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Biomedical subjects

M Sitbon

Publications and source records attributed to M Sitbon.

At least 19 recordsLinked to original sources
PubMed2001

[An index based on the age and free thyroxine rate predicts the likelihood of Graves' disease in hyperthyroidism].

PURPOSE: Graves' disease patients are generally younger and have more severe symptoms than other thyrotoxic patients. We established an index based on the normalized free thyroxine rate and age, capable of predicting Graves' disease in thyrotoxic patients. METHODS: The predictive index was established from a discriminant analysis from a retrospective population of 114 thyrotoxic patients and its predictivity was confirmed by cross-validation on the same population. RESULTS: The index IGD = 41.38 - age + 37.05 x in (normalized free T4) classifies accurately 80.7% of the patients (CI 95%: 72.2-87.5). Sensitivity is 78.5% (CI 95%: 66.5-87.7). Specificity is 83.7% (CI 95%: 70.3-92.7). Predictive positive value is 86.4% (CI 95%: 75.0-94.0). Negative predictive value is 74.5% (CI 95%: 61.0-85.3). Likelihood ratio of Graves' disease in case of prediction by the index is 4.81 (CI 95%: 2.66-9.32). Likelihood ratio of Graves' disease in case of non-prediction by the index is 0.26 (IC 95%: 0.16-0.40). CONCLUSION: A simple index based on the normalized free thyroxine rate and age provides an early diagnosis orientation toward Graves' disease in thyrotoxic patients who are waiting for complementary investigations.

Adult↗
PubMed2000

Definition of an amino-terminal domain of the human T-cell leukemia virus type 1 envelope surface unit that extends the fusogenic range of an ecotropic murine leukemia virus.

Murine leukemia viruses (MuLV) and human T-cell leukemia viruses (HTLV) are phylogenetically highly divergent retroviruses with distinct envelope fusion properties. The MuLV envelope glycoprotein surface unit (SU) comprises a receptor-binding domain followed by a proline-rich region which modulates envelope conformational changes and fusogenicity. In contrast, the receptor-binding domain and SU organization of HTLV are undefined. Here, we describe an HTLV/MuLV envelope chimera in which the receptor-binding domain and proline-rich region of the ecotropic MuLV were replaced with the potentially corresponding domains of the HTLV-1 SU. This chimeric HTLV/MuLV envelope was processed, specifically interfered with HTLV-1 envelope-mediated fusion, and similar to MuLV envelopes, required cleavage of its cytoplasmic tail to exert significant fusogenic properties. Furthermore, the HTLV domain defined here broadened ecotropic MuLV envelope-induced fusion to human and simian cell lines.

Amino Acid Sequence↗
PubMed2000

A novel subgenomic murine leukemia virus RNA transcript results from alternative splicing.

Here we show the existence of a novel subgenomic 4.4-kb RNA in cells infected with the prototypic replication-competent Friend or Moloney murine leukemia viruses (MuLV). This RNA derives by splicing from an alternative donor site (SD') within the capsid-coding region to the canonical envelope splice acceptor site. The position and the sequence of SD' was highly conserved among mammalian type C and D oncoviruses. Point mutations used to inactivate SD' without changing the capsid-coding ability affected viral RNA splicing and reduced viral replication in infected cells.

Alternative Splicing↗
PubMed1999

Systemic adverse effect of antithyroid drugs.

Antithyroid drugs adverse effects are varied and rare. Autoimmune disorders (vasculitis, lupus erythematosus, polyarthritis...) are unusual and serious complications of antithyroid drugs. Since 1945, fewer than 100 cases of systemic manifestations related to antithyroid drugs have been reported in the literature, most frequently with propylthiouracil. The outcome is usually good after drug discontinuation, but some fatal cases have been reported. Because possible cross-sensitivity with other antithyroid drugs, the appropriate treatment for hyperthyroidism relapse if a patient has had an antithyroid drug adverse reaction, should be 131I-Iodine or surgery. We report four new cases of systemic manifestations during propylthiouracil therapy.

Adult↗
PubMed1999

Local gene delivery within the media of rabbit iliac arteries by using the infiltrator intramural delivery device.

Percutaneous transluminal angioplasty continues to be limited by restenosis. Prevention of restenosis is now focusing on local delivery of therapeutic agents, such as proliferation-inhibiting genes, directly to the site of arterial injury. We evaluated use of the Infiltrator catheter (IVT, San Diego, CA. U.S.A.) for gene delivery within the arterial media. The goals of our study were to evaluate the histologic effects of the injection and the suitability of the Infiltrator catheter for local delivery of viral therapy. We injected the femoral arteries of 21 New Zealand White rabbits. Six animals were used for an evaluation of the intramural distribution of dextran/rhodamine injected via the Infiltrator catheter. In seven animals, injection site histology and in vitro vasoreactivity were studied after an injection of saline. In the remaining eight animals, a replication-deficient adenovirus encoding for the firefly luciferase gene (Ad RSVLuc) was injected, and luciferase activity was quantified 3 and 8 days later. After injection via the Infiltrator catheter, the fluorescent tracer was distributed throughout the entire circumference and width of the arteries. Histologic examination showed minimal damage with partial endothelial abrasion and disruption of the internal elastic lamina confined to the penetration sites. In vitro endothelium-dependent vasodilation was present at a reduced level after injection via the Infiltrator (maximal endothelium-dependent acetylcholine-induced relaxation, 51.5 +/- 7.4% vs. 23.8 +/- 14.6%; p < 0.05). Significant luciferase expression was found in all the arteries, with a significant increase from day 3 to day 8 (5,392.5 +/- 2,300 vs. 2,012 +/- 471 cpm/mg; p < 0.05). These data obtained in a rabbit iliac artery model show that the Infiltrator catheter is an efficient and safe local intramural delivery device that provides significant transgene expression in the arterial wall without causing significant structural damage.

Adenoviridae↗
PubMed1999

Introduction of a cis-acting mutation in the capsid-coding gene of moloney murine leukemia virus extends its leukemogenic properties.

Inoculation of newborn mice with the retrovirus Moloney murine leukemia virus (MuLV) results in the exclusive development of T lymphomas with gross thymic enlargement. The T-cell leukemogenic property of Moloney MuLV has been mapped to the U3 enhancer region of the viral promoter. However, we now describe a mutant Moloney MuLV which can induce the rapid development of a uniquely broad panel of leukemic cell types. This mutant Moloney MuLV with synonymous differences (MSD1) was obtained by introduction of nucleotide substitutions at positions 1598, 1599, and 1601 in the capsid gene which maintained the wild-type (WT) coding potential. Leukemias were observed in all MSD1-inoculated animals after a latency period that was shorter than or similar to that of WT Moloney MuLV. Importantly, though, only 56% of MSD1-induced leukemias demonstrated the characteristic thymoma phenotype observed in all WT Moloney MuLV leukemias. The remainder of MSD1-inoculated animals presented either with bona fide clonal erythroid or myelomonocytic leukemias or, alternatively, with other severe erythroid and unidentified disorders. Amplification and sequencing of U3 and capsid-coding regions showed that the inoculated parental MSD1 sequences were conserved in the leukemic spleens. This is the first report of a replication-competent MuLV lacking oncogenes which can rapidly lead to the development of such a broad range of leukemic cell types. Moreover, the ability of MSD1 to transform erythroid and myelomonocytic lineages is not due to changes in the U3 viral enhancer region but rather is the result of a cis-acting effect of the capsid-coding gag sequence.

3T3 Cells↗
PubMed1998

A proline-rich motif downstream of the receptor binding domain modulates conformation and fusogenicity of murine retroviral envelopes.

The entry of retroviruses into cells depends on receptor recognition by the viral envelope surface subunit SU followed by membrane fusion, which is thought to be mediated by a fusion peptide located at the amino terminus of the envelope transmembrane subunit TM. Several fusion determinants have been previously identified in murine leukemia virus (MLV) envelopes, but their functional interrelationships as well as the processes involved in fusion activation upon retroviral receptor recognition remain unelucidated. Despite both structural and functional similarities of their envelope glycoproteins, ecotropic and amphotropic MLVs display two different postbinding properties: (i) while amphotropic MLVs fuse the cells at neutral pH, penetration of ecotropic MLVs is relatively acid pH dependent and (ii) ecotropic envelopes are more efficient than amphotropic envelopes in inducing cell-to-cell fusion and syncytium formation. By exploiting the latter characteristic in the analysis of chimeras of ecotropic and amphotropic MLV envelopes, we show here that substitution of the ecotropic MLV proline-rich region (PRR), located in the SU between the amino-terminal receptor binding domain and the TM-interacting SU carboxy-terminal domains, is sufficient to revert the amphotropic low-fusogenic phenotype into a high-fusogenic one. Furthermore, we have identified potential beta-turns in the PRR that control the stability of SU-TM associations as well as the thresholds required to trigger either cell-to-cell or virus-to-cell fusion. These data, demonstrating that the PRR functions as a signal which induces envelope conformational changes leading to fusion, have enabled us to derive envelopes which can infect cells harboring low levels of available amphotropic receptors.

Amino Acid Sequence↗
PubMed1998

Effect of dexfenfluramine treatment in rats exposed to acute and chronic hypoxia.

The anorexiant dexfenfluramine, which inhibits 5-hydroxytryptamine (5-HT) uptake, has been associated with an increase in the relative risk of developing primary pulmonary hypertension. The aim of this study was to investigate in rats whether dexfenfluramine (1) alters the pulmonary vasomotor effects of 5-HT and (2) aggravates the development of pulmonary hypertension during exposure to various levels of chronic hypoxia. In isolated lungs from normoxic rats, dexfenfluramine up to 10(-4) M did not elicit any vasoactive effects, and neither did pretreatment with dexfenfluramine (10[-5] M in the perfusate) modify the vasoactive effects of 5-HT. In normoxic conscious rats, dexfenfluramine given intravenously potentiated the pulmonary pressor response to acute hypoxia (10% O2). In rats chronically treated with dexfenfluramine during a 2-wk exposure to 15% or 10% O2, plasma 5-HT concentrations were significantly increased compared with hypoxic controls, whereas no differences were found for pulmonary artery pressure, right ventricular hypertrophy, or pulmonary vessel muscularization. In contrast, a continuous 5-HT infusion providing a sustained increase in plasma 5-HT levels was associated with increased muscularization of distal pulmonary arteries in response to 10% O2. Simultaneous administration of dexfenfluramine prevented the effect of exogenous 5-HT on vascular remodeling. Our findings show that dexfenfluramine does not potentiate the development of pulmonary hypertension in rats exposed to chronic hypoxia, despite its effect on plasma 5-HT concentrations.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1997

Treatment with 5-HT potentiates development of pulmonary hypertension in chronically hypoxic rats.

The aim of this study was to investigate the potential role of 5-hydroxytryptamine (5-HT) on development of pulmonary hypertension during chronic exposure to mild (15% O2) and severe (10% O2) hypoxia. In isolated lungs from normoxic rats preconstricted with U-46619, 5-HT (10(-12)-10(-8) M) induced dose-dependent vasodilation (n = 6), which was suppressed by the NO synthesis inhibitor nitro-L-arginine methyl ester (L-NAME, 10(-4) M, n = 5) and reduced by the 5-HT3-receptor antagonist MDL-7222 (10(-5) M, n = 6). The vasoconstriction that was observed with higher concentrations of 5-HT (10(-7)-10(-4) M) was inhibited by ketanserin (10(-5) M) and methiothepin (10(-5) M, n = 6 each). The vasodilator response to 5-HT was suppressed in lungs from rats exposed to 10% O2 but not 15% O2 (n = 6 each). In conscious rats, intravenous administration of 5-HT potentiated the pulmonary pressor response to acute hypoxia (10% O2, n = 5), an effect that remained unchanged after pretreatment with a 5-HT1 and a 5-HT2 antagonist (n = 4) but was attenuated after treatment with the cyclooxygenase inhibitor meclofenamate (n = 4). Treatment with 5-HT (5 nmol/h i.v. by osmotic pumps) for 2 wk in rats simultaneously exposed to 10% O2 increased pulmonary arterial pressure, right ventricular hypertrophy, and muscularization of pulmonary vessels in comparison with their hypoxic controls (n = 12 each). No changes occurred in 15% O2 hypoxic rats (n = 12 each). The present findings show that 5-HT potentiates development of pulmonary hypertension in rats exposed to chronic hypoxia.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1996

Liquid pasteurization of an immunoglobulin preparation without stabilizer: effects on its biological and biochemical properties.

Intravenous immunoglobulins (IVIg) purified by cold ethanol fractionation have a very good safety record with regard to the transmission of many viruses. However, a few cases of non-A-non-B hepatitis have been described after intravenous injection of some immunoglobulin preparations. To ensure even higher safety for our IVIg, an additional virus inactivation step, based on pasteurization, was developed. The heating of aqueous IVIg was performed without stabilizer, and at a very low salt concentration (< 1 mM) at acidic pH. No generation of polymer was detected after pasteurization and a significant decrease in the proportion of dimers was observed. Analysis of the secondary structure by circular dichroism showed a very slight change in the secondary structure. The biological properties of the Fc region as well as the Fab region were not affected by the pasteurization. Our method has several advantages: (1) improvement of viral safety; (2) there is no need to add stabilizer which may stabilize viral particles, and (3) the absence of any hypotensive effect and low anticomplementary activity indicates a good clinical tolerance of IgG preparation.

Animals↗
PubMed1996

TM domain swapping of murine leukemia virus and human T-cell leukemia virus envelopes confers different infectious abilities despite similar incorporation into virions.

We investigated the influence of transmembrane protein (TM) domains on incorporation of retroviral envelopes into virions and on infectivity. We introduced complete, truncated, or chimeric Friend murine leukemia virus (F-MuLV) and human T-cell leukemia virus type 1 (HTLV-1) envelopes into an MuLV particle-producing complementation cell line. As shown previously for HTLV-1 envelopes containing extracellular domains of F-MuLV TM (C. Denesvre, P. Sonigo, A. Corbin, H. Ellerbrok, and M. Sitbon, J. Virol. 69:4149-4157, 1995), reverse chimeric F-MuLV envelopes containing the extracellular domain of HTLV-1 TM were not processed. In contrast, a chimeric MuLV envelope containing the entire HTLV membrane-spanning and cytoplasmic domains (FHTMi) was efficiently processed, fusogenic as tested in a cell-to-cell assay, and efficiently incorporated into MuLV particles. However, these MuLV particles bearing FHTMi envelope proteins could not infect mouse or rat cells which are susceptible to wild-type F-MuLV. Therefore, envelopes which are readily fusogenic in cell-to-cell assays and also efficiently incorporated into virions may not necessarily confer virus-to-cell fusogenicity. HTLV envelopes, whether parental, chimeric (containing the MuLV cytoplasmic tail) or with a truncated cytoplasmic domain, were incorporated into MuLV particles with equal efficiencies, indicating that the cytoplasmic tails of these envelopes did not determine their incorporation into virions. In contrast to FHTMi envelope, HTLV-1 envelopes with F-MuLV membrane-spanning and cytoplasmic domains, as well as wild-type HTLV-1 envelopes, conferred virion infectivity. These results help to define requirements for envelope incorporation into retroviral particles and their cell-free infectivity.

3T3 Cells↗
PubMed1995

Influence of transmembrane domains on the fusogenic abilities of human and murine leukemia retrovirus envelopes.

The envelopes of two highly divergent oncoviruses, human T-cell leukemia virus type 1 (HTLV-1) and Friend murine leukemia virus (F-MuLV), have distinct patterns of cellular receptor recognition, fusion, and syncytium formation. To analyze the influence of the transmembrane envelope subunit (TM) on fusogenic properties, we substituted either the entire TM or distinct domains from F-MuLV for the corresponding domains in the HTLV-1 envelope. Parental, chimeric, and truncated envelopes cloned into a eukaryotic expression vector were monitored for fusogenic potential in human, rat, and murine indicator cell lines by using a quantitative assay. This highly sensitive assay allowed us to assess the fusogenic properties and syncytium-forming abilities of the HTLV-1 envelope in murine NIH 3T3 cells. All chimeric envelopes containing extracellular sequences of the F-MuLV TM were blocked in their maturation process. Although deletions of the HTLV-1 cytoplasmic domain, alone and in combination with the membrane-spanning domain, did not prevent envelope cell surface expression, they impaired and suppressed fusogenic properties, respectively. In contrast, envelopes carrying substitutions of membrane-spanning and cytoplasmic domains were highly fusogenic. Our results indicate that these two domains in F-MuLV and HTLV-1 constitute structural entities with similar fusogenic properties. However, in the absence of a cytoplasmic domain, the F-MuLV membrane-spanning domain appeared to confer weaker fusogenic properties than the HTLV-1 membrane-spanning domain.

3T3 Cells↗