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Biomedical subjects

Michael Weichenthal

Publications and source records attributed to Michael Weichenthal.

16 recordsLinked to original sources
PubMed2006

Psoriasin (S100A7) is significantly up-regulated in human epithelial skin tumours.

PURPOSE: Psoriasin (S100A7) has originally been described to be expressed by psoriatic keratinocytes possibly as a result of altered differentiation and inflammation. As psoriasin was found to be overexpressed in human breast and bladder cancer suggesting a role in tumour progression, we investigated the expression of psoriasin in human epithelial skin tumours. METHODS: Realtime reverse transcription-polymerase chain reaction experiments were performed to analyse the mRNA-expression levels of psoriasin together with involucrin as a marker for epithelial differentiation and interleukin-8 (IL-8) as a marker for inflammation in skin biopsy samples from patients with precancerous skin lesions (PSL, n = 6), squamous cell carcinoma (SCC, n = 11), basal cell carcinoma (BCC, n = 17), and healthy controls (n = 10). RESULTS: Unexpectedly, mRNA expression levels for Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) revealed a variation of up to 600-fold in all cDNA-samples under investigation, indicating that GAPDH is not suitable as a housekeeping gene in human skin samples. Psoriasin mRNA expression was significantly up-regulated in samples of PSL, SCC and BCC. In situ hybridisation and immunohistochemical examinations identified psoriasin mRNA and protein expression in the differentiated layers of the epidermis. IL-8 mRNA expression was significantly up-regulated in SCC, however, there was no correlation between elevated levels of psoriasin and the expression of IL-8. CONCLUSION: Similar to the findings in breast and bladder cancer, the up-regulation of psoriasin might play a role in the progression of skin cancer. The expression of psoriasin in human skin tumours seems to be independent from differentiation and inflammation.

Adolescent↗
PubMed2006

Increased prevalence of the metabolic syndrome in patients with moderate to severe psoriasis.

The role of chronic inflammation causing metabolic and vascular disorders is increasingly recognized. It is hypothesized that proinflammatory cytokines contribute to atherogenesis, peripheral insulin resistance, and the development of hypertension and type II diabetes. Psoriasis as a chronic inflammatory skin disorder is characterized by a variety of immunologic and inflammatory changes and may similarly predispose for those disorders. The objective of this study was to elucidate the association of psoriasis with chronic vascular and metabolic disorders. We investigated a total of 581 adult patients hospitalised for plaque type psoriasis as compared to 1,044 hospital-based controls. A distinct pattern of chronic disorders was found to be significantly associated with psoriasis, including diabetes mellitus type II [odds ratio (OR)=2.48], arterial hypertension (OR = 3.27), hyperlipidemia (OR = 2.09), and coronary heart disease (OR = 1.95). The combined presence of these conditions together with obesity, known as the metabolic syndrome, was clearly more prevalent in psoriasis patients (OR = 5.29). In addition, psoriasis patients were significantly more likely to be smokers (OR = 2.96) and to have a regular or heavy consumption of alcohol (OR = 3.33 and 3.61, respectively). In conclusion, psoriasis patients appear to be at higher risk for diabetes mellitus and cardiovascular disease. This could likely be due to the effects of chronic inflammatory changes, in particular the secretion of proinflammatory cytokines. The risk of late term cardiovascular complications might support the use of systemic treatment in psoriasis.

Adolescent↗
PubMed2006

Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene.

Previous studies have narrowed the interval containing PSORS1, the psoriasis-susceptibility locus in the major histocompatibility complex (MHC), to an approximately 300-kb region containing HLA-C and at least 10 other genes. In an effort to identify the PSORS1 gene, we cloned and completely sequenced this region from both chromosomes of five individuals. Two of the sequenced haplotypes were associated with psoriasis (risk), and the other eight were clearly unassociated (nonrisk). Comparison of sequence of the two risk haplotypes identified a 298-kb region of homology, extending from just telomeric of HLA-B to the HCG22 gene, which was flanked by clearly nonhomologous regions. Similar haplotypes cloned from unrelated individuals had nearly identical sequence. Combinatorial analysis of exonic variations in the known genes of the candidate interval revealed that HCG27, PSORS1C3, OTF3, TCF19, HCR, STG, and HCG22 bore no alleles unique to risk haplotypes among the 10 sequenced haplotypes. SPR1 and SEEK1 both had messenger RNA alleles specific to risk haplotypes, but only HLA-C and CDSN yielded protein alleles unique to risk. The risk alleles of HLA-C and CDSN (HLA-Cw6 and CDSN*TTC) were genotyped in 678 families with early-onset psoriasis; 620 of these families were also typed for 34 microsatellite markers spanning the PSORS1 interval. Recombinant haplotypes retaining HLA-Cw6 but lacking CDSN*TTC were significantly associated with psoriasis, whereas recombinants retaining CDSN*TTC but lacking HLA-Cw6 were not associated, despite good statistical power. By grouping recombinants with similar breakpoints, the most telomeric quarter of the 298-kb candidate interval could be excluded with high confidence. These results strongly suggest that HLA-Cw6 is the PSORS1 risk allele that confers susceptibility to early-onset psoriasis.

Adult↗
PubMed2006

CARD15 mutations in patients with plaque-type psoriasis and psoriatic arthritis: lack of association.

Psoriasis has a strong genetic component in the development of the disease as indicated by familial occurrence and a high concordance rate among monozygotic twins. In genome-wide scans for psoriasis several susceptibility loci have been detected, but the disease-causing genes have not yet been identified. A recent scan, performed on psoriatic arthritis (PsA), which occurs in about 15% of the psoriasis patients showed a significant locus on chromosome 16 in a region that was already described by genome scan for psoriasis. CARD15, a major susceptibility gene for Crohn's disease (CD) on chromosome 16q, is an interesting candidate gene for psoriasis, because there is a documented clinical association of CD with psoriasis, and recently the association of CARD15 mutations with PsA was reported in Newfoundland population. We investigated the association of this variant with PsA and the overall psoriasis genotype in 59 independent patients with PsA in comparison with 361 age and sex-matched controls. In addition, a second cohort of 89 independent North American PsA patients was included. The diagnosis of psoriasis was made by a dermatologist based on standard clinical criteria. In these patients, PsA was defined as an inflammatory joint disease, negative rheumatoid factor, and lack of another causative condition for arthritis. Using case-control analysis, the G908R mutation was weakly associated with psoriasis and PsA, but due to the low frequency of this mutation statistical significance was not reached. All other variants including leu1007fsinsC and R702W did not show any association with psoriasis or PsA. In conclusion, a disease-causing role for CARD15 mutations could not be confirmed in German or American subjects with PsA.

Arthritis, Psoriatic↗
PubMed2006

Positive patch test reactions to nickel sulphate are not modified by neighbouring negative fragrance patch tests. A multicenter-study by the German contact dermatitis research group.

It is tacitly assumed that a positive patch test reaction is not affected by adjacent negative tests. However, despite its fundamental importance for the interpretation of test reactions this assumption has not been proven. To test this assumption, special TRUE-test strips were prepared containing placebo, nickel sulphate and fragrance mix as the only allergens, separated by distances of 1 cm and 7 cm and blinded to the investigators. Patients were synchronously tested with two strips. Out of 493 patients tested in 6 centres, the 93 with positive reactions to nickel sulphate only were evaluated. No relevant difference was found between positive nickel reactions in the two different distances to a negative fragrance patch test. We conclude that a positive patch test reaction is not affected by adjacent negative patch tests, which therefore can be neglected for the interpretation of positive reactions.

Allergens↗
PubMed2005

Reduced Paneth cell alpha-defensins in ileal Crohn's disease.

The pathogenesis of Crohn's disease (CD), an idiopathic inflammatory bowel disease, is attributed, in part, to intestinal bacteria that may initiate and perpetuate mucosal inflammation in genetically susceptible individuals. Paneth cells (PC) are the major source of antimicrobial peptides in the small intestine, including human alpha-defensins HD5 and HD6. We tested the hypothesis that reduced expression of PC alpha-defensins compromises mucosal host defenses and predisposes patients to CD of the ileum. We report that patients with CD of the ileum have reduced antibacterial activity in their intestinal mucosal extracts. These specimens also showed decreased expression of PC alpha-defensins, whereas the expression of eight other PC products either remained unchanged or increased when compared with controls. The specific decrease of alpha-defensins was independent of the degree of inflammation in the specimens and was not observed in either CD of the colon, ulcerative colitis, or pouchitis. The functional consequence of alpha-defensin expression levels was examined by using a transgenic mouse model, where we found changes in HD5 expression levels, comparable to those observed in CD, had a pronounced impact on the luminal microbiota. Thus, the specific deficiency of PC defensins that characterizes ileal CD may compromise innate immune defenses of the ileal mucosa and initiate and/or perpetuate this disease.

Analysis of Variance↗
PubMed2005

Phototherapy: how does UV work?

Phototherapy has been largely empirical. Thus, despite the long term use its mechanisms of action are quite unclear. Because of the recent achievements in photoimmunology and molecular photobiology we are now beginning to understand some of the mechanisms. Many of the effects are certainly mediated via induction of apoptotic cell death. Another major mechanism is the induction of immunosuppression. This review primarily focuses on recent advances in photoimmunology which will contribute to the further understanding how phototherapy acts.

Animals↗
PubMed2005

Malignant melanoma and HIV infection -- aggressive course despite immune reconstitution.

BACKGROUND: Highly active antiretroviral therapy (HAART) has altered the course of most AIDS-related malignancies. There is some evidence that cellular immunity plays an important role in the progression of metastatic melanoma. CASE REPORT: We report on a patient suffering from metastatic melanoma and HIV infection. The 53-year-old man received HAART in order to use both its anti-tumor efficacy and its stimulating effect on cellular and humoral immune functions. Furthermore, our patient was treated with interleukin-2, a drug which has shown efficacy in metastatic melanoma and HIV infection. RESULTS: Although the CD4 and CD8 cell count increased significantly, a fulminant progression of melanoma in the liver and spleen was noted, and the patient died subsequently. CONCLUSION: This case describes that neither immune reconstitution through HAART nor interleukin-2 treatment were able to lead into an anti-tumor response. HIV-infected patients should be monitored routinely for an early diagnosis of this potentially lethal disease.

Anti-HIV Agents↗
PubMed2004

Resistance of human melanoma cells against the death ligand TRAIL is reversed by ultraviolet-B radiation via downregulation of FLIP.

Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is a potential anticancer drug since it induces apoptosis preferentially in malignant but not in normal cells. Not all cancer cells, however, are TRAIL susceptible. Chemotherapeutic drugs and ionizing radiation have been found to be able to sensitize resistant tumor cells for TRAIL-induced apoptosis. Since ultraviolet B radiation (UVB) is a potent inducer of apoptosis but exhibits much less adverse effects, we studied whether UVB sensitizes TRAIL-resistant melanoma cells. Therefore, we analyzed the TRAIL-sensitive human cell line A-375 in comparison to the resistant cell line IGR-37. Both cell lines showed expression of the long form of the antiapoptotic FLICE inhibitory protein FLIP(L) which, however, was partially cleaved into the 43 kDa form in A-375 cells. In addition, only IGR-37 cells expressed the short splicing variant FLIP(S), which exerts high antiapoptotic activity. Accordingly, transient overexpression of FLIP(S) rendered A-375 cells resistant to TRAIL. Upon exposure to low UVB doses, TRAIL-treated IGR-37 cells underwent pronounced apoptosis and TRAIL sensitivity of A-375 cells was dramatically increased. In both cases, UVB caused an inhibition of flip expression. This study indicates that (i) the expression level and the processing status of FLIP may play a crucial role in determining the sensitivity of melanoma cells towards TRAIL and (ii) expression of FLIP is regulated by UVB.

Apoptosis↗
PubMed2003

Prospective randomized trial of interferon alfa-2b and interleukin-2 as adjuvant treatment for resected intermediate- and high-risk primary melanoma without clinically detectable node metastasis.

PURPOSE: Low-dose interferon alfa (IFNalpha) has been shown to have limited effects in the adjuvant treatment of patients with intermediate- and high-risk primary melanoma. We hypothesized that a combination regimen with low-dose interleukin-2 (IL-2) may improve survival prospects in these patients. PATIENTS AND METHODS: After wide excision of primary melanoma without clinically detectable lymph node metastasis (pT3 to 4, cN0, M0), 225 patients from 10 participating centers were randomly assigned to receive either subcutaneous low-dose IFNalpha2b (3 million international units [MU]/m2/d, days 1 to 7, week 1; three times weekly, weeks 3 to 6, repeated all 6 weeks) plus IL-2 (9 MU/m2/d, days 1 to 4, week 2 of each cycle) for 48 weeks, or observation alone. The primary end point was prolongation of a relapse-free interval. RESULTS: Of the 225 enrolled patients, 223 were found to be eligible. Median follow-up time was 79 months. All evaluated prognostic factors were well balanced between the two arms of the study. Relapses were noticed in 36 of 113 patients treated with IFNalpha2b plus IL-2 and in 34 of 110 patients with observation alone. Five-year disease-free survival of those who had routine surgery supplemented by IFNalpha2b and IL-2 treatment was 70.1% (95% confidence interval [CI], 61.3% to 78.9%), compared with 69.9% in those receiving surgery and observation alone (95% CI, 60.7% to 79.1%) in the intention-to-treat analysis. Evaluation of the overall survival did not show any difference between treated and untreated melanoma patients (P =.93). CONCLUSION: Adjuvant treatment of intermediate- and high-risk melanoma patients with low-dose IFNalpha2b and IL-2 is safe and well tolerated by most patients, but it does not improve disease-free or overall survival.

Adolescent↗
PubMed2003

Inducible and constitutive beta-defensins are differentially expressed in Crohn's disease and ulcerative colitis.

Antimicrobial peptides such as defensins provide nonspecific mucosal defense against a multitude of microorganisms. Recently, it has been shown that luminal bacteria may invade the mucosa in inflammatory bowel diseases, suggesting a defect in innate mucosal immunity. The aim of this study was to investigate the expression of human beta-defensins (HBD) in controls, Crohn's disease (CD), ulcerative colitis (UC), and unspecific inflammation. Up to 4 biopsies were taken from 103 patients (33 controls, 24 with Crohn's disease, 36 with ulcerative colitis, 10 with unspecific colitis). Mucosal mRNA was measured using real-time fluorescence temperature cycler reverse-transcription polymerase chain reaction with primers for HBD-1, HBD-2, HBD-3, tumor necrosis factor alpha, and interleukin 8. Mucosal HBD-1 expression was marginally decreased in both CD and UC. HBD-2 was increased exclusively in UC but not in CD. The expression of the novel defensin HBD-3 was strongly correlated with HBD-2 and also raised predominantly in UC. The expression of both inducible beta-defensins was enhanced in the state of inflammation. Expression of HBD-2 showed a weak correlation with interleukin 8 only in inflamed CD biopsies but not with tumor necrosis factor alpha. The missing induction of both inducible beta-defensins in CD as compared with UC may cause a defect in barrier function that predisposes to bacterial invasion.

Adolescent↗
PubMed2002

Sun exposure and number of nevi in 5- to 6-year-old European children.

The occurrence and number of melanocytic nevi are among the most important known risk factors for the development of malignant melanoma. Studying the causes of nevi should lead to successful strategies in the prevention of melanoma. Among 11,478 white German children of preschool age the association between benign melanocytic nevi and a number of risk factors for skin cancer was examined. We found that subjects with a reported history of increased sun exposure, for example, painful sunburns, and an increased number of holidays in foreign countries with a sunny climate had significantly higher nevus counts than individuals without these characteristics. Our results provide further evidence that nevus counts may not only be part of a genetic predisposition but also a result of increased exposure to ultraviolet radiation. Together with the fact that a high nevus count is the most relevant risk factor for malignant melanoma, the results strongly indicate a connection between UV-radiation and the development of melanocytic skin cancer. In conclusion, strategies to reduce the incidence of melanoma should begin with young children.

Child↗
PubMed2002

Soluble CD30 plasma concentrations correlate with disease activity in patients with atopic dermatitis.

The levels of soluble CD30 in 79 patients with atopic dermatitis were compared with those found in 54 patients with psoriasis and 36 control individuals (no psoriasis, no atopic dermatitis). In relation to the control group, patients with atopic dermatitis were found to exhibit an increased concentration of sCD30 of at least 1.5-fold (p < 0.001). In addition, sCD30 concentrations were shown to correlate with the severity of the disease as measured by the score index for atopic dermatitis and different stages of disease activity, such as acute, subacute, or chronic forms, and localized or generalized distribution of atopic dermatitis. The application of topical glucocorticoid therapy for a period of 2 weeks resulted in a decrease in the level of sCD30 by 46% in 8 patients, especially in the acute, generalized form of atopic dermatitis. Psoriasis patients showed no significant differences in sCD30 levels in relation to the control group. This study demonstrates a correlation between sCD30 concentration and the activity of the disease and therefore suggests sCD30 as a prognostic marker, being superior to predictions from measurements of IgE or eosinophil cationic protein.

Administration, Topical↗