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Background During the first waves of the COVID-19 pandemic, many cultural and sporting events were held without spectators or had to be cancelled. Therefore, several containment strategies to provide requirements for safe events were developed and tested. Nonetheless, every second (50.7%) is afraid of becoming infected on an event. We therefore investigated which hygiene and containment measures are perceived to be important from the visitor’s point of view and thus might increase subjective sense of safety. Methods This online study was carried out in November 2020. A total of 1,004 persons, who regularly attended events before the pandemic, took part in the study. The importance of different hygiene and containment measures was evaluated using a 5-point Likert-scale (1 “unimportant” to 5 “extremely important”). Potential statistical differences in socio-demographical aspects (age, gender, net disposable income for leisure activities) and attendance on events were tested with analyses of variance. Results Participants perceived the use of disinfectant (M = 4.10) as the most important element of containment strategies, followed by transparent information on the hygiene strategy (M = 4.00), reduced occupancy (M = 3.98), and optimized ventilation (M = 3.97). Body temperature measurement at the entrance (M = 3.27), a negative SARS-CoV-2 test (M = 3.11), completion of a health questionnaire (M = 3.05), and abandoning breaks and catering (M = 2.98) were considered as less important. Analyses of group differences in socio-demographical aspects found abandoning breaks and catering to be more important to men than to women. This strategy is also more important to people aged 66 and above than to younger age groups (e.g., age 20–40). For women, the use of disinfectant is considerably more important. No other significant differences exist. Conclusion Combining relevant measures appears to be important to provide a safe containment strategy. Measures aimed at positively influencing people’s sense of safety do not fully correspond to researched knowledge of effectiveness. There are also target group-specific differences in the rating of measures, which should be considered while preparing containment strategies. To describe the dynamic development of changes in subjective rating of containment strategies, continuing research is needed.

Water samples from ten German Baltic estuaries were collected in 2012 in order to study the presence of the herbicide glyphosate, its primary metabolite AMPA and their potential transport to the marine environment. For the analyses an LC-MS/MS based analytical method after derivatization with FMOC-Cl was optimized and validated for marine water samples. All investigated estuarine stations were contaminated with AMPA and nine of them also with glyphosate. Concentration ranges observed were 28 to 1690ng/L and 45 to 4156ng/L for glyphosate and AMPA, respectively with strong spatial and temporal fluctuations. Both contaminants were found at inbound sampling sites in the stream Muehlenfliess and concentrations decreased along the salinity gradient to the estuaries of the Baltic Sea. The data obtained in this study clearly depict the transport of glyphosate and AMPA to the Baltic Sea. Hence, detailed fate and risk assessment for both contaminants in marine environments are required.

Neuropeptides and their receptors are present in human skin, and their importance for cutaneous homeostasis and during wound healing is increasingly appreciated. However, there is currently a lack of understanding of the molecular mechanisms by which their signaling modulates keratinocyte function. Here, we show that δ-opioid receptor (DOPr) activation inhibits proliferation of human keratinocytes, resulting in decreased epidermal thickness in an organotypic skin model. DOPr signaling markedly delayed induction of keratin intermediate filament (KRT10) during in vitro differentiation and abolished its induction in the organotypic skin model. This was accompanied by deregulation of involucrin (IVL), loricrin, and filaggrin. Analysis of the transcription factor POU2F3, which is involved in regulation of KRT10, IVL, and profilaggrin expression, revealed a DOPr-mediated extracellular signal-regulated kinase (ERK)-dependent downregulation of this factor. We propose that DOPr signaling specifically activates the ERK 1/2 mitogen-activated protein kinase pathway to regulate keratinocyte functions. Complementing our earlier studies in DOPr-deficient mice, these data suggest that DOPr activation in human keratinocytes profoundly influences epidermal morphogenesis and homeostasis.

Background and Purpose In addition to its analgesic functions, the peripheral opioid receptor system affects skin homeostasis by influencing cell differentiation, migration and adhesion; also, wound healing is altered in δ-opioid receptor knockout mice (DOPr–/–). Hence, we investigated δ-opioid receptor effects on the expression of several proteins of the desmosomal junction complex and on the migratory behaviour of keratinocytes. Experimental Approach Expression levels of desmosomal cadherins in wild-type and DOPr–/– mice, and the morphology of intercellular adhesion in human keratinocytes were analysed by immunofluorescence. To investigate the δ-opioid receptor activation pathway, protein expression was studied using Western blot and its effect on cellular migration determined by in vitro live cell migration recordings from human keratinocytes. Key Results Expression of the desmosomal cadherins, desmogleins 1 and 4, was up-regulated in skin from DOPr–/– mice, and down-regulated in δ-opioid receptor-overexpressing human keratinocytes. The localization of desmoplakin expression was rearranged from linear arrays emanating from cell borders to puncta in cell periphery, resulting in less stable intercellular adhesion. Migration and wound recovery were enhanced in human keratinocyte monolayers overexpressing δ-opioid receptors in vitro. These δ-opioid receptor effects were antagonized by specific PKCα/β inhibition indicating they were mediated through the PKC signalling pathway. Finally, cells overexpressing δ-opioid receptors developed characteristically long but undirected protrusions containing filamentous actin and δ-opioid receptors, indicating an enhanced migratory phenotype. Conclusion and Implications Opioid receptors affect intercellular adhesion and wound healing mechanisms, underlining the importance of a cutaneous neuroendocrine system in wound healing and skin homeostasis. Linked Articles This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2

Im Fruhsommer 2011 wurde Norddeutschland vom bis dato grosten Ausbruch einer Infektion mit EHEC O104:H4 heimgesucht. Im Unterschied zu fruheren EHEC-Ausbruchen betraf die Erkrankung vorwiegend junge Erwachsene und fuhrte in unserem Kollektiv bei 72% unserer 61 hospitalisierten Patienten zu teils schwerwiegenden Komplikationen. Aufgrund der genetischen und klinischen Eigenstandigkeit der Infektion schliesen wir uns dem Vorschlag der von Brzuszkiewicz et al. an, die Erkrankung als EAHEC-Syndrom („Entero-Aggregative-Haemorrhagic Escherichia coli“) zu bezeichnen. Die Wechselhaftigkeit und Vielfalt der Verlaufe zwingt zu einem engmaschigen klinischen Monitoring; wir schlagen den „Altona EAHEC Monitoring Standard“ vor. Einen ungunstigen Einfluss der Gabe von Antibiotika auf den Krankheitsverlauf konnten wir – im Gegensatz zu fruher publizierten Bedenken – nicht beobachten.

The cyclin-dependent kinase inhibitor 2A (CDKN2A) gene on chromosome 9p21 encodes p16 (INK4A), the inhibitor of the CDK4/retinoblastoma (Rb) cell proliferation pathway, as well as p14 (ARF), which controls p53-dependent pathways. Inactivation of p16 has previously been associated with the prognostically unfavourable primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL, LT). In this work, we analysed 22 tumors [nine primary cutaneous follicle centre lymphomas (PCFCL), seven primary cutaneous marginal zone lymphomas (PCMZL) and six PCLBCL, LT] not only for alterations of the p16 gene but also for p14, p53 and Rb by fluorescence in situ hybridization (FISH) and immunohistochemistry. In most PCLBCL, LT (4/6) alterations of CDKN2A (two biallelic deletions, one monoallelic deletion and one trisomy 9) and in addition the highest frequency of deletions of p53 (3/6) and Rb (3/6) were detected. p16 was not expressed but very high levels of phosphorylated Rb, indicating a functional effect of genomic CDKN2A alterations on the protein level in PCLBCL, LT. Regarding the p14/p53 axis, PCLBCL, LT showed a variable expression. Neither PCFCL nor PCMZL showed alterations of CDKN2A and also deletions of p53 or Rb were extremely rare in these subtypes. Exclusively in PCMZL, p53 protein was consistently lacking. In conclusion, only PCLBCL, LT is characterized by a high frequency of aberrations of the CDKN2A network components in both important tumor suppressor pathways regulated by the CDKN2A gene. Moreover, PCLBCL, LT appears to be distinguishable from PCMZL not only by its level of p53 expression but also by its stage of Rb phosphorylation. The latter may also apply to a subgroup of PCFCL.

Background Chronic venous leg ulcers (CVU) cause considerable burden of disease for the patients as well as enormous costs for health care systems. The pathophysiology of CVU is complex and not entirely understood. So far reliable pathogenic and/or prognostic parameters have not been identified. Objectives We studied the role of thrombophilia in patients referred to a University dermatology department for treatment of CVU. Patients and methods A cohort of 310 patients with active chronic venous leg ulcers (CEAP 6) was stratified into two comparably large groups according to the presence or absence of post-thrombotic syndrome (PTS+; PTS−) as determined using duplex scan and/or phlebography. In addition, several thrombophilia parameters were assessed. Results The prevalence of protein S deficiency and factor V Leiden mutation was significantly higher in PTS+ patients compared with the PTS− group. However, patients in both subgroups revealed high prevalences of thrombophilia (antithrombin deficiency, protein C deficiency, protein S deficiency, activated protein C resistance, factor V mutation or elevated homocysteine). Conclusion Based on these data, it is conceivable that thrombophilia contributes to the pathogenesis of CVU, possibly through induction of microcirculatory dysregulations.

Chronic venous leg ulcers are common and cause considerable burden of disease for affected patients with significant costs for health care systems worldwide. The complex pathophysiology of chronic venous leg ulcers is still not entirely understood. In addition, reliable pathogenic and/or prognostic parameters are not known. Published data suggest that patients with chronic venous leg ulcers reveal congenital or acquired thrombophilia. We examined the serum Lipoprotein (a) [Lp(a)] level, a proatherogenic and prothrombotic risk factor, in patients with chronic venous leg ulcers (n=210, stratified into patients with postthrombotic syndrome or without) and in a healthy control group (n=341). Forty-two percent of all patients, compared with 20% of healthy controls, revealed significantly increased Lp(a) serum concentrations above 0.3 g/L. Furthermore, 49% without postthrombotic syndrome but only 35% with postthrombotic syndrome showed increased Lp(a) levels. The increase of Lp(a) level was significantly different between all three groups (p

Background Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare entity characterized by a CD4+/CD56+/CD123+ immunophenotype and a fatal clinical course. The average survival of 12–14 months may be prolonged by allogeneic bone marrow transplantation (BMT). Objectives We report about a male patient who suffered from BPDCN with a typical histology and co-expression of CD4/CD123 and a CD56 expression by 80% of the tumour cells. The cutaneous tumour relapse after chemotherapy and allogeneic BMT was completely negative for CD56. Methods We performed interphase fluorescence in situ hybridization (FISH) analysis of tumour tissue, asserved before and after BMT, using specific probes for chromosome 11, which encompass the CD56 gene region. Results The tumour cells revealed a partial loss of 11q as well as a monosomy of chromosome 11. Conclusion This case demonstrates for the first time that loss of CD56 expression can also occur as a secondary event after chemotherapy and BMT. In our case, DNA loss of 11q23 could be responsible for the negativity of 20% of tumour cells as observed before chemotherapy. However, the complete loss of CD56 expression in the relapsed tumour cannot be explained by the loss of 11q23 alone. Additional factors such as chemotherapy-induced mutations might also have contributed.

The optimal processing for the pathology of sentinel lymph nodes of patients with melanoma is still a matter of debate. We compared two protocols of sentinel lymph node processing, which were consecutively applied. For the first protocol, the sentinel lymph nodes were cut into 1-2 mm thick slices. From each slice, 12 microtome sections were stained (multiple slices protocol). For the second protocol, which is a modification of the recent European Organisation for Research and Treatment of Cancer protocol, the sentinel lymph nodes were bivalved. Five consecutive series of microtome sections, with gaps of 50 microm between them, were prepared from each cut surface (bivalving protocol). H&E and immunohistochemical staining were integral elements of both protocols. A total of 584 sentinel lymph nodes (1.8+/-0.9 per patient) were examined. The percentages of micrometastases (29 versus 27%) and of capsular naevi (13 versus 15%) detected were very similar for both protocols. As shown by multivariate logistic regression, Breslow thickness (P=0.003) and younger age (P=0.01) correlated with nodal metastasis. The type of histological preparation, ulceration and sex were not significant. The multiple slices protocol produced, on average, 4 paraffin blocks and 46 microtome sections per node. The bivalving protocol constantly produced 2 paraffin blocks and 42 microtome sections. For technical processing, the multiple slices protocol required, on average, 38 min per sentinel lymph node, whereas the bivalving protocol required 55 min. Both protocols yielded excellent detection rates with a similar amount of work being required on the part of the pathologist. Compared with the bivalving protocol, the multiple slices protocol was less labor intensive for the technical staff.

We analyzed the value of digital epiluminescence microscopy (DELM) for the long-term follow-up of atypical nevi. Patients (n=530) were prospectively categorized into defined melanoma risk groups and followed by clinical and epiluminescence microscopy (ELM) examinations. Atypical nevi (n=7001) were additionally followed by DELM. During follow-up (median 32.2 months), we detected 53 melanomas among 637 excised lesions (8.3% overall chance of success). The chance of success for melanoma detection among lesions suspicious by ELM criteria was increased to 17% when additional DELM-documented changes were present. Moreover, 18 of the 53 melanomas were exclusively identified by DELM-documented changes, indicating that DELM increased the sensitivity of the ELM analysis by identifying additional melanomas. However, for lesions exclusively excised due to DELM changes, the chance of success was lower than for ELM (5.2 vs 11.8%). Excisions due to mere DELM changes detected 66.7% of melanomas in familial atypical mole and multiple melanoma (FAMMM) and 32.5% of melanomas in atypical mole syndrome (AMS) patients. We conclude that DELM is a valuable tool for the long-term follow-up of atypical nevi, especially in the high-risk groups of FAMMM and AMS patients. Randomized controlled trials are needed to validate the data from this clinical trial.

The variola virus was declared eradicated by the World Health Organization in 1980 but human infections by cowpox virus, another member of the genus Orthopoxvirus, are still observed, mainly in European countries. We report a woman who presented with two umbilicated vesicles surrounded by an indurated erythematous edema within cat scratch injuries on her thigh. The diagnosis of an Orthopoxvirus infection was based on the visualization of characteristic virus particles by electron microscopy and the detection of the A27L gene (14-kd fusion protein gene) of the genus Orthopoxvirus by polymerase chain reaction from a lesional skin biopsy specimen. Differential diagnoses of cat scratch disease, pustula maligna, and bullous impetigo were excluded by microbiologic investigation of the biopsy specimen. Both lesions scarred after 6 weeks of a continuous local antiseptic treatment.

Zusammenfassung Hintergrund: Im Vergleich zur alleinigen Vitalfarbung der Lymphabflusswege bei der Sentinel-Lymphknotendissektion hat die intraoperative Anwendung einer Gamma-Detektionssonde die Identifikationsraten verbessert. In der vorliegenden retrospektiven Studie wird der Einfluss der Gamma-Detektion hinsichtlich weiterer Aspekte ausfuhrlich analysiert. Patienten und Methodik: 81 Patienten, bei denen zur intraoperativen Detektion des Sentinel-Lymphknotens (SLK) ausschlieslich Patentblau zum Einsatz kam, wurden mit 247 Patienten verglichen, bei denen zusatzlich eine Gamma-Sonde verwendet wurde. Ergebnisse: Die Einfuhrung der Gamma-Sonde erbrachte eine Steigerung der SLK-Detektionsrate von 87,7 % auf 99,2 % (P

CXCL8 plays a major role in cell recruitment to sites of inflammation. Apart from neutrophils, little is known, however, about the cellular distribution and regulation of CXCL8 receptors in cells involved in acquired and adaptive immune responses. In previous studies, we have demonstrated the extracellular expression and function of CXCR1/2 on mast cells and also detected an intracellular pool of CXCR1/2. Here, we have addressed the question of receptor regulation during stimulation of human mast cells (HMC-1 cell line) and have studied T cells in comparison. Cell permeabilization was performed to detect both surface and possible intracellular receptor pools. HMC-1 cells stained positive for both receptors on the cell surface (CXCR1, 50%; CXCR2, 51%) and also after cell permeabilization (CXCR1, 86%; CXCR2, 74%). Similarly, T cells exhibited both cell-surface receptor expression (CXCR1, 30%; CXCR2, 23%) and higher total receptor expression (CXCR1, 50%; CXCR2, 36%), although overall values were lower than that in HMC-1 cells. On immunoblot, molecular weights of extra- and intracellular receptors on mast cells were the same, excluding altered receptor glycosylation. On stimulation with phorbol 12-myristate 13-acetate plus calcium ionophore, a time-dependent decrease of surface-membrane receptors was observed in both cell types, while total receptor remained the same, suggesting that receptor shedding is not involved. The kinetics of membrane receptor internalization and replenishment differed for the two cell types. Furthermore, receptor internalization was associated with decreased F-actin polymerization, a basic prerequisite for cell migration. These findings demonstrate for the first time the expression of extra- and intracellular CXCR1/2 receptors on T cells and delineate the dynamics of CXCR1/2 receptors on mast cells and T cells. Furthermore, they suggest a cell-type-specific and finely tuned regulation of chemokine responses at the receptor level in the context of inflammation.

Psoriasis is a chronic inflammatory skin disorder characterized by accumulation of Th1-type T cells and neutrophils, regenerative keratinocyte proliferation and differentiation, and enhanced epidermal production of antimicrobial peptides. The underlying cause is unknown, but there are some similarities with the immunologic defense program against bacteria. Development of psoriasiform skin lesions has been reported after administration of granulocyte colony-stimulating factor (G-CSF), a cytokine induced in monocytes by bacterial antigens. To further investigate the relation between this type of cytokine-induced dermatitis and psoriasis, we analyzed the cutaneous cytokine profile [tumor necrosis factor-alpha (TNF-alpha), interferon-gamma, transforming growth factor-beta1 (TGF-beta1), interleukin-10 (IL-10), IL-12p35 and p40, and IL-8] and expression of markers of epidermal activation [Ki-67, cytokeratin-16, major histocompatibility complex (MHC) class II, intercellular adhesion molecule-1 (ICAM-1)] in a patient who developed G-CSF-induced psoriasiform dermatitis by using quantitative real-time reverse transcriptase-polymerase chain reaction and immunohistology. The histologic picture resembled psoriasis with regard to epidermal hyperparakeratosis and the accumulation of lymphocytes in the upper corium. CD8(+) T cells were found to infiltrate the epidermis which was associated with an aberrant expression of Ki-67, cytokeratin-16, MHC class II, and ICAM-1 on adjacent keratinocytes. As compared to normal skin (n = 7), there was an increased expression of TNF-alpha, IL-12p40, and IL-8, a decreased expression of TGF-beta1, and a lack of IL-10, similar to the findings in active psoriasis (n = 8). Therefore, G-CSF may cause a lymphocytic dermatitis that, similar to psoriasis, is characterized by a pro-inflammatory Th1-type cytokine milieu and an epidermal phenotype indicative of aberrant maturation and acquisition of non-professional immune functions.

Background There is evidence that IL-16, a cytokine that induces chemotactic responses in CD4 + T cells, eosinophils, and dendritic cells, plays an important role during different types of cutaneous inflammatory responses, including allergic contact dermatitis (ACD) and atopic dermatitis (AD). Objectives We sought to test for association between a promoter polymorphism in the IL16 gene (T to C transition at position –295) and ACD and AD, respectively. Methods IL16 –295 genotypes were determined in samples from 2 separate case-control studies with white individuals. The first study included healthy individuals (n = 310) and patients with ACD (n = 86). These patients were polysensitized as defined by a contact sensitization to para-substituted aryl compounds and at least one other structurally unrelated allergen. The second study comprised healthy subjects (n = 214) and patients with AD (n = 94). Results IL16 –295 genotypes were differently distributed among polysensitized and healthy control subjects ( P = .0021). In particular, the IL16 –295∗C/C genotype was overrepresented among polysensitized individuals (7.0% vs 1.0% in the control group; odds ratio, 7.68; 95% CI, 1.59-48.12). In contrast, there was no evidence for an association between the IL16 –295 polymorphism and AD. Conclusion The IL16 –295 promoter polymorphism might influence susceptibility to contact allergy.

SummaryBackground Atopic dermatitis (AD) and psoriasis are genetically determined inflammatory skin disorders characterized by abnormal cytokine production. From association studies there is evidence that functionally relevant cytokine gene polymorphisms contribute to the genetic basis of psoriasis. Association studies in AD have mostly been limited to polymorphisms of T-helper 2-type cytokines, which dominate in acute AD lesions. Unexpectedly, the results of recent genome scans indicate linkage of AD to psoriasis susceptibility loci. Therefore, AD may also be influenced by genes that modulate cutaneous inflammation independently from atopic mechanisms. Objectives To investigate further the role of cytokine gene polymorphisms in AD. Methods Polymorphisms in the genes encoding tumour necrosis factor-α (TNFA−238 G/A, −308 G/A), interleukin (IL)-1β (IL1B−511 T/C, +3953 T/C), IL-6 (IL6−174 C/G), IL-10 (IL10−1082 A/G) and the IL-1 receptor antagonist (IL1RN intron 2) were investigated in German patients with AD (n = 94) and in healthy nonatopic individuals (n = 214) by polymerase chain reaction-based methods and direct cycle sequencing. Results No association was found between AD and any of the polymorphisms analysed. This is in contrast to the recently described association between psoriasis and the TNFA−238 and IL1B−511 polymorphisms. Conclusions Our data indicate that cytokine gene polymorphisms may act as specific markers of inflammatory skin diseases rather than contribute to a general disposition towards cutaneous inflammation.

Malignant melanoma has been shown to be susceptible to T cell-mediated immunity and, therefore, is a candidate for vaccination approaches. Clinical trials using dendritic cells (DC) loaded with peptides corresponding to tumor antigens are ongoing in several institutions, and some promising results have already been published. However, every single peptide-based vaccine can only be used in a patient with a given single HLA type, and this strategy is not appropriate for patients with rare HLA types or with tumors without defined antigens. A clinical pilot study in patients with disseminated melanoma refractory to standard therapy was initiated using a different approach. The authors generated autologous monocyte-derived DC and fused these DC with gamma-irradiated primary autologous tumor cells by incubation in polyethylene glycol. In previous experiments, the authors had shown that these fused cell products are potent inducers of a T-cell response in a mixed lymphocyte tumor cell culture. Seventeen patients were immunized with the cell product by s.c. injection in monthly intervals without any serious side effects. Of these patients, one had a partial response with decrease in size of all evaluable tumor manifestations. In one patient, some of the metastases were regressing despite an overall progressive disease, and one patient achieved disease stabilization for six months. In the responding patient, in parallel to tumor regression, circumscript hair depigmentation occurred. These data show, that a hybrid vaccine of DC and tumor cells can be safely applied and can induce tumor regressions, however, the clinical efficacy of the approach in its present form is insufficient.

2-Biphenylamine reacts with (dimethylamino)trimethylstannane in a 2:1 molar ratio, undergoing transamination to the distannylamine 1a. The extremely air and moisture sensitive (2-biphenyl)-N,N-dilithium amide 2a is obtained by the stannazane cleavage reaction of 1a with nBuLi in MeOtBu. Compound 2a is the first example of a highly reactive, doubly metallated amine that can be used as a precursor in inorganic synthesis under fairly mild conditions. For example, both lithium atoms can be substituted by boryl or silyl groups, which cannot be introduced using other routes. Amide 2a crystallizes as a cluster containing five RNLi2 units, and is unexpectedly stabilized by two methanide anions. When the methanide ions are included, the lattice of the central C2N4Li8 unit represents a section of the antiisomorphic lattice of the CaF2-type. DFT (B3LYP) calculations and population analysis (NBO) have been carried out to get further insights into the thermodynamics of several dilithioamines (RNLi2)n (R = H, CH3, Ph; n = 1−6). (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

The psoriatic inflammatory process is characterized by an overexpression of pro-inflammatory cytokines such as tumor necrosis factor-alpha and interleukin-1beta compared with a relative deficiency of anti-inflammatory factors such as interleukin-10 and the interleukin-1 receptor antagonist (interleukin-1Ra). Gene polymorphisms that affect cytokine production may contribute to the disease-associated cytokine imbalance and influence susceptibility to psoriasis. Here, we investigated the relationship between polymorphisms in the genes encoding for tumor necrosis factor-alpha (G-238A, G-308A), interleukin-1beta (C-511T, T+3953C), and interleukin-1Ra (intron 2), and cytokine production in peripheral blood mononuclear cells of healthy donors, and analyzed the distribution of these polymorphisms in patients with psoriasis vulgaris (n = 231) and healthy controls (n = 345). Carriage of tumor necrosis factor A-238 allele 2 (-238*A) was associated with increased production of tumor necrosis factor-alpha in response to lipopolysaccharide in vitro, and with early onset disease (40 y), especially in male patients with psoriasis [32% vs 7% in male controls; odds ratio = 6.78, 95% confidence interval = (3.18-15.15), p(adjusted) = 2 x 10(-7)]. Carriage of the interleukin-1B-511*1 (-511*C) homozygous genotype was associated with increased production of interleukin-1Ra in response to lipopolysaccharide and interleukin-10, and with late onset psoriasis [or = 40 y; 61% vs 44% in controls; odds ratio = 2.04, 95% confidence interval = (1.19-3.53), p(adjusted) = 0.0419]. These findings indicate that gene polymorphisms associated with altered cytokine responses in vitro may modify age of onset of psoriasis. They also provide further evidence that patients with early and late onset psoriasis differ in their genetic background.

Preferential uptake and presentation of IgE-bound allergens by epidermal Langerhans cells (LC) via the high affinity IgE receptor, FcεRI, is regarded as an important mechanism in the induction of cutaneous inflammation in atopic dermatitis. Here, we show that activation of monocyte-derived LC-like dendritic cells (LLDC) through engagement of FcεRI induces the expression of IL-16, a chemoattractant factor for dendritic cells, CD4+ T cells, and eosinophils. We found that ligation of FcεRI on LLDC derived from atopic dermatitis patients that express high levels of FcεRI increases IL-16 mRNA expression and storage of intracellular IL-16 protein and enhances the secretion of mature IL-16 in a biphasic manner. An early release of IL-16 (peak at 4 h) is independent of protein synthesis, while a more delayed release (peak at 12 h) requires protein synthesis and occurs subsequent to the induction of IL-16 mRNA and intracellular accumulation of pro-IL-16. There was evidence that LLDC use caspase-1 to process IL-16, as inhibition of caspase-1, but not of caspase-3, partially prevented the release of IL-16 in response to ligation of FcεRI. In an in vivo model of IgE-dependent LC activation, the atopy patch test, positive skin reactions were also associated with the induction of IL-16 in epidermal dendritic cells. These data indicate that IL-16 released from LC after allergen-mediated activation through FcεRI may link IgE-driven and cellular inflammatory responses in diseases such as atopic dermatitis.

Wegener's granulomatosis is a rare disease classically characterized by a necrotizing and granulomatous inflammation of the upper and lower respiratory tract, necrotizing glomerulonephritis and systemic vasculitis of small and medium sized vessels. Cutaneous manifestations are observed in 20-50% of cases often resembling pyoderma. We report here on a 72 years old female patient in whom the cutaneous symptom of a histological confirmed leukocytoclastic vasculitis led to the diagnosis of Wegener's granulomatosis. She had also developed the characteristic symptom of a saddle nose and suffered from relapsing keratitis. Clinical symptoms, diagnostic procedure and therapeutic options are discussed.

Although smallpox was eradicated 20 years ago, other members of the genus Orthopoxvirus (OPV), such as cowpox virus (CPXV) or monkeypox virus, are still a threat to humans. Because human CPXV infection is rare, it is seldom suspected on clinical grounds only. We report a boy who presented with two necrotic ulcers with surrounding erythema. Infection with OPV was suspected, as antibiotic treatment had not produced improvement and smears were negative for anthrax. An OPV was isolated and an OPV-specific polymerase chain reaction combined with a subsequent restriction enzyme fragment length polymorphism assay confirmed infection by CPXV. Although the patient's cat had had no skin lesions, OPV-specific antibodies were found at a titre of 1 : 8 in a plaque reduction assay, suggesting that the cat had transmitted the virus to the boy.

The present study addresses the question whether an extended ilioinguinal dissection as compared to an only superficial inguinal dissection improves survival and/or local tumour control after the appearance of palpable melanoma metastases to the groin. We retrospectively analysed the data of 104 patients with 69 ilioinguinal and 35 superficial inguinal dissections (median follow up 127 months). Prognostic factors of survival and groin recurrence were assessed using Kaplan-Meier estimation and Cox proportional hazards model. By multifactorial analysis, metastatic involvement of two lymph nodes or less was associated with a significantly better survival rate than involvement of > 2 or pelvic nodes (p = 0.0002). After radical ilioinguinal dissection, patients with extremity-located primaries had a better prognosis than patients with truncal primaries (p = 0.03). Tumour infiltration of the ilio-obturator compartment was found to be an independent factor of poor prognosis (p = 0.0009). The probability of recurrence in the dissected groin paralleled the number of positive nodes and significantly increased if intransits were observed (p = 0.0002). The extent of surgery, Breslow thickness, epidermal ulceration, sex, age and adjuvant chemotherapy neither significantly influenced survival nor local control rates. In summary, when metastatic inguinal nodes become palpable, the presence of pelvic metastases indicates systemic disease. After therapeutic groin dissection, local recurrence and survival depend rather on regional tumour burden than on the extent of surgery.

Wir berichten uber ein Madchen mit auffallend vielen grosknotigen kongenitalen Xanthogranulomen. Die eineiige Zwillingsschwester war erscheinungsfrei. Die bis zu 1,5 cm grosen, halbkugeligen am Kopf und der oberen Korperhalfte lokalisierten Tumoren waren bei Geburt vorhanden und bestanden aus CD68+ histiozytaren Non-Langerhanszellen. In einem Nachbeobachtungszeitraum von 18 Monaten traten keine neuen Tumoren auf, die bestehenden Tumoren zeigten Regression. Extrakutane Manifestationen bestanden nicht. Die differentialdiagnostische Abgrenzung vor allem gegenuber Langerhanszell-Histiozytosen ist unerlaslich zur richtigen Einschatzung der Prognose.

Sensitization to arylamines such as p-phenylenediamine is frequently diagnosed in patients with allergic contact dermatitis. Reactive metabolites of p-phenylenediamine might be produced in the skin by O-acetylation of N-hydroxylamines catalysed by local N-acetyltransferases (NATs). In this study, we tested whether genetic polymorphisms of NATs, which are known to affect enzyme activity, may influence the susceptibility to para-substituted arylamine-induced contact eczema. Using polymerase chain reaction and restriction enzyme analysis, the distribution of polymorphisms of NAT1 and NAT2 was investigated in 88 patients sensitized to para-substituted aryl compounds and 123 healthy controls. NAT2 rapid acetylators, i.e. carriers of the NAT2*4 wild-type allele, were more common in the contact allergy (44%) than in the healthy control group [30%; P = 0·042, odds ratio 1·9 (95% confidence interval, CI 1·05–3·27)]. Slow acetylators carrying the NAT2*5b/2*6a genotype were significantly less frequent among patients [13% vs. 38% in controls; P = 0·009, odds ratio 0·39 (95% CI 0·19–0·78)]. The carriage rate of the NAT1*10 allele, which is supposed to encode for a rapid NAT1 phenotype, was not significantly different between patients and controls [43% vs. 36%; odds ratio 1·5 (95% CI 0·88–2·68)]. Interactions between NAT2*4 and NAT1*10 were suggested by the increased frequency of the NAT2*4/NAT1*10 haplotype in patients (27%) compared with controls [15%; P = 0·039, odds ratio 2·1 (95% CI 1·04–4·04)]. As the NAT1 and NAT2 encoding genes are located in close proximity on chromosome 8p22, the latter finding could at least partly be due to genetic linkage. In fact, a linkage disequilibrium between NAT2*4 and NAT1*10 was observed in the contact allergy (P = 0·0025) and in the control group (P = 0·042). Our data indicate an association between the NAT2*4/NAT1*10 haplotype and contact sensitization to para-substituted aryl compounds. Therefore, acetylation may either enhance contact sensitization or NAT2*4 and NAT1*10 might be linked to an unknown susceptibility factor.

Paraneoplastic pemphigus (PP) is an autoimmune disease, which is frequently associated with non-Hodgkin's lymphoma. Autoantibodies against components of the cytoplasmic plaque of epithelial desmosomes are usually present in the sera and are believed to play a major pathogenic part in acantholysis and suprabasal epidermal blistering. However, another typical histological feature of PP, interface dermatitis with keratinocyte dyskeratosis, is shared with skin diseases that involve epithelial damage mediated by T cells. Here, we present the detailed characterization of the cutaneous T-cell response in a patient with PP and demonstrate a selective epidermal accumulation of activated CD8+ T cells together with an increased local production of interferon-gamma and tumour necrosis factor-alpha, and a strong expression of HLA-DR and ICAM-1 on keratinocytes. Apoptosis was identified as a key mechanism of keratinocyte death, and appeared independent of the FAS/FAS ligand (FAS-L) pathway, as epidermal expression of FAS was not increased compared with normal skin, and FAS-L was undetectable on the protein and mRNA level. Triple therapy with high-dose corticosteroids, cyclophosphamide and intravenous immunoglobulins reduced levels of pemphigus-like autoantibodies and reversed the cutaneous inflammatory reaction leading to long-standing clinical remission. Our findings support the concept of a major contribution of cytotoxic T lymphocytes to the immunopathology of paraneoplastic pemphigus.

The recombinant form of the extracellular domain of the IL-4 receptor (sIL-4R) is a potential candidate to neutralize IL-4; however, murine sIL-4R displayed both antagonistic and agonistic activity in vivo. Here we show that human recombinant sIL-4R induced the formation of complexed IL-4 in supernatants of activated T cells in a dose-dependent manner as measured by newly developed enzyme-linked immunosorbent assays. These IL-4/sIL-4R complexes liberated free IL-4 even after prolonged culturing. In contrast, in the absence of exogenously added sIL-4R, free IL-4 was rapidly consumed or proteolytically degraded in cultures of activated T cells. Thus, no IL-4 bioactivity could be determined in supernatants of T cells activated in the presence of IL-4 for 6 days. In contrast, the same cultures carried out in the presence of sIL-4R showed marked IL-4 bioactivity. While low concentrations of sIL-4R enhanced IL-4-driven inhibiton of IFN-gamma production by activated T cells, higher concentrations neutralized IL-4. Together, human sIL-4R, besides its activity as an antagonist to IL-4, also possesses protective and agonistic functions for IL-4, which may be relevant for clinical studies aiming to neutralize IL-4 in vivo.

Erosive mucosal lichen planus is a painful and disabling inflammatory skin disease that is highly resistant to topical treatment. We report on six patients with severe recalcitrant erosive mucosal lichen planus who benefited from topical application of tacrolimus ointment. After 4 weeks of treatment, complete resolution was observed in three cases, and substantial improvement was achieved in the other three patients. In these cases, prolonged treatment resulted either in further improvement or in complete healing. All patients reported rapid relief from pain and burning. No severe side-effects were observed.

Background: Soluble interleukin 4 receptors (sIL–4R) are present in biological fluids. In contrast to mice, in man no distinct mRNA coding for sIL–4R has been described, suggesting that human sIL–4R is exclusively produced by proteolytic cleavage of the cell surface receptor. It is not known whether human sIL–4R is actively produced during an immune response. Methods: Human purified T cells, CD4+, CD8+, CD45RA+ and CD45R0+ T cell subpopulations were activated in vitro. sIL–4R was determined in the supernatants, cell surface IL–4R was measured by flow cytometry and RT–PCR. Results: Recombinant sIL–4R inhibited IL–4–mediated proliferation and IL–5 upregulation by T cells. sIL–4R could be detected at low levels in supernatants of nonactivated T cells, but at high levels following TCR engagement. This response was paralleled by enhanced transcription and de novo synthesis of the human cell surface IL–4R. Both, activated naive CD45RA+ and memory CD45R0+ T cells, produced sIL–4R with long–lasting kinetics. IL–4 increased sIL–4R production by activated CD45RA+, but there was less of an increase by CD45R0+ T cells. In addition, interferon–γ enhanced sIL–4R production. Cycloheximide and dexamethasone inhibited sIL–4R production by activated T cells, but did not abolish constitutive release of sIL–4R. Phosphoramidon and 1,10–phenanthroline dose–dependently inhibited shedding of the IL–4R, even in nonactivated T cells. Conclusion: The production of human sIL–4R by T cells is regulated by TCR stimuli, IL–4 and IFN–γ and needs the activity of metalloproteinases. Thus, sIL–4R should be regarded as inducible and due to its IL–4–antagonizing activity an immunoregulatory molecule.

Epidermal cytokines such as interleukin (IL)-1β, tumor necrosis factor-α, and IL-12 have been described to play a crucial role in the induction and elicitation phase of allergic contact dermatitis upon exposure to haptens. In this study we asked whether these cytokines may also play a role in the epidermis of patients with atopic dermatitis after the application of house dust mite antigens (HDM) to their skin. Epidermal samples were collected by scraping healthy appearing skin of atopic patients and healthy individuals 8 h after the application of an extract of HDM. Sodium lauryl sulfate and saline served as controls. Reverse transcriptase-polymerase chain reaction was performed for IL-1β, tumor necrosis factor-α, IL-12 p35, and IL-12 p40. Exposure to HDM led to a significant upregulation of mRNA of these cytokines in atopic patients only. Whereas IL-1β and tumor necrosis factor-α also showed an upregulation in part of these patients after exposure to the irritant sodium lauryl sulfate, IL-12 p40 mRNA was exclusively enhanced by the application of the allergen. In contrast to IL-12 p40, IL-12 p35 mRNA was not detectable in significant amounts. Interestingly, also in untreated, normal appearing skin of atopic individuals (n = 16), the levels of these cytokines were higher than in normal individuals (n = 8), possibly explaining the increased skin irritability of atopic individuals. Finally, comparing epidermal cytokines in the skin of patients who developed a positive allergen patch test to those who stayed negative, suggests that only expression of IL-1β mRNA may be a predictive marker for the development of a positive patch test reaction to HDM.

Wir berichten uber Mutter und Sohn mit Erythrokeratodermia progressiva symmetrica Darier-Gottron. Beide Patienten entwickelten im Alter von 6 Monaten symmetrische erythematosquamose Plaques an den Extremitaten und im Gesicht. Beim Sohn kam es mit 2 1/2 Jahren zu einer raschen Ausbreitung mit Befall des gesamten Integuments. Die Mutter berichtet uber einen ahnlichen Verlauf, jedoch mit spontaner Regression ab dem 10. Lebensjahr. Die Klinik dieses generalisierten Zustandes war identisch mit dem Befund einer kongenitalen lamellaren Ichthyose. Lichtmikroskopisch ergaben sich unspezifische Veranderungen mit Orthohyperkeratose, fokalen Parakeratosearealen und Akanthose. Elektronenmikroskopisch fanden sich im Stratum granulosum eine hohe Keratinosomenanzahl, Keratinosomenlamellen in den Interzellularraumen und teils vermehrtes Keratohyalin mit Verklumpung. Weiterhin waren kurze Tonofilamentbundel mit Verklumpungen im Stratum spinosum auffallig. Systemische Retinoide brachten dem Sohn eine mehrere Monate anhaltende Befundbesserung. Die Mutter berichtet uber ahnlich gute Erfolge unter einer Retinoidintervalltherapie. Die Beobachtung zeigt die Schwierigkeit, die Erythrokeratodermia progressiva symmetrica als eigentlich lokalisierte Verhornungsstorung bei jedoch zwischenzeitlich ausgedehntem, generalisiertem Zustand mit den derzeitig zur Verfugung stehenden klinischen und ultrastrukturellen Kriterien zuverlassig von anderen Verhornungsstorungen abzugrenzen.

Glomustumoren (Glomangiome) sind gutartige, von den Glomuszellen ausgehende Tumoren. Multiple Glomangiome sind seltener und weniger schmerzhaft als die meist subungual lokalisierten, solitaren Glomangiome. Sie konnen aber bei Druckeinwirkung und Temperaturwechsel Beschwerden bereiten. Wegen ihrer Vielzahl stellen die multiplen Glomangiome ein therapeutisches Problem dar. Die Sklerosierung bietet eine therapeutische Alternative bzw. Erganzung zur operativen Entfernung oder zu kryochirurgischen Verfahren. Wir berichten uber die Sklerosierungstherapie bei einer 35jahrigen Patientin mit multiplen familiaren Glomangiomen.