12 research outputs found
Hyperthermie des neuroleptiques secondaires à un antiémétique administré par voie orale: le métopimazine
No full textLe saturnisme chronique chez l'enfant aujourd'hui. Une pathologie de la pauvreté et de l'exclusion
No full textLack of interaction between amisulpride and lorazepam on psychomotor performance and memory in healthy volunteers
No full textMolecular hydrogen in galaxies
No full textThis study aims to understand the key role played by molecular hydrogen in the evolution of galaxies, with a view to constraining its radial distribution in the Galaxy and the CO→H(_2) conversion factor α(_20).The star formation rate is shown to be correlated with the surface density of H(_2). A correlation between the molecular hydrogen fraction and the metallicity of a region allows the time evolution of H(_2) to be described. This leads to a modified 'Schmidt Law' of the SFR which explains quite naturally the production of galactic metallicity gradients and the constancy of the SFR in the absence of infall. A consistent closed model of the chemical evolution of the Galaxy is proposed to solve the G-dwarf problem, the stellar age-metallicity relation and the metallicity gradient, leading to the prediction of some initial amount of pre-disc processing of gas into visible and dark matter. It is found that a constant yield of metals is more appropriate than a yield proportional to metallicity. Possible time variations of the returned fraction, the dark matter fraction and the SFR are also studied. For consistency, we suggest that dark matter in the solar neighbourhood could be totally baryonic provided the Miller-Scalo IMF is modified at the lower end, that is, the dark matter resides in low mass stars or brown dwarfs. The production of metallicity gradients in spiral galaxies is shown to be a direct consequence of the radial variation of the total surface density of matter and the age of the disc. The role of molecular gas in the evolution of the Oort Cloud of comets is examined. It is shown that comet showers with a mean interval of ̴̱ 30My cannot be produced using perturbations of the Oort Cloud by known stars or molecular clouds. If there is indeed an apparent 30My periodicity in the terrestrial mass extinction and geological records, we argue that astronomically induced processes are unlikely to be the primary cause. Evidence is presented that the lifetime of the molecular gas phase is ≤ 2.lO(_8)y, and arguments, particularly from CO observations of the Virgo galaxy cluster, favouring longer lifetimes are shown to be not well founded. We suggest that the ICM in Virgo reduces the value of α(_20) as compared to isolated galaxies. From the above considerations, the radial distribution of in the Galaxy is derived and shown to agree in the inner Galaxy with that derived from ɤ-ray analysis. In the solar neighbourhood we find α(_20) = 2.5±0.5, and present evidence that α(_20) varies as a function of Galactocentric radius and from galaxy to galaxy
Toxicities associated with chemotherapy regimens containing a fluoropyrimidine: A real-life evaluation in France
No full textInternational audienceAIMS: Despite fluoropyrimidines (FPs) constituting the main component of the chemotherapy combination protocols in 50% of chemotherapies for solid tumour treatments, incidence data for FP-related toxicity are poorly documented in real life. This study evaluated the number of patients receiving FP-based chemotherapies in France, along with the true incidence of FP-related serious adverse effects (SAEs) before the recent mandatory dihydropyrimidine dehydrogenase (DPD)-screening was introduced by French health authorities, DPD being the rate-limiting enzyme of 5-fluorouracil (5-FU) catabolism.METHODS: Exhaustive data on the number of patients treated with FP-based chemotherapy in 2013-2014 were collected in the Centre-Val de Loire region of France. True incidence of SAEs was extracted from a cohort of 513 patients with incident solid tumours receiving first-line FP-based chemotherapy.RESULTS: After extrapolation at national level, we estimated that 76,200 patients are currently treated annually with 5FU (53,100 patients, 62% digestive system-related versus 26% breast cancers versus 12% head and neck cancers) or capecitabine (23,100 patients, 45% digestive system-related versus 37% breast cancers versus 18% non-documented). Earlier (in the first two cycles) the SAE incidence rate was 19.3% (95% confidence interval (CI) 16-23%) including one toxic death (0.2%, 95%CI 0-1%). SAE incidence rate was 32.2% (95%CI 28-36%) over the first 6 months of treatment. Incidence of death, life-threatening prognosis or incapacity/disability was 1.4% (95%CI 0.4-2.4%) and 1.6% (95%CI 0.5-2.6%) during first two cycles and first 6 months, respectively.CONCLUSION: These data highlight the significant public health issue related to FP toxicity, with around 1200 patients developing FP-related life-threatening prognosis or incapacity/disability annually in France, including 150 toxic deaths. It is hoped that DPD-deficiency screening will reduce such iatrogenic events and eradicate toxic deaths
Activated double-stranded RNA-dependent protein kinase and neuronal death in models of Alzheimer’s disease
No full textInternational audienc
Efficacy and safety of DPP-4 inhibitors in patients with type 2 diabetes: Meta-analysis of placebo-controlled randomized clinical trials
No full textInternational audienceBACKGROUND:Guidelines for type 2 diabetes (T2D) recommend reducing HbA1c through lifestyle interventions and glucose-lowering drugs (metformin, then combination with dipeptidyl peptidase-4 inhibitors [DPP-4Is] among other glucose-lowering drugs). However, no double-blind randomized clinical trial (RCT) compared with placebo has so far demonstrated that DDP-4Is reduce micro- and macrovascular complications in T2D. Moreover, the safety of DPP-4Is (with increased heart failure and acute pancreatitis) remains controversial.METHODS:A systematic review of the literature (PubMed, Cochrane Library Central Register of Controlled Trials [CENTRAL] and https://clinicaltrials.gov), including all RCTs vs placebo published up to May 2015 and the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), published June 2015, was performed. Primary endpoints were all-cause mortality and death from cardiovascular causes; secondary endpoints were macrovascular and microvascular events. Safety endpoints were acute pancreatitis, pancreatic cancer, serious adverse events and severe hypoglycaemia.RESULTS:A total of 36 double-blind RCTs were included, allowing analyses of 54,664 patients. There were no significant differences in all-cause mortality (RR=1.03, 95% confidence interval [CI]=0.95-1.12), cardiovascular mortality (RR=1.02, 95% CI=0.92-1.12), myocardial infarction (RR=0.98, 95% CI=0.89-1.08), strokes (RR=1.02, 95% CI=0.88-1.17), renal failure (RR=1.06, 95% CI=0.88-1.27), severe hypoglycaemia (RR=1.14, 95% CI=0.95-1.36) and pancreatic cancer (RR=0.54, 95% CI=0.28-1.04) with the use of DPP-4Is. However, DDP-4Is were associated with an increased risk of heart failure (RR=1.13, 95% CI=1.01-1.26) and of acute pancreatitis (RR=1.57, 95% CI=1.03-2.39).CONCLUSION:There is no significant evidence of short-term efficacy of DPP-4Is on either morbidity/mortality or macro-/microvascular complications in T2D. However, there are warning signs concerning heart failure and acute pancreatitis. This suggests a great need for additional relevant studies in future
A polarimetry study of starburst galaxies
No full textOptical imaging polarimetry has been carried out for a number of starburst galaxies under various morphological classifications. In several cases, kpc-scale reflection nebulae are detected which arise from dust grains scattering starburst radiation towards the observer. In general, the scattering medium is displaced up to several kpc from the current star- forming environment and in one case, the dust distribution extends above and below the galactic disk in a manner reminiscent of M82. It is now well established that galactic-scale outflows (superwinds) are prevalent in starburst galaxies and it is tempting to attribute the anomalous dust distributions detected in this thesis with these powerful processes. Furthermore, there is increasing evidence that tidal encounters initiate starburst activity and in some cases a dynamic event of this kind may also be responsible for the observed distribution of scattering material. Mie scattering models were constructed for two of the objects observed in this work. An optically-thin approximation was used which, for many plausible distributions of the dust along the line-of-sight, can be shown to be roughly valid. Although the estimates derived from this technique have a range of values, in all cases the dust component detected in scattered light appears to be at least an order of magnitude more massive than the amount of FIR-emitting dust derived from IRAS data. This is not too surprising - the material detected via polarimetry is probably too cold for IRAS which is sensitive to dust warmer than about 30-50 K
Distinct and common functions of mTORC1 and mTORC2 in Purkinje cells
No full textIn mammalian cells, the serine/threonine protein kinase mTOR (mammalian target of rapamycin) is present in two complexes, called mTORC1 and mTORC2. While several of the components are common to both complexes, raptor and rictor are only associated with mTORC1 or mTORC2, respectively. Due to differences in their molecular composition mTORC1 and mTORC2 possess distinct functions and properties (Laplante & Sabatini, 2012). For example, mTORC1 but not mTORC2 is sensitive to the immunosuppressive drug rapamycin. mTORC1 integrates various extracellular signals (e.g. growth factors, energy status or amino acid availability) to promote protein synthesis, to regulate lipogenesis and to inhibit autophagy (Shimobayashi & Hall, 2014). In line with these features, mTORC1 was found to be essential for cell growth and proliferation. In contrast, activation and function of mTORC2 is less well understood. It phosphorylates and activates members of the AGC kinase family, including Akt, SGK1 and PKC, suggesting a role in cell survival/metabolism and actin cytoskeleton organization.
In the brain, mTOR signalling has been implicated in several neurodevelopmental and neurodegenerative disorders like autism spectrum disorders (ASD) or Huntington’s disease. The availability of approved drugs, such as rapamycin and its analogs (called rapalogs), has made the mTOR signalling pathway an attractive target for the treatment of those diseases. Although rapamycin has been shown to preferentially target mTORC1, prolonged exposure also inhibits mTORC2 (Sarbassov et al., 2006). Thus, it is important to unravel the specific and the common functions of mTORC1 and mTORC2 in the central nervous system.
In this study, the roles of mTORC1 and mTORC2 were analysed in Purkinje cells by conditionally deleting floxed Rptor or Rictor genes, respectively, using an L7/Pcp-2-driven expression of the Cre recombinase. The resulting mouse lines are called RAPuKO or RIPuKO, which stands for raptor or rictor Purkinje knockout, respectively, and allowed to study the functions of mTORC1 and mTORC2 in developing and adult Purkinje cells and to investigate the effect on mouse behaviour.
We found that the phenotypes of RAPuKO and RIPuKO mice only sparsely overlapped but mostly differed, which assigns mTORC1 and mTORC2 distinct functions in these neurons. (I) mTORC1, but not mTORC2 abrogation in Purkinje cells reduced the social interest of mice. (II) Ablation of either mTORC1 or mTORC2 in Purkinje cells was sufficient to cause motor coordination deficits, yet, for RAPuKO mice the onset of these deficits was age-dependent while motor deficits of RIPuKO mice could be detected at any tested age. (III) The motor phenotype of RIPuKO mice was accompanied by developmental aberrations, such as impaired climbing fibre synapse elimination and hampered dendritic self-avoidance, while the age-dependent motor phenotype of RAPuKO mice seemed to be driven by Purkinje cell degeneration that finally led to apoptosis and a loss of these neurons. Vice versa, no signs for deficient climbing fibre elimination or Purkinje cell loss could be detected for RAPuKO or RIPuKO mice, respectively. (IV) mTORC1 and mTORC2 ablation in Purkinje cells both affected neuron morphology in a similar manner, which included multiple primary dendrites and a reduction of the neuron size, yet, last was more pronounced for raptor-deficient cells.
Altogether, both mTORC1 and mTORC2 ablation in Purkinje cells had a pronounced, yet distinct, effect on these neurons and the mouse behaviour, unlike in other tissues where inactivation of mTORC2 has been reported to result in a minor phenotype in comparison to mTORC1 ablation (Bentzinger et al., 2008; Godel et al., 2011).
While ablation of mTORC1 and mTORC2 in Purkinje cells resulted in mostly distinct phenotypes, we found that sustained mTORC1 activation in these neurons by a TSC1 knockout (TSCPuKO) caused a phenotype that was similar to the one of RAPuKO mice. In both RAPuKO and TSCPuKO mice an age-dependent loss of Purkinje cells due to apoptosis was observed, which was paralleled by reactive gliosis. Moreover, in both cases Purkinje cell apoptosis was preceded by signs of neurodegeneration in form of axonal swellings that accumulated neurofilaments. Also in terms of behaviour similar phenotypes were observed since both knockout mice showed reduced social interest (Tsai et al., 2012). These behavioural phenotypes support the growing notion that the cerebellum is important for non-motor related functions (Schmahmann et al., 2007; Wang et al., 2014) and that mTORC1 plays a role therein. TSC1 knockout in Purkinje cells has been reported to cause also repetitive behaviour in mice in addition to abnormal social behaviour and therefore it has been suggested that these mice show an autism-like phenotype (Tsai et al., 2012).
In summary, this study provides in vivo data for the importance of mTORC1 and mTORC2 in developing and adult Purkinje neurons. We find that both complexes are crucial for Purkinje cells, yet, in mostly distinct manners. This finding is in line with the model that mTORC1 and mTORC2 largely feed separate downstream effectors, although they share many molecular components. The knowledge of the function of mTORC1 and mTORC2 in adult neurons is important for the development of treatment options that target the mTOR pathway. This work clearly suggests that such drugs need to be highly selective for the different complexes. Moreover, this work highlights that a complete inhibition of mTORC1 may have detrimental effects on the survival of neurons and that this may also precipitate autism-like pathologies
Characterization of a novel bacterial PAMP - elongation factor Tu - and its role in "Arabidopsis thaliana" defense and immunity
No full textThe discrimination of self and nonself is a primary challenge for all living organisms to detect microbial invasion and to protect and defend against the invader. If a pathogen manages to overcome constitutive barriers, highly specific recognition systems are able to identify common pathogenic signals and activate the innate immune system as a first line of defense. Specialized cells and a circulatory system that is able to spread somatically generated adaptive immune responses to the infection side exist only in animals. Plants lack an adaptive immune system comparable like this, but they independently co-evolved the capability to detect microbial invasions by perception of specific molecules, so called PAMPs (pathogen associated molecular patterns), and subsequent activation of innate immune responses. Flagellin, the major subunit of the bacterial motility organ flagellum (Yonekura, K. et al. 2001), can be regarded as the best characterized bacterial PAMP in plants. Flg22, a synthetic peptide comprising the highly conserved epitope of the flagellin Nterminus, is recognized by the plant cell and is sufficient to activate innate immune responses. In this work based on the model plant Arabidopsis thaliana, experiments with bacterial extracts devoid of elicitor active flagellin, show still the capability to induce a broad set of plant defense reactions as flagellin, suggesting that at least one additional perception system for another elicitor exist. This novel elicitor and the corresponding active site were identified as the first 18-26 amino acids from the Nterminus of bacterial Elongation factor Tu (elf18-elf26). This essential protein, involved in the delivery of aminoacyl-tRNA to the ribosome during the translation process, is highly conserved over all organisms (Appendix 1) and is the most abundant protein in the bacterial cell (Helms, M. K. and Jameson, D. M. 1995). Furthermore it is considered to be the slowest evolving protein (Gaucher, E. A. et al. 2003) containing all characteristics for a classical PAMP (see definition included in General Introduction). Further characterization of the EF-Tu/Arabidopsis thaliana interaction showed that all known plant defense mechanisms are activated upon EFTu elicitation. This includes extra cellular medium alkalinization of suspension cultured cells of Arabidopsis, production of reactive oxygen species (ROS) (Laloi, C. et al. 2004) and increase in the biosynthesis of plant hormone ethylene. Like shown previously for flagellin (Zipfel, C. et al. 2004), pre-treatment of Arabidopsis with elf-peptides led to enhanced resistance against plant pathogenic bacteria Pseudomonas
syringae pv. tomato (DC3000). Gene expression changes were analyzed using
Affymetrix ATH1 array and about 1000 genes with induced expression after 30-60
minutes treatment with elf-peptides were identified. These genes were congruent with
that affected by flg22 treatment (Navarro, L. et al. 2004, Zipfel, C. et al. 2004). The
same genes were also found to be induced in the flagellin insensitive receptor mutant
fls2 upon elf-treatment. Binding studies with radio labeled elf26-125I-TY show that
there is a high affinity binding site for EF-Tu existing in Arabidopsis thaliana, which is
saturable, highly specific and independent of FLS2. Crosslinking experiments
identified a polypeptide band of 150 kDa as potential binding site for EF-Tu. Strikingly
the perception of one PAMP (e.g. flg22) leads to a higher amount of binding sites for
the other elicitor (e.g. elf18). Furthermore the perception of EF-Tu activates, like
flg22, a MAP kinase-based signaling cascade in nearly identical kinetic. Together this
study indicate two independent receptors using a converging signaling cascade that
leads to the activation of the plant innate immune system with the same broad array
of plant defense reactions
