Claire Thalamas

Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial

BACKGROUND Hemiplegia and hemiparesis are the most common deficits caused by stroke. A few small clinical trials suggest that fluoxetine enhances motor recovery but its clinical efficacy is unknown. We therefore aimed to investigate whether fluoxetine would enhance motor recovery if given soon after an ischaemic stroke to patients who have motor deficits. METHODS In this double-blind, placebo-controlled trial, patients from nine stroke centres in France who had ischaemic stroke and hemiplegia or hemiparesis, had Fugl-Meyer motor scale (FMMS) scores of 55 or less, and were aged between 18 years and 85 years were eligible for inclusion. Patients were randomly assigned, using a computer random-number generator, in a 1:1 ratio to fluoxetine (20 mg once per day, orally) or placebo for 3 months starting 5-10 days after the onset of stroke. All patients had physiotherapy. The primary outcome measure was the change on the FMMS between day 0 and day 90 after the start of the study drug. Participants, carers, and physicians assessing the outcome were masked to group assignment. Analysis was of all patients for whom data were available (full analysis set). This trial is registered with ClinicalTrials.gov, number NCT00657163. FINDINGS 118 patients were randomly assigned to fluoxetine (n=59) or placebo (n=59), and 113 were included in the analysis (57 in the fluoxetine group and 56 in the placebo group). Two patients died before day 90 and three withdrew from the study. FMMS improvement at day 90 was significantly greater in the fluoxetine group (adjusted mean 34·0 points [95% CI 29·7-38·4]) than in the placebo group (24·3 points [19·9-28·7]; p=0·003). The main adverse events in the fluoxetine and placebo groups were hyponatraemia (two [4%] vs two [4%]), transient digestive disorders including nausea, diarrhoea, and abdominal pain (14 [25%] vs six [11%]), hepatic enzyme disorders (five [9%] vs ten [18%]), psychiatric disorders (three [5%] vs four [7%]), insomnia (19 [33%] vs 20 [36%]), and partial seizure (one [<1%] vs 0). INTERPRETATION In patients with ischaemic stroke and moderate to severe motor deficit, the early prescription of fluoxetine with physiotherapy enhanced motor recovery after 3 months. Modulation of spontaneous brain plasticity by drugs is a promising pathway for treatment of patients with ischaemic stroke and moderate to severe motor deficit. FUNDING Public French National Programme for Clinical Research.

Partial Inhibition of Adipose Tissue Lipolysis Improves Glucose Metabolism and Insulin Sensitivity Without Alteration of Fat Mass

Partial inhibition of adipose tissue lipolysis does not increase fat mass but improves glucose metabolism and insulin sensitivity through modulation of fatty acid turnover and induction of fat cell de novo lipogenesis.

Enhanced Glucose Metabolism Is Preserved in Cultured Primary Myotubes From Obese Donors in Response to Exercise Training

CONTEXT It was suggested that human cultured primary myotubes retain the metabolic characteristics of their donor in vitro. OBJECTIVES The aim of the present study was to investigate whether the metabolic responses to endurance training are also conserved in culture. DESIGN AND VOLUNTEERS Middle-aged obese subjects completed an 8-week supervised aerobic exercise training program in which vastus lateralis muscle biopsies were collected before and after training. MAIN OUTCOME MEASURES Anthropometric and blood parameters, as well as aerobic capacity, were assessed before and after training. Muscle biopsies were either used for Western blot analysis or digested to harvest myogenic progenitors that were differentiated into myotubes. Glucose oxidation, palmitate oxidation, and glycogen synthesis assays were performed on myotubes before and after training. Gene expression was assessed by real-time quantitative PCR. RESULTS Our data indicate that in parallel of in vivo improvement of whole-body aerobic capacity and glucose metabolism, biopsy-derived primary myotubes showed similar patterns in vitro. Indeed, glucose oxidation, glycogen synthesis, and inhibition of palmitate oxidation by glucose were enhanced in myotubes after training. This was associated with consistent changes in the expression of metabolism-linked genes such as GLUT1, PDK4, and PDHA1. Interestingly, no difference in myogenic differentiation capacity was observed before and after training. CONCLUSION Aerobic exercise training is associated with metabolic adaptations in vivo that are preserved in human cultured primary myotubes. It can be hypothesized that skeletal muscle microenvironmental changes induced by endurance training lead to metabolic imprinting on myogenic progenitor cells.

Borderline personality disorder and rTMS: A pilot trial

A randomized, controlled study was carried out to assess the effect of a series of 10 sessions of high-frequency rTMS to the right DLPFC in 10 Borderline Personality Disorder patients. Patients in the rTMS group showed improvements in anger, affective instability (Borderline Personality Disorder Severity Index) and planning (Tower Of London). Two smoking cessations were observed.

CD36 is a Marker of Human Adipocyte Progenitors with Pronounced Adipogenic and Triglyceride Accumulation Potential

White adipose tissue (WAT) expands in part through adipogenesis, a process involving fat cell generation and fatty acid (FA) storage into triglycerides (TGs). Several findings suggest that inter‐individual and regional variations in adipogenesis are linked to metabolic complications. We aimed to identify cellular markers that define human adipocyte progenitors (APs) with pronounced adipogenic/TG storage ability. Using an unbiased single cell screen of passaged human adipose‐derived stromal cells (hADSCs), we identified cell clones with similar proliferation rates but discordant capabilities to undergo adipogenic differentiation. Transcriptomic analyses prior to induction of differentiation showed that adipogenic clones displayed a significantly higher expression of CD36, encoding the scavenger receptor CD36. CD36+ hADSCs, in comparison with CD36‐cells, displayed almost complete adipogenic differentiation while CD36 RNAi attenuated lipid accumulation. Similar findings were observed in primary CD45‐/CD34+/CD31‐APs isolated from human WAT where the subpopulation of MSCA1+/CD36+ cells displayed a significantly higher differentiation degree/TG storage capacity than MSCA1+/CD36‐cells. Functional analyses in vitro and ex vivo confirmed that CD36 conferred APs an increased capacity to take up FAs thereby facilitating terminal differentiation. Among primary APs from subcutaneous femoral, abdominal and visceral human WAT, the fraction of CD36+ cells was significantly higher in depots associated with higher adipogenesis and reduced metabolic risk (i.e., femoral WAT). We conclude that CD36 marks APs with pronounced adipogenic potential, most probably by facilitating lipid uptake. This may be of value in developing human adipocyte cell clones and possibly in linking regional variations in adipogenesis to metabolic phenotype. Stem Cells 2017;35:1799–1814

Apelin administration improves insulin sensitivity in overweight men during hyperinsulinaemic-euglycaemic clamp

Apelin is a recently identified adipokine known to improve glucose tolerance and insulin sensitivity in murine models. This study was dedicated to the proof of concept that apelin administration also enhances insulin sensitivity in humans.

Phase 1 dose-escalation study of oral abexinostat for the treatment of patients with relapsed/refractory higher-risk myelodysplastic syndromes, acute myeloid leukemia, or acute lymphoblastic leukemia

Abstract Histone deacetylase (HDAC) inhibitor abexinostat is under investigation for the treatment of various cancers. Epigenetic changes including aberrant HDAC activity are associated with cancers, including myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL). In this phase 1 dose-escalation study, 17 patients with relapsed/refractory higher-risk MDS, AML, or ALL received oral abexinostat (60, 80 [starting dose], 100, or 120 mg) twice daily (bid) on Days 1–14 of 21-day cycles. The most common treatment-related grade ≥3 adverse events were thrombocytopenia (29%) and neutropenia (24%), none of which led to discontinuation. Maximum-tolerated dose was not reached. Of 12 evaluable patients, best response was stable disease in 1 patient. This study was closed due to limited clinical benefit. Future development of oral abexinostat 100 mg bid in patients with MDS, AML, or ALL should focus on combination regimens. ISRCTN registry: 99680465

A 15-day course of donepezil modulates spectral EEG dynamics related to target auditory stimuli in young, healthy adult volunteers

OBJECTIVE To identify possible electroencephalographic (EEG) markers of donepezils effect on cortical activity in young, healthy adult volunteers at the group level. METHODS Thirty subjects were administered a daily dose of either 5mg donepezil or placebo for 15days in a double-blind, randomized, cross-over trial. The electroencephalogram during an auditory oddball paradigm was recorded from 58 scalp electrodes. Current source density (CSD) transformations were applied to EEG epochs. The event-related potential (ERP), inter-trial coherence (ITC: the phase consistency of the EEG spectrum) and event-related spectral perturbation (ERSP: the EEG power spectrum relative to the baseline) were calculated for the target (oddball) stimuli. RESULTS The donepezil and placebo conditions differed in terms of the changes in delta/theta/alpha/beta ITC and ERSP in various regions of the scalp (especially the frontal electrodes) but not in terms of latency and amplitude of the P300-ERP component. CONCLUSION Our results suggest that ITC and ERSP analyses can provide EEG markers of donepezils effects in young, healthy, adult volunteers at a group level. SIGNIFICANCE Novel EEG markers could be useful to assess the therapeutic potential of drug candidates in Alzheimers disease in healthy volunteers prior to the initiation of Phase II/III clinical studies in patients.

Assessment of Translocator Protein Density, as Marker of Neuroinflammation, in Major Depressive Disorder: A Pilot, Multicenter, Comparative, Controlled, Brain PET Study (INFLADEP Study)

Background: Major depressive disorder (MDD) is a serious public health problem with high lifetime prevalence (4.4–20%) in the general population. The monoamine hypothesis is the most widespread etiological theory of MDD. Also, recent scientific data has emphasized the importance of immuno-inflammatory pathways in the pathophysiology of MDD. The lack of data on the magnitude of brain neuroinflammation in MDD is the main limitation of this inflammatory hypothesis. Our team has previously demonstrated the relevance of [18F] DPA-714 as a neuroinflammation biomarker in humans. We formulated the following hypotheses for the current study: (i) Neuroinflammation in MDD can be measured by [18F] DPA-714; (ii) its levels are associated with clinical severity; (iii) it is accompanied by anatomical and functional alterations within the frontal-subcortical circuits; (iv) it is a marker of treatment resistance. Methods: Depressed patients will be recruited throughout 4 centers (Bordeaux, Montpellier, Tours, and Toulouse) of the French network from 13 expert centers for resistant depression. The patient population will be divided into 3 groups: (i) experimental group—patients with current MDD (n = 20), (ii) remitted depressed group—patients in remission but still being treated (n = 20); and, (iii) control group without any history of MDD (n = 20). The primary objective will be to compare PET data (i.e., distribution pattern of neuroinflammation) between the currently depressed group and the control group. Secondary objectives will be to: (i) compare neuroinflammation across groups (currently depressed group vs. remitted depressed group vs. control group); (ii) correlate neuroinflammation with clinical severity across groups; (iii) correlate neuroinflammation with MRI parameters for structural and functional integrity across groups; (iv) correlate neuroinflammation and peripheral markers of inflammation across groups. Discussion: This study will assess the effects of antidepressants on neuroinflammation as well as its role in the treatment response. It will contribute to clarify the putative relationships between neuroinflammation quantified by brain neuroimaging techniques and peripheral markers of inflammation. Lastly, it is expected to open innovative and promising therapeutic perspectives based on anti-inflammatory strategies for the management of treatment-resistant forms of MDD commonly seen in clinical practice. Clinical trial registration (reference: NCT03314155): https://www.clinicaltrials.gov/ct2/show/NCT03314155?term=neuroinflammation&cond=depression&cntry=FR&rank=1

P034 - Gender differences in lipolysis-regulating mechanismsduring exercise in overweight subjects

Le rôle du métabolisme des acides gras libres (AGL) dans le comportement alimentaire est mal connu. Il a été montré que les inhibiteurs de l’oxydation lipidique augmentent la prise alimentaire. Nous avons étudié i) si une intervention pharmacologique sur le métabolisme des AGL modifiait le comportement alimentaire spontané chez l’homme et ii) les mécanismes biologiques sous-jacents. Un inhibiteur partiel de l’oxydation des AGL (Etomoxir, ETO, 320 mg), un inhibiteur partiel de la lipogenèse et activateur indirect de l’oxydation des AGL (Hydroxycitrate HCA, 4 g) et un placebo (PLA) ont été administrés à 7 jours d’intervalle à 9 jeunes sujets masculins normo pondéraux. La séquence prandiale spontanée était recréée et un prélèvement sanguin continu effectué [1]. Les quantités consommées au petit déjeuner et au déjeuner étaient déterminées lors de la 1ère session et servies aux autres, le dîner servi en quantité excédentaire à la demande des sujets. Les concentrations plasmatiques de glucose, insuline, AGL, lactate, b-hydroxy-butyrate (BHB), leptine et ghréline étaient mesurées. Sur le plan comportemental, la durée de satiété entre le déjeuner et le dîner était plus longue dans la condition HCA que PLA (+ 77 ± 20 min, P = 0,01) mais non modifiée dans la condition ETO. L’aire sous courbe (ASC) des scores de faim était plus faible dans la condition HCA que PLA (P < 0,005) et ETO (P < 0,05). Les prises énergétiques au dîner ne différaient pas. Sur le plan biologique, l’ASC des BHB plasmatiques était plus faible et celle des AGL plus élevée dans la condition ETO que PLA (respectivement P = 0,01 et P < 0,05), du à l’inhibition de l’oxydation des AGL. Les ASC de glucose, triglycérides, leptine et ghréline plasmatiques étaient plus élevées dans la condition HCA que PLA (P < 0,05) du fait de l’augmentation de la durée de satiété. Ces résultats montrent que l’inhibition partielle de la lipogenèse augmente la satiété mais ne permettent pas d’affirmer un rôle de l’inhibition de l’oxydation des AGL. P033 CALORIMÉTRIE D’EFFORT CHEZ DES TÉMOINS ET DES OBÈSES AVEC OU SANS DIABÈTE : LES PALIERS COURTS DE 3 MIN SOUS-ESTIMENT L’OXYDATION LIPIDIQUE ET SURESTIMENT L’OXYDATION GLUCIDIQUE