-derived compounds (FumET-CORMs) is demonstrated by strong inhibition of lipopolysaccharide-induced pro-inflammatory signaling pathways and blockade of downstream interleukin-12 or -23 production. The data also show that FumET-CORMs are able to transform DCs into an anti-inflammatory phenotype. Thus, these novel compounds have great clinical potential, for example, for the treatment of psoriasis or other inflammatory conditions of the skin.

Background Early paediatric dermatosurgery reveals excellent cosmetic results due to high skin-elasticity and pronounced capacity to recover from trauma. Furthermore, the size of skin lesions increases during life proportionally to skin growth and therefore early removal is of major importance. Selected local anaesthetics like prilocaine can cause methaemoglobinemia. However, in contrast to general anaesthesia many other local anaesthetics do not bare any major risks for infants. Objective In this retrospective study, we analysed infants aged less than 7 months receiving tumescent local anaesthesia (TLA) followed by dermatosurgery at our department between 2005 and 2015. The analysis is mainly based on our records. Additional information for a subset of patients was gained by a postoperative survey. Methods 92 infants (39 male, 53 female) with a median age of 4.2 months (range: 1.5 months; 6.7 months) were included in this study. Additional postoperative information was available for 33 of the 92 studied patients (35%). Results Infants were mainly operated for removal of a melanocytic nevus (n=54), followed by haemangioma (n=23), nevus sebaceous (n=6) and other lesions (n=9). The lesions were located on the scalp or neck (n=31), on the extremities (n=31), on the trunk (n=21), in the face (n=6) or on the buttocks (n=3). The median size of excision was 509mm2 (range: 16mm2; 3600mm2). Primary defect closure was performed by intracutaneous (n=68) or extracutaneous (n=24) suture techniques. No side effects of local anaesthesia were observed in any patient. Postoperative complications include pain (1/33; 3%), wound healing disorder (1/33; 3%) and visible severe scarring (2/33; 6%). Conclusions The combination of TLA and dermatosurgery in infants is a suitable outpatient treatment option for small lesions without any major risks or side effects and the benefit of prolonged postoperative analgesia. This article is protected by copyright. All rights reserved.

Like other immune cells, natural killer (NK) cells show impaired effector functions in the microenvironment of tumors, but little is known on the underlying mechanisms. Since lactate acidosis, a hallmark of malignant tissue, was shown to contribute to suppression of effective antitumor immune responses, we investigated the impact of tissue pH and lactate concentration on NK-cell functions in an aggressive model of endogenously arising B-cell lymphoma. The progressive loss of IFN-γ production by NK cells observed during development of this disease could be ascribed to decreased pH values and lactate accumulation in the microenvironment of growing tumors. Interestingly, IFN-γ expression by lymphoma-derived NK cells could be restored by transfer of these cells into a normal micromilieu. Likewise, systemic alkalization by oral delivery of bicarbonate to lymphoma-developing mice was capable of enhancing IFN-γ expression in NK cells and increasing the NK-cell numbers in the lymphoid organs where tumors were growing. By contrast, NK-cell cytotoxicity was dampened in vivo by tumor-dependent mechanisms that seemed to be different from lactate acidosis and could not be restored in a normal milieu. Most importantly, alkalization and the concomitant IFN-γ upregulation in NK cells were sufficient to significantly delay tumor growth without any other immunotherapy. This effect was strictly dependent on NK cells.

Known in part since antiquity, the salutary effects of sunlight again garnered increasing attention in the second half of the 19(th) century. The development of a device for ultraviolet irradiation of cutaneous tuberculosis by Finnsen at the onset of the twentieth century truly marked the beginning of modern phototherapy. In dermatology, treatment methods almost exclusively use wavelengths below the visible light range (ultraviolet light). Since the early 1970s, increasingly powerful artificial light sources have become available for UVB and UVA therapy as well as the combination of UVA and photosensitizers (photochemotherapy). High structural and procedural quality standards are an essential prerequisite for the implementation of effective as well as safe phototherapy. The following guidelines outline the current consensus of leading experts in the field of phototherapy with respect to indications, contraindications, and side effects of various treatment options available. Particular focus is also on adequate UV doses at the beginning and over the further course of treatment as well as on management of side effects.

Die heilsame Wirkung des Sonnenlichts war teilweise schon im Altertum bekannt und fand in der zweiten Halfte des 19. Jahrhunderts wieder zunehmend Beachtung. Den Beginn der modernen Phototherapien markiert die Entwicklung einer Apparatur zur ultravioletten Bestrahlung der Hauttuberkulose durch Finnsen zu Beginn des zwanzigsten Jahrhunderts. Zur Therapie von Hauterkrankungen finden beinahe ausschlieslich die spektralen Bereiche unterhalb des sichtbaren Lichtes (ultraviolett) Anwendung. Seit den 1970er Jahren stehen zunehmend leistungsfahige kunstliche Strahlenquellen bereit fur die Therapie mit UVB, UVA und die Kombination von UVA mit Photosensibilisatoren (Photochemotherapie). Hohe strukturelle und prozedurale Qualitatsstandards sind unabdingbare Voraussetzung fur die Durchfuhrung einer gleichermasen wirkungsvollen wie auch sicheren Phototherapie. Die Leitlinie formuliert den aktuellen Konsens fuhrender Experten auf dem Gebiet der Phototherapie in Bezug auf die Indikationen fur die jeweiligen Therapieverfahren, deren Gegenanzeigen und Nebenwirkungen und insbesondere fur die Wahl der korrekten Dosis zu Beginn und im Verlauf einer Therapie sowie das Management von Nebenwirkungen.

Forty years of research have brought about the development of antibodies that induce effective antitumor immune responses through sustained activation of the immune system. These "immune checkpoint inhibitors" are directed against immune inhibitory molecules, such as cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1). Disruption of the PD-1/PD-L1 interaction improves the intermediate-term prognosis even in patients with advanced stage IV melanoma. One and a half years after treatment initiation, 30-60 % of these patients are still alive. While cancer immunotherapies usually do not eradicate metastases completely, they do cause a regression by 20-80 %. It is well established that the immune system is able to kill tumor cells, and this has also been demonstrated for immunotherapies. Preclinical data, however, has shown that anti-cancer immunity is not limited to killing cancer cells. Thus, through interferon gamma and tumor necrosis factor, the immune system is able to induce stable tumor growth arrest, referred to as senescence. Ensuring patient survival by long-term stabilization of metastatic growth will therefore become a central goal of antitumor immunotherapies. This therapeutic approach is effective in melanoma and non-small-cell lung cancer. Once immunotherapies also have an indication for common cancer types, drug prices will have to drop considerably in order to be able to keep them available to those dependent on such therapies.

Zusammenfassung Die Erkenntnisse aus 40 Jahren Forschung erlauben es, durch Antikorper-vermittelte Aktivierung des Immunsystems eine therapeutisch wirksame Antitumorantwort zu induzieren. Die „Immun-Checkpoint-Inhibitoren“ sind gegen immuninhibitorische Molekule wie cytotoxic T lymphocyte antigen 4 (CTLA4), programmed-death-1 (PD-1) oder programmed-death-ligand-1 (PD-L1) gerichtet. Die Unterbrechung der PD-1/PD-L1-Interaktion verbessert mittelfristig auch die Prognose bei Patienten mit Melanomen im Stadium IV. So sind unter Therapie mit Anti-PD-1-Antikorpern 30–60 % dieser Patienten nach eineinhalb Jahren am Leben. Antitumorale Immuntherapien verursachen nur selten eine vollstandige Zerstorung der Metastasen, sondern eine Regression um 20–80 %. Fest etabliert ist, dass das Immunsystem Tumorzellen abtoten kann; dies wurde auch fur Immuntherapien belegt. Praklinische Daten zeigten jedoch, dass Immunantworten Tumoren nicht nur toten konnen. So kann das Immunsystem uber die Zytokine Interferon-γ und Tumornekrosefaktor in Tumoren einen stabilen Wachstumsarrest hervorrufen, der Seneszenz genannt wird. Ein Ziel antitumoraler Immuntherapien wird also darin liegen, das Uberleben der Patienten durch eine langfristige Stabilisierung der Metastasen zu sichern. Dies gilt fur das Melanom und das nichtkleinzellige Lungenkarzinom. Sobald Immuntherapien auch bei haufigen Tumoren indiziert sein werden, mussen die Medikamentenpreise deutlich fallen, um sie weiterhin jenen zur Verfugung stellen zu konnen, die die Therapien benotigen.

SummaryBackground and objectives The objective was to determine the diagnostic value of direct immunofluorescence (DIF) in ocular mucous membrane pemphigoid (ocular MMP), taking into account immunofluorescence patterns and biopsy sites. Patients and methods DIF results and medical records of 54 patients with a suspected diagnosis of ocular MMP were reviewed. Results There was an overall prevalence of ocular MMP in 70.4 % of cases. Linear deposition of IgA, IgG, or C3 showed a high positive predictive value (84–100 %). Sensitivity and negative predictive value of IgG, IgM, IgG, and C3 in DIF were higher in cutaneous samples than in conjunctival biopsies, thus yielding a higher diagnostic accuracy. The sensitivity of DIF in ocular MMP seems to be lower than in bullous pemphigoid. Conclusions The diagnostic value of DIF in the workup of ocular MMP was confirmed. However, biopsies taken from non-conjunctival, cutaneous tissue appear to yield more accurate results.

Zusammenfassung Hintergrund und Zielsetzung Ziel war es, den diagnostischen Wert der direkten Immunfluoreszenz (DIF) beim okularen Schleimhautpemphigoid (okulares MMP – „mucous membrane pemphigoid“) unter Beachtung der Immunfluoreszenzmuster und der Biopsiestellen zu bestimmen. Patienten und Methoden Gepruft wurden DIF-Ergebnisse und Krankenakten von 54 Patienten mit Verdachtsdiagnose eines okularen MMP. Ergebnisse Es gab insgesamt eine Pravalenz des okularen MMP in 70,4 % der Falle. Lineare Ablagerungen von IgA, IgG oder C3 zeigten einen hohen positiven pradiktiven Wert (84 - 100 %). Der Empfindlichkeitswert und der negative pradiktive Wert von IgG, IgM, IgG und C3 bei DIF waren bei kutanen Proben hoher als bei Bindehaut-Biopsien, und lieferten daher eine hohere diagnostische Genauigkeit. Die Empfindlichkeit der DIF scheint beim okularen MMP geringer zu sein als beim bullosen Pemphigoid. Schlussfolgerungen Der diagnostische Wert der DIF bei der Abklarung des okularen MMP wurde bestatigt. Biopsien aus nicht-konjunktivalem, kutanen Gewebe scheinen jedoch genauere Ergebnisse zu liefern.

Little is known on the control of lymphomas by NK cells. Here, we study the role of the NK group 2D (NKG2D) receptor for the immunosurveillance of lymphoma. By using transplantable tumors as well as a λ-myc-transgenic model of endogenously arising lymphoma and NKG2D-deficient mice, we show that NK cells eliminate tumor cells in vivo after receiving two signals. One step involved the activation of NK cells giving rise to IFN-γ expression, which was effected by MHCI(low) tumor cells or DCs. However, this was necessary but not sufficient to mediate cytotoxicity. Triggering cytotoxicity additionally required a second step, which could be mediated by engagement of the NKG2D receptor. Thus, NKG2D-deficient NK cells could become activated in vivo, but they were not able to reject transplanted lymphomas or to degranulate in animals bearing autochthonous lymphomas. Tumor growth in NKG2D-deficient λ-myc-transgenic mice was significantly accelerated compared to NKG2D-competent animals. Whereas the latter developed tumors that lost expression of NKG2D ligands (NKG2D-L) in late disease stages, this did not occur in NKG2D-deficient mice. This indicates that NK cells and the NKG2D receptor play a role for control of lymphomas and that selection for NKG2D-L loss mutants provides a mechanism of tumor escape.

Background The difficulty of antifungal substances to penetrate keratin and slow nail growth limit the efficacy of topical therapy in onychomycosis. One promising alternative is photodynamic antimicrobial chemotherapy, or PACT: an irradiated photosensitizer creates singlet oxygen molecules which destroy pathogens without damaging human cells. Objective As PACT has demonstrated strong antifungal capabilities, we wanted to investigate its efficacy in an in vitro model of onychomycosis. Methods PACT was tested in a microdilution assay, in an in vitro onychomycosis model as well as in a patient. Results PACT inhibited fungal growth in the microdilution assay with no colonies of T. rubrum detectable. Fungal growth was also inhibited in an onychomycosis model, after 30 min of LED irradiation. Subsequently, a patient with distolateral onychomycosis was treated on three consecutive days and showed significant and durable improvement of nail morphology 6 months after. Conclusion PACT appears to be an effective treatment of onychomycosis in vitro. The promising results need to be validated by clinical trials.

Summary Background: No consistent data are available on the currently employed diagnostic tools for autoimmune bullous diseases in Germany. The aim of this survey was to describe currently performed diagnostic methods for bullous autoimmune diseases in German dermatology departments. Methods: A standardized questionnaire evaluated the available diagnostic methods i. e. direct immunofluorescence microscopy (IFM), indirect IFM, commercial ELISA systems, and non-commercial serological tests as well as the number of samples per year in all 34 university and 39 non-university dermatology departments. Results: The overall return rate was 89 %, 100 % and 79 % for the university and non-university departments, respectively. Direct IFM was the most frequently used method and was applied in 98 % of the responding departments. In 74 % of the responding departments, indirect IFM was used mainly on monkey esophagus and human salt-split skin. Commercial ELISA systems were employed in 58 % of the clinics; all of them used anti-desmoglein ELISA, while anti-BP180 and anti-BP230 ELISA were established in 49 % and 48 % of departments, respectively. Non-commercial analytic methods were only performed in 22 % of the departments. Conclusions: The high return rate of this survey allows a relatively precise description of the current diagnostic methods used in German dermatology departments. Standard diagnostic tests are available nationwide and in bullous pemphigoid and pemphigus, the antigen-specific detection of autoantibodies is routinely performed in half of the departments. Rare disorders may be diagnosed by cooperation with some specialized centers.

Summary Background: TNM classifications are the basis for diagnostic and therapeutic procedures in oncology. Histopathological reports have to enable a proper indexing of tumor specific findings into recent classifications. Methods: A systematic review of the literature was performed to identify reports dealing with the assessment of mitotic rate and the processing and evaluation of sentinel node biopsies in malignant melanoma. On the basis of this review an expert panel of dermatopathologists and general pathologists discussed and agreed recommendations for general practice. Results: Following recommendations were agreed with a broad consensus (93–100 % agreement): The determination of the mitotic rate in primary melanoma is performed on HE slides. The evaluation of an area of 1 mm2 is sufficient. Only dermal mitoses are considered. The counted number of mitoses is provided as an integer value. The mitotic rate shall be determined in primary melanomas of ≤1.00 mm vertical tumor thickness according to the hot-spot method and provided as an integer value in relation to an area of 1 mm2. The determination of the mitotic rate in the case of thicker primary melanomas is desirable. In general, for the evaluation of each sentinel lymph node, 4 slides should be prepared. For diagnostic purposes, immunohistochemistry (preferably with antibodies against S100s, Melan A and HMB-45) should be performed in addition to HE staining. The pathology report should provide information about micro-metastases and their longest extension (one-tenth of a millimeter). Conclusions: These recommendations are suitable for standardizing the histopathological diagnosis of malignant melanoma and for providing a common basis for clinical decisions and scientific research.

Innate immune sensing of Staphylococcus aureus unravels basic mechanisms leading to either effective antibacterial immune responses or harmful inflammation. The nature and properties of S. aureus-derived pathogen-associated molecular pattern (PAMPs) are still not completely understood. We investigated the innate immune sensing of peptidoglycan (PGN) structures and subsequent immune consequences. Macromolecular PGN (PGN(polymer)) preparations activated NF-κB through human Toll-like receptors 2 (TLR2), as shown by luciferase reporter assays, and induced murine dendritic cell (DC) maturation and cytokine production. In contrast, PGN(polymer) from lgt-mutant S. aureus failed to stimulate human TLR2, demonstrating that lipoproteins within the macromolecular structures of PGN(polymer), but not PGN itself, activate TLR2. Thus, HPLC-purified monomeric PGN (PGN(monomer)) structures were investigated. Strikingly, PGN(monomer) completely lacked NF-κB activation, lacked TLR2 activity, and failed to functionally activate murine DCs. However, PGN(monomer) in concert with various TLR ligands most effectively stimulated DCs to up-regulate IL-12p70 and IL-23 by ≥3- to 5-fold. Consequently, DCs coactivated by PGN(monomer) markedly up-regulated Th1 and Th17 while suppressing Th2 cell priming. Notably, PGN(monomer) failed to coactivate NOD2(-/-) DCs. This demonstrates that PGN(monomer) is a natural ligand of NOD2, which was previously only demonstrated for synthetic compounds like muramyl dipeptide. Interestingly, murine DCs lacking TLR2 remained mute in response to the combinative immune sensing of S. aureus-derived PAMPs, including PGN(monomer), providing for the first time an explanation of why S. aureus can colonize the nasal mucosa in the absence of inflammation. This is very likely based on the lack of TLR2 expression in mucosal epithelial cells under normal conditions, which determines the unresponsiveness to S. aureus PAMPs.

Summary Background: Accurate pre-operative or intra-operative labeling of the skin is often necessary to mark exactly the surgical excision lines. Pre-operative “unsterile” permanent skin labeling systems are needed for example for vein and sentinel lymph node surgery; here the dyes must resist two surgical skin disinfection procedures. In contrast, excision borders are labeled during surgery using a “sterile” skin marking system. Methods: Many commercial and non-commercial pre- and intra-operative skin-labeling systems are available, such as autologous patient blood, fluorescence triphenylmethane dyes and commercial skin markers. The available skin marking systems have specific advantages and disadvantages. We review the different labeling systems, offering guidelines to help choose a cost-effective system appropriate for a given surgical procedure. Results: The Edding® permanent markers 400 und 3000 are well suited for preoperative skin labeling and less expensive than commercial skin labeling systems. Autologous patient blood and eosin are well suited for intra-operative labeling and are most cost effective. Eosin Y is widely used and well suited for labeling of dark skin, bone, cartilage, and muscle tissue and spares the expense of expensive commercial skin markers. Conclusion: Knowledge of the many commercial and non-commercial pre- and intra-operative skin labeling systems and their advantages and disadvantages helps to reduce the use of relatively expensive commercial skin markers.

Psoriasis pathogenesis is closely associated with disease-inducing Th1 and Th17 cells. Yet, several studies suggest that aberrant keratinocyte or endothelial cell signalling significantly contributes to disease manifestation. Histological hallmarks of psoriatic skin include the infiltration of multiple immune cells, keratinocyte proliferation and increased dermal vascularity. Formation of new blood vessels starts with early psoriatic changes and disappears with disease clearance. Several angiogenic mediators like vascular endothelial growth factor, hypoxia-inducible factors, angiopoietins and pro-angiogenic cytokines, such as tumour necrosis factor (TNF), interleukin (IL)-8 and IL-17, are up-regulated in psoriasis development. Contact- and mediator-dependent factors derived from keratinocytes, mast cells and immune cells may contribute to the strong blood vessel formation of psoriasis. New technologies and experimental models provide new insights into the role of angiogenesis in psoriasis pathogenesis. Interestingly, many therapies target not only immune cells, but also protein structures of endothelial cells. Here we summarize the role of pro-angiogenic factors in psoriasis development and discuss angiogenesis as a potential target of novel therapies.

Mast cells are still generally viewed as mediators of type I allergic or pseudoallergic reactions. Research over the past 10 years revealed that our view was too small and that mast cells are of key importance in innate immunity and also types II, III and IV adaptive immune reactions. Understanding their role in modulating and amplifying of inflammatory responses provides important insights into the pathogenesis of skin diseases such as psoriasis, atopic dermatitis, bullous pemphigoid or the control of infections. This helps us to understand the course of these diseases, their trigger mechanisms, and, the new role of agents, which can modulate the function of mast cells. These insights will help to develop new therapeutic approaches.

Tumor-specific T cells are crucial for immunologic control of malignant disease. T cells can be induced in vivo by vaccination or adoptively transferred after activation ex vivo. We investigated the requirements for generating T cells with optimal antitumor effector functions in a murine lymphoma model. Using adoptive transfer, we show that in vivo efficacy of T cells cannot be predicted by tumor reactivity in vitro. A restricted T-cell receptor β chain repertoire of T-cell populations stimulated ex vivo against tumor cells was necessary but not sufficient for tumor protectivity. Tumor elimination furthermore required vaccination of donor mice, hence in vivo priming. The in vivo priming step may allow tumor-specific T cells to accumulate in vitro more rapidly and to survive for longer periods after withdrawal of the antigenic stimulus and adoptive transfer. A possible survival benefit of in vivo induced T cells may be ascribed to the responsiveness to homeostatic cytokines and to unique cytokine milieus encountered in vivo. Most importantly, monoclonal T cells cannot inhibit tumor growth. A prerequisite of tumor rejection was the expression of at least 2 T-cell receptor β chains by transferred T-cell populations. This finding has implications for designing adoptive transfer strategies for the clinic. © 2008 Wiley-Liss, Inc.

Objective Induction of arthritis with autoantibodies against glucose-6-phosphate isomerase (GPI) is entirely independent of T cells and B cells but is strictly dependent on the presence of mast cells. Here, we used this disease model to analyze whether exclusive intraarticular mast cell reconstitution is sufficient for disease induction and whether targeted mast cell silencing can prevent neoangiogenesis and joint destruction, 2 hallmarks of rheumatoid arthritis. Methods Ankle swelling and clinical index scores were determined after injection of either K/BxN mouse–derived serum or control serum in wild-type Kit+/Kit+ mice, congenic mast cell–deficient KitW/KitW-v mice, or mast cell–deficient KitW/KitW-v mice reconstituted with mast cells, either by intraperitoneal or selective intraarticular injection. Angiogenesis was quantified in vivo by measuring activated αvβ3 integrin using 18F–galacto-RGD and positron emission tomography. In addition, staining of joint tissue with hematoxylin and eosin, Giemsa, β3, and α-actin was performed. The effect of mast cell stabilization by treatment with cromolyn or salbutamol was investigated in C57BL/6 or BALB/c mice. Results Comparing wild-type mice, mast cell–deficient KitW/KitW-v mice, and mast cell–reconstituted KitW/KitW-v mice, we first showed that intraarticular and intraperitoneal mast cell engraftment fully restores susceptibility to antibody-induced arthritis, angiogenesis, and αvβ3 integrin activation. Importantly, selective mast cell silencing with either salbutamol or cromolyn prevented αvβ3 integrin activation, angiogenesis, and joint destruction. Conclusion Mast cell engraftment fully restores susceptibility to αvβ3 integrin activation, angiogenesis, and joint destruction in GPI antibody–induced arthritis. Importantly, selective mast cell stabilization prevents αvβ3 integrin activation, angiogenesis, and joint destruction.

Rhythmical changes in microvascular perfusion of the skin depend on various influences, which appear continuously but not in a predictable manner. For identifying and quantifying different physiological influences the authors used wavelet transformation, analyzing continuously and simultaneously measured data.A total of 34 healthy volunteers were included in the study. At the dorsum of the left hand, skin perfusion was measured by laser Doppler fluxmetry (LDF) and skin temperature was measured. Simultaneously, the electrocardiogram and the respiration were recorded. The recorded time series were analyzed with wavelet transformation and scale correlation (S-correlation).Semilinear analysis with wavelet transformation allowed a visualization of temporal changes in LDF frequency and amplitude in a color-coded quasi three-dimensional diagram. The authors found that tissue perfusion over an observation period of 327.68 s is governed by 6 closely connected, overlying waves with different degrees of freedom. The major determinants are low frequencies in LDF, which correlates with changes in skin temperature, responsible for 68.5% of the influence. Surprisingly, though indispensable for blood flow, respiration and heartbeat contributed to less then 2.5% of the rhythmic changes.When wavelet transformation is used in analyzing LDF time series, the different rhythms of cutaneous blood flow are made visible and quantifiable and can be assigned to different physiological origins. The application of this novel analysis method allows identifying mechanisms regulating skin perfusion, which will greatly facilitate the diagnosis of a variety of important vascular diseases, such as chronic venous insufficiency, diabetes, or neurotrophic disorders.

Phototherapy with ultraviolet (UV) irradiation of wavelengths between 280 and 320 nm (UV-B) is a safe and effective treatment for a variety of inflammatory skin diseases. In addition to standard broad band UVB, narrow band phototherapy with fluorescent bulbs emitting near monochromatic UV between 310-315 nm has become an important treatment for diseases such as psoriasis, atopic dermatitis or vitiligo. Other diseases respond favorably to narrow band UV-B phototherapy, the number of potential indications for such phototherapy is continuously growing. The differential effects of narrow band UV-B phototherapy in comparison to other UV phototherapies, as well as new and established indications for this treatment modality are reviewed.

BACKGROUND: Beside the primary goal of complete eradication, the cosmetic result is an important aspect of the treatment of non-melanoma skin tumors especially in the head and neck region. PATIENTS AND METHODS: From 1990 to 2000, we treated a total of 5,227 large basal cell carcinomas (BBC) and 1,189 squamous cell carcinomas (SCC) in the head and neck region by surgical excision in 4,239 inpatients at the Department of Dermatology, University of Tubingen. The procedure used in all patients was a conservative excision controlled by complete three dimensional histology of all margins (3D-histology) and specifically targeted follow-up surgery where required (histographic surgery). As part of the prospective tumor follow-up, we asked the treating outdoor physician one and four years later to evaluate the results of our surgical procedures. RESULTS: Of the 5,565 follow-up questionnaires sent back, 4,868 contained answers regarding the cosmetic result. The data from both answers were pooled. In 1,972 (40,5 %) patients the cosmetic result was evaluated as "excellent", in 1,992 (40,9%) as "good", in 662 (13,6%) as "satisfactory", in 191 (3,9%) as "mediocre" and in 51 (< 1,0%) as "poor". In 697 of the responses, the physician did not comment the cosmetic results or the patient was lost for follow up. CONCLUSION: With respect to both long term safety and cosmetic outcome, tumor surgery with 3D-histology of excisional margins has set very high quality standards in the treatment of non-melanoma skin cancer of the head and neck area.

Psoriasis is a chronic inflammatory disease of the skin and the joints. Multiple factors contribute to the initiation of psoriasis. They include specific genetic characteristics such as major histocompatibility antigens and psoriasis susceptibility genes, as well as trigger factors, namely streptococcal infections. Today, psoriasis is considered as a T-lymphocyte mediated autoimmune disease, even though the putative autoantigen remains unknown. Bacterial proteins with similarity to structural proteins of keratinocytes are potential target antigens. As in other autoimmune diseases, inflammatory cytokines of the innate immune system initiate a cascade that activates inflammation locally in the skin, in the circulation and most likely also in lymph nodes. IFN-gamma-producing CD4+ Th1-lymphocytes seem to be of central importance in the pathogenesis of psoriasis as they critically influence differentiation and functioning of antigen presenting cells, mast cells, neutrophils and endothelial cells. This inflammatory cascade simultaneously provokes neoangiogenesis in the dermis and proliferation of keratinocytes. Based on this hypothesis, cytokines or anticytokine antibodies that either inhibit T-cell mediated inflammation or transform disease-inducing, pro-inflammatory Th1-lymphocytes into a phenotype with anti-inflammatory properties were tested in psoriasis. As both approaches improved psoriasis, they strongly support the current concept that views psoriasis as a Th1-lymphocyte mediated disease.

Zusammenfassung Hintergrund: Bei Melanomen, die im Gesicht lokalisiert sind, lassen sich die am Korper ublichen Sicherheitsabstande aus funktionellen und asthetischen Grunden nicht realisieren. In der Literatur fehlen kontrollierte Studien zu Sicherheitsabstanden bei Gesichtmelanomen. Bei den Melanompatienten der Universitats-Hautklinik Tubingen (1980 – 1999) wurde retrospektiv analysiert, welche klinische Parameter und operativen Strategien die Prognose bei Gesichtsmelanomen beeinflussen. Die Bedeutung der luckenlosen histologischen Kontrolle der Exzisatschnittrander (3D-Histologie) sollte validiert werden. Patienten und Methodik: Die untersuchten 368 Melanome des Gesichts machten 9,3 % aller 3 960 Primarmelanome im klinischen Stadium I/II und 63 % der Melanome des Kopf/Hals-Bereichs aus. Ergebnisse: Operationen, die mehrzeitig durchgefuhrt wurden, eine Exzisonsbiopsie zur Diagnosesicherung gefolgt von einer spateren Nachexzision mit definitivem Sicherheitsabstand oder eine Nachexzision bei histologisch unvollstandiger Primarexzision, waren mit einer hoheren Wahrscheinlichkeit fur das rezidivfreie Uberleben verbunden (p = 0,0007), jedoch ohne prognostische Bedeutung fur das Gesamtuberleben. In der multivariaten Analyse waren Invasionslevel (p = 0,0049), Ulzeration (p = 0,011), 3D-Histologie (p = 0,027) und die Einhaltung definierter Sicherheitsabstande (Tumordicke ≤ 1,00 mm: 10 mm; > 1,00 mm 20 mm; LMM 5 mm unter Einsatz der 3D-Histologie) (p = 0,033) unabhangige signifikante Risikofaktoren fur das rezidivfreie Uberleben. Fur das Gesamtuberleben konnten Invasionslevel (p = 0,032), Ulzeration (p = 0,029), 3D-Histologie (p = 0,0047) als unabhangige signifikante Risikofaktoren identifiziert werden. In der multivariaten Analyse konnte fur den histologischen Tumortyp keine prognostische Bedeutung nachgewiesen werden. Schlusfolgerung: Aufgrund dieser Ergebnisse konnen auch reduzierte Sicherheitsabstande im Gesicht als ausreichend sicher eingeschatzt werden. Die 3D-Histologie ermoglicht eine weitere Reduzierung der Sicherheitsabstande, kann subklinische Tumorauslaufer erkennen und ist mit einer besseren Prognose bei Patienten mit Gesichtsmelanomen assoziiert. Summary Background: In treated facial melanomas, the safety margins generally applied in other body sites cannot be achieved for functional and esthetical reasons. To date there are no controlled studies on safety margins for facial melanomas. Clinical parameters and surgical strategies influencing the prognosis of patients with a facial melanoma were evaluated in a retrospective study of melanoma patients in the Department of Dermatology of the University of Tuebingen (1980 – 1999). Patients and Methods: The 368 melanomas of the face comprised 9.3 % of 3960 primary stage I and II melanomas and 63 % of the melanomas in the head and neck area. Results: Multistep procedures, excisional biopsy for histological diagnosis followed by a subsequent resection of a clinical safety margin or re-excision when the tumor extended to the margin, were associated with a higher probability for recurrence-free survival (p = 0.0007), but had no statistical influence on overall survival. In a multivariate analysis, level of invasion (p = 0.0049), ulceration (p = 0.011), 3D-histology (p = 0.027) and defined safety margins (tumor thickness ≤ 1.00 mm: 10 mm; > 1.00 mm 20 mm; lentigo maligna melanoma 5 mm with 3D-histology) (p = 0,033) were independent significant risk factors for recurrence-free survival. Level of invasion (p = 0.032), ulceration (p = 0.029), 3D-histology (p = 0.0047) were identified as independent significant risk factors for overall survival. Multivariate analysis did not show that the histological type of melanoma was of prognostic significance. Conclusion: Reduced safety margins can be employed in melanomas of the face. 3D-histology allows further reduction of safety margins, detects subclinical tumor strands and is correlated with an improved prognosis in patients with facial melanomas.

The viral CC chemokine macrophage inhibitory protein-II (vMIP-II) encoded by human herpes virus 8 (HHV-8) binds to multiple chemokine receptors, however, its ability to control the initial recruitment of specific leukocyte subtypes from the peripheral circulation has not been fully clarified. Here we show that vMIP-II blocks the firm arrest and transmigration of monocytes or Th1-like T lymphocytes triggered by RANTES immobilized on activated human microvascular endothelium (HMVEC) under flow conditions. The internalization of the receptors CCR1 and CCR5 that mediate arrest and transmigration of these cells in response to RANTES was prevented by vMIP-II, supporting its role as an antagonist of CCR1 and CCR5. In contrast, vMIP-II triggered the firm arrest of eosinophils and Th2-like T cells by engaging CCR3, as confirmed by its down-regulation. Immunohistochemical analysis of HHV-8-associated Kaposi's sarcoma lesions marked by vMIP-II expression and mononuclear cell infiltration revealed a predominance of Th2-type CCR3(+) lymphocytes over Th1-type CXCR3(+)/CCR5(+) leukocytes, indicating that as a CCR3 agonist vMIP-II can drive a Th2-type immune response in vivo. Thus, our data provide evidence for a immunomodulatory role of vMIP-II in directing inflammatory cell recruitment away from a Th1-type towards a Th2-type response and thereby facilitating evasion from cytotoxic reactions.

A 38-year-old woman infected with human immunodeficiency virus (HIV) presented with persistent oral candidosis in which non-albicans Candida strains were the predominant yeasts in most of the examinations performed over a period of 6 years. Oral treatment with fluconazole had no effect on clinical signs of oral candidosis. In 8 of a total of 11 specimens, Candida glabrata, Candida parapsilosis and Candida tropicalis were at least suspected as the causative pathogens of oral candidosis. The non-response to fluconazole in our patient could be explained by in vitro resistance to fluconazole of detected Candida glabrata and Candida tropicalis isolates.

Summary. The introduction of HIV protease inhibitors was accompanied by reduction in HIV-associated opportunistic infections. Therefore, we performed a retrospective study of HIV-infected patients to evaluate the effects of therapy with an HIV protease inhibitor (PI) on oral candidosis. This was of special interest, because an important virulence factor of Candida albicans is the secreted aspartic protease (SAP), which is assigned to the same class of aspartic proteases as HTV protease. Sixty-two patients were examined five times over a period of 2 years. There was a hint at a difference in the frequencies of C. albicans carrier state and manifest oral candidosis in favour of treatment with a PI. In addition, loss of Candida colonization and manifest oral candidosis was observed only in patients with elevation of CD4 cells upon PI. This might explain the effect, which also might go back to a direct inhibition of yeast SAP. Zusammenfassung. Die Einfuhrung von HIV-Protease-Inhibitoren bewirkte eine Reduktion HIV-assoziierter opportunistischer Infektionen. Wir haben daher in einer retrospektiven Studie an HIV-infizierten Patienten die Wirkung der HIV-Protease-Inhibitor-Therapie auf die orale Candidose untersucht. Dies war von besonderem Interesse, weil ein Hauptvirulenzfaktor von Candida albicans die sekretorische Aspartatprotease (SAP) darstellt, die zur selben Klasse der Aspartatproteasen gehort wie die HIV-Protease. Es wurden 62 Patienten funfmal uber eine Periode von zwei Jahren hinweg untersucht. Es zeigte sich ein Trend zum Haungkeitsunterschied des C. albicans-Keimtragerstatus und der manifesten oralen Candidose zugunsten der Behandlung mit Protease-Inhibitoren. Ferner wurde der Ruckgang der Candida-Besiedlung und der manifesten oralen Candidose nach Protease-Inhibitorgaben nur bei Patienten mit erhohter CD4-Zellzahl beobachtet. Diese Beobachtungen legen nahe, die Wirkung als immunologisch eher denn mikrobiologisch vermittelt zu betrachten.

Summary Confluent and reticulated papillomatosis is a rare dermatosis of unknown etiology mostly affecting young males and females most common in adolescence. The eruption consists of confluent, flat, brown papules forming a pigmented reticulated pattern. It occurs primarily in the intermammary and epigastric regions but may spread to the axillae. A 27-yearold patient with typical clinical and histologic features of confluent and reticulated papillomatosis responded well to oral minocycline. Zusammenfassung Die Papillomatosis confluens et reticularis ist eine seltene und atiologisch unklare Dermatose des jungen Erwachsenenalters mit einem Haufigkeitsgipfel kurz nach der Pubertat. Der initiale Befall mit netzartig konfluierenden Papeln findet sich meistens intermammar und im sternoepigastrischen Bereich und kann sich rhombenformig nach kraniokaudal und zu den Achseln ausbreiten.Wir berichten uber einen 27-jahrigen Patienten mit den typischen klinischen und histologischen Befunden einer Papillomatosis confluens et reticularis, welche erfolgreich mit Minozyklin behandelt wurde.

The role of interleukin-4 (IL-4) in the induction of IL-4 in mouse T cells is well established, but conflicting results have been reported with anti-CD3-primed human T cells and T cell clones. Therefore, IL-4 regulation was investigated in short-term cultured human T cells primed in vitro with either a superantigen or a hapten, nickel sulfate (NiSO4), for 3 days and expanded with IL-2 for another 5 days. Under these conditions, antigen-specific IL-4 producing T cells were generated in 35/40 cultures. Priming for IL-4 production was abrogated in all cultures by anti-IL-4 antibody or soluble IL-4 receptor (sIL-4R). Primed T cells that were IL-4- when cultured with IL-2 only developed an IL-4 producing phenotype when primed and expanded in the presence of exogenous IL-4. T cells primed in the presence of either endogenous or exogenous IL-4 produced 10-200-fold more IL-4 than T cells primed in the presence of anti-IL-4 antibody or sIL-4R. While IL-4 induction was absolutely dependent on IL-4, neither endogenous nor exogenous IL-4 influenced IFN-gamma synthesis. Most importantly, IL-4 induced and sIL-4R abolished priming for IL-4 production even in NiSO4-specific memory T cells from sensitized individuals. Thus, IL-4 induction in antigen-specific human memory T cell populations absolutely required IL-4. The IL-4 pathway of memory T cells retained a remarkable plasticity in sensitized individuals.

Confluent and reticulated papillomatosis is a rare dermatosis of unknown etiology mostly affecting young males and females most common in adolescence. The eruption consists of confluent, flat, brown papules forming a pigmented reticulated pattern. It occurs primarily in the intermammary and epigastric regions but may spread to the axillae. A 27-year-old patient with typical clinical and histologic features of confluent and reticulated papillomatosis responded well to oral minocycline.