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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: 1432-2307
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung 21 Lebercirrhosen unterschiedlicher Ätiologie wurden mit Hilfe der indirekten Immunfluorescenztechnik mit typ-spezifischen Kollagenantikörpern auf Vorkommen und Verteilung einzelner Kollagentypen untersucht. In cirrhotischen Bindegewebssepten und Portalfeldern fand sich in allen Cirrhosen Kollagen Typ III stark vermehrt. Dagegen ließen sich mit typ-spezifischen Antikörpern gegen Kollagen Typ I und II keine anderen Kollagentypen nachweisen. Damit werden biochemische Untersuchungen bestätigt, die in Lebercirrhosen neben Kollagen Typ III einen neuen, bisher nicht beschriebenen Kollagentyp zeigen, der elektronenoptisch als Kollagen Typ I erscheint, sich jedoch biochemisch und immunologisch anders verhält. Eine Korrelation zwischen Ätiologie der Cirrhosen und Auftreten oder Verteilungsmuster bestimmter Kollagentypen konnte bisher nicht gefunden werden.
    Notes: Summary Using indirect immunofluorescence technique, 21 cases of hepatic cirrhosis of differing etiology were studied with type-specific antibodies to collagen type I, II, and III. In all cases the fibrous septa and portal tracts showed an increase in type III collagen. No fluorescence could be observed with antibodies to collagen type I and II. Thus, biochemical studies are supported which show, in addition to type III collagen, a new, as yet undescribed type of collagen in liver cirrhosis that is similar to type I collagen electronmicroscopically, but differs from type I collagen biochemically and immunologically. No correlation between the etiology of cirrhosis and the pattern of different collagen types could be found. The origin of different collagen types in liver cirrhosis is briefly discussed.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-1076
    Keywords: Osteogenesis imperfecta ; Collagen types ; Bone ; In vitro study ; Immunofluorescence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Samples of bone from a patient with osteogenesis imperfecta were found to synthesize and contain type III collagen as well as type I collagen. Normal bone contains only type I collagen except in the lining cells of the bone marrow cavities. In the patient's tissue, type III collagen was localized in nonfibrillar structures in discrete areas of the bone. These and previous studies indicate that certain types of osteogenesis imperfecta may be caused by a failure of normal bone maturation and the sites in which the type III collagen is found appear to be defects in the bone.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-1440
    Keywords: Kollagentypen ; Plättchenaggregation ; Collagen types ; platelet aggregation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary Collagen types I, II and III from man and calf are distinctly different with respect to their effect on the induction of the aggregation of human platelets. Collagen type III was found to be a particularly potent inducer of platelet aggregation. The pathogenetic implications of these observations are briefly discussed.
    Notes: Zusammenfassung Die Kollagentypen I, II and III von Mensch und Kalb weisen in löslicher und strukturierter Form deutliche Unterschiede in ihrer Wirkung auf die Aggregation menschlicher Thrombocyten auf. Eine besonders stark aggregierende Wirkung wurde für das Typ III Kollagen gefunden. Die pathogenetische Bedeutung dieses Befundes wird kurz diskutiert.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1432-1440
    Keywords: Kollagen ; Blutgefäßersatz ; Collagen ; Arterial heterograft
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary The immunohistochemical results showed that the distribution of the collagen types in calf carotis is the same as that found in human arteries. Mechanically prepared and ficin-treated vessels showed a removal of cells, elastic fibres and type III collagen. The remaining collagen meshwork was shown by immunohistochemical methods and also by amino acid analysis to be type I collagen. Because of its structural, chemical and immunological properties, the protease treated, aldehyde stabilised Arteria carotis communis of the calf is suitable as a replacement material for arterial segments. Initial successes using man as a recipient support the stated conclusion.
    Notes: Zusammenfassung Die immunhistochemischen Ergebnisse zeigen in der Kollagentypenverteilung der Kalbscarotis den humanen arteriellen Gefäßen vergleichbare Befunde. Mechanisch präparierte, im dynamischen Verfahren mit Ficin behandelte Gefäße zeigen eine Elimination von Zellen, elastischen Fasern und Typ III Kollagen. Der zurückbleibende Kollagenstrumpf wurde nicht nur immunhistochemisch, sondern auch durch die Aminosäureanalyse als Typ I Kollagen identifiziert. Aufgrund ihrer strukturellen, chemischen und immunologischen Eigenschaften ist die mit gesteuerter Proteolyse behandelte und anschließend mit Aldehydgruppen stabilisierte Arteria carotis communis des Kalbes als Ersatz für Arteriensegmente geeignet. Erste Erfolge von Einsätzen beim Menschen bestätigen die erhobenen Befunde.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-1440
    Keywords: Kollagen ; Immunfluorescenz ; Thrombus ; Blutplättchen ; Collagen ; immunofluorescence ; thrombus ; platelets
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary Sections of arterial walls and of thrombi and smears of leukocytes previously incubated in vitro with collagen type III were examined by immunohistochemical technique for the presence of collagen types I, II and III. In arterial walls collagen type III was detected immediately underlaying the endothelial cell layer and in the tissue between tunica elastica interna and adventitia. Collagen type I was not shown in the subendothelial layer. Fresh thrombi contained occasionally collagen, but only of type III. This was associated with leukocytes. Leukocytes were capable in vitro to associate and/or phagocytose collagen type III and this could be visualized immunohistochemically. The data show that collagen type III in vivo may play a crucial role in the initiation of thrombus formation.
    Notes: Zusammenfassung Schnitte von arteriellen Gefäßwänden und von Thromben sowie Ausstriche von Leukocyten, die in vitro mit Kollagen Typ III inkubiert worden waren, wurden mit Hilfe der indirekten Immunfluorescenz auf die Verteilung und Anwesenheit von Kollagen Typ I, II und III untersucht. In Arterienwänden wurde Kollagen Typ III direkt subendothelial gefunden, sowie zwischen Tunica elastica interna und Adventitia. Kollagen Typ I war in der subendothelialen, der Tunica elastica interna direkt aufliegenden Schicht nicht nachweisbar. Frische Thromben enthielten gelegentlich Kollagen, jedoch nur Typ III. Dieses war mit Leukocyten assoziiert. Auch in vitro waren Leukocyten in der Lage, Kollagen Typ III zu assoziieren und/oder phagocytieren. Solches Kollagen war immunohistochemisch nachweisbar. Die Ergebnisse zeigen, daß Kollagen Typ III vermutlich eine entscheidende Rolle bei der arteriellen Thrombusbildung spielt.
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