Evidence for a new post-translational modification in Staphylococcus aureus: Hydroxymethylation of asparagine and glutamine.

Staphylococcus aureus is an opportunistic pathogen whose infectious capacity depends on surface proteins, which enable bacteria to colonize and invade host tissues and cells. We analyzed "trypsin-shaved" surface proteins of S. aureus cultures by high resolution LC-MS/MS at different growth stages and culture conditions. Some modified peptides were identified, with a mass shift corresponding to the addition of a CH(2)O group (+30.0106u). We present evidence that this shift corresponds to a hyxdroxymethylation of asparagine and glutamine residues. This known but poorly documented post-translational modification was only found in a few proteins of S. aureus grown under specific conditions. This specificity seemed to exclude the hypothesis of an artifact due to sample preparation. Altogether hydroxymethylation was observed in 35 peptides from 15 proteins in our dataset, which corresponded to 41 modified sites, 35 of them being univocally localized. While no function can currently be assigned to this post-translational modification, we hypothesize that it could be linked to modulation of virulence factors, since it was mostly found on some surface proteins of S. aureus.

Treatment modification in human immunodeficiency virus-infected individuals starting combination antiretroviral therapy between 2005 and 2008.

BACKGROUND: Adverse effects of combination antiretroviral therapy (CART) commonly result in treatment modification and poor adherence. METHODS: We investigated predictors of toxicity-related treatment modification during the first year of CART in 1318 antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals from the Swiss HIV Cohort Study who began treatment between January 1, 2005, and June 30, 2008. RESULTS: The total rate of treatment modification was 41.5 (95% confidence interval [CI], 37.6-45.8) per 100 person-years. Of these, switches or discontinuations because of drug toxicity occurred at a rate of 22.4 (95% CI, 19.5-25.6) per 100 person-years. The most frequent toxic effects were gastrointestinal tract intolerance (28.9%), hypersensitivity (18.3%), central nervous system adverse events (17.3%), and hepatic events (11.5%). In the multivariate analysis, combined zidovudine and lamivudine (hazard ratio [HR], 2.71 [95% CI, 1.95-3.83]; P < .001), nevirapine (1.95 [1.01-3.81]; P = .050), comedication for an opportunistic infection (2.24 [1.19-4.21]; P = .01), advanced age (1.21 [1.03-1.40] per 10-year increase; P = .02), female sex (1.68 [1.14-2.48]; P = .009), nonwhite ethnicity (1.71 [1.18-2.47]; P = .005), higher baseline CD4 cell count (1.19 [1.10-1.28] per 100/microL increase; P < .001), and HIV-RNA of more than 5.0 log(10) copies/mL (1.47 [1.10-1.97]; P = .009) were associated with higher rates of treatment modification. Almost 90% of individuals with treatment-limiting toxic effects were switched to a new regimen, and 85% achieved virologic suppression to less than 50 copies/mL at 12 months compared with 87% of those continuing CART (P = .56). CONCLUSIONS: Drug toxicity remains a frequent reason for treatment modification; however, it does not affect treatment success. Close monitoring and management of adverse effects and drug-drug interactions are crucial for the durability of CART.

Smad3 deficiency in mice protects against insulin resistance and obesity induced by a high-fat diet.

OBJECTIVE-Obesity and associated pathologies are major global health problems. Transforming growth factor-beta/Smad3 signaling has been implicated in various metabolic processes, including adipogenesis, insulin expression, and pancreatic beta-cell function. However, the systemic effects of Smad3 deficiency on adiposity and insulin resistance in vivo remain elusive. This study investigated the effects of Smad3 deficiency on whole-body glucose and lipid homeostasis and its contribution to the development of obesity and type 2 diabetes.RESEARCH DESIGN AND METHODS-We compared various metabolic profiles of Smad3-knockout and wild-type mice. We also determined the mechanism by which Smad3 deficiency affects the expression of genes involved in adipogenesis and metabolism. Mice were then challenged with a high-fat diet to study the impact of Smad3 deficiency on the development of obesity and insulin resistance.RESULTS-Smad3-knockout mice exhibited diminished adiposity with improved glucose tolerance and insulin sensitivity. Chromatin immunoprecipitation assay revealed that Smad3 deficiency increased CCAAT/enhancer-binding protein beta-C/EBP homologous protein 10 interaction and exerted a differential regulation on proliferator-activated receptor beta/delta and proliferator-activated receptor gamma expression in adipocytes. Focused gene expression profiling revealed an altered expression of genes involved in adipogenesis, lipid accumulation, and fatty acid beta-oxidation, indicative of altered adipose physiology. Despite reduced physical activity with no modification in food intake, these mutant mice were resistant to obesity and insulin resistance induced by a high-fat diet.CONCLUSIONS-Smad3 is a multifaceted regulator in adipose physiology and the pathogenesis of obesity and type 2 diabetes, suggesting that Smad3 may be a potential target for the treatment of obesity and its associated disorders.

Impact of standardised review of intravenous antibiotic therapy 72 hours after prescription in two internal medicine wards.

Post-prescription review of hospital antibiotic therapy may contribute to more appropriate use. We estimated the impact of a standardised review of intravenous antibiotic therapy three days after prescription in two internal medicine wards of a university hospital. In one ward, we assessed the charts of patients under intravenous antibiotic therapy using a standardised review process and provided feedback to the prescriber. There was no intervention in the other ward. After six months we crossed the allocation between the two wards. In all, 204 courses of antibiotic therapy were included in the intervention periods and 226 in the control periods. Post-prescription review led to proposals for modification in 46% of antibiotic courses. Time to treatment modification was 22% shorter in the intervention periods compared with the control periods (3.9+/-5.2 days vs 5.0+/-6.0 days, P=0.007). Patients included in the intervention group had lower antibiotic consumption than patients in the control group, but the intervention had no significant impact on the overall antibiotic consumption of the two wards.

Modified Corneal Collagen Crosslinking (CXL) Reduces Corneal Edema and Diurnal Visual Fluctuations in Fuchs' Dystrophy

Purpose: Crosslinking of corneal collagen with riboflavin and ultraviolet-A irradiation (CXL) induces crosslinks within and between collagen fibers. CXL increases corneal biomechanical and biochemical stability and is currently used clinically to treat keratectasia. CXL also significantly reduces the stromal swelling capacity. We investigated whether a modified CXL treatment protocol would be beneficial in early Fuchs' dystrophy with various degrees of corneal edema and diurnal variations in visual acuity. Methods: CXL was performed as published previously with the following modification: in cases where the stroma was thicker than 450 µm after abrasion and 30 minutes of instillation of isoosmolar riboflavin solution, glycerol 70% solution was applied every 5 seconds for two minutes, and central corneal thickness (CCT) was measured using ultrasound pachymetry. Glycerol 70% solution was administered repeatedly until the target corneal thickness of 370-430 µm was reached. During irradiation, CCT was monitored by ultrasound pachymetry every five minutes and glycerol 70% solution was applied, if necessary. Results: Three eyes in two patients were treated using the modified CXL protocol. Representative case: a 50-year-old woman with Fuchs' dystrophy and a history of 3 years of diurnal visual fluctuations was referred to us in March 2008. Preoperative best spectacle-corrected visual acuity (BSCVA) was 20/50. We performed modified CXL in the left eye. At one month after CXL, Scheimpflug analysis of CCT showed a reduction of more than 100 µm, and the Corneal Thickness Spatial Profile (CTSP) and Percentage of Increase in Thickness (PIT) showed a regularization of the "flattening" typical for Fuchs' dystrophy. Accordingly, diurnal analysis of corneal thickness showed a distinct postoperative reduction in CCT at all time points measured. At one month after CXL, the patient reported a reduction of diurnal visual fluctuations and we measured an increase in BSCVA to 20/32. The patient showed stable topographical and visual acuity at the three months follow-up. Conclusions: We saw a distinct reduction in CCT, an improvement of the corneal thickness spatial profile (CTSP) and an increase in BSCVA at one month after treatment, which remained stable at the three months follow-up. Patients with early Fuchs' dystrophy and disturbing diurnal visual fluctuations represent a novel application for CXL. Although CXL may not prevent the outcome of the dystrophy, it may increase the patients' visual comfort until keratoplasty becomes necessary.

Substrate metabolism, nutrient balance and obesity development in children and adolescents: a target for intervention?

Obesity results from the organism's inability to maintain energy balance over a long term. Childhood obesity and its related factors and pathological consequences tend to persist into adulthood. A cluster of factors, including high energy density in the diet (high fat intake), low energy expenditure, and disturbed substrate oxidation, favour the increase in fat mass. Oxidation of three major macronutrients and their roles in the regulation of energy balance, particularly in children and adolescents, are discussed. Total glucose oxidation is not different between obese and lean children; exogenous glucose utilization is higher whereas endogenous glucose utilization is lower in obese compared with lean children. Carbohydrate composition of the diet determines carbohydrate oxidation regardless of fat content of the diet. Both exogenous and endogenous fat oxidation are higher in obese than in lean subjects. The influence of high fat intake on accumulation of fat mass is operative rather over a long term. Several future directions are addressed, such that a combination of increased physical activity and modification in diet composition, in terms of energy density and glycemic index, is recommended for children and adolescents.

Rates of cultural change and patterns of cultural accumulation in stochastic models of social transmission.

Cultural variation in a population is affected by the rate of occurrence of cultural innovations, whether such innovations are preferred or eschewed, how they are transmitted between individuals in the population, and the size of the population. An innovation, such as a modification in an attribute of a handaxe, may be lost or may become a property of all handaxes, which we call "fixation of the innovation." Alternatively, several innovations may attain appreciable frequencies, in which case properties of the frequency distribution-for example, of handaxe measurements-is important. Here we apply the Moran model from the stochastic theory of population genetics to study the evolution of cultural innovations. We obtain the probability that an initially rare innovation becomes fixed, and the expected time this takes. When variation in cultural traits is due to recurrent innovation, copy error, and sampling from generation to generation, we describe properties of this variation, such as the level of heterogeneity expected in the population. For all of these, we determine the effect of the mode of social transmission: conformist, where there is a tendency for each naïve newborn to copy the most popular variant; pro-novelty bias, where the newborn prefers a specific variant if it exists among those it samples; one-to-many transmission, where the variant one individual carries is copied by all newborns while that individual remains alive. We compare our findings with those predicted by prevailing theories for rates of cultural change and the distribution of cultural variation.

Dietary supplementation with omega-3 in cystic fibrosis patients

Accumulation of neutr ophils releasing proteolytic enzymes and free radicals induceprogressive lung tissue destruction in CF. Among several hfflammatory mediatorsimplicated in this process, leukotriene B 4 (LTB4) product of arachidonic (AA;20:4n 6) omega 6 polytmsaturated fatty acid (PUFA) plays an important role.Various anti inflammatory strategies including dietary supplementation of omega 3PUFA, known to favor the synthesis of less active leukotriene B 5 (LTBs), have beeninvestigated. To further explore this nutritional approach, biological effects of anomega 3 PUFA oral supplementation (n 3 OS) were measured in 17 CF patients haa prospective, randomized, double blind, crossover study. CF patients (mean age:18 + 9 years, FEVI: 66 + 29 %) received a dietary supplementation enriched, or not,ha omega 3 PUFA during a 2 x 6 months period. A modification in neutrophilmembrane PUFA composition was observed under n 3 OS with an increase in EPA(20:5n 3) PUFA (from 0.66 ± 0.56 to 1.60 ± 0.61 ~tmol %, P< 0.01). The LTB jLTB 5ratio was decreased (from 72 + 27 to 24 + 7, P< 0.C~31), in CF patients taking n 3OS. However, n 3 OS supplementation did neither affect the internalization of bothIL 8 receptors following IL 8 exposure, nor IL 8 induced neutrophil chemotaxis.Our results show that n 3 PUFA are absorbed and incorporated in neutrophilmembrmae. The consecutive decrease ha LTBjLTB 5 ratio suggests that, ha theseconditions, neutr ophils may produce less toxic mediators from the AA pathway. Thepotential clinical benefit for CF patients still needs to be assessed with furtherstudies of longer duration and including more patients.

Effect of modafinil on subjective fatigue in multiple sclerosis and stroke patients.

BACKGROUND: Modafinil has anecdotal response to neurological fatigue, but such an effect may depend on the type and location of cerebral impairment. OBJECTIVES: It was the aim of this study to compare fatigue observed in different neurological pathologies, to evaluate the tolerability to modafinil, and to describe changes in subjective fatigue. METHODS: We enrolled 14 brainstem or diencephalic stroke (BDS) patients, 9 cortical stroke (CS) patients and 17 multiple sclerosis (MS) patients. The Fatigue Assessment Instrument severity scale was performed at baseline, after 3 months of modafinil and after 1 month of washout. Cognition, mood and somnolence were assessed. A subgroup of 14 patients underwent activity measures before and during treatment. RESULTS: Thirty-one patients completed the study (10 BDS, 9 CS, 12 MS). The responder profile is more frequent in MS than in CS (p = 0.04), and in BDS than in CS patients (p = 0.04). Actiwatch measures showed no changes in activity during, before and after therapy. CONCLUSION: Modafinil was tolerated in 75% of patients at small doses and seemed to improve the severity of fatigue in the MS and BDS groups but not in the CS group. There was no modification in measured physical activity.

Role of neutrophils in "Leishmania" infection

Résumé : Dans le modèle murin d'infection avec le parasite protozoaire Leishmania major (L. major), la souche de souris C57BL/6 est résistante a |'infection et développe une réponse protectrice Thelper (Th) 1. Inversement, les souris de la souche BALB/c développent une réponse Th2 et sont sensibles a cette infection. A la suite d'une infection avec ce parasite, les neutrophiles sont les premières cellules présentes au site d'infection et sont recrutées de manière égale dans les souches résistantes et sensibles à L. major, Néanmoins, trois jours après l'infection, la majorité des neutrophiles disparaissent du site d'infection chez les souris C57BL/6, tandis que ils restent jusqu'a dix jours chez les souris BALB/c. Un rôle crucial des neutrophiles a été démontré durant l'infection avec L. major. En effet, la déplétion de ces cellules avant |'infection dans les souris BALB/c, conduit a une réduction du développement des lésions, associée à une baisse de la charge parasitaire et a une modification de la réponse immunitaire vers une réponse Th1 dans des souris normalement sensibles a |'infection, suggérant un rôle immunorégulateur de ces neutrophiles durant les premiers jours de l'infection. Dans la première partie de cette thèse, nous avons étudié le rôle des neutrophiles suite à l'infection avec L. major. Nous avons démontré que le parasite induisait des phénotypes de neutrophiles distincts chez les souris résistantes ou sensibles à L. major. Suite à l'exposition au parasite, les neutrophiles de souris C57BL/6 ont montré une expression élevée des récepteurs Toll-like 2, 7 et 9 ainsi que la sécrétion d'lL-12p7O et d'lL-10, alors que ceux de souris BALB/c sécrétaient de l'IL-12p40 et du TGFB. Nous avons ensuite démontré qu'en réponse à L. major, au contraire des neutrophiles de BALB/c, les neutrophiles de souris résistantes C57BL/6, libéraient la chimiokine CCL3 attirant les cellules dendritiques. Le rôle crucial de cette chimiokine dans la migration de la première de vague de cellules dendritiques au site d'infection ainsi que son rôle dans le développement de la réponse immunitaire subséquente a été établi. Ces résultats démontrent que les neutrophiles, suite a |'infection avec le parasite L. major, créent un microenvironnement capable de déterminer le développement d'une réponse immunitaire spécifique a un antigène. Dans un second temps, nous nous sommes intéressés au rôle des neutrophiles suite a l'infection avec d'autres espèces de Leishmania: L, doriovani et L. mexicaria, agents responsables de leishmaniose viscérale et cutanée chronique respectivement. Un rôle crucial des neutrophiles a été démontré dans la réponse protectrice suite a l'infection avec L. donovani, l'absence de ces cellules amenant à une susceptibilité au parasite accrue, associée avec une induction préférentielle d'une réponse Th2. Inversement, la déplétion des neutrophiles lors de l'infection avec L. mexicaria aboutit a une résistance accrue, comme constaté par la baisse dela charge parasitaire, la hausse de la réponse Th1 ainsi la baisse de la réponse Th2 dans les souris déplétées en neutrophiles. Néanmoins, malgré le rôle délétère des neutrophiles sur le développement d'une réponse protectrice suite à |'infection avec L. mexicana, ces cellules sont nécessaires pour une résolution correcte dela réponse inflammatoire. En résumé, cette étude révèle un rôle majeur des neutrophiles lors de |'infection avec plusieurs especes de Leishmania. Résumé pour un large public : Les neutrophiles font partie de la famille des globules blancs. A la suite d'une infection, ces cellules sont les premières a être recrutées au site d'infection et sont impliquées dans |'élimination des pathogènes. Dans cette thèse, nous nous somme donc intéressés au rôle que pouvaient jouer ces neutrophiles durant l'infection avec le parasite protozoaire Leishmania major (L. major). Dans le modèle murin d'infection avec L. major, la majorité des souches de souris utilisées dans la recherche, dont les souris de la souche C57BL/6, développent de petites lésions qui guérissent spontanément après quelques semaines (souris résistantes). ll existe néanmoins, quelques souches de souris, dont la souche de souris BALB/c, qui développent des lésions qui ne guérissent pas (souris sensibles). Il a été observé que lors de l'lnfection avec ce parasites les neutrophiles étaient les premières cellules recrutées au site de l'lnfection dans toutes les souches de souris, toutefois trois jours après le début dela réaction immunitaire, la majorité des neutrophiles disparaissent chez les souris C57BL/6, tandis qu'ils restent jusqu'à dix jours chez les souris BALB/c. De plus, un rôle crucial des neutrophiles a été démontré durant l'infection avec L. major. En effet, l'absence de neutrophiles durant les trois premiers jours de l'infection chez les souris sensibles à |'infection, rend ces souris résistantes. Ces résultats suggèrent donc un rôle régulateur de la réponse immunitaire des neutrophiles durant les premiers jours de l'infection. Dans la première partie de cette thèse, nous avons étudié le rôle des neutrophiles suite à l'infection avec L. major. Nous avons donc analysé la sécrétion des cytokines, molécules essentielles qui déterminent la réponse immunitaire, par les neutrophiles. Nous avons démontré que le parasite induisait une sécrétion de cytokines différente entre les souris résistantes ou sensibles a L. major. Nous avons ensuite démontré que seule la souche de souris résistante sécrétait la chimiokine CCL3, connue pour être impliquée dans le recrutement de différentes cellules au site d'infecti0n, dont les cellules dendritiques. Les cellules dendritiques sont un élément fondamental pour un bon déroulement d'une réponse immunitaire, de par leur rôle décisif de liaison entre une réponse précoce non-spécifique au pathogène et une réponse plus tardive spécifique au pathogène et nécessaire pour |'élimination de dernier. Nous avons démontré que les neutrophiles de souris résistantes sécrétaient CCL3 et recrutaient les cellules dendritiques au site d'infecti0n, jouant de ce fait un rôle essentiel dans le développement de la réponse immunitaire. Ces résultats démontrent que les neutrophiles, suite à l'infection avec le parasite L. major, créent un microenvironnement capable de déterminer le développement d'une réponse immunitaire. Dans un second temps, nous nous sommes intéressés au rôle des neutrophiles suite à l'lnfection avec d'autres espèces de Leishmania, L. donovani et L. mexicana. Nous avons pu montrer un rôle crucial de ces cellules dans la réponse à ces deux parasites. En effet, suite à |'infection avec L. donovani, un rôle protecteur des neutrophiles a été observé, leur absence menant à une susceptibilité accrue aux parasites. Dans le cas de l'infection avec L. mexicana, une réduction de |'infection a été observée en absence de neutrophiles, avec néanmoins une augmentation de la lésion, suggérant un rôle important de ces cellules dans le développement de la réponse immunitaire ainsi que dans le contrôle de la réponse inflammatoire. En résumé, cette étude révèle un rôle majeur des neutrophiles lors de l'lnfection avec plusieurs membres de la famille Leishrnania. Summary : Upon infection with the protozoan parasite Leishmania major (L. major), C57BL/6 mice show a resistant phenotype, developing a protective Thelper (Th) 1 response. ln contrast, BALB/c mice develop a Th2 response and are susceptible to infection. Following inoculation with the parasite, neutrophils are the first cells migrating at the site of infection and are equally recruited in both L. major- resistant and susceptible mouse strains. However, after three days of infection, almost all neutrophils disappear from the site of infection in C57BL/6 mice, while they persist until ten days in BALB/c mice. Neutrophils were shown to play a crucial role during infection with L. major. indeed, depletion of these cells in BALB/c mice prior to infection with the parasite led to a lower Iesion development, associated with a lower parasite burden and a modification in the immune response towards a Th1 response in these otherwise susceptible mice, suggesting an immunomodulatory role for neutrophils during the first days of infection. ln the first part of this thesis, we were interested in better understanding the role of neutrophils in infection with L. major. \/\/e found that this parasite was inducing distinct neutrophil phenotypes in L. major-resistant and susceptible mice. Upon exposition with L. major, C57BL/6 neutrophils were reported to express high level of Toll-like receptors 2, 7, 9 mRNA and secrete IL-12p70 and IL-10, while BALB/c neutrophils secreted homodimers of IL-12p40, and TGFB. We then demonstrated that in response to L. major, neutrophils from L. major-resistant C57BL/6 mice release the CCL3 dendritic cell attracting chemokine, which is critical for the first wave of dendritic cell migration to the site of infection and in the development of the subsequent immune response. Altogether, these results demonstrated that upon infection with L. major, neutrophils create a microenvironment that can determine the development of an antigen-specific immune response. ln the second part of the thesis we were interested in understanding the role of neutrophils upon infection with of other species of Leishmania: L. donovani causing visceral leishmaniasis and L. mexicana, agent of chronic cutaneous leishmaniasis. Upon infection with L. donovani, neutrophils were found to play a crucial role in the early protective response, their absence leading to an increased susceptibility to the parasite, associated with the preferential induction of a Th2 response. ln contrast, depletion of these cells early in infection with L. mexicana was leading to an increased resistance, as observed by a decreased parasite burden, increased Th1 and decreased Th2 response in neutrophil-depleted mice. However, despite the deleterious role of neutrophils on the development of a protective immune response upon L. mexicana infection, these cells were required for the proper resolution of the inflammatory response. Altogether, these results highlight a major immunomodulatory role for neutrophils in infection with several species of Leishmania.

Bilan préopératoire en chirurgie viscérale [Preoperative assessment in visceral surgery]

The purpose of preoperative assessment is to evaluate the patient's health status, to address known or unidentified co-morbidities and to perform adequate complementary exams if necessary. On the other hand, it allows to prepare and protect the patient in order to reduce perioperative risk. The assessment consists of patient's history and physical examination, both focusing on cardiovascular and respiratory assessment. Complementary exams have to be chosen selectively depending on the patient's risk factors and the type of surgery. They are indicated if their result leads to a potential patient's benefit only, either by a modification in anesthetic and/or surgical management or by introduction of a pharmacological strategy, adequate and maximal if necessary, especially for cardioprotection.

Carbon-isotope stratigraphy and ammonite faunal turnover for the Middle Jurassic in the Southern Iberian palaeomargin

Variations in the stable carbon-isotope ratio of marine and continental sediments can reflect changes in sink and flux modifications of the palaeocarbon cycle. Here we report carbon-isotope compositions of Middle Jurassic marine carbonates from the Betic Cordillera (southern Spain), which represents an ideal region to link the stable carbon-isotope curves directly to ammonite zones and subzones, and thereby for the first time achieve an accurate chronostratigraphic calibration. The five sections studied represent basin and high swell deposits of the Southern Iberian palaeomargin. We find a similar delta C-13 of carbonates between different oceanic areas, suggesting a homogeneous carbon-isotope oceanic reservoir through the Middle Jurassic. The Aalenian-Bajocian transition is a critical period in ammonite evolution; hence the Early Jurassic fauna are replaced by new ammonite families which become dominant throughout the Middle and Late Jurassic. For this reason, we compared the delta C-13 values of carbonates with ammonite diversity and extinction rates at different taxonomical levels in order to explore the possible relationship between the carbon cycle and ammonite evolution. The carbon-isotope values of carbonates are not exactly linearly correlated with the extinction rate and ammonite diversity, but the main faunal turnovers follow minimum delta C-13 values, where extinct taxa are replaced by new ones. Likewise, radiation episodes are associated with increasing delta C-13 values and with transgressive sea-level rise. All these data support the idea that perturbations in the global carbon cycle reflect rapid palaeoenvironmental changes. We made detailed analyses of these faunal turnovers, using them as a proxy to identify major palaeoenvironmental crises in their ecosystems forced by modification in the carbon cycle. (c) 2006 Elsevier B.V All rights reserved.

Occasional adnominal idiom modification : a cognitive linguistic approach

abstract:occasional Adnominal Idiom Modification - A Cognitive Linguistic Approach From a cognitive-linguistic perspective, this paper explores alternative types of adnoniinal modification in occasional variants of English verbal idioms. Being discussed against data extracted from the British National Corpiis (BNC), the model claims that in idioni-production idiomatic constructions are activated as complex linguistic schemas to code a context-specific target-conceptualisation. Adnominal pre- and postmodifications are one specific form of creative alteration to adapt the idiom for this purpose. Semantically, idiom-interna1 NPextension is not a uniforni process. It is necessary to distinguish two systematic types of adnominal modification: external and internal modification (Ernst 1981). While external NPmodification has adverbial function, ¡.e. it modifies the idiom as a unit, internal modification directly applies to the head-noun and thus depends on the degree of motivation and analysability of a given idiom. Following the cognitive-linguistic framework, these dimensions of idiom-transparency result from the language user's ability to remotivate the bipartite semantic structure by conceptual metaphors and metonymies.

Multimodal MRI analysis of structural and functional networks in the human brain : application to two clinical studies : driving abilities under THC intoxication and early white matter changes in FXTAS

Les approches multimodales dans l'imagerie cérébrale non invasive sont de plus en plus considérées comme un outil indispensable pour la compréhension des différents aspects de la structure et de la fonction cérébrale. Grâce aux progrès des techniques d'acquisition des images de Resonance Magnetique et aux nouveaux outils pour le traitement des données, il est désormais possible de mesurer plusieurs paramètres sensibles aux différentes caractéristiques des tissues cérébraux. Ces progrès permettent, par exemple, d'étudier les substrats anatomiques qui sont à la base des processus cognitifs ou de discerner au niveau purement structurel les phénomènes dégénératifs et développementaux. Cette thèse met en évidence l'importance de l'utilisation d'une approche multimodale pour étudier les différents aspects de la dynamique cérébrale grâce à l'application de cette approche à deux études cliniques: l'évaluation structurelle et fonctionnelle des effets aigus du cannabis fumé chez des consommateurs réguliers et occasionnels, et l'évaluation de l'intégrité de la substance grise et blanche chez des jeunes porteurs de la prémutations du gène FMR1 à risque de développer le FXTAS (Fragile-X Tremor Ataxia Syndrome). Nous avons montré que chez les fumeurs occasionnels de cannabis, même à faible concentration du principal composant psychoactif (THC) dans le sang, la performance lors d'une tâche visuo-motrice est fortement diminuée, et qu'il y a des changements dans l'activité des trois réseaux cérébraux impliqués dans les processus cognitifs: le réseau de saillance, le réseau du contrôle exécutif, et le réseau actif par défaut (Default Mode). Les sujets ne sont pas en mesure de saisir les saillances dans l'environnement et de focaliser leur attention sur la tâche. L'augmentation de la réponse hémodynamique dans le cortex cingulaire antérieur suggère une augmentation de l'activité introspective. Une investigation des ef¬fets au niveau cérébral d'une exposition prolongée au cannabis, montre des changements persistants de la substance grise dans les régions associées à la mémoire et au traitement des émotions. Le niveau d'atrophie dans ces structures corrèle avec la consommation de cannabis au cours des trois mois précédant l'étude. Dans la deuxième étude, nous démontrons des altérations structurelles des décennies avant l'apparition du syndrome FXTAS chez des sujets jeunes, asymptomatiques, et porteurs de la prémutation du gène FMR1. Les modifications trouvées peuvent être liées à deux mécanismes différents. Les altérations dans le réseau moteur du cervelet et dans la fimbria de l'hippocampe, suggèrent un effet développemental de la prémutation. Elles incluent aussi une atrophie de la substance grise du lobule VI du cervelet et l'altération des propriétés tissulaires de la substance blanche des projections afférentes correspondantes aux pédoncules cérébelleux moyens. Les lésions diffuses de la substance blanche cérébrale peu¬vent être un marquer précoce du développement de la maladie, car elles sont liées à un phénomène dégénératif qui précède l'apparition des symptômes du FXTAS. - Multimodal brain imaging is becoming a leading tool for understanding different aspects of brain structure and function. Thanks to the advances in Magnetic Resonance imaging (MRI) acquisition schemes and data processing techniques, it is now possible to measure different parameters sensitive to different tissue characteristics. This allows for example to investigate anatomical substrates underlying cognitive processing, or to disentangle, at a pure structural level degeneration and developmental processes. This thesis highlights the importance of using a multimodal approach for investigating different aspects of brain dynamics by applying this approach to two clinical studies: functional and structural assessment of the acute effects of cannabis smoking in regular and occasional users, and grey and white matter assessment in young FMR1 premutation carriers at risk of developing FXTAS. We demonstrate that in occasional smokers cannabis smoking, even at low concentration of the main psychoactive component (THC) in the blood, strongly decrease subjects' performance on a visuo-motor tracking task, and globally alters the activity of the three brain networks involved in cognitive processing: the Salience, the Control Executive, and the Default Mode networks. Subjects are unable to capture saliences in the environment and to orient attention to the task; the increase in Hemodynamic Response in the Anterior Cingulate Cortex suggests an increase in self-oriented mental activity. A further investigation on long term exposure to cannabis, shows a persistent grey matter modification in brain regions associated with memory and affective processing. The degree of atrophy in these structures also correlates with the estimation of drug use in the three months prior the participation to the study. In the second study we demonstrate structural changes in young asymptomatic premutation carriers decades before the onset of FXTAS that might be related to two different mechanisms. Alteration of the cerebellar motor network and of the hippocampal fimbria/ fornix, may reflect a potential neurodevelopmental effect of the premutation. These include grey matter atrophy in lobule VI and modification of white matter tissue property in the corresponding afferent projections through the Middle Cerebellar Peduncles. Diffuse hemispheric white matter lesions that seem to appear closer to the onset of FXTAS and be related to a neurodegenerative phenomenon may mark the imminent onset of FXTAS.

Development of mavoglurant and its potential for the treatment of fragile X syndrome.

Introduction: Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. With no curative treatment available, current therapeutic approaches are aimed at symptom management. FXS is caused by silencing the FMR1 gene, which encodes FMRP; as loss of FMRP leads to the development of symptoms associated with FXS. Areas covered: In this evaluation, the authors examine the role of the metabotropic glutamate receptor 5 (mGluR5) in the pathophysiology of FXS, and its suitability as a target for rescuing the disease state. Furthermore, the authors review the evidence from preclinical studies of pharmacological interventions targeting mGluR5 in FXS. Lastly, the authors assess the findings from clinical studies in FXS, in particular the use of the Aberrant Behavior Checklist-Community Edition (ABC-C) and the recently developed ABC-C for FXS scale, as clinical endpoints to assess disease modification in this patient population. Expert opinion: There is cautious optimism for the successful treatment of the core behavioral and cognitive symptoms of FXS based on preclinical data in animal models and early studies in humans. However, the association between mGluR5-heightened responsiveness and the clinical phenotype in humans remains to be demonstrated. Many questions regarding the optimal treatment and outcome measures of FXS remain unanswered.