Glutathione-S-transferase T1 genotyping and phenotyping in psoriasis patients receiving treatment with oral fumaric acid esters.

BACKGROUND: Glutathione S-transferases (GSTs) are involved in detoxification of xenobiotics such as fumaric acid esters (FAE). OBJECTIVES: To perform GSTT1 geno- and phenotyping in psoriasis patients treated with FAE to find out whether the responder status and/or occurrence of side-effects are associated with allelic variants and enzymatic activity of GSTT1. METHODS: We treated 106 psoriasis patients with FAE. GSTT1 genotyping was performed using PCR, phenotyping was carried out by means of a validated high performance liquid chromatography assay at baseline and under treatment. RESULTS: The distribution of GSTT1 genotypes was as follows: 31% *A/*A; 49% *A/*0; 20% *0/*0. GSTT1 phenotypes as expressed in enzyme activity significantly differed between conjugators classes. (P < 0.001). GSTT1 activity under treatment was significantly (P = 0.0001) increased when compared with baseline. There were no significant associations between the aforementioned GSTT1 pheno- and genotypes and clinical parameters such as psoriasis area and severity index (PASI)50, adverse effects and FAE dosage (P > 0.05), except for the frequent occurrence of reduction (>50%) of circulating lymphocytes in patients with *0/*0 GSTT1 status (P = 0.036; odds ratio: 6, 95% CI: 1.1-32). CONCLUSION: GSTT1 geno- and phenotypes significantly correlate in psoriasis patients and do not substantially differ from healthy controls. Response to FAE does likely not depend on GSTT1. However, *0/*0 GSTT1 status is a predictor for the occurrence of marked reduction of lymphocyte counts under FAE therapy. Notably, FAE seem to enhance GSTT1 enzyme activity in high and low conjugators.

Serum levels of antimicrobial peptides and proteins do not correlate with psoriasis severity and are increased after treatment with fumaric acid esters.

Overexpression of antimicrobial peptides and proteins (AMPs) such as human ß-defensin-2 (hBD2), LL37, and psoriasin has frequently been observed in lesional skin of psoriasis patients. We aimed to evaluate whether circulating AMP levels correlate with disease severity, and change under therapy with fumaric acid esters (FAE). We studied psoriasis patients who underwent systemic therapy using oral FAE (Fumaderm(®)). An enzyme-linked immunosorbent assay for the detection of serum protein expression of hBD2, LL37, and psoriasin was performed at baseline and after 12-week therapy. After 12-week FAE treatment of 28 patients, the median PASI significantly (P < 0.0001) decreased from 27.1 to 12.5. In psoriasis patients, mean ± SD serum hBD2, psoriasin, and LL37 levels at baseline were 295.6 ± 93.5 pg/ml, 79.4 ± 32.7 ng/ml, and 106.3 ± 90 ng/ml, respectively, which were significantly increased when compared to healthy controls (110 ± 53.7 pg/ml, P ≤ 0.0001; 3.1 ± 0.7 ng/ml, P ≤ 0.0001; 3.8 ± 0.9 ng/ml, P = 0.0004, respectively). After 12-week FAE treatment, a significant increase of serum hBD2 (339.7 ± 74.3 pg/ml; P = 0.0046), psoriasin (106 ± 58.9 ng/ml; P = 0.0014), and LL37 (136.6 ± 115.1 ng/ml; P = 0.0035) was observed. Correlation studies did not reveal significant relationships between serum AMP levels and PASI (r < 0.1; P > 0.05). In contrast to AMP expression in psoriatic skin serum, AMP levels seem not to correlate with disease severity. Increased serum AMP protein levels in psoriasis resolution are an unexpected observation that needs to be investigated more in detail in future studies.

GNAS1 T393C polymorphism and disease progression in patients with malignant melanoma.

BACKGROUND: Once metastasized, despite a variety of therapeutic options, the prognosis of patients with malignant melanoma (MM) is still poor. Therefore, the search for reliable markers to identify patients with high risk of disease progression is of high clinical importance. We have recently shown that TT genotypes of the single-nucleotide polymorphism (SNP) T393C in the gene GNAS1 are significantly associated with better outcome in a variety of carcinomas. - PATIENTS: In the present study we assessed whether the T393C SNP is also related to the clinical course in MM. 328 patients with MM were retrospectively genotyped and genotypes were correlated with clinical outcome. - RESULTS: While the allele frequency in the MM group (fC 0.52) did not significantly differ from that of healthy blood donors, the T393C SNP was associated with tumor progression of MM. Carriers of the C-allele showed a significantly more severe tumor progression as estimated from the time period to develop metastasis (HR 2.2, 95% CI 1.1-3.2, p = 0.017). Proportions of 5-year metastasis-free intervals were 87.1% for TT genotypes and 66.0% for C-allele carriers. Moreover, multivariable Cox regression analysis including tumor stage and melanoma subtype proved the T393C polymorphism to be an independent factor for metastasis (p = 0.012). - CONCLUSIONS: In summary, the GNAS1 T393C SNP represents a genetic host factor for predicting tumor progression also in patients with MM; genotyping of this SNP may contribute to better define patients who could benefit from an early individualized therapy.

Evaluation of sun awareness with an emphasis on ultraviolet protection by clothing: a survey of adults in Western Germany.

BACKGROUND: Little is known about the sun habits of the population in Germany. OBJECTIVE: We aimed to assess the sun awareness and notion on ultraviolet (UV) radiation protection by fabrics in adult subjects from North Rhine-Westphalia in Germany. METHODS: During regular skin cancer screening campaigns, 1206 subjects completed and returned a structured questionnaire on constitutional parameters and the respondents' sun habits. RESULTS: Staying in the shade and the use of high-factor sunscreens are the most commonly performed sun-protective measures reported by the respondents. Males and lower-educated people use clothing in conjunction with sunscreens more infrequently. Most respondents, particularly females, know that sun protection provided by clothing is variable. However, the elderly more frequently consider sun protection by clothing as excellent. Notably, more than two-thirds of the respondents would prefer clothing with a labelled ultraviolet protection factor. The respondents of this survey mainly considered baby wear, children wear, and leisure wear for sun-protective clothing, whereby light-weighted, breathable, natural fabrics preferably made of cotton and linen were the most frequently reported protective textiles. CONCLUSIONS: Given the lack of epidemiological observations on people's sun habits and protection in Germany, the present relatively large survey provides useful information and implications for counselling in sun protection and marketing of UV-protective clothing.

Expression of minichromosome maintenance proteins in Merkel cell carcinoma.

OBJECTIVE: Minichromosome maintenance (MCM) nuclear proteins have barely been employed in the diagnosis of skin malignancies. We aimed to assess whether MCM immunohistochemistry can be utilized to examine tumour proliferation in Merkel cell carcinoma (MCC). METHODS: In this pilot study, we studied skin specimens of eight patients with MCC. As a control, eight patients with cutaneous malignant melanoma (MM) were included. Immunohistochemistry was performed for MCM4, MCM6, MCM7, Ki-67, p53, and p21. RESULTS: Protein expression of MCM4 (66.0 +/- 26.5% vs. 33.9 +/- 22.4%; P = 0.017), MCM6 (70.9 +/- 11.9 vs. 31.7 +/- 22.7; P = 0.0031), and MCM7 (76.5 +/- 16.4% vs. 34.9 +/- 25.5%; P = 0.0013) was significantly increased in tumour cells of MCC when compared to tumour cells of MM. Ki-67 immunoreactivity was also significantly higher in MCC than in MM (28.7 +/- 7.9 vs. 11.0 +/- 9.2; P = 0.0012). Immunolabelling of p53 (68.6 +/- 26.2 vs. 58.4 +/- 28.8; P = 0.46) and p21 (40.1 +/- 38.8 vs. 25.8 +/- 16.1; P = 0.35) was relatively high but not significantly increased in MCC when compared to MM. CONCLUSION: Our preliminary data indicate that MCM immunohistochemistry may be a useful tool for the determination of tumour cell proliferation in MCC.

Versican overexpression in cutaneous malignant melanoma.

OBJECTIVE: Tumor growth regulation by extracellular matrix components has been one of the main topics on tumor biology in the last years. We aimed to investigate the protein expression pattern of decorin and versican in superficial spreading melanoma (SSM) and its precursors. PATIENTS AND METHODS: Paraffin-embedded sections of benign nevi (BN), dysplastic nevi (DN), and primary SSM were assessed. Immunohistochemistry was performed for decorin and versican antibodies. RESULTS: We investigated 64 patients with BN (n = 29), DN (n = 15), and SSM (n = 20) with a median Breslow thickness of 0.8 mm (0.2 - 4.6 mm). We did not observe decorin or versican immunoreactivity in melanocytes but in peritumoral stroma. Kruskal-Wallis ANOVA did not reveal significant differences of decorin expression between the groups investigated (P = 0.19). However, compared to BN and DN median expression of versican was significantly increased in SSM (P = 0.016 and P = 0.019, respectively). Decorin as well versican expression of SSM did not significantly correlate with Breslow tumor thickness or Clark level. CONCLUSION: Our data indicate that decorin is not differentially expressed in peritumoral stroma of SSM, DN, BN, and thus unlikely of pathogenetic significance in melanoma transformation and/or progression. By contrast, we have demonstrated that SSM is associated with a significant overexpression of peritumoral versican suggesting a role for versican in the pathogenesis of melanoma.

Fumaric acid esters in necrobiosis lipoidica: results of a prospective noncontrolled study.

BACKGROUND: Necrobiosis lipoidica (NL) is an uncommon granulomatous skin disease with association to diabetes mellitus. To date, no proven effective therapy for NL has been implemented. The standard treatment is topical application of corticosteroids, but numerous agents have been reported for NL, with varying degrees of success. In recent case reports, fumaric acid esters (FAE) have been reported to be effective in granulomatous skin diseases such as granuloma annulare, cutaneous sarcoidosis and NL. OBJECTIVES: We sought to investigate the efficacy of FAE in a larger number of patients with NL. METHODS: Eighteen patients with histopathologically proven NL were consecutively recruited into a prospective noncontrolled study. Dosage of FAE was given according to the standard therapy regimen for psoriasis. FAE were administered for at least 6 months. The treatment outcome was evaluated by means of clinical and histological scoring and 20-MHz ultrasound assessments. RESULTS: Three patients discontinued therapy with FAE, while the remaining 15 patients finished the study. After a mean +/- SD treatment period of 7.7 +/- 2.9 months, a significant (P < 0.001) decrease in the mean +/- SD clinical score, from 7.4 +/- 1.8 at the beginning to 2.5 +/- 1.3 at the end of therapy, was observed. Significant clinical improvement of NL was accompanied by significant (P = 0.019) increase of dermal density as assessed by means of 20-MHz ultrasound, and significant (P = 0.011) reduction of the histological score. Adverse effects were moderate and consisted mainly of gastrointestinal complaints and flushing. During follow-up of at least 6 months, clinical outcome remained stable in all patients. CONCLUSIONS: The results of this study demonstrate that FAE are beneficial and safe in the treatment of patients with NL.

Histomorphologic correlation with routine histology and optical coherence tomography.

BACKGROUND: Optical coherence tomography (OCT) is a new and promising diagnostic technique for investigation of skin tumours. We describe a method that makes evaluation and definition of specific morphologic structures of skin tumours via OCT more accurate. MATERIALS AND METHOD: We investigated three patients with basal cell carcinoma and three patients with melanocytic nevi. Three-dimensional (3D) images were obtained from these skin tumours via OCT according to previously applied marks, which were tattooed with special histological marking dye after excision of the tumours. Corresponding to these marks, we investigated serial histological sections (haematoxylin&eosin staining). RESULTS: We could prove similar morphological structures both in OCT and histology. Due to tissue deformation, the compared measurements of structures like cell nests or epidermal thickness were slightly deviated. However, by this method we could prove similar tissue formations in OCT and histology. CONCLUSIONS: Due to the deformation by histological processing and slightly different sectioning levels, the comparison of histological pictures and OCT images seems difficult. Nevertheless, in two cases it was possible to demonstrate the same morphological structures with OCT imaging and histological investigation. Our method could play an important role for further evaluation of OCT images. We estimate better evaluation of OCT imaging using a 3D reconstruction method.

Hepatitis B-assocciated adult-onset Still's disease presenting with neutrophilic urticaria.

Adult-onset Still's disease (AOSD) is an uncommon systemic inflammatory disorder that is characterized by quotidian fever, articular manifestations, neutrophilic leukocytosis, and maculopapular rash. The aetiology of the disease is unknown, however, an infectious cause has been suggested. Here we describe a patient in whom neutrophilic urticaria was the cutaneous manifestation of AOSD. In addition, the patient suffered from chronic hepatitis B infection that may be a potential trigger factor of AOSD. In patients with AOSD, serological investigations for detection of infection should include hepatitis serology. Further, we suggest that urticarial lesions may be a more common cutaneous manifestation of AOSD than has been recognized previously. Thus it is important to include AOSD in the differential diagnosis of urticaria.

Investigation of basal cell carcinoma [correction of carcionoma] by confocal laser scanning microscopy in vivo.

BACKGROUND/PURPOSE: In vivo confocal laser scanning microscopy (CLSM) allows to study human skin up to 200 micro m deep non-invasively. Aim of this study was to investigate basal cell carcinoma (BCC) using in vivo CLSM, and to compare the micromorphologic features of BCC with uninvolved skin. METHODS: Twelve patients with histological diagnosis of BCC referred to our department for tumor excision were investigated on the lesion(s) and on clinically uninvolved sites preoperatively by in vivo CLSM using the Vivascope 1000 (Lucid Inc., Rochester, USA). The images were compared to histological examinations of the excised tissue. RESULTS: Typical changes in vasculature such as increase in number and diameter of the blood vessels, loss of the vascular architecture, parallelly and horizontally orientated vessels, and accumulation and rolling phenomena of bright reflecting cells of 11.88 +/- 1.75 micro m in diameter along the vessel wall were observed in all BCCs. The tumor stroma of the BCCs showed a strong reflectance mainly due to numerous bundles of collagen fibers encoating dark, cell-rich areas of tumor parenchym. In five patients, slim basaloid cells with relatively large, elongated dark nuclei were observed in the periphery of the tumor parenchym. In the fibrosing type of BCC, curled bundles of collagen with large cells represented the tumor stroma. CONCLUSIONS: BCC can be investigated by CLSM and provide typical features. Besides the tumor parenchym and stroma, typical changes in vasculature seem to be a sensitive criteria for BCC and may in future help in diagnosing BCC by CLSM as well as in assessing the margins of large tumors. We suggest that CLSM is a promising non-invasive tool for the diagnostics of BCC and the assessment of tumor margins prior to surgery.

Protection against ultraviolet radiation by commercial summer clothing: need for standardised testing and labelling.

BACKGROUND: The use of clothing as a means of sun protection has been recommended in recent education campaigns. Contrary to popular opinion, however, some fabrics provide insufficient ultraviolet (UV) protection. MATERIAL AND METHODS: We investigated 236 apparel textiles of the spring/summer collections 2000 and 2001. In accordance with the forthcoming European standard the UV protection factor (UPF) of the fabrics was determined spectrophotometrically. RESULTS: Seventy-eight (33%) fabrics had UPF < 15, 45 (19%) had UPF = or > 15 and < 30, and 113 (48%) had UPF = or > 30 (30+). More than 70% of the wool, polyester, and fabric blends, and only less than 30% of the cotton, linen, and viscose fabrics had UPF values of 30+. Fabrics with black, navy-blue, white, green, or beige colours provided most frequently UPF values of 30+. CONCLUSIONS: It is difficult for the sun-aware consumer to choose the 'right' garment, with a third of summer clothing providing insufficient UV protection and only half of the fabrics having UPF 30+, the UPF recommended by the European standard. Therefore, apparel summer fabrics should be measured and labelled in accordance with a standard document.

Autonomic neurocardiac function in patients with major depression and effects of antidepressive treatment with nefazodone.

BACKGROUND: Major depression (MD) is associated with an augmented risk of cardiovascular mortality. One possible explanation for this association is that MD influences autonomic neurocardiac regulation (ANR). However, previous studies on this subject revealed conflicting results. METHODS: Using an autonomic test battery, which consisted of standardised measurements of heart rate variability (HRV) and blood pressure, we (1) compared ANR between 25 patients with DSM-III-R diagnosed MD and 60 healthy controls, and (2) investigated the autonomic effects of antidepressive treatment with nefazodone. RESULTS: Following multivariate analysis of all tests a significant reduction in HRV could only be shown for the Valsalva ratio amongst the depressives compared to controls. There was a significant inverse correlation between the HRV during deep respiration and both the severity of depression and the duration of the depressive episode. Serial HRV recordings revealed that both the mean resting heart rate and systolic blood pressure significantly decreased after 21 days of nefazodone treatment (average dosage 413 mg/day), whereas after 10 days (average dosage 270.8 mg/day) there were no striking changes compared to the pre-treatment values. During nefazodone treatment no significant changes in parasympathetic tone occurred. LIMITATIONS: ANR was not assessed in a randomised, placebo-controlled fashion. CONCLUSIONS: (1) Patients with MD may suffer from functional disturbances in the interaction between the sympathetic and parasympathetic autonomic tree. (2) The pattern of autonomic changes during treatment suggests that nefazodone induced a dose dependent, serotonergically-mediated down-regulation of the sympathetic tone. This mechanism might be responsible for nefazodone's properties of reducing anxiety.