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Biomedical subjects

Jürgen Kopp

Publications and source records attributed to Jürgen Kopp.

At least 19 recordsLinked to original sources
PubMed2006

Plasminogen activator inhibitor-I-related regulation of procollagen I (alpha1 and alpha2) by antitransforming growth factor-beta1 treatment during radiation-impaired wound healing.

PURPOSE: Plasminogen activator inhibitor (PAI)-1 mediates transforming growth factor-beta1 (TGF-beta1)-related signaling by stimulating collagen Type I synthesis in radiation-impaired wound healing. The regulation of alpha(I)-procollagen is contradictory in fibroblasts of different fibrotic lesions. It is not known whether anti-TGF-beta1 treatment specifically inhibits alpha(I)-procollagen synthesis. We used an experimental wound healing study to address anti-TGF-beta1-associated influence on alpha(I)-procollagen synthesis. METHODS AND MATERIALS: A free flap was transplanted into the preirradiated (40 Gy) or nonirradiated neck region of Wistar rats: Group 1 (n = 8) surgery alone; Group 2 (n = 14) irradiation and surgery; Group 3 (n = 8) irradiation and surgery and anti-TGF-beta1 treatment. On the 14th postoperative day, skin samples were processed for fibroblast culture, in situ hybridization for TGF-beta1, immunohistochemistry, and immunoblotting for PAI-1, alpha1/alpha2(I)-procollagen. RESULTS: Anti-TGF-beta1 significantly reduced TGF-beta1 mRNA (p < 0.05) and PAI-1 expression (p < 0.05). Anti-TGF-beta1 treatment in vivo significantly reduced alpha1(I)-procollagen protein (p < 0.05) and the number of expressing cells (p < 0.05) in contrast to significantly increased (p < 0.05) alpha2(I)-procollagen expression. CONCLUSION: These results emphasize anti-TGF-beta1 treatment to reduce radiation-induced fibrosis by decreasing alpha1(I)-procollagen synthesis in vivo. alpha1(I)-procollagen and alpha2(I)-procollagen might be differentially regulated by anti-TGF-beta1 treatment. Increased TGF-beta signaling in irradiated skin fibroblasts seemed to be reversible, as shown by a reduction in PAI-1 expression after anti-TGF-beta1 treatment.

Animals↗
PubMed2006

The SWISS-MODEL Repository: new features and functionalities.

The SWISS-MODEL Repository is a database of annotated 3D protein structure models generated by the SWISS-MODEL homology-modelling pipeline. As of September 2005, the repository contained 675,000 models for 604,000 different protein sequences of the UniProt database. Regular updates ensure that the content of the repository reflects the current state of sequence and structure databases, integrating new or modified target sequences, and making use of new template structures. Each Repository entry consists of one or more 3D models accompanied by detailed information about the target protein and the model building process: functional annotation, a detailed template selection log, target-template alignment, summary of the model building and model quality assessment. The SWISS-MODEL Repository is freely accessible at http://swissmodel.expasy.org/repository/.

Computer Graphics↗
PubMed2006

Increased metabolic activity of fibroblasts derived from cords compared with nodule fibroblasts sampling from patients with Dupuytren's contracture.

BACKGROUND: The pathogenesis of Dupuytren's contracture is characterized by progress in several stages. The disease process includes two structurally distinct fibrotic elements, the so-called nodule and the cord. Several hypotheses have been proposed regarding the cause. Until now, there has been ongoing discussion regarding whether cords or nodules are the primary source of the disease. METHODS: Tissues from 24 patients with Dupuytren's disease were obtained during hand surgery, providing samples from nodules and cords for cell culture. Tissue from the flexor retinaculum excised from healthy patients during surgical procedures on the hand served as control. By using the explant culture technique, fibroblasts were isolated and grown in standard medium. Besides morphological analysis, XTT proliferation tests were performed at various time periods to measure the metabolic activity of the cultivated fibroblasts. RESULTS: Statistical analysis revealed significant differences of nodule- and cord-derived fibroblasts after 1 hour (p = 0.0150), 8 hours (p < 0.0001), and 16 hours (p < 0.0001). CONCLUSIONS: The authors suggest that distinct proliferative properties of Dupuytren-derived fibroblasts are dependent on the cells' origin. Conclusions about the cause or pathogenesis cannot yet be drawn. Further investigation concerning their apparently different fibroproliferative properties is necessary.

Cells, Cultured↗
PubMed2005

The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling.

MOTIVATION: Homology models of proteins are of great interest for planning and analysing biological experiments when no experimental three-dimensional structures are available. Building homology models requires specialized programs and up-to-date sequence and structural databases. Integrating all required tools, programs and databases into a single web-based workspace facilitates access to homology modelling from a computer with web connection without the need of downloading and installing large program packages and databases. RESULTS: SWISS-MODEL workspace is a web-based integrated service dedicated to protein structure homology modelling. It assists and guides the user in building protein homology models at different levels of complexity. A personal working environment is provided for each user where several modelling projects can be carried out in parallel. Protein sequence and structure databases necessary for modelling are accessible from the workspace and are updated in regular intervals. Tools for template selection, model building and structure quality evaluation can be invoked from within the workspace. Workflow and usage of the workspace are illustrated by modelling human Cyclin A1 and human Transmembrane Protease 3. AVAILABILITY: The SWISS-MODEL workspace can be accessed freely at http://swissmodel.expasy.org/workspace/

Algorithms↗
PubMed2005

Abrogation of transforming growth factor-beta signaling by SMAD7 inhibits collagen gel contraction of human dermal fibroblasts.

Human fibroproliferative disorders like hypertrophic scarring of the skin are characterized by increased contractility and excess extracellular matrix synthesis. A beneficial role of transforming growth factor (TGF)-beta in wound healing was proposed; however, chronic stimulation by this cytokine leads to fibrosis. In the present report, the intracellular TGF-beta signaling in fibroblasts derived from hypertrophic scars and normal skin was examined. In an attempt to intervene in profibrogenic TGF-beta functions, ectopic expression of Smad7 or dominant negative Smads3/4 completely inhibited contractility of scar-derived and normal fibroblasts after suspension in collagen gels. Both cell types displayed constitutive Smad2/3 phosphorylation and (CAGA)9-MLP-Luc activity with expression and phosphorylation of Smad3 being predominant in hypertrophic scar-derived fibroblasts. Down-regulation of intrinsic signaling with various TGF-beta antagonists, e.g. soluble TGF-beta receptor, latency-associated peptide, and anti-TGF-beta1 antibodies, confirms autocrine TGF-beta stimulation of both cell populations. Further, Smad7 expression inhibited alpha1 (I) collagen and alpha-smooth muscle actin expression. In summary, our data indicate that autocrine TGF-beta/Smad signaling is involved in contractility and matrix gene expression of fibroblasts from normal and hypertrophic scars. Smad7 inhibits these processes and may exert beneficial effects on excessive scar formation.

Actins↗
PubMed2005

Treatment of second degree facial burns with allografts--preliminary results.

Facial burns are very common and have significant clinical impact. However, the treatment regimen for superficial to deep facial burns is not well defined. The purpose of this study was to investigate the effects of cadaver skin grafting in deep partial thickness facial burns in comparison to standard care. In a prospective open study design severely injured patients with superficial and deep partial thickness burns were randomized into the group receiving open treatment with silversulfadiazine (standard n=5) or into the group receiving early superficial debridement followed by coverage with glycerolized cadaver skin (n=5). The outcome measures were time and quality of wound healing, and incidence of hypertrophic scarring at 3 and 6 months post burn. There were no significant differences in demographics between groups. In the group treated with the allogenic material time to reepithelialization was 10.5 days, while it was 12.4 days in the silversulfadiazine group (p<0.05). Scar quality was found to be significantly improved in the allogenic treatment group. Three and 6 months postburn there were no patients with significant hypertrophic scarring in the allogenic group while there were two patients who developed hypertrophic scars in the silversulfadiazine group (p<0.05). In this study, we demonstrated that glyzerolized cadaver allograft skin represents a superior biological dressing for shallow and deep partial thickness facial burns. This is in concordance with other reports on scalds. It would be worthwhile to perform more clinical studies with a larger number of patients to further evaluate the effect and function of allogenic skin for facial burns.

Adult↗
PubMed2005

Expression of bone morphogenic protein 2/4, transforming growth factor-beta1, and bone matrix protein expression in healing area between vascular tibia grafts and irradiated bone-experimental model of osteonecrosis.

PURPOSE: For the surgical treatment of osteoradionecrosis after multimodal therapy of head-and-neck cancers, free vascular bone grafts are used to reconstruct osseous structures in the previously irradiated graft bed. Reduced, or even absent osseous healing in the transition area between the vascular graft and the irradiated graft bed represents a clinical problem. Inflammatory changes and fibrosis lead to delayed healing, triggered by bone morphogentic protein 2/4 (BMP2/4) and transforming growth factor (TGF)-beta(1). Given the well-known fibrosis-inducing activity of TGF-beta(1), an osteoinductive effect has been reported for BMP2/4. However, the influence of irradiation (RT) on this cytokine expression remains elusive. Therefore, the aim of the present in vivo study was to analyze the expression of BMP2/4, TGF-beta(1), collagen I, and osteocalcin in the transition area between the bone graft and the graft bed after RT. METHODS AND MATERIALS: Twenty Wistar rats (male, weight 300-500 g) were used in this study. A free vascular tibia graft was removed in all rats and maintained pedicled in the groin region. Ten rats underwent RT with 5 x 10 Gy to the right tibia, the remainder served as controls. After 4 weeks, the previously removed tibia grafts were regrafted into the irradiated (Group 1) and nonirradiated (Group 2) graft beds. The interval between RT and grafting was 4 weeks. After a 4-week osseous healing period, the bone grafts were removed, and the transition area between the nonirradiated graft and the irradiated osseous graft bed was examined histomorphometrically (National Institutes of Health imaging program) and immunohistochemically (avidin-biotin-peroxidase complex) for the expression of BMP2/4, TGF-beta(1), collagen I, and osteocalcin. RESULTS: Absent or incomplete osseous healing of the graft was found in 9 of 10 rats after RT with 50 Gy and in 1 of 10 of the rats with nonirradiated osseous grafts. Histomorphometrically, the proportion of osseous healing in the transition area was 17% in Group 1 and 48% in Group 2 (p = 0.001). Compared with the nonirradiated rats, reduced enchondral and perichondral ossification was found in the healing area after RT, with a reduction of BMP2/4 and osteocalcin expression. TGF-beta(1) and collagen I expression in the transition area to the irradiated osseous graft bed was significantly increased compared with that in the nonirradiated osseous graft bed. CONCLUSION: After RT, osseous healing of vascular bone grafts is significantly reduced and may be a result of radiation-induced inhibition of BMP2/4 and osteocalcin expression. In addition, induction of TGF-beta(1) and collagen I expression occurs. Because the effects of the TGF-beta superfamily are manifold and partially unknown, additional research directions could be in the exogenous application of BMP2/4 and inhibition of TGF-beta(1) by antibody treatment to search for appropriate therapeutic approaches for improving osseous healing in the irradiated graft bed.

Animals↗
PubMed2005

Vacuum application increases therapeutic safety and allows intensified local radiation treatment of malignant soft-tissue tumors.

PURPOSE: In order to simplify and improve outcome of radiation therapy and final defect coverage in patients suffering from invasive soft-tissue tumors, brachytherapy and application of V.A.C.uum-assisted closure (V.A.C.) were combined with delaying flap incision. PATIENTS AND METHODS: Two patients were excised as radically as possible and brachytherapy tubes were implanted directly on the tumor bed. At the same time, flaps for later defect coverage were preconditioned by circumcision. Brachytherapy and external- beam irradiation were performed directly on the vacuum sponge followed by subsequent defect coverage with the preconditioned flaps. RESULTS: Excision significantly reduced tumor masses in both patients; in one case sensible and motor function of the involved extremity was clearly improved. V.A.C. coverage allowed repeated brachytherapy and external-beam applications following exact placing of plastic tubes and FLABs on the tumor bed. Sequential irradiation had no effect on neighboring flap tissues, which healed without impairment following transposition. CONCLUSION: Combination of V.A.C. and brachytherapy can effectively replace circumstantial and laborious IORT (intraoperative radiotherapy) procedures. Exact placement of tubes on the tumor bed without subsequent tissue coverage is conserving preconditioned flap tissues, which are transposed for final defect coverage at the end of radiotherapy. However, by circumventing radiation exposure of these tissues, a possible later irradiation sequence can be performed without endangering defect-covering flaps.

Adult↗
PubMed2004

The versatility of the free osteocutaneous fibula flap in the reconstruction of extremities after sarcoma resection.

BACKGROUND: An understanding of the biology of bone and soft-tissue sarcomas, knowledge of adjuvant therapies and refinement in techniques of reconstructive surgery have allowed limb-sparing and limb salvage surgery to become a reality in the management of malignant tumors of the extremities. Functional limb salvage following radical resection has become a possibility in many resectable tumors by the use of alloplastic prostheses, homograft or autogenous bone for skeletal reconstitution combined with vascularized soft tissue coverage. Although the free fibula flap has been well described for reconstructions of the mandible and oral cavity, it has not been widely presented as an ideal tool to preserve extremities and to circumvent amputation. PATIENTS AND METHODS: We describe the complex surgical reconstruction in four patients with primary sarcomas of the extremities. The sarcomas (Ewing's sarcoma, osteosarcoma and epitheloid sarcoma) were resected radically and the massive bone and soft tissue defect was replaced by vascularized free fibula transfer. RESULTS: We present our experience with versatility of this osteocutaneous flap to allow reconstruction and salvage of extremitity sarcomas. There were no operative or postoperative complication and all the four patients had good limb function. The flap was found to be versatile as it could be used for either upper limb or lower limb and for large defects. The results were better in upper limb than in lower limb. CONCLUSIONS: Free fibular graft was found to be effective for salvaging limb function where a massive bone defect resulted from wide tumor resection in the extremities.

Journal Article↗
PubMed2004

The SWISS-MODEL Repository of annotated three-dimensional protein structure homology models.

The SWISS-MODEL Repository is a database of annotated three-dimensional comparative protein structure models generated by the fully automated homology-modelling pipeline SWISS-MODEL. The Repository currently contains about 300,000 three-dimensional models for sequences from the Swiss-Prot and TrEMBL databases. The content of the Repository is updated on a regular basis incorporating new sequences, taking advantage of new template structures becoming available and reflecting improvements in the underlying modelling algorithms. Each entry consists of one or more three-dimensional protein models, the superposed template structures, the alignments on which the models are based, a summary of the modelling process and a force field based quality assessment. The SWISS-MODEL Repository can be queried via an interactive website at http://swissmodel.expasy. org/repository/. Annotation and cross-linking of the models with other databases, e.g. Swiss-Prot on the ExPASy server, allow for seamless navigation between protein sequence and structure information. The aim of the SWISS-MODEL Repository is to provide access to an up-to-date collection of annotated three-dimensional protein models generated by automated homology modelling, bridging the gap between sequence and structure databases.

Animals↗
PubMed2004

Correlation between serum creatinine kinase levels and extent of muscle damage in electrical burns.

The relationship between clinical course and changes of laboratory findings in patients with high-voltage electrical burns with regard to creatinine kinase activity was analyzed in order to determine the value of this prognostic parameter with regard to patients survival and risk of limb amputation. In a retrospective study 42 patients with electrical burns were reviewed. CK serum levels were determined every day during the first 10 days following submission. Analysis of data revealed a relation between strongly elevated CK levels and patients risk of limb amputation and mortality. Although further research is necessary, there is strong evidence that the amount of burned body surface area does not directly correlate with the true extent of tissue damage caused by high tension injuries. Our data suggest that the degree of muscle tissue violation corresponds with the initial excess of creatinine kinase levels in blood serum. This may be an additional factor to support the decision for early surgical decompression of electrically burned extremities and aggressive surgical management of the high-voltage burn victim. Furthermore, it may provide a prognostic parameter for the clinical outcome of these patients.

Adolescent↗
PubMed2004

Smad-3 and Smad-7 expression following anti-transforming growth factor beta 1 (TGFbeta1)-treatment in irradiated rat tissue.

BACKGROUND AND PURPOSE: Wound healing disorders and the development of fibrosis following surgery in preirradiated tissue are clinically well characterised and may even become more pronounced with increasing use of neoadjuvant radiochemotherapy. The cytokine transforming growth factor beta 1 TGFbeta1 has a key role either in the wound healing process or induction of fibrosis. Following activation of the TGFbeta receptors, intracellular signal transduction is mediated by a variety of Smad proteins. Smad-3 acts as an activator of signal transduction, whereas Smad-7 has an inhibitory effect. This study evaluated the biological effect of neutralizing TGFbeta1 antibodies, the relationship between TGFbeta1 and Smad-3/7 expression and changes of collagen synthesis, following inhibition of TGFbeta1 activity in irradiated rat tissue. PATIENTS AND METHODS: A total of 45 Wistar rats (male, weight 300-450 g) were used. A free myocutaneous gracilis flap was transplanted in all rats and animals were allocated into 3 groups as follows: Group 1 (n = 15 rats) treated with surgery alone (TX); Group 2 (n = 15 rats) preoperative radiotherapy (RT) followed by TX; Group 3 (n = 15 rats) RT+TX+anti-TGFbeta1-treatment. The interval between end of radiotherapy and grafting was 10 days. For anti-TGFbeta1 treatment, 1 microg anti-TGFbeta1/500 microl PBS were locally applied s.c. intraoperatively and on day 1 to 7 after surgery. Tissue samples were collected perioperatively and on days 3, 7, 14, 28 following surgery from the transition area between the graft and the graft bed. ECM synthesis and expression of TGFbeta1, Smad-3, Smad-7, prolyl-hydroxyprolinase-beta were quantitated by immunohistochemistry (labelling indices). Changes in collagen synthesis were assessed qualitatively by polarisation microscopy of sirius red staining and collagen I immunohistochemistry. The different regulation of inhibitory Smad-7 was detected in irradiated and irradiated plus anti-TGFbeta1 treated animals by semiquantitative RT-PCR and the nucleocytoplasmic shuttling of phosphorylated Smad-3 was shown by isolation of nuclear proteins and Western blot analysis. RESULTS: Following anti-TGFbeta1 treatment, an attenuated expression of TGFbeta1, a reduction in EMC synthesis and fibrosis could be observed in irradiated tissue compared to the irradiated tissue without anti-TGFbeta1-treatment. While preoperative RT increases the expression of Smad-3/7 proteins, an upregulation of Smad-7 from day 3 until day 14 following surgery and a downregulation of Smad-3 on day 14 after surgery could be observed following anti-TGFbeta1-treatment. The samples which were irradiated alone displayed a reduced signal for Smad-7 mRNA and an induction of Smad-3 protein phosphorylation shown by nucleocytoplasmic shuttling. In contrast, the anti-TGFbeta1-treated samples showed an increase in Smad-7 mRNA and a downregulation of Smad-3 phosphorylation. Prolyl-hydroxyprolinase-beta expression and collagen I synthesis were reduced following anti-TGFbeta1-treatment. CONCLUSIONS: A reduction of Smad-3 proteins in parallel with an increase of Smad-7 may contribute to the inhibitory effect and the reduction of ECM synthesis after blocking of TGFbeta1 activity by treatment with neutralizing antibodies. This may indicate a molecular mechanism in the therapeutic intervention to reduce fibrosis, hypertrophic scar formation and chronic wound healing disorders.

Animals↗
PubMed2004

Accelerated wound healing by in vivo application of keratinocytes overexpressing KGF.

Epidermal regeneration is a complex process, strongly influenced by growth factors, including keratinocyte growth factor (KGF). The objective of this study was to establish immortalized HaCaT keratinocytes and KMST-6-fibroblasts stably expressing KGF. Transfection efficiency, genomic integration, and functionality of the transgene were determined by ELISA and PCR, and KGF-expressing clones were selected using an air-liquid interface test system. HaCaT cells displayed stronger transgene expression compared to transfected fibroblasts, and the most effective HaCaT clone was incubated on a membrane carrier to form a "membrane cell graft." Twenty-one superficial second-degree burn wounds were created in each of three pigs, and wound healing capacity of the generated "polypeptide cell delivery system" after grafting was examined. Untransfected HaCaT keratinocytes and membrane-covered and untreated burn wounds served as controls. Histological and macroscopical follow-up revealed that grafting of transfected HaCaT cells resulted in complete reepithelialization within 5 days, while wounds covered with untransfected cells needed 2 days longer. At untreated sites, a thin epithelium was detectable after 10 days. The results indicate that wound healing processes can be stimulated distinctly by growth factors secreted from HaCaT cells, with a prominent role for transgenic KGF.

Animals↗
PubMed2004

Applied tissue engineering in the closure of severe burns and chronic wounds using cultured human autologous keratinocytes in a natural fibrin matrix.

Whereas in severe burns cultured human epithelial cells may well serve as a life saving method, the true value of tissue-engineered skin products in chronic wound care has yet to be clearly defined. Among other well-known clinical problems, the engraftment rate of commercially available multilayered "sheet grafts" has been shown to vary extremely. Adherence of transplanted cells to the wound bed--especially in the presence of potential wound contamination-- is one of the crucial aspects of this technique. Keratinocyte suspensions in a natural fibrin sealant matrix can potentially treat a variety of skin defects. In acute burn wounds, as well as in chronic wounds the clinical application of this type of tissue-engineered skin substitute demonstrates the capacity of cultured human autologous keratinocytes in a fibrin sealant matrix to adhere to wound beds, attach and spread over the wound resulting in reepithelialization of both acute and chronic wounds. In full thickness burns the combination of this new tool with allogenic dermis is a promising option to achieve complete dermal-epidermal reconstitution by means of tissue engineering and guided tissue repair. When transferring this technique into the treatment of chronic wounds we found an optimal preparation of such recipient wound beds to be crucial to the success. The additional application of continuous negative pressure (vacuum therapy) and preliminary chip skin grafting to optimally prepare the recipient site may be helpful tools to achieve such well-prepared and graftable surfaces. Prospective controlled comparative studies should be designed to further assess the clinical efficacy of this technique.

Burns↗
PubMed2004

Buried chip skin grafting in neuropathic diabetic foot ulcers following vacuum-assisted wound bed preparation: enhancing a classic surgical tool with novel technologies.

In patients with diabetes mellitus, complications such as polyneuropathy and peripheral angiopathy inevitably lead to diabetic foot complications including foot ulcers, gangrene, and osteoarthropathy. These conditions necessitate minor or major amputation as part of treatment. In patients with Charcot's arthropathy and predominant neuropathy, recurrent foot ulcers are common in areas of high pressure. Such high pressure is caused by the degrading of the architecture of the foot and inadequate footwear. These patients are a clinical challenge. A select group of such patients may benefit from free surgical tissue transfer, though free or local flap surgery is often difficult or even impossible owing to an impaired arterial circulation. In such wounds, surgical debridement followed by skin grafts often fail due to bacterial burden in the wounds. To circumvent these problems, the authors developed a therapeutic approach using buried chip skin grafting to close granulation wound beds in diabetic feet. Locally applied vacuum therapy (VAC) for wound bed preparation of chronic, nonresponsive foot ulcers and subsequent grafting using the burying technique with a minute fraction of skin was used. Firm closure was achieved. The closed wound was resistant to mechanical irritation.

Journal Article↗