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Biomedical subjects

M Laurent

Publications and source records attributed to M Laurent.

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

A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. The THESEE Study Group. Tinzaparine ou Heparine Standard: Evaluations dans l'Embolie Pulmonaire.

BACKGROUND: Low-molecular-weight heparin appears to be at least as effective and safe as standard, unfractionated heparin for the treatment of deep-vein thrombosis, but only limited data are available on the use of low-molecular-weight heparin to treat acute symptomatic pulmonary embolism. METHODS: We randomly assigned 612 patients with symptomatic pulmonary embolism who did not require thrombolytic therapy or embolectomy to either subcutaneous low-molecular-weight heparin (tinzaparin) given once daily in a fixed dose or adjusted-dose, intravenous unfractionated heparin. Oral anticoagulant therapy was begun between the first and the third day and was given for at least three months. We compared the treatments at day 8 and day 90 with respect to a combined end point of recurrent thromboembolism, major bleeding, and death. RESULTS: In the first eight days of treatment, 9 of 308 patients assigned to receive unfractionated heparin (2.9 percent) reached at least one of the end points, as compared,with 9 of 304 patients assigned to low-molecular-weight heparin (3.0 percent; absolute difference, 0.1 percentage point; 95 percent confidence interval, -2.7 to 2.6). By day 90, 22 patients assigned to unfractionated heparin (7.1 percent) and 18 patients assigned to low-molecular-weight heparin (5.9 percent) had reached at least one end point (P=0.54; absolute difference, 1.2 percentage points; 95 percent confidence interval, -2.7 to 5.1). The risk of major bleeding was similar in the two treatment groups throughout the study. CONCLUSIONS: Under the conditions of this study, initial subcutaneous therapy with the low-molecular-weight heparin tinzaparin appeared to be as effective and safe as intravenous unfractionated heparin in patients with acute pulmonary embolism.

Acute Disease↗
PubMed1997

Signal-induced Ca2+ oscillations through the regulation of the inositol 1,4,5-trisphosphate-gated Ca2+ channel: an allosteric model.

We propose a molecular model for InsP3-sensitive Ca2+ oscillations based on the allosteric properties of the InsP3 receptor/Ca2+ channel. Our model interprets the cooperatively towards InsP3 saturation, of calcium efflux from intravesicular stores as well as the absence of cooperativity in the binding process of InsP3 on the receptor. It takes into account quantitatively the two antagonist, concentration-dependent effects (fast activator and slow inhibitor) that cytosolic Ca2+ exerts on the InsP3 receptor/Ca2+ channel. Assuming that a single pool of releasable Ca2+ exists in the endoplasmic reticulum, the model leads to cytosolic and intravesicular oscillations in Ca2+ at fixed InsP3 concentration. Activation of the receptor by cytosolic calcium is essential for the triggering of oscillations whereas the slow Ca2+ inhibition effect is irrelevant in this respect, although this regulation loop might prevent the system from entering the unstable domain in absence of a true agonist stimulation. Activating cytosolic Ca2+ and InsP3 have quite distinct functions for the induction of Ca2+ release: cytosolic Ca2+ triggers oscillations whereas InsP3 only brings the receptor into a potentially oscillatory regime. Hence, the increasing slope of Ca2+ spiking is constitutively independent from the intensity of the hormonal stimuli in our model, in accord with experimental observations. Comparisons with other existing models are given and additional possible coupling mechanisms are discussed in order to explain particular facts (such as possible oscillations of InsP3) which do not depend on the intrinsic properties of the oscillator.

Animals↗
PubMed1997

Autocatalytic processes in cooperative mechanisms of prion diseases.

According to the leading theory, the agent responsible for prion diseases would be the conformational isomer PrP(Sc) of a cellular protein PrP(C), the pathogenic form PrP(Sc) multiplying by converting the normal protein into a likeness of itself. The pathogenic isoform could catalyze the conformational transition so that the process, taken as a whole, is autocatalytic. However, in this simple but atypic model, unrealistic values of rate parameters are needed in order to account for the kinetics of the propagation of prion diseases. In this paper, I show that these limits can be overcome by assuming that catalysis proceeds through a multimeric assembly of the pathogenic isoform of the prion protein. Such a structure would indeed be able to provide cooperativity both at the assembly and conformational change levels, strongly reinforcing the autocatalytic character of the activated process. Moreover, such a property is a prerequisite to endow the metabolic system with dynamic bistability. Together with a good agreement regarding experimental data, this analysis is closely akin to Griffith's original idea concerning the thermodynamic conditions required for autocatalyzed modifications of any protein.

Allosteric Regulation↗
PubMed1997

The effects of task constraints on the organization of interception movements.

In the light of the intensity coupling effects reported in the literature, subjects' capacities for independently controlling the absolute velocity of their movement at the point of interception was evaluated by asking them to learn to propel orthogonally approaching balls, varying in their speed of approach, into target boxes placed at various distances from the interception point. As required for successful accomplishment of the task, movement velocity was found to be adapted to the distance to be covered, with the near target giving rise to lower velocities and the far target giving rise to higher velocities even when the conditions were presented in random order. Nevertheless, even though target distance accounted for a substantial proportion of the total variance, a small but significant effect of ball approach speed on movement velocity was found, suggesting that intensity coupling is a persistent but modulable phenomenon in interception tasks.

Adaptation, Physiological↗
PubMed1997

Controlling locomotion during the acceleration phase in sprinting and long jumping.

The production of a stabilized locomotor pattern is crucial in sporting activities such as the run-up in long jumping, a task which is characterized by high spatio-temporal constraints. The aims of this study were as follows. First, we wished to investigate how athletes stabilize their stride patterns so as to strike the take-off board accurately. Previous studies have argued that during the initial accelerative phase of the run-up, athletes attempt to produce a stereotyped stride pattern. We investigated this initial phase in more detail by examining the kinematic parameters of long jumpers' strides and their spatial consequences. These data were then compared with the stride patterns observed in a sprinting task, which did not impose the same spatio-temporal constraints. Our second aim was to compare the stride patterns of skilled and unskilled jumpers. Kinematic stride parameters were measured in two ways. The temporal parameters (flight time, stance time) were recorded by a microcomputer attached to the athlete, whereas the spatial parameters (stride length) were measured directly from the footprints the subjects made on the track. The results confirmed those of previous studies, showing that long jumpers initiate locomotor adjustments in the last 3-4 strides before take-off, but a more detailed analysis revealed that long jumping is characterized by adjustments during the first few strides. These adjustments were not seen in the sprinting task, where systematic variations of accumulated error were observed. These stride adjustments differed from those seen in previous studies and thus permit a more comprehensive understanding of the control involved in the tasks studied. The patterns exhibited by the skilled and unskilled subjects were very similar overall, but differed in that variations in accumulated error were less marked for the skilled subjects, who tended to make early stride adjustments sooner than the unskilled subjects. These results are discussed in relation to the cognitive and ecological approaches to movement coordination.

Acceleration↗
PubMed1997

Dynamics of calcium regulation in Paramecium and possible morphogenetic implication.

This paper is the first report of the use of a fluorescent indicator (Dextran-coupled calcium green-1) for imaging of cytosolic free calcium in ciliate cells. Using this technique in Paramecium, we show that a very transient increase in the mean intracellular calcium concentration accompanied exocytosis. It has long been postulated based on indirect experimental evidence, that a calcium wave which would spread across the cortex at the time of cell division, would be the primary event that triggers morphogenesis in these species. We theoretically show that a unifying interpretation can be given for the possible occurrence of a single wave and that of multiple oscillations of cytosolic calcium: both of which correspond to two different behaviors of the same dynamic system. Experimental conditions allowing the visualization of possible calcium periodicities in the interphase Paramecium cell are much more easily fulfilled than those permitting the observation of a single wave at the time of cell division. Hence, experiments were performed on interphase cells. After microinjection of calcium indicator into a mutant strain which is defective in exocytosis, we observed Ca2+ oscillations with a period close to 2 minutes. Hence, we conclude that Paramecium possesses all the dynamic elements required to generate, at the time of cell division, a morphogenetic calcium wave.

Animals↗
PubMed1997

Molecular clues to pathogenesis in prion diseases.

The infectious agent of the transmissible spongiform encephalopathies (TSE) resembles a virus in that it propagates in vivo and has distinct strains. However, compelling evidence strongly suggests that a posttranslational structural alteration in a glycoprotein PrPC (the normal, cellular isoform of the so-called prion protein) is responsible for pathogenesis of these diseases. According to this hypothesis-now close to being generally accepted-iatrogen, sporadic and familial forms of TSE would have the same molecular mechanism: the conversion of PrPC into a protease-resistant isoform PrPSc kinetically behaves as an autocatalytic process which, combined with the high turnover rate of the normal isoform, may endow the system with bistability properties and subsequent threshold behavior between normal and pathogenic steady-states. Normal prion protein seems to be necessary for long-term survival of Purkinje neurons, regulation of circadian rhythms and, more controversially, for normal synaptic function. At least part of the pathology might be due to the unavailability of normal isoform rather than to the accumulation of PrPSc. NMR structure of the normal mouse prion protein reveals a short, unexpected beta-sheet which might be a nucleation site for the conformational transition between PrPC and PrPSc. Prion diseases may challenge the edged distinction that we use to make between informational (DNA) and functional (proteins) macromolecules. Pathogenic mechanism of prions might also be involved in other proteins to achieve and pass on their conformation. Hence, structural inheritance at the molecular level might be the missing link for the understanding of the structural inheritance processes featured at the cellular level. Moreover, evolutionary paradigm postulating a primitive RNA world is weakened by the mechanism of prion diseases.

Animals↗
PubMed1996

Prion diseases and the 'protein only' hypothesis: a theoretical dynamic study.

In the 'protein only' hypothesis, prion diseases are thought to result from the conformational change of a normal isoform of a prion protein (PrPC) to a protease-resistant, pathogenic form called PrPSc. This conversion rests on an autocatalytic process requiring the presence of pre-existing PrPSc. Theoretical kinetic analysis of the dynamic process, including the turnover of the normal prion protein, shows that the system exhibits bistability properties, indicating that the very slow accumulation of the abnormal form of the protein in the brain could in fact be the consequence and not the cause of the disorders. The cause would be a transition between two alternative steady states of the system. The presence of a small amount of the PrPSc protein in lymphocytes does not necessarily constitute any indication of a non-symptomatic but infectious pathogenic state. Moreover, infectious prion particles should not be seen as necessarily composed of the abnormal isoform of the protein, as usually stated. Particles containing only an excess of the normal form of the protein might also be pathogenic. Compounds that can act on the turnover rate of the normal PrPC protein could be a therapeutic strategy against prion diseases.

Animals↗
PubMed1996

Expression and regulation by serum of multiple FGF1 mRNA in normal transformed, and malignant human mammary epithelial cells.

In normal (NMEC), transformed (HBL-100) and malignant human mammary epithelial cells (MCF 7, BT-20, MDA-MB 231), we have examined the expression and the regulation by serum of FGF1 and FGF2 mRNA. FGF2 mRNA level was higher in NMEC and in a HBL-100 than in malignant cell lines (MDA-MB-231, BT-20). No FGF2 mRNA was detected in the malignant cell line, MCF-7. In contrast, the FGF1 mRNA was detected in all the mammary epithelial cells but at different levels. NMEC, HBL-100 and MDA-MB231 cells expressed similar level of FGF1 and higher than that observed in BT-20 and MCF-7. In contrast to FGF2 which is only expressed in nonmalignant cells, no correlation between FGF1 mRNA expression and the phenotype of the cells was observed. We followed the expression of four FGF1 mRNA, heterogenous in their 5' untranslated regions. This study demonstrated that (i) the FGF1 mRNA 1.A was not expressed by mammary epithelial cells, (ii) the FGF1 mRNA 1.B was only expressed in normal mammary epithelial cells and (iii) the transcripts 1.C and 1.D were expressed in normal and malignant cells with specific patterns. The expression of FGF1 mRNAs responded in a cell specific manner to serum starvation. The mRNA 1.A was only expressed in normal cells cultured in the absence of serum while 1.C was either up- or down-regulated by serum in transformed cells and the expression of 1.D was greater in presence of serum in all cell lines. These results show that the regulation of FGF1 mRNAs expression is cell specific and does not correlate with a tumorigenic or transformed cell phenotype.

Base Sequence↗
PubMed1996

Kinetic modelling of the nitric oxide gradient generated in vitro by adherent cells expressing inducible nitric oxide synthase.

Inducible nitric oxide (NO) synthase produces a long-lasting NO flux which can exert cytotoxic effects on target cells. A prerequisite for the understanding of the molecular basis of NO action is quantitative data on the availability of this small neutral radical molecule at both the spatial and temporal levels. The limits of NO availability depend on the respective rates of NO production, diffusion and autoxidation by molecular oxygen. Kinetic modeling of these processes has been performed for a widely used experimental system consisting of a monolayer of adherent cells cultured in vitro for hours in unstirred culture medium. It appears that: (i) the maximal NO concentration in the culture is in the immediate vicinity of the monolayer, where target cells will sediment; (ii) the steady-state NO concentration in this area is lower than 4 to 5 microM; and (iii) measurements of nitrite/nitrate or citrulline accumulation in the bulk cell medium culture during a given time period significantly underestimate (by a factor of up to 3 to 4) the true rate of NO synthesis at the level of the producer cell. This rate can be, nevertheless, easily estimated from the rate of production of the stable NO synthase products.

Cell Adhesion↗
PubMed1996

The neurotrophic activity of fibroblast growth factor 1 (FGF1) depends on endogenous FGF1 expression and is independent of the mitogen-activated protein kinase cascade pathway.

The expression of fibroblast growth factor (FGF) 1, a potent neurotrophic factor, increases during differentiation and remains high in adult neuronal tissues. To examine the importance of this expression on the neuronal phenotype, we have used PC12 cells, a model to study FGF-induced neuronal differentiation. After demonstrating that FGF1 and FGF2 are synthesized by PC12 cells, we investigated if FGF1 expression could be a key element in differentiation. Using the cell signaling pathway to determine the effects of FGF1 alone, FGF1 plus heparin, or a mutated FGF1, we showed an activation to the same extent of mitogen-activated protein (MAP) kinase kinase and MAP kinase (extracellular regulated kinase 1). However, only FGF1 plus heparin could promote PC12 cell differentiation. Thus, the MAP kinase pathway is insufficient to promote differentiation. Analysis of the PC12 cells after the addition of FGF1 plus heparin or FGF2 demonstrated a significant increase in the level of FGF1 expression with the same time course as the appearance of the neuritic extensions. Transfection experiments were performed to enhance constitutivly or after dexamethasone induction the level of FGF1 expression. The degree of differentiation achieved by the cells correlated directly with the amount of FGF1 expressed. The MAP kinase pathway did not appear to be involved. Interestingly, a 5-fold increase in FGF1 in constitutive transfected cells extended dramatically their survival in serum-free medium, suggesting that the rise of FGF1 synthesis during neuronal differentiation is probably linked to their ability to survive in the adult. All of these data demonstrate that, in contrast to the MAP kinase cascade. FGF1 expression is sufficient to induce in PC12 cells both differentiation and survival. It also shows that auto- and trans-activation of FGF1 expression is involved in the differentiation process stimulated by exogenous FGFs through a new pathway which remains to be characterized.

Adult↗
PubMed1996

External radiotherapy for carcinoma of the eyelid: report of 850 cases treated.

PURPOSE: We report a retrospective series of 850 patients treated by external irradiation for carcinoma of the eyelid at Institut Curie and we compare our results with other techniques: brachytherapy and surgery. METHODS AND MATERIALS: Eight hundred fifty patients were treated by external radiotherapy for carcinoma of the eyelid. None of these patients have been previously treated. All the patients were classified according to the TNM classification of (UICC). We distinguished five histological types and five clinical groups according to the site of the skin tumor. Three modalities of external radiotherapy were used: contact therapy, conventional radiotherapy, and electrontherapy. We reviewed the clinical files of the 850 patients who went regularly at follow-up visits. RESULTS: We report the 5-year survival results--alive with no evidence of disease: 72%; alive with progression: 2%; died from tumor progression: 0.5%; died from intercurrent disease: 19.5%; and lost to follow-up: 5%. The 5-year local control rate was 97.5%. We observed 45 failures--lymph node, metastatic, and local--and emphasize this last group by presenting the results of treatment of these local failures. We studied the complications of treatment: 2.3% of corneal complications, 2% of cataracts, and 1.4% of serious ocular complications. CONCLUSIONS: Our results concerning local failures and loss of the eye are comparable to those reported for other techniques involving brachytherapy or surgery. Overall, external radiotherapy is a safe and effective treatment, as it ensures a high local control rate and provides perfectly satisfactory functional and esthetic results. It seemed particularly useful to report this series in that few publications are available on this subject that, nevertheless, constitutes a topical issue.

Adult↗
PubMed1996

Cloning of multiple chicken FGF1 mRNAs and their differential expression during development of whole embryo and of the lens.

Five different 5' untranslated regions (5' UTRs) of FGF1 mRNAs were cloned in chicken. The structure of these transcripts suggests that, as in mammals, distinct 5' untranslated exons are spliced to the first coding exon via alternative splicing and alternative promoter usage. In an attempt to correlate the expression of specific transcripts to distinct biological activities, the distribution of these transcripts in different tissues and during the development of both the whole embryo and the lens was studied. In tissues, we have shown a differential, but not exclusive, expression of these transcripts. In the whole embryo, the expression of one transcript correlates with later developmental processes. In the lens, only two transcripts were detected that are both differently expressed and distributed. These results suggest that the biological properties of FGF1 depend on the expression of specific FGF1 mRNAs. Because these transcripts only differ in their 5' UTRs, they could be involved in distinct translational controls.

Animals↗
PubMed1996

Hysteretic behavior and differential apparent stability properties of microtubule species emerge from the regulation of post-translational modifications of microtubules.

At the epigenetic level, microtubule diversity is generated by several mechanisms of reversible post-translational modifications of tubulin subunits. In most cases, modification enzymes preferentially act on the tubulin subunits of microtubules, whereas the substrate of the enzymes which ensure the reverse reaction is preferentially the alpha beta-dimer of nonpolymerized tubulin. Most modifications identified to date appear to be nearly ubiquitous within the animal kingdom. Moreover, modifications are generally not mutually exclusive, so that cellular microtubules often bear several distinct biochemical alterations whose biological role is yet unknown. Post-translational modifications often (but not always) occur on microtubule species with low turnover rate. However, in vitro comparison of the polymerization and depolymerization rates of modified or unmodified forms of tubulin did not reveal any significant difference between molecular species. Thus, post-translational modifications are thought to be the result rather than the cause of microtubule stability. We re-examine this contention in the light of a regulated kinetic scheme for multiple and non-exclusive enzymatic modifications of microtubules. This study shows that different apparent stability properties of microtubule species emerge under such a kinetic regulation, although all the species were assumed to have identical intrinsic stability properties. This model can be used to reinterpret the results of well-known studies bearing on the relationship between microtubule stability and post-translational modifications. Another important finding is that the existence of a regulation loop in one of the multiple pathways of enzymatic differentiation of microtubules endows the system with hysteretic properties. These properties may be viewed, under restrictive conditions, as a buffering mechanism for the transitions between microtubule growing and shrinking phases during fluctuations in the regulation of centrosomal nucleating activity.

Enzymes↗
PubMed1996

Effects of competitive activation on precision movement control.

Models of emotional activity consider that the emotional state can have general effects on movement control. This control depends on programmed movement invariants (movement sequence, duration of the relative phases, etc.) and on the setting of the movement parameters (amplitude, velocity, etc.). This study of 14 adults shows an influence of the emotional state upon movement kinematics, namely, the peak velocity and the peak acceleration, the amplitude, and the duration of the acceleration phase.

Acceleration↗
PubMed1996

[Primary pericardial thymoma: an unusual etiology of neoplastic pericarditis].

We present a case of a primary pericardic thymoma, revealed by a pericardic effusion. This ectopic localisation is very unusual; neoplastic pericarditis are usually due to metastasis of carcinomas or lymphomas. Sometimes, they are secondary to pericardic invasion by mediastinal malignant thymomas or a metastasis of thymomas. Our patient presented a single pericardic localisation of thymoma without any other site. We discuss ectopic localisations of thymic tissue and thymomas and the diagnostic usefulness of the MIC 2 antibody.

Humans↗