Determinants of disability, quality of life and depression in dermatological patients with systemic scleroderma.

BACKGROUND: Systemic scleroderma (SSc) is a rare disease and knowledge about the relationship between clinical signs, disability, quality of life and depressive symptoms is still limited. Although patients with SSc are frequently treated by dermatologists, the vast majority of published evidence is based on rheumatological samples. OBJECTIVES: To identify determinants of disability, decreased quality of life, and depression in a sample of dermatological patients with SSc. METHODS: This was a cross-sectional study on consecutive patients with SSc attending one specialist dermatological centre between April 2008 and November 2009. Validated questionnaires, the Health Assessment Questionnaire (HAQ), EuroQol (EQ-5D) and the Center for Epidemiologic Studies Depression scale (CES-D) were utilized to measure disability, quality of life and depressive symptoms. Additionally, disease characteristics (SSc subtype, skin thickness, organ involvement), subjective symptoms of SSc, treatment and socioeconomic characteristics were collected by trained investigators. Based on an a priori hypothesized causal model, multivariate logistic regression models were used to analyse determinants of disability, quality of life and depression in patients with SSc. RESULTS: A total of 72 patients [59 female (82%), mean age 59years] were enrolled. According to the CES-D, 69% (48 out of 70) were screened positive for depression. Quality of life impairment and female sex and were independent risk factors for depressive symptoms. Disease-specific disability was the main determinant of quality of life impairment in SSc. Pain involvement of the musculoskeletal system and male sex were the main determinants of disability in our sample of patients with SSc. CONCLUSIONS: The high psychosomatic morbidity in our sample of consecutive patients with SSc calls for the investigation of interdisciplinary models of care.

[Fast and efficient healing of scleroderma-associated acral ulcers with sildenafil]. / Rasche Abheilung von akralen Ulzera bei systemischer Sklerodermie unter Sildenafil.

Acral ulcers in patients with progressive systemic sclerosis (PSS) are often recalcitrant to therapy. Sildenafil, an inhibitor of phosphodiesterase-5, dilates small arteries by increasing endothelial cGMP. Oral administration of sildenafil to a 35-year-old white male patient suffering from incapacitating PSS with severe pulmonary arterial hypertension and acral ulcers induced a clinically significant reduction in dyspnea and increase in walking distance within one week as well as complete and long-lasting healing of all ulcers within five weeks. This case demonstrates the efficacy of sildenafil in the treatment of scleroderma-associated refractory acral ulcers.

[Therapy of systemic sclerosis]. / Therapie bei systemischer Sklerodermie.

The therapy of systemic sclerosis (SSc) remains a challenge for dermatology, rheumatology, internal medicine, and other disciplines. Organ involvement, above all kidney and lungs, is a key therapeutic issue. The current developments in organ-specific therapy are the main topic of the article. Finally, possibilities of disease-modifying drugs and value of HSCT are discussed.

[Therapy of cutaneous metastases of malignant melanoma]. / Therapie von Hautmetastasen beim malignen Melanom.

Malignant melanoma represents a particular challenge for dermatologists and oncologists because of its high and increasing incidence and the poor prognosis of patients with thick primary tumors (T3, T4). In advanced stages of melanoma, cutaneous and subcutaneous metastases have a special significance, as they markedly affect the patient and may lead to a limitation in quality of life. While topical therapy is possible, there are only limited clinical studies. The location, number, size and distribution of skin metastases, involvement of internal organs, age and general condition should be considered in assessing therapeutic options. Especially with solitary, easily accessible metastases, surgical excision represents the therapy of choice. Ablation using CO(2) laser is an alternative. With extensive metastases in just one extremity, isolated limb perfusion (ILP) with melphalan is an option, while multiple, smaller metastases can be irradiated. Further, several chemotherapeutic agents and immune modulators can be used topically, peri- and intralesionally.

Protein-kinase-Cmu expression correlates with enhanced keratinocyte proliferation in normal and neoplastic mouse epidermis and in cell culture.

In order to gain insight into the biological function of a PKC iso-enzyme, the protein kinase Cmu, we analyzed the expression pattern of this protein in mouse epidermis and keratinocytes in culture. Daily analysis of neonatal mouse epidermis immediately after birth showed a time-dependent reduction in the PKCmu content. Expression of the proliferating-cell nuclear antigen (PCNA), indicative of the proliferative state of cells, was reduced synchronously with PKCmu as the hyperplastic state of the neonatal tissue declined. In epidermal mouse keratinocytes, fractionated according to their maturation state, PKCmu expression was restricted to PCNA-positive basal-cell fractions. In primary cultures of those cells, growth arrest and induction of terminal differentiation by Ca2+ resulted in strongly reduced PKCmu expression, concomitantly with the loss of PCNA expression. Treatment of PMK-R1 keratinocytes with 100 nM of the mitogen 12-O-tetradecanoylphorbol-13-acetate (TPA) resulted in activation of PKCmu, reflected by translocation from the cytosolic to the particulate fraction and by shifts in electrophoretic mobility. DNA synthesis was significantly inhibited by the PKCmu inhibitor Goedecke 6976, while Goedecke 6983 did not inhibit PKCmu. Carcinomas generated according to the 2-stage carcinogenesis protocol in mouse skin consistently exhibited high levels of PKCmu. These data correlate PKCmu expression with the proliferative state of murine keratinocytes and point to a role of PKCmu in growth stimulation. A correlation between PKCmu expression and enhanced cell proliferation was also observed for NIH3T3 fibroblasts transfected with and overexpressing human PKCmu.

Differential expression of the regularly spliced wild-type p53 and its COOH-terminal alternatively spliced form during epidermal differentiation.

In the present study, we investigated the role of p53 in the differentiation of epidermal keratinocyte cells. The interrelationship between p53 expression and the various stages of epidermal differentiation and the role of the COOH terminus of the p53 molecule in this process were determined by comparing the expression of the regularly spliced p53 (RSp53) molecule and that of the COOH-terminal alternatively spliced (ASp53) form. p53 mRNA distribution was studied by in situ analysis of frozen skin sections and by reverse transcription-PCR analysis of the various wild-type p53 forms expressed in neonatal skin cell fractions separated by Percoll gradient. p53 protein levels were measured by fluorescence-activated cell sorting analysis and immunohistochemistry, using antibodies that recognize either the COOH terminus of RSp53 or ASp53. The results show that although less mature keratinocyte cells predominantly express the RSp53 form, the more mature cells preferentially express the ASp53 form. Therefore, it is possible that the two p53 forms are associated with different functions required at the various stages of keratinocyte differentiation. The results suggest that the COOH-terminal domain of the p53 molecule is important for its activity in the process of keratinocyte differentiation.

Cloning and characterization of murine p16INK4a and p15INK4b genes.

Progression through the G1 phase of the cell cycle is regulated in part by the D-type cyclin-dependent kinases, cdk4 and cdk6. Genes encoding two specific inhibitors of these kinases, human p16(INK4a/MTS1) and p15(INK4b/MTS2), map to a region of common cytogenetic abnormalities on chromosome 9p21. The murine cognates of these genes were isolated and identified as mouse p16INK4a and p15INK4b based on their homology to their human counterparts and their selective transcriptional induction by SV40T-antigen and TGF-beta, respectively. Both genes map to position C3-C6 on mouse chromosome 4, in a region syntenic with human chromosome 9p. Amplification of polyadenylated mRNA by polymerase chain reactions revealed no expression of mouse p16INK4a in many normal tissues, whereas p15INK4b was expressed ubiquitously. Like human p16INK4a, mouse p16INK4a binds specifically to cdk4 and cdk6 in vitro and inhibits the phosphorylation of the retinoblastoma protein, pRb, by each of these cyclin D-dependent kinases. In mouse MEL erythroleukemia cells, p16INK4a associates preferentially with cdk6 under conditions where cdk4 and cdk6 are coexpressed at equivalent levels. Expression vectors encoding human or mouse p16INK4a caused G1 phase arrest in NIH3T3 fibroblasts, and cyclin D1- and cdk4-dependent pRb kinase activities were inhibited in the p16INK4a-arrested cells.

Heterotetrameric structure of the human progesterone receptor.

Nonactivated progesterone receptors in extracts of human T47D mammary carcinoma cells were investigated. Chemical cross-linking with dimethyl suberimidate resulted in complete stabilization of the A and B receptors with an average molecular mass of 340 kDa. For analyzing the subunit structure, we concentrated on the larger B receptor, which was separated from the A form by immunoaffinity chromatography. Progressive cross-linking of the photoaffinity-labeled receptor resulted in patterns of labeled bands in SDS gels, which are indicative of a heterotetrameric structure. It consists of one receptor polypeptide in association with two 90-kDa subunits and one polypeptide of approximately 60 kDa. The completely cross-linked B receptor has a molecular mass of approximately 390 kDa. To identify the subunits, the oligomeric B receptor was cross-linked with a cleavable bisimidate, highly purified by immunoaffinity chromatography, and analyzed by gel electrophoresis and immunoblotting. The receptor polypeptide has a mass of 116.5 kDa. The 90-kDa band was identified as the heat shock protein hsp90 and was roughly twice as intense as the receptor polypeptide. By use of specific antibodies, we identified the fourth receptor subunit as a 59-kDa protein (p59); we did not obtain any evidence for the heat shock protein hsp70 being a receptor component. We suggest an analogous heterotetrameric structure for the nonactivated A receptor.