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N Mathieu

Publications and source records attributed to N Mathieu.

18 recordsLinked to original sources
PubMed2006

TRF2 inhibition promotes anchorage-independent growth of telomerase-positive human fibroblasts.

Although telomere instability is observed in human tumors and is associated with the development of cancers in mice, it has yet to be established that it can contribute to the malignant transformation of human cells. We show here that in checkpoint-compromised telomerase-positive human fibroblasts an episode of TRF2 inhibition promotes heritable changes that increase the ability to grow in soft agar, but not tumor growth in nude mice. This transforming activity is associated to a burst of telomere instability but is independent of an altered control of telomere length. Moreover, it cannot be recapitulated by an increase in chromosome breaks induced by an exposure to gamma-radiations. Since it can be revealed in the context of telomerase-proficient human cells, telomere dysfunction might contribute to cancer progression even at late stages of the oncogenesis process, after the telomerase reactivation step.

Alleles↗
PubMed2005

A second locus for Aicardi-Goutieres syndrome at chromosome 13q14-21.

BACKGROUND: Aicardi-Goutières syndrome (AGS) is an autosomal recessive, early onset encephalopathy characterised by calcification of the basal ganglia, chronic cerebrospinal fluid lymphocytosis, and negative serological investigations for common prenatal infections. AGS may result from a perturbation of interferon alpha metabolism. The disorder is genetically heterogeneous with approximately 50% of families mapping to the first known locus at 3p21 (AGS1). METHODS: A genome-wide scan was performed in 10 families with a clinical diagnosis of AGS in whom linkage to AGS1 had been excluded. Higher density genotyping in regions of interest was also undertaken using the 10 mapping pedigrees and seven additional AGS families. RESULTS: Our results demonstrate significant linkage to a second AGS locus (AGS2) at chromosome 13q14-21 with a maximum multipoint heterogeneity logarithm of the odds (LOD) score of 5.75 at D13S768. The AGS2 locus lies within a 4.7 cM region as defined by a 1 LOD-unit support interval. CONCLUSIONS: We have identified a second AGS disease locus and at least one further locus. As in a number of other conditions, genetic heterogeneity represents a significant obstacle to gene identification in AGS. The localisation of AGS2 represents an important step in this process.

Basal Ganglia Diseases↗
PubMed2004

Telomeres and chromosomal instability.

Telomeres are distinctive structures, composed of a repetitive DNA sequence and associated proteins, which enable cells to distinguish chromosome ends from DNA double-strand breaks. Telomere alterations, caused by replication-mediated shortening, direct damage or defective telomere-associated proteins, usually generate chromosomal instability, which is observed in senescence and during the immortalization process. In cancer cells, this chromosome instability could be extended by their ability to 'repair' chromosomes and terminate in break-fusion-bridge cycles. Dysfunctional telomeres can be healed by activation of telomerase or by the 'alternative mechanism' of telomere lengthening. Activation of such telomere maintenance mechanisms may help to preserve the integrity of chromosomes even if they play a role in chromosomal instability. This review focuses on molecular processes involved in telomere maintenance and chromosomal instability associated with dysfunctional telomeres in mammalian cells.

Animals↗
PubMed2002

[The anesthesiology-recovery department].

The Department of Anesthesiology and Reanimation is organised in units with clinical activities, which include the pre-operative care of patients, anesthesiological care and immediate post-operative supervision. Two post-operative treatment rooms also form part of the department. The main fields of research of the various units result from collaborations with other departments of Hôpital Erasme, in particular with regard to the development of advanced techniques or fit within the confines of the speciality.

Anesthesia↗
PubMed2001

Comparative effects of red blood cell transfusion and increasing blood flow on tissue oxygenation in oxygen supply-dependent conditions.

Red blood cell (RBC) transfusion is usually administered to improve oxygen delivery (DO(2)) in order to sustain tissue oxygen demand. However, this practice is not supported by firm clinical or experimental data. Using a randomized two-period crossover design, this study compared the efficacy of "fresh" RBC transfusion and increased blood flow to restore tissue oxygenation in oxygen supply-dependent conditions. In 12 ketamine-anesthetized mongrel dogs submitted to nonpulsatile normothermic cardiopulmonary bypass, DO(2) was reduced by a progressive decrease in pump flow. DO(2) dependency was defined as an O(2) uptake (V O(2)) decrease by more than 15% from baseline value. Then, intervention consisted of a 40% increase in DO(2) obtained either by transfusion of "fresh" dog's RBC (stored < 3 d) or by increase in pump flow. Animals received both interventions sequentially in a random order, while O(2) saturation was maintained constant. In O(2) supply-dependent conditions, rising pump flow from 1.6 +/- 0.4 to 2.7 +/- 0.7 L/ min increased DO(2) from 5.4 +/- 1.1 to 9.0 +/- 1.3 ml/kg/min (p < 0.01) and V O(2) from 3.5 +/- 0.4 to 4.1 +/- 0.5 ml/kg/min (p = 0.02). "Fresh" RBC transfusion, which increased the hemoglobin concentration from 6.4 +/- 0.9 to 11.1 +/- 1.3 g/dl, increased DO(2) from 5.4 +/- 1.2 to 9.0 +/- 1.4 ml/kg/min (p < 0.01) and V O(2) from 3.6 +/- 0.4 to 4.1 +/- 0.5 ml/kg/min (p = 0.02). There was no difference in V O(2) resulting from both interventions. In oxygen supply-dependent conditions, "fresh" RBC transfusion and increased blood flow are equally effective in restoring tissue oxygenation.

Animals↗
PubMed2000

Chromatin remodeling by the T cell receptor (TCR)-beta gene enhancer during early T cell development: Implications for the control of TCR-beta locus recombination.

Gene targeting studies have shown that T cell receptor (TCR)-beta gene expression and recombination are inhibited after deletion of an enhancer (Ebeta) located at the 3' end of the approximately 500-kb TCR-beta locus. Using knockout mouse models, we have measured, at different regions throughout the TCR-beta locus, the effects of Ebeta deletion on molecular parameters believed to reflect epigenetic changes associated with the control of gene activation, including restriction endonuclease access to chromosomal DNA, germline transcription, DNA methylation, and histone H3 acetylation. Our results demonstrate that, in early developing thymocytes, Ebeta contributes to major chromatin remodeling directed to an approximately 25-kb upstream domain comprised of the Dbeta-Jbeta locus regions. Accordingly, treatment of Ebeta-deleted thymocytes with the histone deacetylase inhibitor trichostatin A relieved the block in TCR-beta gene expression and promoted recombination within the Dbeta-Jbeta loci. Unexpectedly, however, epigenetic processes at distal Vbeta genes on the 5' side of the locus and at the 3' proximal Vbeta14 gene appear to be less dependent on Ebeta, suggesting that Ebeta activity is confined to a discrete region of the TCR-beta locus. These findings have implications with respect to the developmental control of TCR-beta gene recombination, and the process of allelic exclusion at this locus.

3T3 Cells↗
PubMed2000

T cell development in TCR beta enhancer-deleted mice: implications for alpha beta T cell lineage commitment and differentiation.

T cell differentiation in the mouse thymus is an intricate, highly coordinated process that requires the assembly of TCR complexes from individual components, including those produced by the precisely timed V(D)J recombination of TCR genes. Mice carrying a homozygous deletion of the TCR beta transcriptional enhancer (E beta) demonstrate an inhibition of V(D)J recombination at the targeted TCR beta locus and a block in alpha beta T cell differentiation. In this study, we have characterized the T cell developmental defects resulting from the E beta-/- mutation, in light of previously reported results of the analyses of TCR beta-deficient (TCR beta-/-) mice. Similar to the latter mice, production of TCR beta-chains is abolished in the E beta-/- animals, and under these conditions differentiation into cell-surface TCR-, CD4+CD8+ double positive (DP) thymocytes depends essentially on the cell-autonomous expression of TCR delta-chains and, most likely, TCR gamma-chains. However, contrary to previous reports using TCR beta-/- mice, a minor population of TCR gamma delta+ DP thymocytes was found within the E beta-/- thymi, which differ in terms of T cell-specific gene expression and V(D)J recombinase activity, from the majority of TCR-, alpha beta lineage-committed DP thymocytes. We discuss these data with respect to the functional role of E beta in driving alpha beta T cell differentiation and the mechanism of alpha beta T lineage commitment.

Animals↗
PubMed2000

The Pim-1 kinase stimulates maturation of TCRbeta-deficient T cell progenitors: implications for the mechanism of Pim-1 action.

We demonstrate that overexpression of Pim-1, a cytoplasmic serine/threonine kinase of poorly defined function, results in the development of substantial numbers of CD4(+)CD8(+) double-positive thymocytes in two independent knock-out mouse models (i.e. the RAG-1-deficient and TCRbeta gene enhancer-deleted mice) in which production of a functionally rearranged TCRbeta gene (hence the pre-TCR) is impaired. This activity of Pim-1, however, does not affect signaling through the Ras/Raf/MAP kinase cascade nor signaling which mediates suppression of TCRbeta gene recombination (i.e. allelic exclusion). While overexpression of Pim-1 positively affects cell cycle progression in selected CD4(-)CD8(-) double-negative precursors, it did not affect expression of components of the cell cycle machinery, with the exception of the G(1)-specific phosphatase Cdc25A upon antigen receptor stimulation. We propose that Pim-1 acts downstream, or in parallel, to pre-TCR-mediated selection as one factor involved in the proliferative expansion of beta-selected pre-T cells.

Alleles↗
PubMed2000

Definition of a T-cell receptor beta gene core enhancer of V(D)J recombination by transgenic mapping.

V(D)J recombination in differentiating lymphocytes is a highly regulated process in terms of both cell lineage and the stage of cell development. Transgenic and knockout mouse studies have demonstrated that transcriptional enhancers from antigen receptor genes play an important role in this regulation by activating cis-recombination events. A striking example is the T-cell receptor beta-chain (TCRbeta) gene enhancer (Ebeta), which in the mouse consists of at least seven nuclear factor binding motifs (betaE1 to betaE7). Here, using a well-characterized transgenic recombination substrate approach, we define the sequences within Ebeta required for recombination enhancer activity. The Ebeta core is comprised of a limited set of motifs (betaE3 and betaE4) and an additional previously uncharacterized 20-bp sequence 3' of the betaE4 motif. This core element confers cell lineage- and stage-specific recombination within the transgenic substrates, although it cannot bypass the suppressive effects resulting from transgene integration in heterochromatic centromeres. Strikingly, the core enhancer is heavily occupied by nuclear factors in immature thymocytes, as shown by in vivo footprinting analyses. A larger enhancer fragment including the betaE1 through betaE4 motifs but not the 3' sequences, although active in inducing germ line transcription within the transgenic array, did not retain the Ebeta recombinational activity. Our results emphasize the multifunctionality of the TCRbeta enhancer and shed some light on the molecular mechanisms by which transcriptional enhancers and associated nuclear factors may impact on cis recombination, gene expression, and lymphoid cell differentiation.

Animals↗
PubMed2000

[Invasive techniques in chronic pain control].

A wide range of invasive techniques are available for pain treatment. Treatment must be adapted to the severity of the underlying disease and the intensity of pain. Very few controlled studies concerning these techniques have been performed, and it is therefore difficult to assess their short and long term efficacy. Optimal effectiveness will be obtained if the indication is correct. This non exhaustive revue presents the indications, techniques and results of neural conduction blocks as peripheral blocks, Alcock canal block, zygapophysial joint blocks and also central blocks illustrated by epidural and intrathecal injections and finally sympathetic nervous system blocks as celiac plexus block, stellate ganglion block and intravenous blocks for complex regional pain syndromes. The indications, techniques and results of thermal neurolyse (radiofrequency, thermocoagulation), transcutaneous electrical nervous stimulation (TENS) and implant central stimulation are also presented. A multidisciplinary approach is used to evaluate the risk/benefit ratio of these invasive techniques for each patient.

Catheter Ablation↗
PubMed1998

Enhancer control of V(D)J recombination at the TCRbeta locus: differential effects on DNA cleavage and joining.

Deletion of the TCRbeta transcriptional enhancer (Ebeta) results in nearly complete inhibition of V(D)J recombination at the TCRbeta locus and a block in alpha beta T cell development. This result, along with previous work from many laboratories, has led to the hypothesis that transcriptional enhancers affect V(D)J recombination by regulating the accessibility of the locus to the recombinase. Here we test this hypothesis by performing a detailed analysis of the recombination defect in Ebeta-deleted (Ebeta-/-) mice using assays that detect various reaction intermediates and products. We found double-strand DNA breaks at recombination signal sequences flanking Dbeta and Jbeta gene segments in Ebeta-/- thymuses at about one-third to one-thirtieth the level found in thymuses with an unaltered TCRbeta locus. These sites are also subject to in vitro cleavage by the V(D)J recombinase in both Ebeta-/- and Ebeta+/+ thymocyte nuclei. However, the corresponding Dbeta-to-Jbeta coding joints are further reduced (by 100- to 300-fold) in Ebeta-/- thymuses. Formation of extrachromosomal Dbeta-to-Jbeta signal joints appears to be intermediately affected and nonstandard Dbeta-to-Dbeta joining occurs at the Ebeta-deleted alleles. These data indicate that, unexpectedly, loss of accessibility alone cannot explain the loss of TCRbeta recombination in the absence of the Ebeta element and suggest an additional function for Ebeta in the process of DNA repair at specific TCRbeta sites during the late phase of the recombination reaction.

Alleles↗
PubMed1998

High-titre, cryostable cell-free varicella zoster virus.

Work with varicella-zoster virus has been seriously hampered by the difficulty of preparing high-titre cell free virus, and by the instability of such virus when frozen and thawed. We have evaluated the use of a range of protocols and demonstrate that relatively high titres of 19,000 plaque forming units per millilitre may be recovered after freezing in PBS-sucrose-glutamate-serum buffer (PSGC). In addition, we have shown that the virus obtained by this method gives similar results in neutralisation and antiviral susceptibility assays to that freshly prepared from infected cells, allowing the use of high titre, titrated virus stocks in such assays.

Antibodies, Monoclonal↗
PubMed1998

Critical haemoglobin concentration in anaesthetized dogs: comparison of two plasma substitutes.

We have explored systemic and regional tolerance to haemodilution during anaesthesia with two different synthetic colloids. Eighteen dogs undergoing mechanical ventilation during anaesthesia with ketamine were submitted to progressive normovolaemic haemodilution with either gelatin (GEL; n = 9) or hydroxyethylstarch (HES; n = 9) administered on a 1:1 ratio. Systemic oxygen delivery was calculated from measurement of thermodilution cardiac output and arterial oxygen content, while systemic oxygen consumption was determined from expired gas analysis. Mesenteric oxygen delivery and consumption were determined using ultrasonic flow measurements, and arterial and mesenteric venous oxygen contents. The critical haemoglobin concentration (i.e. the haemoglobin value below which oxygen consumption becomes oxygen delivery dependent) was mean 3.6 (SD 0.8) g dl-1 in the GEL and 3.5 (1.5) g dl-1 in the HES group. The mesenteric critical oxygen extraction ratio (O2ER) (GEL 50.1 (12.1)%; HES 48.5 (13.4)%) was significant lower than the systemic critical O2ER (GEL 66.1 (8.4)%; HES 67.7 (7.1)%). There were no significant differences between the GEL and HES groups for any of these variables, or in the amount of colloid administered. During the study, oxygen delivery decreased almost linearly with reduction in haemoglobin, indicating a lack of cardiac output response to anaemia during ketamine anaesthesia.

Anesthesia, Intravenous↗
PubMed1996

Influence of running different distances on renal glomerular and tubular impairment in humans.

Strenuous exercise has been claimed to modify renal glomerular and tubular function, the relative involvement of the two sites being unknown. These changes may be assessed by the determination of plasma high and low molecular mass proteins. A group of 13 man performed five runs (100, 400, 800, 1,500, 3,000 m) at maximal speed. The excretion rates and renal clearances of creatinine, albumin (Alb), beta 2-microglobulin (beta 2-m) and retinol-binding protein (RBP) were determined before and after each run. The glomerular filtration rate remained stable during the shorter runs and declined by about 40% during the longer runs. The excretion rate for Alb rose from 10-fold above the basal value (6 micrograms.min-1) for the 100 m to 49-fold for the 800 m and then declined for distances up to 3,000 m. The beta 2-m and RBP had a lesser initial increase, 3.5-(rest 55 ng.min-1) and 7.6-(rest 116 ng.min-1) fold, respectively, for the 100 m run and thereafter showed a higher excretion rate than Alb for the 400 m and 800 m runs. The renal clearances of these high (Alb) and low molecular mass (beta 2-m and RBP) proteins followed the changes observed for excretion rates. There was a linear relationship (r2 = 0.996) between plasma lactate concentration and total protein excretion in the postexercise period when taking all five runs into consideration. Glomerular permeability was primarily affected by the 100-m run while the longer runs modified both the glomerular and the tubular sites. To conclude, the present study demonstrated a differential response of the kidney to strenuous exercise with respect to the intensity and duration of the events.

Adult↗
PubMed1996

UVA-induced oxidative damage in fibroblasts cultured in a 3-dimensional collagen matrix.

The exposure of dermal equivalent, i.e., fibroblasts cultured in a 3-dimensional collagen matrix to realistic doses of UVA (< or = 200 kJ/m2), results in a lipid peroxidation process as evidenced by the release of thiobarbituric acid-reactive substances in the supernatant. This peroxidative process is shown to be associated with the presence of fibroblasts and is inhibited by preincubation with vitamin E, the well-known chain-breaking antioxidant. Moreover, the UVA irradiation triggers cytotoxic effects which can also be reversed by preincubation with vitamin E. While the peroxidation extent is similar for fibroblasts cultured in monolayers or in dermal equivalent, the cytotoxic response to UVA is more pronounced in dermal equivalent.

Adult↗