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Biomedical subjects

E Dupont

Publications and source records attributed to E Dupont.

At least 73 records · Page 4Linked to original sources
PubMed1997

Increased in vitro immunosuppressive action of anti-CMV and anti-HBs intravenous immunoglobulins due to higher amounts of interferon-gamma specific neutralizing antibodies.

BACKGROUND AND OBJECTIVES: We previously found that interferon-gamma (IFN-gamma) antibodies in intravenous immunoglobulins (IVIG) can block not only IFN-gamma production and tumor necrosis factor-alpha secretion, but also T-cell proliferation. Since the presence of IFN-gamma antibodies has been attributed to previous viral infection, we hypothesized that the viral status of the plasma donors used for IVIG pools might be a decisive factor in controlling the immunosuppressive capacity of IVIG. MATERIALS AND METHODS: We tested three different pooled, human IVIG preparations for the presence of IFN-gamma antibodies by ELISA. RESULTS: Comparison of the immunomodulatory activity of polyvalent IVIG with that of specific CMV and HBs IVIG showed that the latter-had higher levels of IFN-gamma antibodies and an increased capacity to block mixed lymphocyte reaction and cytokine production. CONCLUSION: We propose that these in vitro assays constitute a basis for the selection of plasma intended for manufacturing IVIG aimed at immunosuppression in the transplant setting.

Antibodies, Viral↗
PubMed1997

Importance of ionized magnesium measurement for monitoring of citrate-anticoagulated plateletpheresis.

BACKGROUND: The infusion of citrate during apheresis may affect the levels of ionized magnesium in the blood. Hypomagnesemia and concomitant hypocalcemia could influence the parathormone response and could be responsible for some of the symptoms observed during apheresis. STUDY DESIGN AND METHODS: The study reports measurement of ionized magnesium by the new ion-selective electrode technique in response to citrate infusion in 15 donors undergoing continuous flow high-yield plateletpheresis. The monitoring included measurement of ionized calcium and parathormone every 30 minutes during the 120-minute apheresis (plus the next 30 minutes to assess recovery). RESULTS: Ionized magnesium fell by 30 +/- 4 percent (mean +/- SD, p<0.01), which contrasts with minor changes in total concentrations. Comparison of variations in the levels of ionized and total magnesium found major formation of complexes during citrate infusion. Ionized calcium fell by 15 +/- 3 percent (p<0.01), while parathormone peaked at 356 +/- 114 percent (p<0.01) of initial value after 30 minutes. Ionized cations and parathormone recovered by more than 50 percent within 30 minutes of the end of apheresis. CONCLUSION: An acute and steep drop in ionized magnesium occurs during citrate administration. The measurement of ionized magnesium should be included in future prospective studies of donor safety and parathormone regulation during apheresis.

Anticoagulants↗
PubMed1997

Upregulation of connexin43 gap junctions between smooth muscle cells after balloon catheter injury in the rat carotid artery.

Phenotypic transformation of smooth muscle cells (SMCs) to the synthetic state in vitro and in human coronary atherosclerosis is reported to be associated with upregulation of connexin43 gap junctions. To determine whether cellular interactions mediated by gap junctions participate in the phenotypic transformation of SMCs in arterial injury and disease in general and to establish the spatial and temporal pattern of any such change in relation to neointimal development, we investigated SMC connexin43 gap junction expression during vascular healing in the rat carotid artery after balloon catheter injury. Quantitative immunoconfocal microscopy was applied to localize and to quantify connexin43 gap junctions 1, 3, 9, and 14 days after injury. Parallel studies were conducted by electron microscopy (direct morphological demonstration of SMC gap junctions) and immunoconfocal microscopy (localization of altered actin expression). Synthetic-state SMCs in the neointima (first apparent from 9 days postinjury) revealed abundant expression of gap junctions, with levels of immunodetectable connexin43 threefold greater than those of medial cells. However, the first detectable changes were found in the media, before neointimal formation; at 1 to 3 days postinjury, an increase in SMC gap junction expression was apparent in the innermost (subluminal) zone, the major site from which the cells subsequently found in the neointima are recruited. We conclude that upregulation of connexin43 gap junctions is intimately linked to SMC phenotypic transition and that interactions mediated by gap junctions may be a hitherto unrecognized contributor to the cellular mechanisms underlying the vascular response to injury.

Angioplasty, Balloon↗
PubMed1997

Gap junction localization and connexin expression in cytochemically identified endothelial cells of arterial tissue.

Vascular endothelial cells interact with one another via gap junctions, but information on the precise connexin make-up of endothelial gap junctions in intact arterial tissue is limited. One factor contributing to this lack of information is that standard immunocytochemical methodologies applied to arterial sections do not readily permit unequivocal localization of connexin immunolabeling to endothelium. Here we introduce a method for multiple labeling with specific endothelial cell markers and one or more connexin-specific antibodies which overcomes this limitation. Applying this method to localize connexins 43, 40, and 37 by confocal microscopy, we show that the three connexin types have quite distinctive labeling patterns in different vessels. Whereas endothelial cells of rat aorta and coronary artery characteristically show extensive, prominent connexin40, and heterogeneous scattered connexin37, the former, unlike the latter, also has abundant connexin43. The relative lack of connexin43 in coronary artery endothelium was confirmed in both rat and human using three alternative antibodies. In the aorta, connexins43 and 40 commonly co-localize to the same junctional plaque. Even within a given type of endothelium, zonal variation in connexin expression was apparent. In rat endocardium, a zone just below the mitral valve region is marked by expression of greater quantities of connexin43 than surrounding areas. These results are consistent with the idea that differential expression of connexins may contribute to modulation of endothelial gap junction function in different segments and subzones of the arterial system.

Animals↗
PubMed1997

Hyperinsulinemia-induced hypoglycemia is enhanced by overexpression of connexin 43.

To assess whether cell to cell communications via connexins (Cx) participate to insulin secretion in vivo, we studied insulinoma cells (INS1) implanted in rats after stable transfection with connexin 43 (Cx43). We found that compared to wild-type and transfected cells, which in vivo express modest levels of Cx43 and junctional communication, cells overexpressing Cx43 communicated extensively, featured decreased growth, and induced a much higher hyperinsulinemia. As a result, rats with insulinomas made of these cells became more severely hypoglycemic than rats implanted with either wild-type, neomycin-transfected cells or cells transfected with a Cx43 antisense complementary DNA. Rats implanted with transfected cells that expressed modest level of Cx43 showed levels of circulating insulin similar to those in rats implanted with wild-type INS1 cells. The data show that overexpression of Cx43 influences the growth and secretion of the implanted insulinoma cells, providing evidence for a contribution of Cx-mediated cell to cell communication in the functioning of insulin-producing cells in vivo.

Animals↗
PubMed1997

Cabergoline in the treatment of early Parkinson's disease: results of the first year of treatment in a double-blind comparison of cabergoline and levodopa. The PKDS009 Collaborative Study Group.

Cabergoline is a potent D2 receptor agonist with a half-life of 65 hours that may provide continuous dopaminergic stimulation administered once daily. In this study, we randomized de novo Parkinson's disease (PD) patients to treatment with increasing doses of cabergoline (0.25 to 4 mg/d) or levodopa (100 to 600 mg/d) up to the optimal or maximum tolerated dose. Decreases of > 30% in motor disability (Unified Parkinson's Disease Rating Scale Factor III) versus baseline were considered indicative of clinical improvement. If 30% improvement was not achieved, levodopa/ carbidopa could be added on an open basis. Of the 208 patients entered in the cabergoline group, 175 remained in the study for 1 year at a mean dose of 2.8 mg/d; in the levodopa group, 176 of the 205 patients entered were still on study after 1 year at a mean dose of 468 mg/d. The proportion of patients requiring additional levodopa/carbidopa increased in the cabergoline group from 18% at 6 months to 38% at 1 year versus 10% (p = 0.05) at 6 months and 18% (p < 0.01) at 1 year in the levodopa group. The proportion of patients showing clinical improvement did not differ significantly between the two groups, or between the subgroups on monotherapy, at any endpoint. Irrespective of levodopa/carbidopa addition, 81% of patients in the cabergoline group and 87% of patients in the levodopa group were clinically improved at 1 year (p = 0.189); the corresponding figures for the subgroup on monotherapy were 79% in the cabergoline-treated patients and 86% in the levodopa-treated patients (p = 0.199). The mean difference versus baseline in Unified Parkinson's Disease Rating Scale Factor III scores in patients who remained on monotherapy up to 1 year was 12.6 (95% confidence interval [CI]: 10.8, 14.3) in the cabergoline group and 16.4 (95% CI: 14.8, 18.0) in the levodopa group. Adverse events occurred in 76% of patients on cabergoline and in 66% of patients on levodopa. The severity profile for reported events was similar for the two agents. The results of this study indicate that cabergoline treatment for up to 1 year is only marginally less effective than levodopa in the proportion of patients who can be treated in monotherapy. More than 60% of de novo PD patients could be managed on cabergoline alone up to 1 year. In the patients in whom levodopa/carbidopa was needed, the combination therapy provided efficacy similar to that obtained with levodopa alone, with a relevant sparing of levodopa.

Aged↗
PubMed1997

[Identification of NPDC-1, gene involved in the control of proliferation and differentiation of neural and glial precursors].

Most of the genes involved in the regulation of proliferation and differentiation of neural cells remain to be identified. With the aim of identifying such genes, the strategy we used was to search for cDNAs which both hybridized with helix-loop-helix degenerated probes and corresponded to RNAs expressed preferentially when neural precursor cells become growth-arrested and began to differentiate. This led to the isolation of NPDC-1 cDNA and then of the genomic sequence. We observed that NPDC-1 is specially expressed in the nervous system and that the transfection of neural precursors with NPDC-1 cDNA results in the inhibition of cell proliferation. Moreover, the stable introduction of NPDC-1 into transformed cells downregulates cell proliferation both by increasing the generation time and by suppressing transformed and tumorigenic properties. We verified that these biological effects were reversed by NPDC-1 anti-sense oligonucleotides. Then we have examined the expression of NPDC-1 mRNA along mouse development and the interactions of the NPDC-1 protein with cell cycle regulatory proteins. The results showed that NPDC-1 mRNA begins to be expressed in a variety of neural structures, when the precursors enter their terminal differentiation. In addition, we have observed that NPDC-1 protein interacts with the transcription factor E2F-1. As a whole, the present results show that NPDC-1 down-regulates the proliferation of neural precursors, is able to suppress oncogenic transformation, is involved in the terminal differentiation of neural cells and acts probably through interactions with E2F-1.

Animals↗
PubMed1996

Blockade of proliferation and tumor necrosis factor-alpha production occurring during mixed lymphocyte reaction by interferon-gamma-specific natural antibodies contained in intravenous immunoglobulins.

The mechanism of action of intravenous immunoglobulins (IVIg) for prevention of graft rejection and graft-versus-host disease (GVHD) is poorly understood. Recently, it has been shown that these preparations contain natural antibodies directed toward interferon (IFN)-gamma. During mixed lymphocyte reaction (MLR), which constitutes an in vitro model of allograft rejection and GVHD, T cell recognition of HLA differences induces IFN-gamma release. This cytokine promotes T cell proliferation and acts as a macrophage-activating factor to provoke tumor necrosis factor-alpha secretion. The aim of the present work is to investigate the influence of IVIg on IFN-gamma production occurring during MLR and its subsequent impact on T cell proliferation and tumor necrosis factor (TNF)-alpha secretion. We tested IVIg preparations for the presence of anti-IFN-gamma and anti-TNF-alpha antibodies. High amounts of anti-IFN-gamma, but not anti-TNF-alpha antibodies, were found. IVIg addition at the initiation of culture resulted in IFN-gamma secretion blockade. Likewise, lymphocyte proliferation and TNF-alpha secretion were inhibited. This inhibition was reversed by the addition of recombinant human IFN-gamma. Furthermore, the inhibitory properties of IVIg were mimicked by an IFN-gamma-specific neutralizing monoclonal antibody. We conclude that the capacity of IVIg to inhibit proliferation and TNF-alpha release during MLR is due to IFN-gamma blockade by natural antibodies. This immunosuppressive mechanism could contribute to the effect of IVIg on prophylaxis of organ graft rejection and GVHD after allogeneic bone marrow transplantation.

Antibodies↗
PubMed1996

Optimal control of interferon-gamma and tumor necrosis factor-alpha by interleukin-10 produced in response to one HLA-DR mismatch during the primary mixed lymphocyte reaction.

Interleukin (IL)-10 is an immunosuppressive cytokine potentially involved in the control of the allogeneic response. Several studies failed to detect it in mixed lymphocyte reaction supernatants. However, experiments using IL-10-specific antibodies, revealing its inhibitory action on interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha, provided indirect evidence that endogenous IL-10 was produced. The aim of the present work is to elucidate the role of IL-10 during mixed lymphocyte reaction and to investigate the influence of HLA-DR antigens on its production and on the regulatory loop involving TNF-alpha and IFN-gamma. Using a highly sensitive ELISA, a significant (P < 0.0001) but low IL-10 release could be detected (33.7 +/- 3.6 pg/ml) in response to HLA-DR disparities. However, IL-10 release was not graded as 1 DR mismatch (MM)-induced maximal secretion (32.3 +/- 5.1 pg/ml). This contrasted with TNF-alpha and IFN-gamma productions, which significantly increased in 2 DR MM pairs. Addition to IL-10-specific antibodies resulted in higher enhancement of INF-gamma (235 +/- 38% vs. 122 +/- 39%, P = 0.02) and, to a lesser extent, TNF-alpha (147 +/- 56% vs. 112 +/- 20%, NS) in 1 compared with 2 DR MM pairs. We conclude that the 1 DR MM setting is associated with optimal IL-10 secretion and more efficient inhibition of IFN-gamma and TNF-alpha compared with the 2 DR MM configuration. Although promoting enhanced IFN-gamma and TNF-alpha release, introduction of an additional DR MM does not result in increased IL-10 production. These data indicating that the IL-10 regulatory feedback loop is more effective in 1 DR rather than complete DR incompatibility could have an impact on matching policies for planned transfusion.

Antibodies, Blocking↗
PubMed1996

Blood lactate levels are better prognostic indicators than TNF and IL-6 levels in patients with septic shock.

OBJECTIVE: Both serum levels of tumor necrosis factor-alpha (TNF alpha) and interleukin-6 (IL-6) and blood lactate levels in patients with septic shock have been shown to correlate with prognosis. The aim of the study was to define the relative predictive value of these measures. PATIENTS: 38 hospitalized patients with septic shock, including 18 survivors and 20 non-survivors. INTERVENTION: Blood TNF alpha (immunoradiometric assay), IL-6 (bioassay) and lactate (enzymatic method) levels were serially measured at the onset of septic shock and after 24 and 48 h. RESULTS: TNF alpha levels tended to be higher in the non-survivors than in the survivors at the onset of shock (204 +/- 392 vs 129 +/- 195 pg/ml, p = NS) but decreased similarly in both groups with time (p = 0.03). IL-6 levels at admission were highly variable (9656 +/- 19851 U/ml in the non-survivors and 69,222 +/- 248,804 U/ml in the survivors). Log IL-6 decreased similarly in both groups with time (p = 0.004). Admission blood lactate levels were higher in the non-survivors than in the survivors (6.11 +/- 4.78 mEq/l vs 3.49 +/- 2.00 mEq/l, p < 0.05) and decreased significantly with time in all patients (p = 0.024). However, this decrease was greater in the survivors than in the non-survivors (p = 0.003). CONCLUSION: These data indicate that the large variability in TNF alpha and IL-6 levels limit their prognostic significance in patients with septic shock. The predictive value of the trend in cytokine levels over time is not superior to that of trends in blood lactate levels.

Adult↗
PubMed1996

Sustained-release Madopar HBS compared with standard Madopar in the long-term treatment of de novo parkinsonian patients.

In this Danish-Norwegian randomized double-blind parallel-group multicentre study, we compared the therapeutic response of slow-release Madopar HBS to standard Madopar in 134 de novo patients with idiopathic Parkinson's disease during a 5-year period. The drugs were dosed according to the individual need of the patients. The Webster, NUDS, UPDRS and Hoehn & Yahr scales were used for evaluation of symptoms. Addition of a morning dose of standard Madopar 62.5 mg was allowed after 6 months. Bromocriptine could be administered but not Selegiline. Sixty-five patients got Madopar HBS and 69 standard Madopar. Surprisingly, no differences were found as to the mean daily levodopa dose, the mean number of daily doses or the use of the doses of bromocriptine. Unexpectedly, we found a trend towards a more frequent use of a morning dose of standard Madopar in the group treated with the standard formulation. No differences were observed in the occurrence of motor fluctuations or dyskinesia, the incidence of which was relatively low. Sustained-release Madopar (HBS) thus proved to be as effective as standard Madopar in the long-term treatment of de novo parkinsonian patients, but the drug showed no advantage in postponing or reducing the long-term levodopa treatment problems.

Aged↗
PubMed1996

Hemifacial spasm: magnetic resonance angiography.

Twenty-three consecutive patients with hemifacial spasm were studied. Magnetic resonance imaging angiography of the brain was performed in 20 patients and 15 controls. The angiograms were evaluated by two independent observers and blinded for side-location of the spasm. Contact between an artery from the vertebrobasilar circulation and the intracranial part of the facial nerve was observed ipsilaterally to the spasm in 17 patients (85%) and in two of 30 control half-brains (7%), respectively. Treatment is discussed. The study confirms that arterial relation to the facial nerve root is the most frequent cause of hemifacial spasm. Magnetic resonance imaging is recommended to exclude mass lesions in the posterior cranial fossa, and magnetic resonance angiography is recommended in preoperative evaluation and in research.

Adult↗
PubMed1996

Simplification of the blood stem cell transplantation (BSCT) procedure: large volume apheresis and uncontrolled rate cryopreservation at -80 degrees C.

Very high-dose chemotherapy with autologous blood stem cell (BSC) rescue becomes more and more widely performed. In order to simplify the technique, a large volume apheresis programme combined with an uncontrolled rate cryopreservation at -80 degrees C was developed. Twenty-six patients suffering from multiple myeloma (n = 8), non-Hodgkin's lymphoma (n = 7), dysgerminoma (n = 4), breast cancer (n = 3), Hodgkin's disease (n = 2), acute lymphoblastic leukaemia (n = 1) and acute myelocytic leukaemia (n = 1) were autografted after a classical high-dose chemotherapy regimen. A single large volume apheresis was sufficient to obtain the threshold value of CD34+ BSC in 24/26 transplantations. The haematological recovery was favourably comparable with the previously published data obtained with controlled rate frozen BSC: median time to granulocytes > 1000/microL and to a self-supporting platelet count > 20,000/microL, respectively, 10.5 and 12 d. The treatment-related mortality was confined to 1/26 BSCT. These results indicate that this easy and cost-saving policy of BSCT is efficacious and safe: sustained long-term haematopoiesis, reduced morbidity and mortality were observed.

Adult↗