[Giant papillomas of the tongue and pharynx in focal dermal hypoplasia: a case report]. / Riesenpapillome der Zunge und des Rachens bei fokal dermaler Hypoplasie: Ein Fallbericht.

Focal dermal hypoplasia is a rare congenital syndrome with dominant X-linked mode of inheritance characterized by a wide range of meso-ectodermal anomalies. The clinical variation is great, as explained by the Lyon hypothesis and mosaicism. Findings include skin atrophy along the lines of Blaschko and papillomas. Our case is striking with rapidly-growing giant pharyngeal papillomas which caused dysphagia and required resection.

Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study.

PURPOSE: To compare fotemustine and dacarbazine (DTIC) in terms of overall response rate (ORR) as primary end-point and overall survival, duration of responses, time to progression, time to occurrence of brain metastases (BM), and to assess safety and quality of life in patients with disseminated cutaneous melanoma. PATIENTS AND METHODS: Patients received either intravenous fotemustine 100 mg/m2 weekly for 3 weeks or DTIC 250 mg/m2/d for 5 consecutive days every 4 weeks (two cycles). Nonprogressive patients received a maintenance treatment every 4 weeks (fotemustine 100 mg/m2 or DTIC 250 mg/m2 for 5 days). RESULTS: Two hundred twenty-nine patients were randomly assigned to fotemustine or DTIC arms. The best ORR was higher in the fotemustine arm than in the DTIC arm in the intent-to-treat population (n=229; 15.2% v 6.8%; P=.043) and in full analysis set (n=221) (15.5% v 7.2%; P=.053). Similar median durations of responses (5.8 months with fotemustine v 6.9 months with DTIC) and time to progression (1.8 v 1.9 months, respectively) were observed. In patients without BM at inclusion, the median time to BM was 22.7 months with fotemustine versus 7.2 months with DTIC (P=.059). Median survival was 7.3 months with fotemustine versus 5.6 months with DTIC (P=.067). The main toxicity was grade 3 to 4 neutropenia (51% with fotemustine v 5% with DTIC) and thrombocytopenia (43% v 6%, respectively). No significant difference was noted for quality of life between arms. CONCLUSION: ORR was higher in the fotemustine arm compared to the DTIC arm in first-line treatment of disseminated melanoma. A trend in favor of fotemustine in terms of overall survival and time to BM was evidenced.

Treosulfan is an effective alkylating cytostatic for malignant melanoma in vitro and in vivo.

The therapy of metastatic malignant melanoma is limited by poor responses and short overall survival. Thus it remains an important issue to identify and test potential new drugs in this disease. This study was performed to examine the effects of the bifunctional alkylating cytostatic treosulfan in vitro. Using an in vitro microplate ATP bioluminescence tumour chemosensitivity assay (ATP-TCA) five highly chemoresistant melanoma cell lines and melanoma cells freshly isolated from metastases surgically resected from stage IV melanoma patients (n = 10) were incubated with treosulfan. Three cell lines and eight of the 10 tested tumour cells isolated from melanoma metasteses showed tumour growth inhibition >50% after incubation with treosulfan. Therefore, 14 patients with rapidly progressing stage IV malignant melanoma who had been pretreated with at least one standard chemotherapy regimen received treosulfan. In this population of patients with highly refractory advanced melanoma, one complete remission (7.1%), two partial remissions (14.3%) and three cases of stable disease (21.4%) were observed. The median survival time for all the patients measured from the beginning of treosulfan treatment was 9 months, and the median overall survival was 17 months. Except for two patients who developed grade 3 leucopenia, only moderate side effects were observed. Therefore, we conclude that treosulfan was well tolerated in this small series of patients and seems to be a promising alkylating cytostatic for the treatment of metastatic melanoma. Further studies are warranted to test these findings.

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

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

Effects of whole-body UVB irradiation on cytokine production by peripheral blood mononuclear cells from stage I melanoma patients.

Ultraviolet (UV) radiation causes significant impairment of immunological function in human skin. The immunosuppressive effects of UV radiation are thought to be due to local release of cytokines by human keratinocytes, leading to impaired function of epidermal antigen-presenting cells (APC) and failure to induce cutaneous delayed-type hypersensitivity (DTH) reactions. Recent studies have shown that individuals susceptible to UV-induced suppression of DTH may be more prone to develop skin cancer including malignant melanoma (MM). Since the causal relationship between UV radiation and the induction of MM still seems obscure, we investigated the immunological reactions of peripheral blood mononuclear cells (PBMC) to whole-body irradiation with UVB in 15 stage I melanoma patients as compared to PBMC from normal volunteers matched for age, gender and skin type. Whole-body irradiation was performed with 0.8 minimal erythema dosages on five consecutive days. Peripheral blood was obtained before and after the procedure. Overall, there were no major effects of UVB irradiation on peripheral lymphocyte subsets and proliferation of PBMC from patients or normal controls, but UVB irradiation led to a significant increase in PWM-stimulated production of IL-6, IL-2R and TNF by PBMC. These changes were independent of the individual UVB dosages administered and appeared in both groups similarly. UVB irradiation did not lead to significant changes on IL-1 and IL-2 expression by PBMC. Our results suggest that PBMC participate in the cytokine response to UV, even in the absence of inflammatory reactions, but that this participation is not specific to MM patients.

Indoor air pollution by lindane and DDT indicated by head hair samples of children.

The use of the pesticides DDT and lindane as wood preservatives causes indoor air contamination and subsequently exposure of the occupants of these rooms. As hair acts as a passive sampler for air contaminants, we tested pesticide concentrations in hair measured by the GC/MS technique. A comparison of the DDT and lindane concentrations in hair samples of 193 pre-school children from a rural area around Rostock with information concerning their home environments showed that this is a suitable method for screening purposes.

Autoantibodies against CD28 are associated with atopic diseases.

The B7-1/B7-2-CD28/CTLA-4 pathway is crucial in regulating T cell activation and tolerance. Autoantibodies to surface molecules on lymphocytes have already been described in various immune conditions, such as autoimmune diseases, infections and blood transfusions. The objective of this study was to test sera from healthy individuals and from patients for association of CD28 autoantibodies with inflammatory and non-inflammatory diseases. First, CD28 was obtained by digestion of CD28-Ig fusion protein with trypsin. The cleavage products were separated by sodium dodecyl sulphate-page gel electrophoresis. Additionally, a CD28/GST fusion protein was expressed in Escherichia coli and was used to establish an enzyme-linked immunosorbent assay for detection of autoantibodies against CD28. Sera from healthy individuals (n = 72) and patients with different inflammatory and non-inflammatory skin diseases (n = 196) were tested for the presence of autoantibodies against CD28. Using mixed lymphocyte reaction (MLR), purified autoantibodies against CD28 were tested for their effects on CTLA-4-Ig-induced T cell anergy. In this study, for the first time, we describe the existence of autoantibodies against CD28 in humans which are associated with atopic diseases, e.g. allergic rhinitis and asthma. These antibodies stimulate T cells and overcome the CTLA-4-Ig-induced anergy of T cells in an MLR. The existence of autoantibodies against CD28, which may have a T cell-stimulating function, has been shown. The data indicate that autoantibodies against CD28 could be a new immunological mechanism in allergic inflammation. Additionally, autoantibodies against CD28 could be an important new marker to discriminate between atopic diseases and other inflammatory skin diseases.

Age-associated decrease of CD1d protein production in normal human skin.

BACKGROUND: CD1d belongs to a family of antigen-presenting molecules structurally related to the classical major histocompatibility complex class I proteins. OBJECTIVES: To examine the expression pattern of CD1d protein in normal human skin with ageing. METHODS: Twenty normal human skin biopsy specimens were obtained from 20 healthy individuals. The latter were divided into three age groups: children (5-20 years), adults (21-50 years) and the elderly (51-81 years). The intensity of CD1d protein production was examined in human skin using immunofluorescent and immunoalkalinephosphatase staining methods. RESULTS: In the epidermis, CD1d protein production was strong in the skin of the children and declined gradually with age, being moderate in adults and weak in the elderly. As compared with values in children, there was a statistically significant decrease (P<0.05) in CD1d protein production in the elderly. In the dermis, CD1d protein production was strong in the fibroblasts, sweat glands, sebaceous glands, blood vessels and hair follicles regardless of age. CONCLUSIONS: Our study reports a decreased CD1d protein production in normal human skin with ageing. The clinical ramifications of these observations mandate further investigations.

Comparison of standard phenotypic assays with a PCR method to discriminate Candida albicans and C. dubliniensis.

In 1995, Candida dubliniensis was described as a new species in the genus Candida. Its close relationship to C. albicans has proved problematic in the identification of C. dubliniensis in clinical specimens. The objective of this study was to determine if reproducible differentiation between both species can be obtained by phenotypic assays. Therefore, 100 strains from 86 patients with the ability to produce chlamydospores were examined with different methods including API ID 32 C, colour development on CHROMagar, chlamydospore formation on Staib agar, growth at different temperatures and germ tube formation at 39 degrees C. Additionally, polymerase chain reaction (PCR) was used as gold standard. Six of the investigated strains were C. dubliniensis. The results suggest that there is still no single phenotypic method satisfactory to distinguish between C. albicans and C. dubliniensis.

Effects of Staphylococcus aureus cell wall products (teichoic acid, peptidoglycan) and enterotoxin B on immunoglobulin (IgE, IgA, IgG) synthesis and CD23 expression in patients with atopic dermatitis.

The influence of staphylococcal cell wall products (teichoic acid, peptidoglycan) and enterotoxin B on peripheral blood lymphocytes (PBL) from patients with atopic dermatitis (AD) was investigated. The parameters studied were spontaneous and interleukin-inducible immunoglobulin (IgA, IgE, IgG) synthesis and CD23 expression. PBL from non-atopic donors served as controls. Teichoic acid and peptidoglycan induced an enhanced synthesis of IgA and IgG in normal donors. However, IgA and IgG synthesis in PBL from patients with AD was significantly suppressed by teichoic acid and enterotoxin B. The incubation of PBL from normal donors with enterotoxin B and interleukin-4 (IL-4) or IL-5 led to a significant suppression of IgA and IgG synthesis. Co-stimulation of PBL with teichoic acid or peptidoglycan and IL-4 led to a pronounced increase in IgE synthesis and CD23 expression in patients with AD. Our data indicate that cell wall products and toxins of staphylococci modulate the cytokine-dependent humoral immunity in patients with AD and may be responsible for allergic skin reactions in AD.

Staphylococcus aureus enterotoxins induce histamine and leukotriene release in patients with atopic eczema.

BACKGROUND: Chronic skin colonization with Staphylococcus aureus is a characteristic feature of atopic eczema (AE), and about 60% of S. aureus strains isolated from the skin of patients with AE secrete enterotoxins. Furthermore, IgE antibodies to S. aureus enterotoxins have been identified in 78% of patients with AE. OBJECTIVES: To examine the S. aureus enterotoxin-induced histamine and leukotriene release of basophils from patients with AE. METHODS: Peripheral blood basophils from patients with AE were stimulated with the staphylococcal enterotoxins A, B, D, E and toxic shock syndrome toxin-1. Additionally, priming experiments were performed with interleukin (IL)-3, IL-8 and granulocyte/macrophage colony-stimulating factor followed by stimulation with S. aureus enterotoxins. RESULTS: In patients with AE, basophils secreted significantly higher amounts of histamine and leukotriene C4 (LTC4) than in healthy controls. The priming experiments showed additional histamine and LTC4 release in the group of AE patients. CONCLUSIONS: Histamine and leukotriene generation from atopic basophils stimulated with staphylococcal enterotoxins may indicate a role for these toxins as possible allergens in at least a subgroup of patients with AE.

Atopic eczema: role of microorganisms on the skin surface.

The pathophysiology of atopic eczema (AE) is still poorly understood. One possible concept favors IgE-mediated reactivity towards allergens that enter the skin from the outside or through the blood. Microorganisms of the cutaneous flora also might represent a stimulus for allergic skin reactions. Abnormal bacterial skin colonization is a characteristic feature of AE. Staphylococcus aureus (S. aureus) is the most common pathogen. Binding to host cells involves special receptors, such as fibronectin or laminin. Specific IgE antibodies to S. aureus can be detected in the blood. Whereas the clinical relevance of anti-staphylococcal antibodies is still controversial, specific IgE antibodies to Pityrosporum species as well as positive type I prick test reactions to these yeasts seem to correlate with the intensity of eczematous lesions in the head and neck regions of patients with AE. Both antimicrobial and antifungal treatment has been shown helpful in some cases of AE.

Staphylococcal enterotoxin B affects in vitro IgE synthesis, interferon-gamma, interleukin-4 and interleukin-5 production in atopic eczema.

Peripheral blood mononuclear cells from patients with atopic eczema (AE) stimulated with the 'superantigen' Staphylococcus enterotoxin B (SEB) secreted significantly more interleukin (IL)-4 and IL-5 as well as IgE, and markedly less interferon-gamma than those from healthy controls. Our results support the assumption that SEB produced by S. aureus colonizing the skin of patients with AE may induce expansion of IL-4- and IL-5-producing Th2 clones, leading to increased IgE synthesis and eosinophil activation.

Decreased monocyte interleukin-1 beta production in atopic eczema.

It has been suggested that in atopic eczema (AE) a reduced lymphocyte response to T-cell mitogens in vitro is secondary to altered production of cytokines or inflammatory mediators. We investigated, in parallel, the mitogen-induced T-cell proliferation, monocyte interleukin-1 beta (IL-1 beta) production, and prostaglandin E2 (PGE2) production of monocytes and of peripheral blood mononuclear cells (PBMC) in AE patients and non-atopic controls. After stimulation with concanavalin A (Con A) PBMC of AE patients showed a significantly reduced proliferative response compared with the controls. The monocyte production of IL-1 beta after stimulation with lipopolysaccharide (LPS) was significantly decreased in AE. No differences between AE patients and controls were observed with regard to the PGE2 production of PBMC after stimulation with Con A or the monocyte release of PGE2 after LPS stimulation. Because IL-1 plays a central role in the activation of T-cell proliferation, the decreased monocyte IL-1 beta production may provide a plausible explanation for the reduced mitogen response of T cells in AE.

Responsiveness of peripheral blood mononuclear cells from normal and atopic donors to microbial superantigens.

Patients with atopic dermatitis (AD) are frequently colonized with Staphylococcus aureus strains secreting exotoxins such as the staphylococcal enterotoxin B (SEB) and A (SEA). Nonetheless the role of SEB and SEA in AD is yet unknown. We analyzed the responsiveness of peripheral blood mononuclear cells (PBMCs) and isolated T cells from donors with AD and from normal donors to SEB and SEA. PBMCs as well as T cells from normal donors showed a significantly enhanced proliferation after stimulation with enterotoxin B, whereas the 3H-thymidine uptake of the T lymphocytes from patients with AD was markedly suppressed. Furthermore, we show that IFN-gamma mRNA and protein and mRNA for both chains of IL-12 (p35 and p40) are produced in human PBMCs from normal donors upon stimulation with SEB and SEA. In contrast to normal donors T cells from donors with AD predominantly express mRNA for IL-4, IL-5, and only diminished levels for IFN-gamma and IL-12 upon stimulation with SEB and SEA. Furthermore, in contrast to normal donors, PBMCs from donors with AD spontaneously produce high levels of IgE and express increased levels of CD23, the low-affinity receptor for IgE. Nonetheless, the superantigens by themselves, from 0.1 fg up to 1 microgram/10(6) cells, induced neither IgE secretion nor CD23 expression on PBMCs. Moreover, the addition of superantigens to IL-4-treated PBMC cultures diminished or totally suppressed the IL-4-induced IgE synthesis and CD23 expression. No differences were observed between PBMCs from normal donors of donors with AD. Both PBMCs isolated from normal and atopic donors produced high levels of soluble IL-4-receptor (up to 210 +/- 90 pg/ml). Addition of soluble IL-4-receptor to PBMC cultures downregulated the IL-4-induced IgE synthesis and CD23 expression in unstimulated as well as in SEB-stimulated PBMCs from normal donors and donors with AD. Our results suggest that superantigen-producing staphylococcal strains on the skin of patients with AD may modulate and/or amplify allergic inflammation.

[Staphylococcus aureus and atopic eczema]. / Staphylococcus aureus und atopisches Ekzem.

The bacterial skin flora of patients with atopic eczema is different from that in healthy normal persons. In addition, such patients more often suffer from microbial infections. Differences in sebum and sweat secretion and increased bacterial adhesion to epithelial cells in atopic eczema may predispose to enhanced amounts of Staphylococcus aureus, for example, on the skin. Defective host-defence mechanisms with dysfunction of cellular and humoral immune reactions have been suggested. On the other hand, bacterial antigens may induce allergic reactions, e.g. increased IgE synthesis and enhanced expression of the low-affinity receptor for IgE (CD23, Fc epsilon RII), and the release of inflammatory mediators such as leukotrienes and histamine. The production of bacterial toxins might be important for the pathophysiology of atopic eczema. This paper summarizes the present data and tries to integrate them into a model for the induction of atopic eczema.

Effects of recombinant human soluble interleukin-4 receptor on interleukin-4/staphylococcal enterotoxin B-stimulated peripheral mononuclear cells from patients with atopic eczema.

In atopic eczema both in local inflammatory reactions and in peripheral blood high interleukin (IL) 4: interferon-gamma (IFN-gamma) production ratios have been demonstrated, indicating predominance of TH2 cell subsets resulting in increased IL-4 production and high serum IgE. The in vitro immunomodulatory effects of recombinant human soluble IL-4 receptor (rsIL-4R) on IL-4-stimulated lymphocyte proliferation, IgE and IFN-gamma production were studied in peripheral blood mononuclear cells from 10 patients with atopic eczema and seven healthy donors. In addition to control cultures (without any stimulus) and cultures with simultaneous application of rsIL-4R and IL-4, time-kinetic experiments were performed. We further investigated the influence of rsIL-4R on IL-4 production in staphylococcal enterotoxin B (SEB) stimulated peripheral blood mononuclear cells. Early addition of rsIL-4R to IL-4-stimulated peripheral blood mononuclear cells resulted in an increase in IFN-gamma production and in suppression of IL-4 induced proliferation and IgE secretion. Unexpectedly, rsIL-4R in combination with SEB exhibited an IL-4 protective effect with a significant increase in detectable IL-4 in the culture supernatants. The present data support the assumption that rsIL-4R might be a promising new immunomodulatory substance in the treatment of atopic eczema.

Staphylococcus aureus modifies the cytokine-induced immunoglobulin synthesis and CD23 expression in patients with atopic dermatitis.

The influence of Staphylococcus aureus on peripheral blood lymphocytes (PBL) of patients with atopic dermatitis (AD) was analysed. The parameters studied were spontaneous and interleukin-inducible immunoglobulin (IgA, IgE, IgG) synthesis, as well as CD23 expression. Various heat-killed, clinical isolates of S. aureus were analysed. PBL from non-atopic donors served as controls. The time-course of co-cultured PBL with S. aureus showed a dose-dependent increase in immunoglobulin (Ig) synthesis from PBL of normal donors, whereas the Ig synthesis of atopic cells was significantly depressed. Additional stimulation with interleukin-4 (IL-4) also led to a pronounced suppression of the IgE and IgA synthesis in normal donor cells, while the effect of S. aureus on PBL of atopic donors was not markedly affected by IL-4. Transwell cultures of bacteria separated from PBL by a semi-permeable membrane induced stimulation of IgA and IgE synthesis in patients with AD. The Ig synthesis in the control group was not altered. Co-stimulation of S. aureus and IL-4 in this system led to a suppression of IgA with cells of both atopic and normal donors. IgE synthesis from atopic PBL was significantly stimulated. The CD23 expression of atopic PBL was increased by S. aureus and IL-4. Our data indicate that S. aureus may modulate the cytokine-dependent humoral immunity in patients with AD and that chronic colonization of the skin may be responsible for allergic skin reactions in AD.