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Biomedical subjects

G R Burmester

Publications and source records attributed to G R Burmester.

At least 109 records · Page 6Linked to original sources
PubMed1999

Beware of the heart: the multiple picture of cardiac involvement in myositis.

A 42-yr-old woman with dermatomyositis had two myocardial infarctions, episodes of acute chest pain and an acute lung oedema. These events were initially misinterpreted as atherosclerotic ischaemic heart disease accompanying the autoimmune disease. The lack of improvement of cardiac symptoms with anti-ischaemic and immunosuppressive drugs indicated other mechanisms. Intracoronary drug provocation as well as myocardial biopsy revealed a coincidence of small-vessel disease and vasospastic angina as a cause for the severe cardiac symptoms. After initiating therapy with high doses of calcium channel blockers, marked improvement of cardiac symptoms occurred. In the pathogenesis of cardiac involvement in dermatomyositis, two different mechanisms should be considered: inflammatory processes due to dermatomyositis and vasoconstriction caused by an impaired regulation of vascular tone, such as abnormal vessel reactivity or disturbed neuropeptide release. Signs of this generalized vasopathy are Raynaud's phenomenon, Prinzmetal's angina and small-vessel disease, which can coincide. In patients with severe cardiac symptoms and autoimmune diseases, Prinzmetal's angina should be excluded by intracoronary drug provocation using acetylcholine.

Angina Pectoris, Variant↗
PubMed1999

Preactivated peripheral blood monocytes in patients with essential hypertension.

The purpose of this study was to investigate the possible involvement of human peripheral blood monocytes in the pathology of hypertensive disease. We determined the in vitro secretion patterns of proinflammatory cytokines obtained from isolated peripheral monocytes from normal controls and from hypertensive patients either after in vitro stimulation with angiotensin II (Ang II) with or without preincubation with an Ang II type 1 receptor antagonist (losartan) or after stimulation with lipopolysaccharide. Blood samples were obtained from 22 patients with essential hypertension (before any drug administration or after interruption of antihypertensive therapy) and from 24 normotensive healthy individuals used as a control group. Peripheral blood monocytes were isolated by density gradient centrifugation and plastic adherence. The state of monocyte activity was determined by the capacity to secrete tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6, (IL-6) either spontaneously or after stimulation. Cytokine concentrations were determined in culture supernatants by specific ELISA. Proinflammatory cytokine levels were assessed by semiquantitative reverse transcribed polymerase chain reaction. After stimulation with Ang II, the IL-1beta secretion of peripheral blood monocytes was significantly increased in hypertensive patients versus healthy individuals (P<0.05). In contrast, in monocytes preincubated with losartan before exposure to Ang II, IL-1beta secretion was diminished in both groups to comparable levels. The secretion of IL-1beta and TNF-alpha was significantly increased in peripheral blood monocytes from hypertensive patients versus healthy individuals after stimulation with lipopolysaccharide (TNF-alpha, P<0.02; IL-1beta, P<0.05). Upregulation of IL-1beta and TNF-alpha secretion in peripheral blood monocytes from hypertensive patients was also seen at the RNA level. Our results indicate preactivated peripheral blood monocytes in hypertensive patients. Ang II may be directly involved in the process of monocyte activation.

Adult↗
PubMed1999

Effects of anti-CD4 antibodies on the release of IL-6 and TNF-alpha in whole blood samples from patients with systemic lupus erythematosus.

Anti-CD4 antibodies have been recently introduced into the therapy of various autoimmune diseases, among them systemic lupus erythematosus (SLE). Their modes of action are not yet fully understood. Interference with cytokine release may be one possible mechanism. Therefore, the effects of anti-CD4 antibodies on the cytokine release of IL-6 (interleukin-6) and TNF-alpha (tumor necrosis factor alpha) were investigated in a whole blood culture system. Basal and phytohemagglutin/lipopolysaccharide (PHA/LPS)-stimulated cytokine patterns were compared to cytokine release after the addition of anti-CD4 antibodies (MAX.16H5) or methylprednisolone in short time whole blood cell culture systems from 12 patients with active SLE, 23 patients with inactive SLE and 12 healthy volunteers. TNF-alpha and IL-6 concentrations were determined in the supernatants by ELISA. High disease activity correlated with an increased production of proinflammatory cytokines. Cell cultures of patients with inactive SLE showed a diminished capacity to respond to mitogenic stimulation. Anti-CD4 antibodies added in vitro suppressed significantly the unstimulated production of IL-6 (P<0.02) in the cell cultures of patients with active SLE and in the PHA/LPS-stimulated cell cultures from both groups of SLE patients (both P<0.001) and healthy volunteers (P<0.01). However, MAX.16H5 did not affect the release of TNF-alpha. In control samples methylprednisolone considerably reduced stimulated and unstimulated IL-6 and TNF-alpha production in all SLE patients, irrespective of the disease state, and in all healthy controls. These data indicate that the proinflammatory cytokines are involved in the pathogenesis of SLE. It is assumed that anti-CD4 antibodies, which can be effective in the treatment of highly active lupus patients, may act via their influence on cytokine release. The decrease of the proinflammatory cytokines IL-6 under therapy with MAX.16H5 could explain the observations of clinical trials and animal studies which showed a reduction of inflammatory parameters and diminished production of autoantibodies following treatment with anti-CD4 antibodies.

Antibodies, Monoclonal↗
PubMed1999

Circulating levels of matrix metalloproteinases MMP-3 and MMP-1, tissue inhibitor of metalloproteinases 1 (TIMP-1), and MMP-1/TIMP-1 complex in rheumatic disease. Correlation with clinical activity of rheumatoid arthritis versus other surrogate markers.

OBJECTIVE: To investigate whether plasma levels of matrix metalloproteinases 3 (MMP-3, stromelysin), MMP-1 (collagenase), tissue inhibitor of metalloproteinases 1 (TIMP-1), and MMP1/TIMP-1 complex (MT complex) are specifically elevated in erosive joint diseases compared to nonerosive rheumatic diseases, and to assess how these markers reflect the clinical activity of rheumatoid arthritis (RA) compared to circulating cytokines and markers of connective tissue turnover as well as established variables [C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and rheumatoid factor titer]. METHODS: Plasma levels of MMP-3, MMP-1, TIMP- 1, and MT complex were determined by ELISA. One hundred fifteen patients with RA, 20 with osteoarthritis (OA), 28 with psoriasis arthritis (PsA), 24 with ankylosing spondylitis (AS), 3 groups with systemic autoimmune diseases, and 30 healthy controls were analyzed. In patients with RA routine laboratory variables, circulating inflammatory cytokines [interleukin 1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), and IL-6], collagen degradation products, and markers of bone formation were determined in parallel and were correlated to 4 variables of clinical activity. RESULTS: MMP-3 levels were markedly elevated in RA compared to controls and OA, but also in all other groups, including 26 patients with systemic lupus erythematosus (SLE). MMP-1 levels were significantly elevated in RA, but also in OA, PsA, SLE, and mixed connective tissue disease. In contrast, MT complex was elevated in RA only. TIMP-1 was not different from controls. CRP levels, MMP-3, and ESR correlated best with clinical activity of RA. In contrast, there was no correlation of IL-1 and TNF-alpha and only a weak correlation of IL-6 with clinical measures. Among variables of connective tissue turnover, only pyridinoline and deoxypyridinoline crosslinks were weakly correlated with disease activity. CONCLUSION: Elevated MMP-3 and MMP-1 levels are not specific for RA or for erosive joint diseases in general. In contrast, elevated MT complex levels were observed in patients with RA. However, the correlation of MT-1 with clinical data was weaker than that of MMP-3. Elevated MMP-3 levels reflected disease activity of RA better than cytokine levels or markers of connective tissue turnover. However, MMP-3 levels do not exceed the association of CRP with clinical activity.

Arthritis↗
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

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↗
PubMed1998

[Iloprost administration over 21 days as an effective therapy in systemic scleroderma--case report and review of the literature].

A 57-years old female patient with systemic sclerosis underwent a prolonged intravenous therapy during 21 consecutive days with iloprost, a stable analogue of prostacyclin. Beginning with 0.5 ng/ kg/minute the dose was increased every 2 days up to 2 ng/kg/minute. At the end of follow up, Iloprost was shown to enhance the perfusion of the finger and to improve pulmonary-function tests including the diffusion-capacity. Furthermore, the Erythrocyte Sedimentation Rate and the C-reactive protein decreased. The case report shows the necessity of a controlled study of prolonged iloprost therapy.

Clinical Trials as Topic↗
PubMed1998

[Anti-CD4 therapy in treatment of rheumatoid arthritis--have the die been cast?].

The hypothesis of rheumatoid arthritis (RA) as a T cell mediated disease has led to the development of numerous therapeutic approaches that target the function of T cells. The development of monoclonal antibodies against the T cell surface molecule CD4 has raised hopes to achieve a major progress in the treatment of RA. However, after encouraging results in early open studies, double blind trials were unable to demonstrate the efficacy of anti-CD4-therapy in RA. There are numerous reasons to explain the failure of this treatment approach. Besides the fact that the T cell hypothesis of RA has repeatedly been challenged, pharmacological problems or an inappropriate selection of outcome criteria have to be considered. The final evaluation of anti-CD4 therapy in RA will be possible only after the testing of newly developed non-depleting anti-CD4 antibodies.

Antibodies, Monoclonal↗
PubMed1998

Matrix metalloproteinases, but not cathepsins B, H, and L or their inhibitors in peripheral blood of patients with rheumatoid arthritis are potentially useful markers of disease activity.

OBJECTIVE: The clinical activity of rheumatoid arthritis (RA) is not reliably reflected by laboratory measures. Proteolytic enzymes involved in the cascade of joint destruction are potentially useful parameters to monitor the extent of joint inflammation in RA. This study compares the validity of two classes of proteolytic enzymes, matrix metalloproteinases (MMP) and lysosomal cysteine proteinases (cathepsin B, H, and L) as well as their respective inhibitors to serve as parameters of RA disease activity. METHODS: The proteolytic activity of cathepsin B, H, and L was determined by fluorometry in sera of 20 patients with active RA and of 20 healthy donors. In addition, the concentrations of cathepsin B and L as well as of cathepsin inhibitors stefin A, stefin B, and cystatin C were measured by ELISA. The plasma concentrations of MMP-1 (collagenase), MMP-3 (stromelysin), tissue inhibitor of metalloproteinases 1 (TIMP-1), and of MMP-1/TIMP-1 complex (MT complex) were analyzed by ELISA as well. RESULTS: A significant increase of MMP-1, MMP-3, and MT complex was observed in RA plasma, compared to normal controls, whereas TIMP-1 concentrations did not differ. In contrast, neither serum activity nor protein concentration of any of the cathepsins or cathepsin inhibitors were elevated in RA. CONCLUSION: Despite ample evidence in the literature that cathepsin activity contributes to the pathogenesis of inflammatory joint disease, this is not reflected by the conditions in peripheral blood. In contrast to the cysteine proteinases, MMP-1 and MMP-3 as well as MT complex are elevated in RA. In the context of findings in the literature, this stresses the importance of MMP as disease activity markers, compared to cysteine proteinases or their inhibitors.

Aged↗
PubMed1998

Coiling phagocytosis discriminates between different spirochetes and is enhanced by phorbol myristate acetate and granulocyte-macrophage colony-stimulating factor.

The mechanisms involved in coiling phagocytosis are not yet known, and it is not even clear whether this phenomenon is either an incidental event or a specific response. Therefore, the phagocytic uptake of Borrelia burgdorferi and other spirochetes by human monocytes in vitro was used to investigate the involvement of both sides--microbes and phagocytes--in coiling phagocytosis. As seen with electron microscopy, morphologically similar Borrelia, Leptospira and Treponema strains induced markedly different frequencies of coiling phagocytosis. The monocytes used coiling phagocytosis for both live (motile) and killed (nonmotile) B. burgdorferi, but pseudopod coils were observed neither with fragmented B. burgdorferi nor with cell-free supernatant from B. burgdorferi cultures. Investigation of the relationship of coiling phagocytosis with other pseudopod-based cellular mechanisms revealed that the use of bioreagents that inhibit conventional phagocytosis also inhibited coiling phagocytis but did not affect membrane ruffling. Bioreagents that increase membrane ruffling did not affect phagocytosis of B. burgdorferi, except for granulocyte-macrophage colony-stimulating factor and phorbol myristate acetate, which increased coiling phagocytosis selectively. These results demonstrate that coiling phagocytosis is not induced by microbial motility, viability, or a certain morphology and that it is not a random event. Rather, it is a selective uptake mechanism actively driven by the phagocytes. However, whether coiling phagocytosis represents an independent alternative to conventional phagocytosis or, alternatively, a fault in conventional phagocytosis remains to be determined.

Borrelia burgdorferi Group↗