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T Häupl

Publications and source records attributed to T Häupl.

At least 19 recordsLinked to original sources
PubMed2006

[Low-grade-/high-grade-synovitis: synovitis-score as a gold standard?].

BACKGROUND: Synovectomy specimens represent important material submitted from the orthopedist to the pathologist. However, no consistent histopathological grading system for chronic synovitis has been established so far. PATIENTS AND METHODS: The three compartments of chronic synovitis (enlargement of lining cell layer, density of synovial stroma cells, leukocytic infiltrate) are graded semiquantitatively (from 0=absent to 3=strong), and the points for each compartment add up to the synovitis score: 0-1 = no synovitis, 2-4 = low-grade synovitis, 5-9 = high-grade synovitis. A total of 618 synovial specimens (resections n=559, biopsies n=59) from degenerative and inflammatory joint diseases were graded by two independent observers. RESULTS: Median synovitis scores when correlated to clinical diagnoses were: 1, control; 2, osteoarthritis and post-traumatic arthritis; 3, psoriatic arthritis; 5, reactive and rheumatoid arthritis. The differences between rheumatic and non-rheumatic diseases were significant (p<0.001). The correlation between the two observers was high (p<0.001). CONCLUSIONS: The proposed synovitis score enables stratification of chronic synovitis into low-grade (score 2-4) and high-grade (score >4), which is correlated to the nature of the disease (low-grade to non-rheumatic, high-grade to rheumatic), and it therefore contributes to the diagnosis of rheumatic and non-rheumatic joint diseases.

Adolescent↗
PubMed2005

[Bone morphogenetic proteins in the skeletal system].

Bone morphogenetic proteins (BMPs) belong to the transforming growth factor-beta superfamily. Their potential for organ and tissue regeneration and repair has been intensively investigated in recent years. Studies on fetal development have demonstrated the important role of these proteins for the development and differentiation of different organs. Miss-expression or mutation of BMPs may lead to severe abnormalities or even abortion. However, a regenerative potential has also been recognized for the adult organism. BMPs support fracture healing and may contribute to treatment of joint diseases. Thus, BMP-7 is one of the first BMPs approved for clinical application in non-unions of bone fractures resistant to conventional therapy. In degenerative and inflammatory joint diseases, experimental data suggest a decrease of BMP expression in cartilage tissue. Therefore, BMPs could be promising therapeutic candidates in these diseases, although more detailed analyses are necessary. In this review we will focus on bone morphogenetic proteins and discuss present and putative future clinical applications.

Animals↗
PubMed2005

[Synovialitis score: histopathological grading system for chronic rheumatic and non-rheumatic synovialitis].

Standardization of the histopathological assessment of synovial membrane specimens might facilitate the diagnosis of chronic rheumatic and non-rheumatic joint diseases. We would like to propose a histological graduation scheme ("synovialitis score"), which is applicable to all forms of synovitis, irrespective of its etiology. This score evaluates the three compartments of chronic synovialitis [enlargement of lining cell layer, activation of synovial stroma (i. e. resident cells), leukocytic infiltrate] semiquantitatively (from 0=absent to 3=strong). Each compartment is graded separately, and the sum resembles the synovialitis score, which is interpreted as follows: 0-1: no synovialitis, 2- 3: slight synovialitis, 4-6: moderate synovialitis, 7-9: strong synovialitis (for sample photos see also www.charite.de/ch/patho/Webpage/pages/forschung/arbeitsgruppen/ag-krenn/index.htm). A total of 483 synovial specimens (resections n=462, biopsies n=21) were graded by two independent observers. Clinical diagnoses were osteoarthrosis (OA; n=153), posttraumatic arthritis (PtA; n=31), rheumatoid arthritis (RA; n=239), psoriatic arthritis (PsA; n=32), reactive arthritis (ReA; n=7), and controls (Co, n=21) from necropsies of patients without joint damage. The correlation between two observers was high (p<0.001). The correlation coefficient between the different samples from the same joint in n=112 cases was between 0.86 and 0.95. Median synovialitis scores when correlated with clinical diagnoses were: Co 0.5, OA 2, PtA 3, PsA 3, ReA 4, RA 5. The differences in scores between Co and all other groups were highly significant (p<0.001). A synovialitis score of 4 points and more was strongly associated with rheumatic joint diseases (sensitivity 73%, specificity 86%). Validation of the synovialitis score by gene expression data showed good correlations for the lining cell enlargement with MMP1 (0.685), for the leukocytic infiltrate with CD3 (0.754) and CD138 (0.744) and for the stroma activation with CD14 (0.744). The proposed synovialitis score is based on well definable histopathologic criteria and contributes to the diagnosis of rheumatic and non-rheumatic joint diseases.

Adolescent↗
PubMed2003

[Tissue engineering: chances and challenges for application in rheumatic diseases].

Current technologies of tissue engineering offer new strategies for the treatment of cartilage and bone defects. Beyond implantation of cell suspensions, second generation products of biomaterial enforced with in vitro preformed tissues are clinically applied. Ongoing research and development focus on differentiation factors and tissue protection. In search for sources of autologous cells which are easier to collect and which may serve for more complex tissues like osteochondral implants, mesenchymal stem cells are investigated. The design of in vitro experiments, which are required for these investigations, has produced tissue engineering technologies, which may serve for pathophysiology research in inflammatory joint diseases and for exploration of treatment strategies. These together with the advances in biological therapies of rheumatic diseases are the basis of new concepts, which promise application of tissue engineering also in inflammatory joint diseases.

Animals↗
PubMed2002

Human platelet supernatant promotes proliferation but not differentiation of articular chondrocytes.

The objective of the study was to evaluate the growth-promoting activity of human platelet supernatant on primary chondrocytes in comparison with fetal calf serum (FCS) supplemented cell culture medium. Furthermore, the differentiation potential of platelet supernatant was determined in three-dimensional artificial cartilage tissues of bovine articular chondrocytes. Proliferation of articular and nasal septal chondrocytes was assayed by incorporation of BrdU upon stimulation with ten different batches of human platelet supernatant. On bovine articular chondrocytes, all these batches were at least as growth-promoting as FCS. On nasal septal chondrocytes, nine out of ten batches revealed increased or equivalent mitogenic stimulation compared with medium supplemented with FCS. Three-dimensional culture and subsequent histological analysis of matrix formation were used to determine the differentiation properties of platelet supernatant on articular chondrocytes. Human platelet supernatant failed to induce the deposition of typical cartilage matrix components, whereas differentiation and matrix formation were apparent upon cultivation of articular chondrocytes with FCS. Proliferation assays demonstrated that human platelet supernatant stimulates growth of articular and nasal septal chondrocytes; however, platelet supernatant failed to stimulate articular chondrocytes to redifferentiate in three-dimensional chondrocyte cultures. Therefore platelet lysate may be suitable for chondrocyte expansion, but not for maturation of tissue-engineered cartilage.

Blood Platelets↗
PubMed2002

[New aspects of molecular biology diagnosis. Array technology and expression profile for characterization of rheumatic diseases].

Increasing availability of high throughput technologies, exponentially growing information about the human genome and gene expression, and the growing global network of databases on systematic biomedical information will change our view on inflammatory rheumatic diseases in a revolutionary way. Several research laboratories have already generated initial extensive datasets on gene expression analysis. Application of this technique has demonstrated that in addition to a precise analysis, verification and validation of the results also on the level of cell populations, a meticulous characterization of the patients according to current conventional clinical, laboratory, imaging and histological standards is essential. For functional interpretation, in vitro tests, animal models and therapeutic studies will provide further information. Bioinformatic structuring and development is needed for the large amounts of data. After an initial genome-wide screening, the objective is to identify those genes, which will allow characterization of the disease, classification according to molecular pathophysiology, evaluation of the prognosis and prediction of the correct and most potent therapeutic regimen. Derived from the improved knowledge about the molecular mechanisms, new and--as to expect--the crucial approaches for an effective therapy against chronic inflammation, organ destruction and pathological immune response in rheumatic diseases will emerge.

Autoantibodies↗
PubMed2002

Grading of chronic synovitis--a histopathological grading system for molecular and diagnostic pathology.

The following is a proposition for a simple histopathological classification system to measure inflammation in synovial tissue. This synovitis-score is employed in conventionally stained routine sections, and is applicable to every kind of synovitis, irrespective of etiology and including the following relevant morphological alterations. First: hyperplasia/enlargement of synovial lining cell layer. Second: activation of resident cells/synovial stroma. Third: inflammatory infiltration. All defined histopathological qualities are graded from absent (0), slight (1) and moderate (2) to strong (3), with summaries ranging from 0 to 9. 0 to 1 corresponds to no synovitis (inflammatory grade = 0), 2 to 3 to a slight synovitis (inflammatory grade 1), 4 to 6 to a moderate synovitis (inflammatory grade 2), and 7 to 9 to a strong synovitis (inflammatory grade 3). Using this score, we analyzed 308 random specimens of synovial tissue from degenerative (osteoarthritis (OA)) and inflammatory joint diseases - reactive arthritis (ReA), psoriasis arthritis (PA) and rheumatoid arthritis (RA) - as well as synovial tissue from healthy individuals. The mean grade given to synovitis of RA turned out to be significantly higher than the mean grade of OA (p < 0.0005) and of healthy controls (p < 0.0005). On the contrary, no significant differences could be found between the mean grades of synovitis scores from patients with RA and those with PA and ReA. Another comparison between RA-synovitis types I and II according to the Stiehl classification resulted in type I (p < 0.0005), showing significantly higher values of inflammatory infiltration, and type II (p = 0.037), showing significantly higher values of stroma activation. Since in OA, synovitis is regarded as a result of degenerative cartilage destruction whereas in inflammatory joint diseases (RA, PA, ReA), synovitis is regarded to be the cause of cartilage destruction, it can be concluded that scores with considerable high values indicate the pathogenetic potential of synovitis and that the inflammatory score may be helpful in estimating the destructive potential of synovitis at the same time. Furthermore, the comparison of the score data with the Stiehl RA-synovitis types shows that the score enables us to discriminate the morphological peculiarities of the synovitis types. In experimental pathology, it could provide standardized information on molecular synovial tissue analyses where a correlation of molecular with morphological data is essential. In diagnostic pathology, this synovitis score (in combination with other typing systems) could provide basic and standardized information concerning the degree of inflammatory alterations in synovial tissue.

Arthritis↗
PubMed2002

Shwartzman phenomenon in a patient with active systemic lupus erythematosus preceding fatal disseminated intravascular coagulation.

The recurrence of widespread and diverse vascular lesions is a hallmark of systemic lupus erythematosus (SLE). Inflammatory and thrombotic mechanisms almost invariably associated with circulating antiphospholipid antibodies play a role in the pathogenesis of SLE-related vascular disease. Both mechanisms can coexist in the same patient. Vasculitis is most commonly induced by the local deposition of immune complexes. However, some SLE patients have an inflammatory complement-mediated vascular injury in the absence of immune complex deposition. We report on a fatal case of disseminated intravascular coagulation (DIC) in a young woman with active SLE. Hemorrhagic lesions due to localized intravascular coagulation (Shwartzman phenomenon) preceded disseminated intravascular coagulation accompanied by disseminated cardiac necrosis. Immune complex 'independent' and other mechanisms of vascular injury and states of hypercoagulability will be discussed.

Adult↗
PubMed2000

Autologous stem-cell transplantation in refractory autoimmune diseases after in vivo immunoablation and ex vivo depletion of mononuclear cells.

Autoimmune diseases that are resistant to conventional treatment cause severe morbidity and even mortality. In the present study we demonstrate that complete remissions can be achieved in refractory polychondritis and systemic lupus erythematosus (SLE), even at advanced stage, with the use of autologous stem-cell transplantation (SCT). Remissions persisted after reconstitution of the immune system. In the treatment of advanced systemic sclerosis (SSc), stable disease may be achieved with autologous SCT.

Adult↗
PubMed1999

Joint cartilage regeneration by tissue engineering.

The research field of tissue engineering combines cells biology, biomaterial science, and surgery. Major long-term goals are tissue and organ replacement therapies using the patients' own cells. Our work is focused on the treatment of severe joint defects and on plastic surgery using in vitro engineered cartilage tissues. The practical approaches in cartilage engineering face problems with three-dimensional cell distribution or cell immobilization raising biocompatibility problems. The tissue engineering of cartilage is based on combining biocompatible cell embedding substances such as fibrin, agarose, alginate, hyaluronic acid and fiber fleece scaffolds of poly alpha-hydroxy acids (PLLA/PGLA). Different technical approaches were established: a) three-dimensional in vitro cultures of chondrocytes for the development of vital tissue transplants and b) interacting three-dimensional cultures consisting of different cell populations, such as BMP-transfected mesenchymal cells. The preshaped artificial tissue constructs were cultured in perfusion chambers to maintain a stable diffusion of nutrients during the in vitro pre-formation step. Subsequently, pre-formed tissues were implanted into nude mice and into 4 mm articular joint defects of rabbits. Transplants were found to produce cartilage typic morphological patterns and matrix. 80% of the transplants remained stable in vivo. However, 20% of the tissues are resorbed or replaced by a fibrous tissue. These results demonstrate that current artificial cartilage transplants are already feasible for plastic reconstruction. The treatment of severe joint defects, however, faces additional problems which are addressed in ongoing studies: (a) the fixation of engineered cartilage in joints, (b) the protection against chronic inflammatory degradation, and (c) the required enormous mechanical stability.

Animals↗
PubMed1999

Bone engineering on the basis of periosteal cells cultured in polymer fleeces.

Large bone defects caused by severe trauma, infection or tumor resection are still a major challenge for orthopaedic surgery. The key concept for successful bone regeneration consists of combining the osteoinductive effect of osteogenic cells with a suitable carrier structure to promote osteoblastic differentiation and optimal matrix production. Therefore, periosteal cells cultured in polyglycolic-polylactid acid (PGLA) fleeces were investigated for their osteogenic differentiation and used to repair critical size bone defects in a rabbit model. Periosteal cells were isolated from New Zealand White rabbits and expanded in vitro. Osteogenic differentiation was investigated by analysis of alkaline phosphatase and osteocalcin production in vitro depending on culture conditions and passage number. Cells were seeded into PGLA fleeces. After further cultivation, tissue constructs were examined histologically and by immunohistochemistry for cell distribution and osteogenic differentiation. These constructs of defined size were used to repair critical size calvarial defects (group I) in rabbits compared to a defect repair with polymers only (group II) or to untreated defects (group III). Bone healing was evaluated after 4 weeks by radiodensitometry and a special histological scoring system. For early evaluation, radiodensitometry was not sensitive enough to detect differences in calcification. However, on histologic examination the group with cell/fleece constructs revealed intense formation of uncalcified bone. The mean defect closure of the experimental group I was 65%, compared to control groups II and III with 31% and 22%, respectively. The established methods of 3-D-cell culture and ex-vivo transplant assessment proved to be a valuable tool for quality assurance. The results demonstrate that the combination of periosteal cells and polymer fleeces is a tissue engineering approach, which may have clinical applications in various fields of reconstructive surgery.

Journal Article↗
PubMed1998

A novel epitope on the C-terminus of SmD1 is recognized by the majority of sera from patients with systemic lupus erythematosus.

The SmD1 protein is a specific target for the autoantibody response in SLE. To further analyze this reactivity epitope, mapping was performed with cellulose-bound 13-mer peptides overlapping 10 amino acids (aa). In this initial approach, 4 out of 15 SLE sera recognized more than five overlapping peptides of the SmD1 C-terminus. Therefore, longer oligopeptides of up to 37 aa of this region were generated and probed for as antigens by ELISA. For the SmD1 aa 83-119 polypeptide, there was a striking increase of reactivity with 70.0% positive reactions out of 167 SLE sera. In contrast, 105 healthy control sera were negative, and only 8.3% of sera from patients with other inflammatory diseases (n = 267) exhibited a response, which was of low level only. The anti-SmD183-119 reactivity was significantly higher in anti-dsDNA antibody positive vs. negative sera (P < 0.001) and correlated with disease activity. Four of five human monoclonal anti-dsDNA antibodies also reacted with SmD183-119. The specificity for SmD1 was demonstrated by inhibition experiments and immunization of rabbits with SmD183-119 inducing SmD1-specific antibodies. In conclusion, the SmD183-119 peptide was demonstrated to be an important and highly specific target of the autoimmune response in SLE. The high sensitivity of this ELISA probably depends on a conformational epitope, which appears not to be accessible in the full-size SmD1 protein.

Amino Acid Sequence↗
PubMed1998

Use of differential subtraction method to identify genes that characterize the phenotype of cultured rheumatoid arthritis synoviocytes.

OBJECTIVE: To identify the genes that characterize the distinctive phenotype of cultured rheumatoid arthritis (RA) fibroblastoid synoviocytes. METHODS: A representational difference method was used to subtract complementary DNA (cDNA) from cultured RA fibroblastoid synoviocytes with cDNA from noninflammatory osteoarthritis synoviocytes. The genes were identified by DNA sequencing, and their relative expression was determined by Northern blot analysis. RESULTS: Twenty-four genes were identified, including novel genes such as a human homolog of mouse semaphorin E and one homologous to N-acetylglucosamine-6-sulfatase. Eleven of these genes were constitutively overexpressed in the rheumatoid synoviocyte line, including a chemokine, stromal cell-derived factor 1, and several genes capable of mediating synoviocyte-leukocyte interactions, including vascular cell adhesion molecule 1 and Mac-2 binding protein. Three genes (lumican, biglycan, and insulin-like growth factor binding protein 5) encoded extracellular matrix components, suggesting that distinct stromal-synoviocyte interactions may be mediated by this phenotype. Two interferon-inducible genes of unknown function were also found, emphasizing the presence of activation-like features in the phenotype. CONCLUSION: A general method for the identification of differences in patterns of gene expression revealed that cultured RA fibroblastoid synoviocytes overexpress certain proinflammatory genes that are potentially relevant to lymphocyte and monocyte entry and interactions. The features of the genes identified in these mesenchymal cells suggest that they facilitate localization of immune reactions to the joint through leukocyte chemokinesis, cell-cell adhesion, and matrix specialization. The further characterization of these genes should help in resolving whether this phenotype is the consequence of modulation and imprinting by an inflammatory milieu or, more likely, whether it reflects the intrinsic lineage characteristics of intimal lining synoviocytes.

Amino Acid Sequence↗
PubMed1998

Differential expression of cathepsins B and L compared with matrix metalloproteinases and their respective inhibitors in rheumatoid arthritis and osteoarthritis: a parallel investigation by semiquantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry.

OBJECTIVE: To study the expression of the cysteine proteinases cathepsin B and L and their most potent inhibitor cystatin C in the synovial membrane of patients with rheumatoid arthritis (RA) and osteoarthritis (OA) on both the messenger RNA (mRNA) level and the protein level. METHODS: The expression of both cysteine proteinases and cystatin C was investigated in synovial tissue from 15 RA and 11 OA patients and compared with the expression of matrix metalloproteinase 1 (MMP-1; collagenase), MMP-3 (stromelysin), and tissue inhibitor of metalloproteinases 1 (TIMP-1). Expression of mRNA was analyzed by semiquantitative reverse transcriptase-polymerase chain reaction. Protein expression was evaluated by immunohistochemistry. The results were correlated with the histologic evidence of inflammatory activity. RESULTS: A significantly more pronounced expression of MMP mRNA was observed in RA synovium compared with OA. In contrast, the mRNA expression of cysteine proteinases, as well as TIMP-1 and cystatin C, did not differ between the patient groups. However, the protein expression of both MMP and cysteine proteinases was significantly more prominent in RA synovial lining compared with OA, whereas cystatin C and TIMP-1 protein were expressed equally. CONCLUSION: The data indicate a more pronounced expression of MMP mRNA compared with cysteine proteinases in RA. The higher levels of cathepsin B and L proteins in RA synovial lining cells compared with OA are consistent with previous studies that assert a post-transcriptional up-regulation of these enzymes in RA.

Adult↗
PubMed1997

Activation of monocytes by three OspA vaccine candidates: lipoprotein OspA is a potent stimulator of monokines.

The outer surface protein (Osp) A of Borrelia burgdorferi is the first Lyme antigen to be tested in a vaccine for humans. Three forms of OspA vaccine candidates were investigated by the induction of the cytokines interleukin (IL)-1 beta, IL-6, tumor necrosis factor (TNF)-alpha, IL-10 and interferon (IFN)-gamma as markers of monocyte activation and immune stimulation: lipidated OspA (L-OspA), non-lipidated OspA (NL-OspA), and a fusion protein of 81 amino acids of the nonstructural protein 1 of influenza virus with OspA (NS1-OspA). All OspA preparations induced IL-1 beta, IL-6 and TNF-alpha in a concentration-dependent manner with peak levels at 12-24 h. These cytokines were entirely derived from the monocyte fraction. In peripheral blood mononuclear cells from 10 healthy donors, L-OspA at 10 micrograms ml-1 induced up to 4-fold more IL-1 beta, IL-6, and TNF-alpha than the other OspA preparations (P < or = 0.0068), followed by NS1-OspA, which was still superior to NL-OspA. L-OspA. L-OspA also induced high levels of IL-10 within 24 h but no significant amounts of IFN-gamma. This superior stimulating activity of L-OspA on unstimulated monocytes predominantly depended on N-terminal lipidation of OspA. Similarities to other lipoproteins and synthetic lipopeptides suggest that lipidation confers adjuvant properties on OspA. High induction of IL-10 by L-OspA further suggested a negative feedback on monocyte activation by the lipidated form. The in vitro results are in line with in vivo results in mice, monkeys and humans and indicates that lipoprotein OspA has the best potential for induction of a protective effect in humans, compared to non-lipidated antigens.

Adjuvants, Immunologic↗
PubMed1994

Borrelia burgdorferi-induced ultrastructural alterations in human phagocytes: a clue to pathogenicity?

A chronic infection with the spirochaete Borrelia burgdorferi typically results in a multistage, multisystem illness. Thus, Lyme borreliosis may provide an interesting model to study the pathomechanisms of microbial persistence. In the present investigation, human peripheral blood monocytes, polymorphonuclear leukocytes, and synovial macrophages were incubated with B. burgdorferi and examined by light and electron microscopy. It was found that incubation with the spirochaetes induced distinct features in the phagocytes. Features which may be related to the pathogenesis of Lyme disease included the segmental uptake of spirochaetes with leaky lysosomes, the invagination of large membrane areas, the extra-lysosomal degradation of internalized B. burgdorferi cells and, finally, the formation of mononuclear syncytial cells and homotypic cell clusters. Features of unknown relevance were the occurrence of two types of cytoplasmic inclusion bodies and exocytic vesicles. These novel findings suggest that reactive alterations of the phagocytes may contribute to the pathogenesis of Lyme borreliosis, which could help to focus future histopathological studies. Moreover, these results may provide new insights into the pathogenesis of other infectious diseases characterized similarly by microbial persistence.

Borrelia burgdorferi Group↗
PubMed1993

Persistence of Borrelia burgdorferi in ligamentous tissue from a patient with chronic Lyme borreliosis.

OBJECTIVE: To document the persistence of Borrelia burgdorferi in ligamentous tissue samples obtained from a woman with chronic Lyme borreliosis. METHODS: Spirochetes were isolated from samples of ligamentous tissue, and the spirochetes were characterized antigenetically and by molecular biology techniques. The ligamentous tissue was examined by electron microscopy. Humoral and cellular immune responses were analyzed. RESULTS: Choroiditis was the first recognized manifestation of Lyme disease in this patient. Despite antibiotic therapy, there was progression to a chronic stage, with multisystem manifestations. The initially significant immune system activation was followed by a loss of the specific humoral immune response and a decrease in the cellular immune response to B burgdorferi over the course of the disease. "Trigger finger" developed, and a portion of the flexor retinaculum obtained at surgery was cultured. Viable spirochetes were identified. Ultramorphologically, the spirochetes were situated between collagen fibers and along fibroblasts, some of which were deeply invaginated by these organisms. The cultured bacteria were identified as B burgdorferi by reactions with specific immune sera and monoclonal antibodies, and by polymerase chain reaction amplification and Southern blot hybridization techniques. CONCLUSION: To our knowledge, this is the first report of the isolation of B burgdorferi from ligamentous tissue. This suggests that tendon tissues serve as a specific site of spirochete residence in human hosts.

Base Sequence↗