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Biomedical subjects

Thomas Ruzicka

Publications and source records attributed to Thomas Ruzicka.

At least 37 records · Page 2Linked to original sources
PubMed2006

Plantar warts in twins after successful bone marrow transplantation for severe combined immunodeficiency.

Nine-year-old twin sisters presented with long-standing severe plantar warts following bone marrow transplantation for severe combined immunodeficiency (SCID). Combination therapy with keratolysis, cidofovir and water-filtered infrared coagulation (WIRA) led to complete clearance after 8 months of therapy. This dermatologic problem and the treatment of SCID including gene therapy are discussed.

Bone Marrow Transplantation↗
PubMed2006

Fluorescence diagnosis and photodynamic therapy in dermatology from experimental state to clinic standard methods.

The role of photodynamic therapy (PDT) in the treatment of in situ neoplasias and tumors of the skin is steadily increasing. An intratumoral enriched photosensitizer and its activation by light are the principles of photodynamic action. Aminolevulinic acid (ALA) has been shown to be the drug with most experimental and clinical use in the past. The highest efficacy with most selectivity in topical PDT is postulated for methyl aminolevulinate or methyl aminooxopenoat (MAL, MAOP, Metvix). For solar keratoses, topical PDT using MAL is already considered to be the treatment of choice. Epithelial skin tumors such as basal cell carcinomas also respond very well, however, a debulking procedure of the exophytic tumor tissue is an absolute prerequisite to a successful cure. In addition to functioning as a novel therapeutic tool, photodynamic sensitization of skin cancer cells is increasingly used for fluorescence diagnosis (FD) (also known as photodynamic diagnosis or PDD). The fluorescence of induced porphyrins is effective in detecting and delineating neoplastic skin areas. Future approaches of FD and PDT are nontumoral applications, especially psoriasis, viral-induced diseases, or acne vulgaris. Topical PDT is well tolerated and leads to excellent aesthetic results with only minor side effects.

Aminolevulinic Acid↗
PubMed2006

Treatment of palmoplantar psoriasis with monochromatic excimer light (308-nm) versus cream PUVA.

Palmoplantar psoriasis is a chronic disease, which is very resistant to treatment and often leads to severe disabilities. Photochemotherapy employing psoralens combined with UVA irradiation (PUVA) is a well-accepted therapy for palmoplantar psoriasis. Its topical application (bath PUVA; cream PUVA) avoids the typical side effects of orally applied psoralens. We compared the efficacy of cream PUVA therapy with monochromatic excimer light therapy, a treatment modality employing 308-nm UVB radiation generated by a new kind of light source. Ten patients with psoriasis of the palms and soles were randomly assigned to receive cream PUVA on one side and 308-nm UVB on the contralateral side. Based on the psoriasis area and severity index (PASI) score, clinical assessment was carried out before and 5 weeks after the beginning of the study. At the end of the treatment period both test groups showed a remarkable PASI score reduction (308-nm UVB, 63.57%; cream PUVA, 64.64%). No relevant adverse effects were observed, except for mild irritation in a few patients. After a 12-week follow-up, a relapse of the disease was only observed in one patient. Thus, mono-chromatic excimer light cleared palmoplantar psoriasis as rapidly as cream PUVA. In contrast to cream PUVA, monochromatic excimer light therapy is not associated with prior drug application. This might lead to a lower incidence of adverse reactions and better compliance. Therefore, monochromatic excimer light therapy seems to be a useful new therapeutic option for palmoplantar psoriasis.

Adolescent↗
PubMed2005

Genetic variation in the human androgen receptor gene is the major determinant of common early-onset androgenetic alopecia.

Androgenetic alopecia (AGA), or male-pattern baldness, is the most common form of hair loss. Its pathogenesis is androgen dependent, and genetic predisposition is the major requirement for the phenotype. We demonstrate that genetic variability in the androgen receptor gene (AR) is the cardinal prerequisite for the development of early-onset AGA, with an etiological fraction of 0.46. The investigation of a large number of genetic variants covering the AR locus suggests that a polyglycine-encoding GGN repeat in exon 1 is a plausible candidate for conferring the functional effect. The X-chromosomal location of AR stresses the importance of the maternal line in the inheritance of AGA.

Alopecia↗
PubMed2005

Arginase-1 overexpression induces cationic amino acid transporter-1 in psoriasis.

Regulated uptake of extracellular l-arginine by cationic amino acid transporters (CATs) is required for inducible nitric oxide synthase and arginase activity. Both enzymes were recently recognized as important in the pathophysiology of psoriasis because of their contribution to epidermal hyperproliferation. We here characterize the expression pattern of CATs in psoriatic skin compared to healthy skin. CAT-1 mRNA expression was strongly upregulated in lesional and nonlesional areas of psoriatic skin compared to healthy skin, whereas expression of CAT-2A and the inducible isoform CAT-2B was unaltered in psoriatic skin. Furthermore, we tested the hypothesis that arginase-1 overexpression regulates CAT expression via intracellular l-arginine concentration. In in vitro experiments with arginase-1 overexpressing HaCaT cells, CAT-1 mRNA expression was increased. Likewise, this occurs in l-arginine-starved HaCaT cells. Both CAT-2 isoforms were not affected. Arginase-1 overexpression limits the synthesis of NO at physiological, but not supraphysiological, l-arginine levels. Plasma l-arginine concentration was diminished in psoriasis patients and the arginase product l-ornithine was significantly increased compared to healthy controls. In summary, arginase-1 overexpression leads to upregulated CAT-1 expression in psoriatic skin, which is due to lowered intracellular l-arginine levels and limits NO synthesis at physiological l-arginine concentrations.

Arginase↗
PubMed2005

CCL1-CCR8 interactions: an axis mediating the recruitment of T cells and Langerhans-type dendritic cells to sites of atopic skin inflammation.

Atopic dermatitis represents a chronically relapsing skin disease with a steadily increasing prevalence of 10-20% in children. Skin-infiltrating T cells, dendritic cells (DC), and mast cells are thought to play a crucial role in its pathogenesis. We report that the expression of the CC chemokine CCL1 (I-309) is significantly and selectively up-regulated in atopic dermatitis in comparison to psoriasis, cutaneous lupus erythematosus, or normal skin. CCL1 serum levels of atopic dermatitis patients are significantly higher than levels in healthy individuals. DC, mast cells, and dermal endothelial cells are abundant sources of CCL1 during atopic skin inflammation and allergen challenge, and Staphylococcus aureus-derived products induce its production. In vitro, binding and cross-linking of IgE on mast cells resulted in a significant up-regulation of this inflammatory chemokine. Its specific receptor, CCR8, is expressed on a small subset of circulating T cells and is abundantly expressed on interstitial DC, Langerhans cells generated in vitro, and their monocytic precursors. Although DC maintain their CCR8+ status during maturation, brief activation of circulating T cells recruits CCR8 from intracytoplamic stores to the cell surface. Moreover, the inflammatory and atopy-associated chemokine CCL1 synergizes with the homeostatic chemokine CXCL12 (SDF-1alpha) resulting in the recruitment of T cell and Langerhans cell-like DC. Taken together, these findings suggest that the axis CCL1-CCR8 links adaptive and innate immune functions that play a role in the initiation and amplification of atopic skin inflammation.

Allergens↗
PubMed2005

Signaling networks in cutaneous melanoma metastasis identified by complementary DNA microarrays.

BACKGROUND: Melanoma is a complex multigenic disease, susceptibility to which is determined by several parallel and stepwise progressive pathways affecting growth control, differentiation, cell adhesion, and survival. Melanoma and human cancers in general undergo a continuous development from benign to malignant states, as most thoroughly documented in the multistep mole-to-melanoma transition. OBJECTIVE: To examine how high-throughput microarrays are being used in expression profiling to identify regulated genes, patterns, and pathways that may lead to functional characterization and tumor subclassification. DESIGN: Ten melanoma metastases were analyzed by DNA array technology for important regulated candidate genes, with subsequent confirmation by real-time reverse transcription polymerase chain reaction. RESULTS: Hepatocyte growth factor receptor c-met, growth factor receptor-bound protein 10, B-raf proto-oncogene, and several mitogen-activated protein kinase kinase genes were significantly up-regulated in melanoma metastases and several melanoma cell lines relative to normal human melanocytes (P = .03). Among the up-regulated genes, phosphorylated growth factor receptor-bound protein 10 is known to serve a molecular switch turning on the mitogen-activated protein kinase pathway in response to hepatocyte growth factor receptor binding. CONCLUSIONS: As suggested by the DNA arrays, we found the mitogen-activated protein kinase kinase/extracellular-regulated kinase pathway to be activated in most of the cutaneous melanoma metastasis specimens. These findings are in the context of the current microarray technology in melanoma research. Additional steps are needed to gain insights into the pluralistic signaling milieu of this malignancy as we enter the postgenomic era.

Biomarkers, Tumor↗
PubMed2005

Recruitment of topoisomerase I (Scl-70) to nucleoplasmic proteasomes in response to xenobiotics suggests a role for altered antigen processing in scleroderma.

OBJECTIVE: Scleroderma, also known as systemic sclerosis (SSc), is a chronic, life-threatening autoimmune disease characterized by a wide spectrum of manifestations and a variable evolution. The presence of particular antinuclear antibodies is often predictive of the clinical expression and prognosis of the disease, but the molecular mechanisms of the immune responses remain unclear. Recently, we have shown xenobiotic-induced recruitment of nuclear autoantigens to proteasomes in the cell nucleus in cell culture and in animal models in correlation with a unique autoantibody response. In this study, we attempted to validate our findings in patients with SSc. METHODS: Using indirect immunofluorescence microscopy, run-on replication and transcription assays, immunoblotting, and proteasome activity assays, we analyzed the nuclear structure, function, and proteasomal proteolysis in HEp-2 cells treated with xenobiotics or left untreated. Blood dendritic cells (DCs) were isolated from 30 patients with SSc and age- and sex-matched control subjects to determine the subcellular localization of SSc autoantigens in relation to proteasomes. RESULTS: Xenobiotics induced a relocation of the SSc autoantigen DNA topoisomerase I (Scl-70, topo I) to nucleoplasmic clusters, where proteasomes degrade topo I. Colocalization of topo I with proteasomes occurred exclusively in DCs from patients with SSc who developed antibodies against this autoantigen. Neither centromeres nor other SSc autoantigens colocalized with proteasomes in DCs from patients with SSc or from control subjects. CONCLUSION: Alteration of nuclear structure and function by xenobiotics induces recruitment of the nuclear autoantigen topo I for proteasomal processing. This event may, in turn, lead to subsequent presentation of the resulting peptides on the cell surface and the autoimmune responses against topo I in SSc.

Antigen Presentation↗
PubMed2005

Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment: An amplification cycle triggering cutaneous lupus erythematosus.

OBJECTIVE: To investigate the activation and recruitment pathways of relevant leukocyte subsets during the initiation and amplification of cutaneous lupus erythematosus (LE). METHODS: Quantitative real-time polymerase chain reaction was used to perform a comprehensive analysis of all known chemokines and their receptors in cutaneous LE lesions, and the cellular origin of these chemokines and receptors was determined using immunohistochemistry. Furthermore, cytokine- and ultraviolet (UV) light-mediated activation pathways of relevant chemokines were investigated in vitro and in vivo. RESULTS: In the present study, we identified the CXCR3 ligands CXCL9 (interferon-gamma [IFNgamma]-induced monokine), CXCL10 (IFNgamma-inducible protein 10), and CXCL11 (IFN-inducible T cell alpha chemoattractant) as being the most abundantly expressed chemokine family members in cutaneous LE. Expression of these ligands corresponded with the presence of a marked inflammatory infiltrate consisting of mainly CXCR3-expressing cells, including skin-homing lymphocytes and blood dendritic cell antigen 2-positive plasmacytoid dendritic cells (PDCs). Within cutaneous LE lesions, PDCs accumulated within the dermis and were activated to produce type I IFN, as detected by the expression of the IFNalpha-inducible genes IRF7 and MxA. IFNalpha, in turn, was a potent and rapid inducer of CXCR3 ligands in cellular constituents of the skin. Furthermore, we demonstrated that the inflammatory CXCR3 ligands cooperate with the homeostatic chemokine CXCL12 (stromal cell-derived factor 1) during the recruitment of pathogenically relevant leukocyte subsets. Moreover, we showed that UVB irradiation induces the release of CCL27 (cutaneous T cell-attracting chemokine) from epidermal compartments into dermal compartments and up-regulates the expression of a distinct set of chemokines in keratinocytes. CONCLUSION: Taken together, our data suggest an amplification cycle in which UV light-induced injury induces apoptosis, necrosis, and chemokine production. These mechanisms, in turn, mediate the recruitment and activation of autoimmune T cells and IFNalpha-producing PDCs, which subsequently release more effector cytokines, thus amplifying chemokine production and leukocyte recruitment, finally leading to the development of a cutaneous LE phenotype.

Cells, Cultured↗
PubMed2005

Creatine supplementation normalizes mutagenesis of mitochondrial DNA as well as functional consequences.

Mutations of mitochondrial (mt) DNA play a role in neurodegeneration, normal aging, premature aging of the skin (photoaging), and tumors. We and others could demonstrate that mtDNA mutations can be induced in skin cells in vitro and in normal human skin in vivo by repetitive, sublethal ultraviolet (UV)-A-irradiation. These mutations are mediated by singlet oxygen and persist in human skin as long-term biomarkers of UV exposure. Although mtDNA exclusively encodes for the respiratory chain, involvement of the energy metabolism in mtDNA mutagenesis and a protective role of the energy precursor creatine have thus far not been shown. We assessed the amount of a marker mutation of mtDNA, the so-called common deletion, by real-time PCR. Induction of the common deletion was paralleled by a measurable decrease of oxygen consumption, mitochondrial membrane potential, and ATP content, as well as an increase of matrix metalloproteinase-1. Mitochondrial mutagenesis as well as functional consequences could be normalized by increasing intracellular creatine levels. These data indicate that increase of the energy precursor creatine protects from functionally relevant, aging-associated mutations of mitochondrial DNA.

Adenosine Triphosphate↗
PubMed2005

Expression of hurpin, a serine proteinase inhibitor, in normal and pathological skin: overexpression and redistribution in psoriasis and cutaneous carcinomas.

Hurpin was identified by differential display analysis studying UV-repressible genes in the keratinocyte cell line HaCaT. We have previously reported that hurpin mRNA is overexpressed in psoriatic skin compared to non-lesional or normal skin; hurpin inhibits cathepsin L and that, after overexpression in keratinocytes, hurpin decreases UV-induced apoptosis. To further study the expression of hurpin, we have isolated monoclonal antibodies against hurpin and analyzed its expression in normal and diseased skin by immunohistochemistry (IHC). In the epidermis of normal skin, we found hurpin to be mainly expressed in the stratum basale. In contrast, we found an enhanced expression of hurpin in the stratum spinosum and stratum granulosum in the majority of diseased skin samples. Within the dermis of normal and diseased skin, hurpin was detected in sebaceous and sweat glands, hair follicles, and endothelial cells of blood vessels. Hurpin was localized in the cytoplasm in normal and diseased skin. Additionally to IHC, we analyzed hurpin expression in selected skin diseases by semiquantitative reverse-transcription polymerase chain reaction. We found overexpression of hurpin mRNA in psoriasis, squamous cell carcinoma (SCC), and actinic keratosis. In contrast, expression of hurpin in melanoma and basal cell carcinoma was comparable to that in normal skin. Overall, the strongest overexpression was observed in SCC and psoriasis. Individual differences in hurpin expression between patients were observed. The increased expression and redistribution of hurpin in diseased skin suggests its possible involvement in inflammatory processes or the regulation of endogenous or pathogen-derived proteinase activity. Additional studies will elucidate the physiological role of hurpin.

Antibodies, Monoclonal↗
PubMed2005

Ultraviolet-free phototherapy.

BACKGROUND: Ultraviolet (UV) radiation phototherapy has been used for decades in the management of common skin diseases. On the other hand, UV radiation is a complete carcinogen and as a consequence, UV phototherapy is usually not used for the long-term management of children and young adults and in combination with topical or systemic immunosuppressants. PURPOSE: The therapeutic effectiveness of a new UV-free irradiation device in the treatment of patients with atopic hand and/or foot eczema was studied. METHODS: In a single-blinded trial 10 patients with atopic hand and/or foot eczema were treated with a sham irradiation device and with the new developed UV-free irradiation device DermoDyne during the following 4 weeks. All irradiation's lasted 30 min per treatment three times weekly. RESULTS: UV-free irradiation was found to induce a significant clinical improvement of atopic hand and foot eczema (P = 0.0001) in marked contrast to the sham-irradiation (P = 0.39). CONCLUSION: Our studies demonstrate that visible light can be successfully used for the treatment of patients with atopic eczema.

Eczema↗