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Biomedical subjects

D Burger

Publications and source records attributed to D Burger.

At least 55 records · Page 3Linked to original sources
PubMed1997

Crucial role of tumor necrosis factor (TNF) receptor 2 and membrane-bound TNF in experimental cerebral malaria.

Tumor necrosis factor (TNF) has been implicated in the pathogenesis of experimental cerebral malaria (CM), but the respective role of its two types of receptors has not been established. A significant increase in the expression of TNF-receptor 2 (TNFR2, p75), but not of TNFR1 (p55), was found on brain microvessels at the time of CM in susceptible animals. Moreover, mice genetically deficient for TNFR2 (Tnfr2null) were significantly protected from experimental CM, in contrast to TNFR1-deficient (Tnfr1null) mice, which were as susceptible as wild-type mice. To identify the factors involved in the protection from CM conferred by the lack of TNFR2, we assessed in both knockout and control mice the serum concentrations of mediators that are critical for the development of CM, as well as the up-regulation of intercellular adhesion molecule-1 (ICAM-1) in the brain microvessels. No significant difference in serum levels of TNF and interferon-gamma was found between infected wild-type and Tnfr1null or Tnfr2null mice. Interestingly, the pronounced ICAM-1 up-regulation and leukocyte sequestration, typically occurring in brain microvessels of CM-susceptible animals, was detected in infected control and Tnfr1null mice-both of which developed CM-whereas no such ICAM-1 up-regulation or leukocyte sequestration was observed in Tnfr2null mice, which were protected from CM. Making use of microvascular endothelium cells (MVEC) isolated from wild-type, Tnfr1null or Tnfr2null mice, we show that soluble TNF requires the presence of both TNF receptors, whereas membrane-bound TNF only needs TNFR2 for TNF-mediated ICAM-1 up-regulation in brain MVEC. Thus, only in MVEC lacking TNFR2, neither membrane-bound nor soluble TNF cause the up-regulation of ICAM-1 in vitro. In conclusion, these results indicate that the interaction between membrane TNF and TNFR2 is crucial in the development of this neurological syndrome.

Animals↗
PubMed1997

Direct contact with stimulated T cells induces the expression of IL-1beta and IL-1 receptor antagonist in human monocytes. Involvement of serine/threonine phosphatases in differential regulation.

Imbalance in the production of cytokines and their inhibitors plays a part in inflammation in chronic destructive diseases. Direct cell-cell contact with stimulated T cells markedly induces the production of pro-inflammatory cytokines and matrix metalloproteinases in monocytes. This study demonstrates that direct contact with stimulated T cells favours the production of IL-1beta over that of IL-1 receptor antagonist (IL-1Ra) in both peripheral blood monocytes and the monocytic cell line THP-1. In contrast, soluble factors secreted by stimulated T cells favour the production of IL-1Ra. Differentiation of THP-1 cells with 1,25-(OH)2D3 did not affect the balance between IL-1beta and IL-1Ra production, enhancing both cytokines 2.3- and 1.6-fold, respectively. Among different inhibitors of phosphorylation and dephosphorylation processes, only okadaic acid, an inhibitor of serine/threonine phosphatases, differentially modulates the production of IL-1beta and IL-1Ra. Indeed, okadaic acid upregulated IL-1beta and decreased IL-1Ra at the mRNA and protein level in monocytic cells activated by membranes of stimulated T cells. These results suggest that serine/threonine phosphatases play a part in the differential regulation of the production of IL-1beta and IL-1Ra by monocytes upon direct cell-cell contact with stimulated T cells. This mechanism may regulate the balance between the pro-inflammatory cytokine and its inhibitor, which balance dictates in part the outcome of the inflammatory process.

Cell Line↗
PubMed1997

Modulation of soluble and membrane-bound TNF-induced phenotypic and functional changes of human brain microvascular endothelial cells by recombinant TNF binding protein I.

In this study, the effects of TNF binding protein I (TBP I) on TNF-induced changes of human brain microvascular endothelial cells (MVEC) were investigated. TBP I completely abolished TNF-induced IL-6 production and E-selectin induction, while it partially inhibited TNF-induced IL-8 production and up-regulation of ICAM-1 and VCAM-1. Moreover, TBP I significantly inhibited TNF-induced cytotoxicity and leukocyte adherence on human brain MVEC. The inhibitory activity of TBP I for TNF was dose-dependent and related to the time of administration after TNF stimulation. In addition, TBP I inhibited membrane-bound TNF induced activation of human brain MVEC, but the concentration required was about 10-fold higher than that for soluble TNF. These results indicate a therapeutic potential for TBP I in diseases of the central nervous system associated with TNF overproduction.

Brain↗
PubMed1997

Fluorouracil plus racemic leucovorin versus fluorouracil combined with the pure l-isomer of leucovorin for the treatment of advanced colorectal cancer: a randomized phase III study.

PURPOSE: To compare the efficacy and toxicity of fluorouracil (FU) and racemic leucovorin (d,l-LV) versus FU combined with the l-isomer of leucovorin (l-LV) in the treatment of advanced colorectal cancer. PATIENTS AND METHODS: A total of 248 patients with advanced measurable colorectal cancer previously unexposed to chemotherapy were randomly assigned to treatment with either FU (400 mg/m2/d by intravenous [I.V.] infusion for 2 hours) and racemic LV (100 mg/m2/d by I.V. bolus injection) given for 5 consecutive days, or the combination of FU and the pure l-isomer of LV using the same dose schedule. In both treatment arms, courses were administered every 28 days if toxicity allowed for a total of 6 months, unless evidence of tumor progression was documented earlier. RESULTS: There were no significant differences between the FU/racemic LV and the FU/l-LV arm in the overall response rate (25% v 32%), duration of response (7.2 v 8.0 months), median time to progression or death (6.25 v 8.0 months), or median overall survival time (14.5 v 15.0 months). Except for minor myeloid toxic effects associated with FU/l-LV, there was also no significant difference in terms of adverse reactions. Gastrointestinal symptoms, specifically mucasitis and diarrhea, were less frequent and less severe in both treatment arms compared with other trials with FU/racemic LV reported in the literature, which might be because of the prolonged administration of FU used in both arms. CONCLUSION: The combination of FU/l-LV produced response rates, response durations, and survival times similar to those with FU/d,l-LV. Biochemical modulation of FU by either pure l-LV or racemic LV thus appears to result in equivalent clinical efficacy.

Adult↗
PubMed1997

Interferon-beta not only inhibits interleukin-1beta and tumor necrosis factor-alpha but stimulates interleukin-1 receptor antagonist production in human peripheral blood mononuclear cells.

Imbalance between pro-inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) and their respective inhibitors is likely to be involved in the pathogenesis of chronic inflammatory disorders such as multiple sclerosis and rheumatoid arthritis. Increasing evidence suggests that the administration of interferon-beta (IFN-beta) displays some efficacy in the treatment of patients with relapsing-remitting multiple sclerosis. The aim of the present study was to determine the effect of IFN-beta on the production of pro-inflammatory cytokines and their inhibitors by stimulated peripheral blood mononuclear cells (PBMC). IFN-beta decreased the production of both IL-1beta and TNF-alpha in a dose-dependent manner, by up to 80% and 55%, respectively. Simultaneously, IFN-beta increased the production of IL-1 receptor antagonist (IL-1Ra) by 37% and did not modulate the release of TNF-soluble receptors (TNF-sRs) p55 and p75. Therefore, by favoring the production of cytokine antagonists over that of pro-inflammatory cytokines, IFN-beta induces an imbalance supporting anti-inflammatory processes. This effect might account for some of the therapeutic benefit of IFN-beta.

Humans↗
PubMed1996

Expression and cleavage of tumor necrosis factor-alpha and tumor necrosis factor receptors by human monocytic cell lines upon direct contact with stimulated T cells.

Tumor necrosis factor-alpha (TNF-alpha) is a potent cytokine in inflammatory processes. A variety of mechanisms that modulate its activity have been described, one being its binding to soluble receptors (sTNFR). In this study, we demonstrate that human monocytic cells such as THP-1 respond to direct contact with a membrane preparation of stimulated HUT-78 cells by producing TNF-alpha and by releasing sTNFR-p75, but not sTNFR-p55, with different kinetics. TNF-alpha concentration peaked after 12 h of contact and then decreased, whereas sTNFR-p75 production increased progressively upon cell/cell contact. The decrease in TNF-alpha concentration is not due to trapping of TNF-alpha by its soluble receptors or other soluble or cell-associated molecules, but rather to a proteolytic activity associated to THP-1 cells. On the other hand, the increase in sTNFR-p75 release does not result from an increase in the cleavage of pre-existing cell-associated sTNFR-p75 but from an increase in TNFR-p75 expression, immediately followed by the cleavage of its extracellular domain. Phenylmethylsulfonylfluoride, a serine protease inhibitor, has a negative effect on both TNF-alpha degradation and sTNFR-p75 release by THP-1 cells. Thus, there may be an enzymatic activity associated to THP-1 cells that plays an important role in the neutralization of TNF-alpha activity both by degrading the molecule and by cleaving its receptors at the cell surface.

Cell Membrane↗
PubMed1996

Direct cell/cell contact with stimulated T lymphocytes induces the expression of cell adhesion molecules and cytokines by human brain microvascular endothelial cells.

Upon inflammation, stimulated, but not resting T lymphocytes cross the blood-brain barrier and migrate into the central nervous system. This study shows that direct contact between stimulated T lymphocytes and human brain microvascular endothelial cells (HB-MVEC) induces phenotypic and functional changes on the latter cells. Plasma membranes isolated from stimulated T lymphocytes (S-PM) up-regulated the expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin on isolated HB-MVEC. In addition, HB-MVEC activated by S-PM secreted interleukin (IL)-6 and IL-8. The levels of ICAM-1, E-selectin, IL-6, and IL-8 expressed in S-PM-activated HB-MVEC were similar to those observed with 1000 U/ml tumor necrosis factor (TNF). In contrast, VCAM-1 expression was 15% of that induced by TNF. Inhibitors of TNF diminished (< or = 45%), but did not abolish the expression of cell adhesion molecules and IL-6 induced by S-PM, IL-8 production being insignificantly affected (< or = 10%). This suggests that membrane-associated TNF was partially involved in HB-MVEC activation. The present study demonstrates that stimulated T lymphocytes are able to activate HB-MVEC upon direct cell contact. This novel mechanism of inducing the expression of cell adhesion molecules may prompt the initial adhesion of stimulated T lymphocytes to brain endothelium.

Brain↗
PubMed1996

Effective treatment of advanced breast cancer with vinorelbine, mitomycin C plus human granulocyte colony-stimulating factor.

A phase II trial was performed to evaluate the efficacy and tolerance of vinorelbine (VNB), mitomycin C (MMC), and recombinant human granulocyte colony-stimulating factor (G-CSF) in advanced breast cancer. Between October 1992 and July 1994, 55 patients entered this trial. Nine patients had locally advanced disease and 46 had distant metastases, including 14 who had received previous palliative chemotherapy with (n = 9) or without anthracyclines (n = 5). Therapy consisted of VNB 40-50 mg m(-2) diluted in 250 ml saline infused over 30 min every 3 weeks, and MMC 15 mg m(-2) administered by intravenous bolus injection every 6 weeks. G-CSF was given at 5 microg kg(-1) day(-1) subcutaneously from days 2 to 7 following each cytotoxic drug administration. Treatment was continued in case of response or stable disease for a total of six courses. The overall response rate was 73% for all 55 patients (95% confidence interval, 59-84%), including 12 (22%) complete response (CR) and 28 (51%) partial response (PR); 13 patients (24%) had stable disease (SD), and only two (4%) progressed. All nine patients with locally advanced disease were rated responsive (two pCR, seven PR) and underwent surgery with curative intent. Eight out of nine remain disease free after a median observation period of 18 months (range, 13.5-28 months). Among the 32 previously untreated patients with metastatic disease, nine (28%) achieved CR, 15 PR (47%), seven SD (22%) and one PD (3%). Second-line chemotherapy with this regimen resulted in 7/14 (50%) objective remissions (one CR, six PR), six had SD and one PD. The median time to progression was 12 months (range, 2-24+ months) in previously untreated patients with disseminated disease, and 6.0 months (range, 2-22 months) in those who had failed prior chemotherapy. After a median follow-up time of 20 months, 24 patients with distant metastases are still alive with disease; median survival has not been reached yet. The dose-limiting toxicity was myelosuppression: six (11%) and ten patients (18%) had World Health Organization grade 3, and eight (14%) and nine patients (16%) had grade 4 leucopenia and granulocytopenia respectively. Severe (WHO grade 3) non-haematological toxicities included nausea/vomiting in 7%, constipation in 9%, peripheral neuropathy in 5%, infectious episodes in 7%, phlebitis due to drug extravasation in 5%, alopecia in 9%, and acute reversible pulmonary toxicity in 11%. Our data suggest that vinorelbine, mitomycin C plus G-CSF has an excellent anti-tumour activity in advanced breast cancer, probably superior to most other available combination chemotherapy regimens. This combination does not seem to present significant cross-resistance with previous CMF or anthracycline regimens. Apart from reversible, acute pulmonary toxicity, a rare adverse reaction that had previously been described for VNB, as well as the combination of natural vinca alkaloids with mitomycin C, and few episodes of grade 3 neurotoxicity (all of which occurred at the initial 50 mg m(-2) VNB dose level), the tolerance of this regimen seems acceptable and justifies further evaluation in front-line and salvage therapy of advanced breast cancer.

Adult↗
PubMed1995

Substitution of didanosine sachets by chewable tablets: a pharmacokinetic study in patients with AIDS.

We have conducted a pharmacokinetic study of didanosine (ddI), formulated in sachets and in tablets, in patients with acquired immune deficiency syndrome (AIDS). Fifteen subjects received 250 or 167 mg of ddI twice daily as the sachet formulation and used this for at least 1 month. Subsequently, the patients were converted to receive ddI chewable/dispersible tablets (250-mg sachets to 200-mg tablets; 167-mg sachets to 125-mg tablets). Four subjects withdrew because of clinical deterioration or adverse effects. Serial blood samples were collected for pharmacokinetic monitoring during the use of the sachets and after 1 month of use of the tablets. No statistically significant differences were found in the maximum plasma concentration (Cmax), the time to reach Cmax (tmax), the area under the plasma concentration-time curve (AUC), or the terminal elimination half-life (t1/2) between the two formulations. Patients who received low-dose ddI (sachets, 167 mg; tablets, 125 mg) displayed lower plasma concentrations than did the patients receiving high-dose ddI (sachets, 250 mg; tablets, 200 mg), despite an equal weight-normalized dose of ddI in these two groups.

Absorption↗
PubMed1995

The inhibitory activity of human interleukin-1 receptor antagonist is enhanced by type II interleukin-1 soluble receptor and hindered by type I interleukin-1 soluble receptor.

Interleukin-1 (IL-1) is a major proinflammatory cytokine produced by monocytes/macrophages. At the inflammatory site, IL-1 is a potent inducer of the production of prostaglandin E2 (PGE2) and metalloproteinases on fibroblast-like cells, thus triggering tissue damage. The biological activity of IL-1 is counterbalanced by two types of inhibitors: the IL-1 receptor antagonist (IL-1Ra) which competitively binds IL-1 receptor without inducing signal transduction; and IL-1 soluble receptors (IL-1sR) which bind IL-1 and diminish the free concentration of soluble cytokine, thus hampering its binding to the cell surface receptor. Since IL-1sR can also bind IL-1Ra, we studied the simultaneous effects of both inhibitors on the production of interstitial collagenase (C'ase) and PGE2 by human dermal fibroblasts and synovial cells stimulated by either IL-1 alpha or IL-1 beta. IL-1Ra inhibited fibroblast and synovial cell stimulation by approximately 90%, with the exception of C'ase production by synovial cells which was inhibited by approximately 55%. Type I IL-1sR (IL-1sRI) preferentially inhibited IL-1 alpha, whereas type II IL-1sR (IL-1sRII) mainly inhibited IL-1 beta. When IL-1Ra was used simultaneously with IL-1sRI, the final inhibition was lower than that of either of the inhibitors. The simultaneous presence of IL-1Ra and IL-1sRII abolished the IL-1-induced production of PGE2 and C'ase on both dermal fibroblasts and synovial cells, demonstrating that concurrently these two inhibitors are able to abolish most of the inflammatory response. To our knowledge, this is the first example of two types of inhibitors that abolish each other's effects, one of which acts at the receptor level and the other at the ligand level, thus leaving ligand activity unimpaired.

Cells, Cultured↗
PubMed1995

Inhibitory cytokines and cytokine inhibitors.

Cytokines such as interleukin-1 and tumor necrosis factor are involved in the triggering of the immune response, induction of acute inflammatory events, and transition to, or persistence of, chronic inflammation. The action of proinflammatory cytokines is regulated by their receptor expression, downregulation and shedding, by specific inhibitors, and by inhibitory cytokines mainly produced by lymphocytes. This review aims to pinpoint recent findings in the assessment of the biologic activities of cytokine inhibitors and inhibitory cytokines. The suitability of these agents as therapeutic tools is discussed.

Cytokines↗
PubMed1995

Contact-dependent stimulation of monocytic cells and neutrophils by stimulated human T-cell clones.

By means of direct cell-cell contact, fixed, stimulated T lymphocytes trigger the production of interleukin-1 beta (IL-1 beta) and tumour necrosis factor by monocytes and prime polymorphonuclear leucocytes (PMN) for the respiratory burst induced by N-formyl-methionyl-leucyl-phenylalanine (FMLP). In order to assess whether this activity is displayed by a particular subpopulation of T lymphocytes, 88 T-cell clones (TCC) were generated from healthy human peripheral blood. The clones were stimulated by Phaseolus vulgaris agglutinin (PHA) and phorbol 12-myristate acetate monocytic cell line THP-1. All fixed, stimulated TCC induced IL-1 beta production by THP-1 cells, although to varied degrees. The activity of TCC on THP-1 cells correlated with their activity on PMN (r2 = 0.84, P < 0.001), suggesting that this pro-inflammatory activity of TCC may similarly affect both types of infiltrating cells. The ability of TCC to modulate target cells did not correlate with either their phenotype (CD4 or CD8) or their cytokine production profile (interferon-gamma, IL-4 and IL-6), although it tended to correlate inversely with their capacity to produce IL-6 (P < 0.02). These observations suggest that a large proportion, if not all, of human peripheral blood T lymphocytes may potentially affect monocytes and PMN by direct cell-cell contact. This activity may be relevant to the maintenance of chronic inflammation.

Antigens, CD↗
PubMed1994

Experimental treatment of equine sarcoid using a xanthate compound and recombinant human tumour necrosis factor alpha.

A xanthate compound with antiviral and antitumoural activities, tricyclodecan-9-yl-xanthogenate (D609) in combination with the potassium salt of the lauric acid (KC12) and, in a further investigation, the above-mentioned substances together with recombinant human TNF alpha (rh-TNF alpha), were tested on equine sarcoid tumours for therapeutic efficacy. A pilot investigation on 5 healthy horses showed that the compounds were well-tolerated; apart from a local, temporary oedema at the injection site, no other clinical symptoms were observed after subcutaneous administration of volumes from 0.1 to 10 ml per injection. The tested concentrations of D609 and KC12 (5 mg/ml solution) and of rh-TNF alpha (50 micrograms/ml) were used for the treatment experiments. The repeated injections of the compounds to 11 sarcoid affected horses were also well-tolerated, except by one horse. In this case the treatment had to be interrupted after two injections because of severe reaction, i.e. fever and lameness due to oedemas. Five horses (n = 6 sarcoids) were treated by local, subcutaneous injection of D609 and KC12 under the tumour at intervals of 3 weeks. On one periocular sarcoid the compounds were applied as an ointment. After a follow-up period of 18 months, 5 tumours did completely regress and one remained unchanged. The periocular tumour showed a reduction in size. Five horses (n = 9 sarcoids) were then treated with a combination of D609, KC12 and rh-TNF alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Immunoreactive insulin-like growth factor I and insulin in blood plasma and milk of mares and in blood plasma of foals.

Concentration of (total) globulin was relatively stable in blood plasma of mares, but rapidly decreased in colostrum to very low levels within 2 days after parturition. In foals, after intake of the first colostrum, globulin increased within 1 day in blood plasma, but remained at lower concentrations than those measured in mare plasma. Concentrations of immunoreactive insulin (iI) were high during the first 2 months of lactation in blood plasma of mares and then decreased, were high in first colostrum and then decreased drastically, and remained at low concentrations up to weaning in blood of foals. In mares, concentration of immunoreactive insulin-like growth factor I (iIGF-I) in plasma increased during late pregnancy, peaked 2 days after parturition, and then gradually declined until weaning. iIGF-I was highest in first colostrum and then dramatically decreased within the first 2 days of lactation. In foals, iIGF-I gradually increased over the first 2 months of life. IGF-I in the horse appears to be bound to proteins of similar molecular weight as in cattle. The study demonstrates different patterns of changes in plasma iIGF-I and iI concentrations in mares and their foals, whereas iI, iIGF-I and globulin changes in colostrum and milk occurred in parallel. Furthermore, plasma iI and iIGF-I behaved differently, while colostrum iI and iIGF-I behaved similarly, in mares compared with dairy cows.

Animals↗