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  • 1
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  42. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh); 28. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh); 24. wissenschaftliche Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR); 20140917-20140920; Düsseldorf; DOCER.25 /20140912/
    Publication Date: 2014-09-13
    Keywords: Rheumatoid arthritis ; synovial fibroblasts ; T lymphocytes ; tryptophan metabolism ; ddc: 610
    Language: English
    Type: conferenceObject
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  • 2
    Keywords: CELLS ; IN-VITRO ; BLOOD ; CELL ; COMBINATION ; Germany ; MODEL ; THERAPY ; VITRO ; DRUG ; METABOLISM ; PATIENT ; MACROPHAGES ; murine ; CONTRAST ; treatment ; antibody ; TARGET ; NUMBER ; DELIVERY ; PHARMACOKINETICS ; DOUBLE-BLIND ; PERIPHERAL-BLOOD ; T lymphocytes ; MONONUCLEAR-CELLS ; METHOTREXATE ; COLLAGEN-INDUCED ARTHRITIS ; albumin ; DRUG-DELIVERY ; rheumatoid arthritis ; RHEUMATOID-ARTHRITIS ; II COLLAGEN ; LOW-DOSE METHOTREXATE ; PLACEBO-CONTROLLED TRIAL ; RHEUMATOID-ARTHRITIS PATIENTS
    Abstract: Objective. To evaluate the anti-arthritic effects of the new inflammation-targeted drug MTX-HSA and to investigate whether peripheral blood mononuclear cells (PBMC) are potential target cells for albumin-mediated drug delivery. Methods. The murine model of collagen-induced arthritis (CIA) was used to measure the anti-arthritic effect of MTX, MTX-HSA or a combination of both (n = 30 to 35 per group). In addition, the uptake of fluorescence-labelled albumin (AFLc-HSA) in PBMC of 14 patients with RA was measured by fluorescence-activated cell sorting (FACS). Results. In equivalent doses of 7.5 mg/kg intravenously (IV) twice a week, MTX-HSA is significantly (P〈0.02) superior to MTX in inhibiting the development of CIA and reducing the joint count as well as the number of affected paws. When given in lower doses as combination therapy, both drugs act synergistically (P〈0.03). A mean of 96, 72 and 64% of the CD14-, CD16- and CD20-positive cells from peripheral blood of rheumatoid arthritis (RA) patients showed an uptake of albumin after incubation with AFLc-HSA in vitro. This finding was not significantly different in comparison to healthy controls. In contrast, the number of CD3-positive cells taking up albumin is increased significantly in RA patients in comparison to controls (26.3 +/- 12.9% s.d. vs 11.6 +/- 7.3% s.d.; P = 0.005). Conclusion. The data show that the effectiveness of MTX-HSA in CIA is superior to MTX and that both drugs act synergistically. In addition, albumin appears to be taken up by peripheral blood cells, suggesting that they might be one of the potential target cells of this novel anti-arthritic treatment approach
    Type of Publication: Journal article published
    PubMed ID: 15199219
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  • 3
  • 4
    Keywords: CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; tumor ; CLINICAL-TRIAL ; human ; IN-VIVO ; MODEL ; liver ; PROTEIN ; PROTEINS ; DRUG ; TISSUE ; TUMORS ; MICE ; PATIENT ; SERA ; fibroblasts ; treatment ; MOUSE ; EFFICACY ; drug delivery ; CONJUGATE ; PHARMACOKINETICS ; BEARING RATS ; COLLAGEN-INDUCED ARTHRITIS ; FIBROBLAST-LIKE SYNOVIOCYTES ; LOW- DOSE METHOTREXATE ; SYNOVIAL FIBROBLASTS
    Abstract: We reported recently that albumin is a suitable drug carrier for targeted delivery of methotrexate (MTX) to tumors. Due to pathophysiological conditions in neoplastic tissue, high amounts of albumin accumulate in tumors and are metabolized by malignant cells. MTX, covalently coupled to human serum albumin (MTX-HSA) for cancer treatment, is currently being evaluated in phase II clinical trials. Because synovium of patients with rheumatoid arthritis (RA) shares various features observed also in tumors, albumin-based drug targeting of inflamed joints might be an attractive therapeutic approach. Therefore, the pharmacokinetics of albumin and MTX in a mouse model of arthritis was examined. Additionally, uptake of albumin by synovial fibroblasts of RA patients and the efficacy of MTX and MTX-HSA in arthritic mice were studied. The results show that when compared with MTX, significantly higher amounts of albumin accumulate in inflamed paws, and significantly lower amounts of albumin are found in the liver and the kidneys. The protein is metabolized by human synovial fibroblasts in vitro and in vivo. MTX-HSA was significantly more effective in suppression of the onset of arthritis in mice than was MTX. In conclusion, albumin appears to be a suitable drug carrier in RA, most likely due to effects on synovial fibroblasts, which might increase therapeutic efficacy and reduce side effects of MTX
    Type of Publication: Journal article published
    PubMed ID: 12707361
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  • 5
    Keywords: INVASION ; Germany ; human ; IN-VIVO ; MODEL ; VIVO ; MICE ; GENE-TRANSFER ; REDUCTION ; INDUCTION ; CONTRAST ; fibroblasts ; treatment ; MOUSE ; score ; IMMUNODEFICIENT MICE ; DEGRADATION ; MOUSE MODEL ; METHOTREXATE ; BEARING RATS ; albumin ; fibroblast ; rheumatoid arthritis ; RHEUMATOID-ARTHRITIS ; CYTOKINE INHIBITORS ; DESTRUCTION ; INTERLEUKIN-1
    Abstract: Objective: To investigate the effect of methotrexate (MTX) and albumin coupled with methotrexate (MTX-HSA) on cartilage invasion and induction of perichondrocytic degradation by rheumatoid arthritis synovial fibroblasts ( RA SF) in vivo. Methods: Human cartilage and RA SF were co-transplanted in three groups of severe combined immunodeficient mice ( SCID), which received 1 mg/kg free MTX (n = 9), 1 mg/kg MTX-HSA ( n = 6), or 0.9% NaCl ( n = 5), respectively, intraperitoneally twice a week. After 4 weeks' treatment, the mice were killed and the implants analysed histologically. Results: The control group had a mean (SEM) score for cartilage invasion of RA SF of 2.0 (0.26) and for perichondrocytic cartilage degradation of 1.5 (0.34). In contrast, mice which received MTX showed a significantly reduced invasion (0.78 (0.14), p〈 0.01) and a reduction in perichondrocytic cartilage degradation scores (0.69 (0.2), p〈 0.05) in comparison with the control group. Mice treated with MTX-HSA also had significantly reduced scores for RA SF invasion into the cartilage (0.92 (0.41), p〈 0.05) and for cartilage degradation (0.83 (0.44), p〈 0.05) compared with controls. The effects of MTX and MTX-HSA were not significantly different between these two groups. Conclusion: Treatment with MTX or MTX-HSA significantly ameliorates cartilage destruction in the SCID mouse model for human RA
    Type of Publication: Journal article published
    PubMed ID: 15194591
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  • 6
    ISSN: 1573-6865
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary An improved technique is described that addresses the problems of sensitivity, specificity, the use of hazardous radioactive equipment and time consumption in immunohistochemical labelling and double labelling ofin situ hybridization of tissue specimens. It consists of a two-step protocol in which digoxigenin-uridine triphosphate (UTP) labelled riboprobes in thein situ hybridization step are visualized by the immunogold-silver staining method, and double labelling of tissue antigens is achieved by the application of an alkaline phosphatase-anti-alkaline phosphatase staining step. We tested this protocol using snap-frozen tissue sections of synovial tissue from patients with rheumatoid arthritis. The target mRNA was detected by perforin or cathepsin D riboprobes, the double labelling was performed using anti-collagen type IV and alpha-smooth muscle actin antibodies. It is concluded that, in comparison with an established three-to four-day double-labelling protocol used in many laboratories, this one-day combination is currently the most rapid assay of reliable quality for double labelling ofin situ hybridization products and tissue antigens.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1437-160X
    Keywords: Arthritis ; Scanning electron microscopy ; Cartilage destruction ; MRL/lpr mice
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The articular surfaces of disarticulated knee joints from MRL/lpr and MRL/n mice, aged 4–33 weeks were examined by light microscopy (LM) and scanning electron microscopy (SEM). Light microscopy did not reliably predict SEM findings. Most of the abnormalities detected by SEM were related to surface disruption of articular cartilage. However, areas of articular cartilage covered by tightly adherent non-confluent monolayers of stallate-shaped cells with intertwinning cytoplasmic processes were observed. In these areas the integrity of the underlying cartilage matrix was disrupted, with exposure of collagen fibers. These findings suggested that outgrowth of proliferating synovial cells in the joints of arthritic MRL/lpr mice may lead to cartilage destruction.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1437-160X
    Keywords: Key words Chemokines ; Systemic sclerosis ; RANTES ; Keratinocytes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Inflammatory infiltrates and upregulated collagen production are hallmarks of systemic sclerosis (SSc). There are indications that chemokines are involved in accumulation of inflammatory and matrix-synthesizing cells in SSc skin lesions. Therefore, we searched for the expression and localization of the chemokine RANTES (“regulated upon activation and normal T cells expressed and secreted”) in skin and esophageal biopsies from patients with SSc. Using immunohistochemistry and in situ hybridization, skin biopsies derived from clinically involved and noninvolved skin of 18 patients with early and long-term SSc were examined for RANTES expression and compared with nondiseased skin sections of seven patients without SSc. In addition, esophageal snap biopsies were taken in a subgroup of six SSc patients. Strong expression of RANTES could be detected in the epidermis in keratinocytes of patients with short-term and long-term disease, both on the mRNA and protein level. The percentage of RANTES-expressing cells were significantly higher in clinically noninvolved skin sections than in involved skin areas. In contrast, no RANTES expression was found in esophageal biopsies or in the control group. The results indicate that RANTES is present in human sclerodermatous skin. RANTES may be involved in early pathogenesis of SSc as well as in fibrosis pathways, either by chemoattraction of immunocompetent cells and/or by modulation of collagen production.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1437-160X
    Keywords: Key words Cartilage oligomeric protein ; Knee joint injury ; Osteoarthritis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The objective was to assess whether changes of cartilage oligomeric matrix protein (COMP) serum levels can predict the development of osteoarthritis following traumatic knee injury. Sera and synovial fluids were acquired at surgery (T0) and postoperatively during the first (T1) and second (T2) year from 30 knee-injured patients. COMP levels and anti-COMP autoantibodies were quantified by ELISA. Radiographs and patient questionnaires were used to assess outcomes. At T0, compared with controls (1.6±1.6 μg/ml), the serum COMP concentration was significantly elevated (6.5±2.8 μg/ml) with a tendency to further increase (T0 vs. T1, P=0.076) and subsequently decrease (T1 vs. T2, P=0.074). However, individual variations are observed, e.g. persistently high (8/30) or increasing (T0 to T2, 8/30) serum COMP. Ten of these patients have elevated COMP at T2 that increased from T0. COMP levels in serum and synovial fluid correlated significantly (P=0.012). Interestingly, some patients who revealed increasing serum levels of COMP from T0 to T2 displayed anti-COMP autoantibodies. These data suggest that local immune response could contribute to further joint damage. The subgroup of 10 patients (33%) with elevated and increasing serum COMP levels and in particular the patients with antibodies against cartilage matrix molecules appear at increased risk for developing posttraumatic osteoarthritis.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1437-160X
    Keywords: Collagenase ; c-fos ; egr-1 ; Pathogenesis of rheumatoid arthritis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In view of the important role of interstitial collagenase in the pathogenesis of rheumatoid arthritis (RA), we studied the expression of fibroblast-type collagenase in rheumatoid synovium and searched for its potential transcription factors, namely the oncoprotein c-fos and the early-growth-response gene-1 (egr-1), an inducible zinc-finger encoding gene. Elevated levels of RNA sequences complimentary to c-fos and egr-1 cDNA probes could be detected in cytoplasmic extracts of collagenase-expressing synovial fibroblast-like cells when compared to equivalent RNA amounts isolated from control fibroblasts. Utilizing immunocytochemistry, immunoreactivity for c-fos oncoprotein was found in 13 of 19 joint specimens obtained from patients with active RA. These oncoprotein data were positively correlated to the collagenase expression in the same specimens. Moreover, immunohistochemical analysis confirmed the localization of both oncoprotein c-fos and fibroblast-type collagenase within synovial fibroblast-like cells attached to bone erosions.
    Type of Medium: Electronic Resource
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