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Biomedical subjects

I Leconte

Publications and source records attributed to I Leconte.

At least 19 recordsLinked to original sources
PubMed2007

Safety and tolerability of bosentan in idiopathic pulmonary fibrosis: an open label study.

Idiopathic pulmonary fibrosis (IPF) is a fatal disease for which no effective treatment exists. In the present study, 12 IPF patients underwent analysis of gas exchange properties using the multiple inert gas elimination technique on day 1 before and after the administration of 125 mg bosentan, a dual endothelin antagonist. Following this, patients received chronic administration for 12 weeks (62.5 mg b.i.d. in week 1, 125 mg b.i.d. thereafter). The primary objective was to determine the effect of bosentan on gas exchange (day 1) and on oxygen saturation and minute ventilation (week 2). With one exception, where redistribution of total pulmonary blood flow from normal ventilation/perfusion (V'/Q') areas (93% before, 72% after bosentan) to low V'/Q' areas (0% before, 22.2% after) was encountered, no patient showed any change in gas exchange (mean+/-SD shunt flow (% of cardiac output) 8.5+/-3.4% before, 6.1+/-2.3% after bosentan; day 1) or oxygen saturation and minute ventilation (week 2). Similarly, none of the secondary parameters was significantly changed either at week 2 or at the end of the study period (week 12). Five patients developed respiratory infections and two died because of pneumonia; this was judged as being unrelated to bosentan intake. In conclusion, bosentan administration does not seem to induce clinically relevant gas exchange abnormalities in idiopathic pulmonary fibrosis patients.

Administration, Oral↗
PubMed2006

[Juvenille papillomatosis].

The authors report a patient with juvenile papillomatosis of the breast presenting with a palpable mass and illustrate the correlation between mammographic, sonographic and pathologic features.

Adolescent↗
PubMed2001

Early changes in liver perfusion caused by occult metastases in rats: detection with quantitative CT.

PURPOSE: To determine whether computed tomography (CT) can depict liver hemodynamic changes caused by occult hepatic micrometastases in rat. MATERIALS AND METHODS: Liver micrometastases (mean diameter, 500 micrometer +/- 300) were produced in seven BD IX rats by injecting 10(7) DHDK12 PROb colorectal carcinoma cells into the spleen. Macrometastases (mean diameter, 7 mm +/- 3) were produced in four other rats. Five normal rats were studied as controls. CT images were obtained every 300 msec for 30 seconds during the injection of 1 mL per kilogram of body weight of contrast medium. The time-attenuation curves of the aorta, portal vein, and liver were used to calculate liver perfusion with a deconvolution model designed for the dual blood supply. RESULTS: Micrometastases in an apparently normal liver caused a 34% decrease in portal blood flow and a 25% increase in the mean transit time for the blood to pass through the liver. These findings suggest increased resistance in the sinusoidal capillaries. Similar but greater changes were found in the macrometastases. CONCLUSION: Occult liver micrometastases in rats generate changes in liver perfusion that can be detected with CT.

Animals↗
PubMed2001

Hepatic perfusion parameters in chronic liver disease: dynamic CT measurements correlated with disease severity.

OBJECTIVE: The aim of our study was to determine if hepatic perfusion parameters measured with CT change in relation to disease severity in patients with chronic liver disease. SUBJECTS AND METHODS: Dynamic contrast-enhanced single-section CT scans of the liver were obtained in 40 individuals who included six control subjects, 16 patients with noncirrhotic chronic liver disease, and 18 patients with cirrhosis. Hepatic, aortic, and portal venous time-density curves were fitted to a dual-input one-compartment model to calculate the liver perfusion, arterial fraction, distribution volume, and mean transit time. RESULTS: Liver perfusion decreased in patients with cirrhosis (67 +/- 23 mL. min(-1). 100 mL(-1) versus 108 +/- 34 mL. min(-1). 100 mL(-1) in control subjects [p = 0.009] and 98 +/- 36 mL. min(-1). 100 mL(-1) in patients with noncirrhotic chronic liver disease [p = 0.003]), and the arterial fraction and the mean transit time increased (41 +/- 27% and 51 +/- 79 sec versus 17 +/- 16% and 16 +/- 5 sec in control subjects, and 19 +/- 6% and 17 +/- 8 sec in patients with noncirrhotic chronic liver disease [p < 0.05]). A significant correlation was seen between these three perfusion parameters and the severity of chronic liver disease based on clinical and biologic data (p < 0.001). No significant change in distribution volume was observed. CONCLUSION: Hepatic perfusion parameters measured with CT were significantly altered in cirrhosis and correlated with the severity of chronic liver disease.

Case-Control Studies↗
PubMed2000

Adenoviral-mediated expression of antisense RNA to basic fibroblast growth factor reduces tangential stress in arterialized vein grafts.

PURPOSE: The purpose of this study was to test whether basic fibroblast growth factor (bFGF) participates in arterialized vein graft remodeling. METHODS: Rabbits underwent in vivo gene transfer and carotid interposition vein grafting. Segments of external jugular vein were infected with an adenovirus that expressed antisense bFGF RNA (Ad.ASbFGF) at 1 x 10(10) PFU/mL to inhibit new synthesis of bFGF by cells in the vein graft wall. Control rabbits were treated with either adenovirus that encoded beta-galactosidase (Ad.lacZ) at 1 x 10(10) PFU/mL or vehicle (phosphate-buffered saline solution [PBS]). At 3 days, 3 grafts per treatment group were harvested for the determination of gene expression of ASbFGF RNA by reverse transcriptase-polymerase chain reaction. Rabbits were killed, and perfusion was fixed 2 months after the grafting. Total wall thickness and lumen circumference of vein grafts and normal arteries were measured in cross sections. Calculated mean tangential stress (+/-SD) for the ASbFGF-treated group and controls was compared for significance. Grafts were immunohistochemically stained to assess bFGF protein production. RESULTS: Only the grafts infected with the Ad.ASbFGF gene expressed ASbFGF RNA. Grafts that were treated with Ad.ASbFGF displayed lower tangential stress (10.9 +/- 2.3 dynes/cm(2)) than PBS alone (22 +/- 2.8 dynes/cm(2)) or Ad. lacZ-treated controls (20.6 +/- 5.4 dynes/cm(2); P <.001). Tangential stress in the Ad.ASbFGF group was comparable to a normal carotid artery (13.9 +/- 2.1 dynes/cm(2)). The difference in mean total wall thickness was significant among the 3 treatment groups: Ad.ASbFGF, 164 +/- 3.4 microm); Ad.lacZ, 100 +/- 3.3 microm; and PBS, 96 +/- 3.6 microm; P <.01). Luminal circumference was not different among the groups. The Ad.ASbFGF-treated vein graft wall was composed of thick layers of concentric smooth muscle cells and elastin fibers in contrast to the sponge-like appearance observed in control arterialized vein grafts. Reduction in bFGF protein was noted only in the Ad.ASbFGF-treated group. CONCLUSION: Inhibition of bFGF synthesis in vivo with the use of adenoviral gene transfer of antisense RNA to bFGF promotes a vein graft with decreased tangential stress while maintaining the luminal area. The vein graft wall is remodeled and qualitatively resembles an artery so that wall tangential stress in Ad.ASbFGF and normal artery are not significantly different. The lack of significant difference in lumen circumference among groups suggests that wall thickening in the Ad. ASbFGF grafts is not at the expense of luminal narrowing. Our results suggest that ASbFGF RNA expression may represent an effective strategy in limiting the failure of arterialized venous conduits.

Adenoviridae↗
PubMed2000

Non-invasive quantification of liver perfusion with dynamic computed tomography and a dual-input one-compartmental model.

Various liver diseases lead to significant alterations of the hepatic microcirculation. Therefore, quantification of hepatic perfusion has the potential to improve the assessment and management of liver diseases. Most methods used to quantify liver perfusion are invasive or controversial. This paper describes and validates a non-invasive method for the quantification of liver perfusion using computed tomography (CT). Dynamic single-section CT of the liver was performed after intravenous bolus administration of a low-molecular-mass iodinated contrast agent. Hepatic, aortic and portal-venous time-density curves were fitted with a dual-input one-compartmental model to calculate liver perfusion. Validation studies consisted of simultaneous measurements of hepatic perfusion with CT and with radiolabelled microspheres in rabbits at rest and after adenosine infusion. The feasibility and reproducibility of the CT method in humans was assessed by three observers in 10 patients without liver disease. In rabbits, significant correlations were observed between perfusion measurements obtained with CT and with microspheres (r=0.92 for total liver perfusion, r=0.81 for arterial perfusion and r=0.85 for portal perfusion). In patients, total liver plasma perfusion measured with CT was 112+/-28 ml.min(-1).100 ml(-1), arterial plasma perfusion was 18+/-12 ml.min(-1).100 ml(-1) and portal plasma perfusion was 93+/-31 ml.min(-1).100 ml(-1). The measurements obtained by the three observers were not significantly different from each other (P>0.1). Our results indicate that dynamic CT combined with a dual-input one-compartmental model provides a valid and reliable method for the non-invasive quantification of perfusion in the normal liver.

Adult↗
PubMed1999

A peptide leptin antagonist reduces food intake in rodents.

OBJECTIVE: The purpose of the present study was to investigate the continuing validity of the hypothesis that leptin is a physiologically important regulator of food intake, using the human leptin mutant R128Q leptin. DESIGN: In a cellular proliferation assay, based on BAF-3 cells transfected with the murine ObRb receptor, R128Q leptin was shown to be devoid of agonistic activity and to competitively inhibit the proliferative effects of leptin. To determine whether R128Q leptin was also an antagonist of leptin in vivo, the leptin mutant was injected intracerebroventricularly (i.c.v.) into rats in the absence and presence of leptin. R128Q was also injected intraperitoneally (i.p.) into ob/ob and into db/db mice expressing, respectively, either normal or defective ObRb receptors. RESULTS: R128Q was shown to be a competitive antagonist of leptin induced cellular proliferation in vitro. Surprisingly, in vivo R128Q leptin produced a strong dose-dependent decrease in food intake, and was only slightly less potent than leptin itself. In fasted rats, the inhibitory effects of leptin and R128Q leptin (i.c.v.) on post-fast refeeding were additive. Finally, R128Q leptin produced the same inhibition of food intake as leptin when injected i.p. in ob/ob mice and, like leptin, was inactive after i.p. injection to db/db mice. CONCLUSION: R128Q leptin is a leptin agonist in vivo, but behaves as an antagonist against leptin induced proliferation in vitro. The data demonstrate that the human leptin mutant R128Q leptin is not a suitable tool for investigating the physiological actions of leptin.

Animals↗
PubMed1999

Mechanisms of action of liver contrast agents: impact for clinical use.

New contrast agents for magnetic resonance imaging are continually being developed by pharmaceutical companies in order to better image the liver. These agents can be divided into hepatobiliary agents directed to the hepatocytes and nanoparticulate agents directed to the reticulo-endothelial system. After intravenous injection, all these agents concentrate in the liver and induce profound changes in signal intensity. Particulate agents induce predominantly a darkening of the liver parenchyma, while hepatobiliary agents induce a brightening. In both cases, liver-lesion conspicuity is enhanced, leading to a better visualization of the lesion. After a brief description of the principal characteristics of the agents, this paper will attempt to summarize the utility of these agents for the detection and characterization of focal liver disease.

Contrast Media↗
PubMed1998

Gscl, a gene within the minimal DiGeorge critical region, is expressed in primordial germ cells and the developing pons.

Gscl, a paired-type homeobox gene, has been implicated in the pathology of DGS/VCFS by virtue of its genomic location and its structural similarity to the Gsc gene family. Immunohistochemical and in situ studies were performed to examine the expression pattern of this gene during embryonic development. A polyclonal antibody, generated to the full-length protein and shown to be specific for GSCL by both Western blotting and immunofluorescence, was used for immunohistochemical localization. Both in situ and antibody staining localized GSCL expression to a cluster of cells in the pons region of the developing brain. This GSCL expression pattern showed partial overlap with that of Pax6. More detailed immunohistochemistry revealed the GSCL in primordial germ cells during migration from the epithelium of the hindgut and later as they colonize the developing gonads. GSCL was not detected in tissues affected in DGS/VCSF.

3T3 Cells↗
PubMed1998

Adenoviral-mediated expression of antisense RNA to fibroblast growth factors disrupts murine vascular development.

Fibroblast growth factors (FGFs) are expressed in the developing embryo and are postulated to regulate embryonic and vascular growth. The goal of this study was to elucidate the role of basic fibroblast growth factor (FGF-2) in early murine embryonic cardiovascular development in the mouse embryo. Gestation day 7.5 embryos were harvested and placed in culture, and 12 hr later replication-defective adenovirus (0.5 x 10(6) plaque forming units) encoding either beta-galactosidase or antisense FGF-2 RNA was injected into the sinus venosus of the cultured embryos. Embryos receiving only replication-defective adenovirus expressing the beta-galactosidase gene continued to develop normally over the next 12 hr. In contrast, those receiving adenovirus encoding antisense FGF-2 RNA displayed marked morphogenetic abnormalities, including cessation of growth and abnormal yolk sac vascular development, even though the embryonic hearts continued to beat. Abnormal development of the yolk sac vasculature was confirmed by microangiography and by histologic examination. Coinjection of virus carrying FGF-2 cDNA in the sense orientation reversed the effects of antisense FGF-2 RNA expression. These results confirm the efficacy of the replication-defective adenovirus for targeting gene expression to the developing vasculature and provide evidence for a critical role of FGF in the normal vascular assembly in the early embryo. Cessation of embryonic growth on expression of antisense FGF-2 RNA was most likely attributable to failure of efficient circulation of the early embryonic blood cells from the yolk sac into the embryo.

Adenoviridae↗
PubMed1998

Autocrine FGF signaling is required for vascular smooth muscle cell survival in vitro.

Expression of both basic fibroblast growth factor (bFGF) and FGF receptors (FGFR) by vascular smooth muscle cells suggests that autocrine FGF signaling mechanisms may have important functions. Inhibition of smooth muscle cell bFGF expression provokes apoptosis, suggesting that endogenous bFGF generates an anti-apoptotic signal. The purpose of this study was to determine whether the survival function of endogenous bFGF requires signaling through FGFR. A recombinant adenovirus encoding a truncated murine FGFR-1 lacking the kinase domain (DN-FGFR) efficiently expressed the transgene in cultured rat aortic smooth muscle cells. The truncated receptor acted in a dominant negative fashion to effectively prevent receptor-mediated signaling, assessed by phosphorylation of p42/p44 MAP kinase. Expression of DN-FGFR provoked apoptosis of SMC in a dose-dependent fashion that was insensitive to recombinant bFGF but could be rescued by platelet derived growth factor or epidermal growth factor. Heterologous growth factor rescue was inhibited by PD98059, an inhibitor of MEK (MAP kinase-kinase). These data demonstrate that inhibition of FGF receptor activation results in apoptosis and suggest that an intact autocrine FGF signaling loop is required for vascular smooth muscle cell survival in vitro. These findings also implicate the Ras/Raf/MEK/MAP kinase cascade in generating or sustaining the survival signal. The functional significance of an autocrine FGF signaling loop in non-transformed cells has important implications for cardiovascular development, remodeling and disease.

Adenoviridae↗
PubMed1997

[Mediastinal neuroectodermal tumor. Apropos of a case].

Peripheral malignant neuroectodermal tumors are rare and aggressive small-cell tumors seen predominantly in children and young adults. Mediastinal location is very uncommon. A mediastinal primitive neuroectodermal tumor was diagnosed in a 27-year-old man. Despite treatment combining surgery, radiotherapy and chemotherapy, disease recurred locally along with lungs, spinal and epidural metastases, leading to death. CT and MRI examinations show heterogeneous masses with necrosis, hemorrhage and intense enhancement after Gadolinium injection. The CT and MRI findings are not specific and the diagnosis is based on pathologic, immunohistochemical and electron microscopic features. Although uncommon, peripheral neuroectodermal tumor should be considered in the differential diagnosis of posterior mediastinal masses in children and young adults.

Adult↗
PubMed1996

The natural mutation Y248C of human angiotensinogen leads to abnormal glycosylation and altered immunological recognition of the protein.

Common molecular variants of the angiotensinogen gene have been associated with human hypertension. The rare Tyr to Cys change at residue 248 of mature angiotensinogen was identified in one pedigree. Heterozygous individuals (Y248C) had a 40% decrease in plasma angiotensinogen concentration and a 35% reduction of the angiotensin I production rate. Recombinant wild-type (Tyr-248) and mutant (Cys-248) proteins were stably expressed in Chinese hamster ovary cells. Angiotensinogen monoclonal antibodies revealed marked differences in the epitope recognition of the mutant protein and allowed the demonstration of its presence in plasma of Y248C individuals. Similar kinetic constants of angiotensin I production with human renin were observed for both proteins. Western blot analysis showed similar heterogeneities; however, a 3-kDa increase in molecular mass for the Cys-248 protein was observed after immunopurification. Metabolic labeling of the intracellular Cys-248 protein showed a 61-kDa band in addition to the 55.5- and 58-kDa bands observed for the Tyr-248 protein, with all bands being sensitive to endoglycosidase H. In addition, pulse-chase studies revealed a slower intracellular processing for the Cys-248 protein. In conclusion, the Cys-248 mutation alters the structure, glycosylation, and secretion of angiotensinogen in Chinese hamster ovary cells and is accompanied by a decrease in plasma angiotensinogen concentration in Y248C individuals.

Amino Acid Sequence↗
PubMed1996

The influence of body weight on open field and swimming maze performance during the post-weaning period in the rat.

The open field and swimming maze tests are frequently used as part of a behavioural assessment battery in reproduction or developmental toxicology studies in the rat. Interpretation of the results of these tests is very difficult when the body weight of the rats is not similar in the various treatment groups. In order to better understand this problem, data from approximately 500 untreated rats tested under identical conditions were analysed with respect to body weight. No correlation was found in water maze performance or open field motor activity. A very slight but significant correlation was identified, however, in the time spent by female rats in various regions of the open field, with the smaller rats spending more time in the corners of the testing arena.

Analysis of Variance↗
PubMed1995

Two sequences flanking the major autophosphorylation site of the insulin receptor are essential for tyrosine kinase activation.

The tyrosine kinase domain of the human insulin receptor (IR) contains several short amino acid motifs which are strictly conserved in all protein kinases and two sequence motifs which are specific to the tyrosine kinases (AAR or RAA and P(I)/VK/RWT/M). In the serine/threonine kinases these motifs are replaced by the sequences KPE and GT/SXXY/PX respectively. In the present work, the tyrosine kinase-specific sequences of the IR (1134AAR1136 and 1172PVRWM1176) were replaced using site-directed mutagenesis by sequences which confer a serine kinase specificity on the receptor. Five different IR mutants were expressed in Chinese hamster ovary (CHO) or COS cells and their structural and functional properties compared with those of the wild-type recombinant human IR. These mutants are processed normally and bind insulin with normal affinities. None of the mutants containing a putative serine kinase-specific sequence display detectable autophosphorylation or tyrosine kinase activity in response to insulin, either in vitro or in vivo. These mutants were also unable to phosphorylate serine/threonine kinase substrates after insulin stimulation. Unexpectedly, they showed impaired ATP binding, as studied by an original technique consisting of cross-linking adenosine 5'-([35S]thio)triphosphate to partially purified receptors. Finally, none of the studied mutants transmit the insulin signal necessary to stimulate either DNA or glycogen synthesis. These data provide evidence for the importance of these conserved sequences in the kinase domain for both receptor activation and kinase activity. Furthermore, they demonstrate that the exchange of sequences specific to the catalytic domain of tyrosine kinases for those specific to the serine/threonine kinases is not sufficient to confer serine/threonine specificity on the insulin receptor.

Adenosine Triphosphate↗
PubMed1995

[Insulin receptor].

The cloning of the insulin receptor not only established the primary structure of this membrane-bound glycoprotein but also offered the material necessary for the study of the molecular functions of this tyrosine-kinase receptor using molecular biology tools. This short review will summarize the actual knowledge of the structure, the functions (molecular structure of the binding site, tyrosine-kinase functions and role of autophosphorylation) and of the pathology of this receptor in extreme insulin resistances and type II diabetes.

Diabetes Mellitus, Type 1↗
PubMed1994

The functions of the human insulin receptor are affected in different ways by mutation of each of the four N-glycosylation sites in the beta subunit.

The functional role of the oligosaccharide chains linked to the insulin receptor (IR) beta subunit was investigated by site-directed mutagenesis of each of the 4 acceptor asparagines (N1 to N4 from the amino to the carboxyl terminus) and stable expression of the receptors in CHO cells. All mutant receptors are expressed normally at the cell surface, bind insulin with similar affinity, but have a beta subunit of smaller molecular mass, and a defect in ligand-induced internalization as compared to wild type receptor. In terms of receptor activation and signal transduction, the N1 and N2 mutants function normally, whereas the N4 mutant exhibits major alterations in in vitro tyrosine kinase activity and autophosphorylation and is unable to transduce the signal for either glycogen or DNA synthesis. By contrast, in vivo autophosphorylation and IRS-1 phosphorylation appear quantitatively normal, and only partial alterations of phosphatidylinositol 3-kinase and mitogen-activated protein kinase activation are observed. Mutation of the N3 site results in partial defect of IR activation. These data provide evidence for (i) glycosylation of each N-linked glycosylation site of the IR beta subunit, (ii) absence of correlation between internalization and transmembrane signaling, and (iii) a major role for oligosaccharide side chain(s) located close to the cell membrane in IR activation and transmembrane signaling.

Animals↗