L'impératif en français et en anglais contemporains

As a deontic mode of enunciation, the imperative excludes any operation which implies a certain degree of agreement between speaker and addressee - presupposition, referential construction, etc. In order to make up for this fundamental disjunction, the speaker resorts to a range of compensatory devices such as the use of person desinences, the ethical dative, the position of clitic pronouns or the function of the first person plural. Yet an imperative utterance is also related to the declarative context in which it occurs, and this sometimes causes co-locution to give way to co-enunciation - witness the problem of negative imperatives, or markers of discourse consistency such as voyons in French. This twofold theoretical approach is here presented as applying to the French language, and then put to the test of the English language

Exome Sequencing in Suspected Monogenic Dyslipidemias

Abstract BACKGROUND: -Exome sequencing is a promising tool for gene mapping in Mendelian disorders. We utilized this technique in an attempt to identify novel genes underlying monogenic dyslipidemias. METHODS AND RESULTS: -We performed exome sequencing on 213 selected family members from 41 kindreds with suspected Mendelian inheritance of extreme levels of low-density lipoprotein (LDL) cholesterol (after candidate gene sequencing excluded known genetic causes for high LDL cholesterol families) or high-density lipoprotein (HDL) cholesterol. We used standard analytic approaches to identify candidate variants and also assigned a polygenic score to each individual in order to account for their burden of common genetic variants known to influence lipid levels. In nine families, we identified likely pathogenic variants in known lipid genes (ABCA1, APOB, APOE, LDLR, LIPA, and PCSK9); however, we were unable to identify obvious genetic etiologies in the remaining 32 families despite follow-up analyses. We identified three factors that limited novel gene discovery: (1) imperfect sequencing coverage across the exome hid potentially causal variants; (2) large numbers of shared rare alleles within families obfuscated causal variant identification; and (3) individuals from 15% of families carried a significant burden of common lipid-related alleles, suggesting complex inheritance can masquerade as monogenic disease. CONCLUSIONS: -We identified the genetic basis of disease in nine of 41 families; however, none of these represented novel gene discoveries. Our results highlight the promise and limitations of exome sequencing as a discovery technique in suspected monogenic dyslipidemias. Considering the confounders identified may inform the design of future exome sequencing studies

Cannabis use disorder: from neurobiology to treatment.

Cannabis has been legalized for medical and recreational purposes in multiple countries. A large number of people are using cannabis and some will develop cannabis use disorder (CUD). There is a growing recognition that CUD requires specific interventions. This Review will cover this topic from a variety of perspectives, with a particular emphasis on neurobiological findings and innovative treatment approaches that are being pursued. We will first describe the epidemiology and burden of disease of CUD, including risk factors associated with CUD (both in terms of general risk and genetic risk variants). Neurobiological alterations identified in brain imaging studies will be presented. Several psychosocial interventions that are useful for the management of CUD, including motivational enhancement therapy, behavioral and cognitive therapy, and contingency management, will be covered. Although no pharmacological interventions are yet approved for CUD, we present the most promising pharmacological interventions being tested

Salience network and parahippocampal dopamine dysfunction in memory-impaired Parkinson disease

Objective: Patients with Parkinson disease (PD) and mild cognitive impairment (MCI) are vulnerable to dementia and frequently experience memory deficits. This could be the result of dopamine dysfunction in corticostriatal networks (salience, central executive networks, and striatum) and/or the medial temporal lobe. Our aim was to investigate whether dopamine dysfunction in these regions contributes to memory impairment in PD. Methods: We used positron emission tomography imaging to compare D2 receptor availability in the cortex and striatal (limbic and associative) dopamine neuron integrity in 4 groups: memory‐impaired PD (amnestic MCI; n = 9), PD with nonamnestic MCI (n = 10), PD without MCI (n = 11), and healthy controls (n = 14). Subjects were administered a full neuropsychological test battery for cognitive performance. Results: Memory‐impaired patients demonstrated more significant reductions in D2 receptor binding in the salience network (insular cortex and anterior cingulate cortex [ACC] and the right parahippocampal gyrus [PHG]) compared to healthy controls and patients with no MCI. They also presented reductions in the right insula and right ACC compared to nonamnestic MCI patients. D2 levels were correlated with memory performance in the right PHG and left insula of amnestic patients and with executive performance in the bilateral insula and left ACC of all MCI patients. Associative striatal dopamine denervation was significant in all PD patients. Interpretation: Dopaminergic differences in the salience network and the medial temporal lobe contribute to memory impairment in PD. Furthermore, these findings indicate the vulnerability of the salience network in PD and its potential role in memory and executive dysfunction

Are we optimizing medical students’ preparation for clerkship? A content analysis of narrative comments on clinical skills during preclinical training

Introduction: The progression from preclinical medical training to clerkship is a pivotal yet steep transition for medical students. Effective feedback on clinical skills during preclinical training can better equip students for clerkship and allows time for them to address difficulties promptly. The goal of this study was to explore whether and how narrative comments at this stage were being leveraged to achieve this transition. Methods: We conducted a content analysis to categorize narrative comments on the clinical skills of two cohorts of third-year preclinical students at one academic institution. Results: Teachers made narrative comments for 272 students. Each comment was divided into analysis units (n = 1,314 units). Comments were either general (n = 187) or focused on attitude (n = 628), knowledge and cognitive processes (n = 357), or clinical reasoning (n = 142). They were abundantly positive (n = 1,190) and marginally negative (n = 39). Few (6%) contained suggestions for improvement. Discussion: In this study, narrative comments on clinical skills before clerkship seemed minimally helpful, as they were overwhelmingly positive and seldom offered suggestions.  This could suggest missed opportunities for early interventions. Pre-clerkship narrative comments could potentially be optimized by increasing emphasis on clinical reasoning, addressing challenges early and providing actionable steps for improvement

Exploring brain glutathione and peripheral blood markers in posttraumatic stress disorder: a combined [1H]MRS and peripheral blood study

IntroductionOxidative stress has been implicated in psychiatric disorders, including posttraumatic stress disorder (PTSD). Currently, the status of glutathione (GSH), the brain's most abundant antioxidant, in PTSD remains uncertain. Therefore, the current study investigated brain concentrations of GSH and peripheral concentrations of blood markers in individuals with PTSD vs. Healthy Controls (HC).MethodsGSH spectra was acquired in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) using MEGA-PRESS, a J-difference-editing acquisition method. Peripheral blood samples were analyzed for concentrations of metalloproteinase (MMP)-9, tissue inhibitors of MMP (TIMP)-1,2, and myeloperoxidase (MPO).ResultsThere was no difference in GSH between PTSD and HC in the ACC (n = 30 PTSD, n = 20 HC) or DLPFC (n = 14 PTSD, n = 18 HC). There were no group differences between peripheral blood markers (P > 0.3) except for (non-significantly) lower TIMP-2 in PTSD. Additionally, TIMP-2 and GSH in the ACC were positively related in those with PTSD. Finally, MPO and MMP-9 were negatively associated with duration of PTSD.ConclusionsWe do not report altered GSH concentrations in the ACC or DLPFC in PTSD, however, systemic MMPs and MPO might be implicated in central processes and progression of PTSD. Future research should investigate these relationships in larger sample sizes

Effects of FAAH Inhibition on Corticosterone Release: A Systematic Review of Preclinical Studies

Anxiety disorders are one of the most common mental health conditions experienced world-wide. Unfortunately, currently available pharmacological treatments are associated with many side-effects and as many as 40% of individuals prescribed pharmacological interventions to treat anxiety do not experience symptom relief, necessitating new interventions. Fatty Acid Amide Hydrolase (FAAH) a major metabolizing enzyme of the endocannabinoid neurotransmitter anandamide (AEA) has been investigated as a therapeutic target of interest. Specifically, inhibition of FAAH has been shown to reduce anxious behaviours in animal models of anxiety. The endocannabinoid system and FAAH has also been reported to interact with the Hypothalamic Pituitary Adrenal (HPA) Axis, but not much is known regarding the effects of FAAH inhibition on the output of HPA axis stimulation, glucocorticoids. This review aims to investigate the effects of pharmacological inhibition of FAAH on the levels of the glucocorticoid, corticosterone, in pre-clinical literature