Synaptic plasticity through a naturalistic lens

From the myriad of studies on neuronal plasticity, investigating its underlying molecular mechanisms up to its behavioral relevance, a very complex landscape has emerged. Recent efforts have been achieved toward more naturalistic investigations as an attempt to better capture the synaptic plasticity underpinning of learning and memory, which has been fostered by the development of in vivo electrophysiological and imaging tools. In this review, we examine these naturalistic investigations, by devoting a first part to synaptic plasticity rules issued from naturalistic in vivo-like activity patterns. We next give an overview of the novel tools, which enable an increased spatio-temporal specificity for detecting and manipulating plasticity expressed at individual spines up to neuronal circuit level during behavior. Finally, we put particular emphasis on works considering brain-body communication loops and macroscale contributors to synaptic plasticity, such as body internal states and brain energy metabolism

The complex viscosity of Möbius macromolecules

Using general rigid bead–rod theory, we explore the effect of twisting a macromolecule on its rheological properties in suspensions. We thus focus on macromolecules having the form of Möbius bands so that the number of twists can be incremented. We call these Möbius macromolecules. When represented in general rigid bead–rod theory, these macromolecules comprise beads whose centers all fall on a Möbius band. From first principles, we calculate the complex viscosity of twisted rings with zero to seven twists. We find that the zero-shear values of the viscosity and first normal stress coefficient increase with twisting. Furthermore, we find that the real part of the complex viscosity descends more rapidly, with frequency, with extent of twist. For the imaginary part of the complex viscosity, the more twisted, the higher the peak. For each part of the dimensionless complex viscosity and the first normal stress coefficient, the results fall on one of just three curves corresponding to zero, even, or odd numbers of twists. We also explore the effects of the length and the aspect ratio of twisted macromolecular suspensions. We close with a worked example for a suspension of triply twisted Möbius annulene

Comparison between periarticular infiltration, pericapsular nerve group and suprainguinal fascia iliaca blocks on postoperative functional recovery in total hip arthroplasty: preliminary results from a randomized controlled clinical study

peer reviewe

Effect of preoperative warming on intraoperative hypothermia and postoperative functional recovery in total hip arthroplasty: a randomized clinical trial

peer reviewe

Masitinib as an adjunct therapy for mild-to-moderate Alzheimer's disease: a randomised, placebo-controlled phase 2 trial

International audienceIntroductionNeuroinflammation is thought to be important in Alzheimer's disease pathogenesis. Mast cells are a key component of the inflammatory network and participate in the regulation of the blood-brain barrier's permeability. Masitinib, a selective oral tyrosine kinase inhibitor, effectively inhibits the survival, migration and activity of mast cells. As the brain is rich in mast cells, the therapeutic potential of masitinib as an adjunct therapy to standard care was investigated.MethodsA randomised, placebo-controlled, phase 2 study was performed in patients with mild-to-moderate Alzheimer's disease, receiving masitinib as an adjunct to cholinesterase inhibitor and/or memantine. Patients were randomly assigned to receive masitinib (n = 26) (starting dose of 3 or 6 mg/kg/day) or placebo (n = 8), administered twice daily for 24 weeks. The primary endpoint was change from baseline in the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-Cog) to assess cognitive function and the related patient response rate.ResultsThe rate of clinically relevant cognitive decline according to the ADAS-Cog response (increase >4 points) after 12 and 24 weeks was significantly lower with masitinib adjunctive treatment compared with placebo (6% vs. 50% for both time points; P = 0.040 and P = 0.046, respectively). Moreover, whilst the placebo treatment arm showed worsening mean ADAS-Cog, Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory, and Mini-Mental State Examination scores, the masitinib treatment arm reported improvements, with statistical significance between treatment arms at week 12 and/or week 24 (respectively, P = 0.016 and 0.030; P = 0.035 and 0.128; and P = 0.047 and 0.031). The mean treatment effect according to change in ADAS-Cog score relative to baseline at weeks 12 and 24 was 6.8 and 7.6, respectively. Adverse events occurred more frequently with masitinib treatment (65% vs. 38% of patients); however, the majority of events were of mild or moderate intensity and transitory. Severe adverse events occurred at a similar frequency in the masitinib and placebo arms (15% vs. 13% of patients, respectively). Masitinib-associated events included gastrointestinal disorders, oedema, and rash.ConclusionsMasitinib administered as add-on therapy to standard care during 24 weeks was associated with slower cognitive decline in Alzheimer's disease, with an acceptable tolerance profile. Masitinib may therefore represent an innovative avenue of treatment in Alzheimer's disease. This trial provides evidence that may support a larger placebo-controlled investigation.Trial registrationClinicaltrials.gov NCT0097611

Muscle RANK is a key regulator of calcium storage, SERCA activity, and function of fast-twitch skeletal muscles

Receptor-activator of nuclear factor kB (RANK), its ligand RANKL and the soluble decoy receptor osteoprotegerin (OPG)are the key regulators of osteoclast differentiation and bone remodeling. Here we show that RANK is also expressed in fully differentiated myotubes and skeletal muscle. Muscle RANK deletion (RANKmko) has inotropic effects in denervated, but not in sham, extensor digitorum longus (EDL) muscle preventing the loss of maximum specific force while promoting muscle atrophy, fatigability and increased proportion of fast-twitch fibers. In denervated EDL muscles, RANK deletion markedly increased stromal interaction molecule 1 (Stim1) content, a calcium sensor, and altered activity of the sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) modulating Ca2+ storage. Muscle RANK deletion had no significant effects on the sham or denervated slow-twitch soleus (Sol) muscles. These data identify a novel role for RANK as a key regulator of calcium storage and SERCA activity, ultimately affecting denervated skeletal muscle function

Results of successive EORTC-CLG 58 881 and 58 951 trials in paediatric T-cell acute lymphoblastic leukaemia (ALL)

Outcomes in childhood T-cell acute lymphoblastic leukaemia (T-ALL) are steadily improving due to intensive therapy. Between 1989 and 2008, 599 children with newly diagnosed T-ALL were enrolled in two successive European Organization for Research and Treatment of Cancer - Children's Leukaemia Group trials (58881 and 58951), both based on the Berlin-Frankfurt-Munster protocol and without cranial irradiation. In the latter trial induction chemotherapy was intensified. The most important randomizations were Medac Escherichia coli asparaginase versus Erwinia asparaginase in trial 58881, and dexamethasone (6 mg/m(2)/day) versus prednisolone (60 mg/m(2)/day) and prolonged versus conventional asparaginase duration in trial 58951. 8-year event-free survival (EFS) increased from 65 center dot 1% to 74 center dot 0% in trial 58951. Improvement was most profound for patients with white blood cell (WBC) counts E. coli asparaginase was associated with longer EFS [hazard ratio (HR) 0 center dot 54, P = 0 center dot 0015] and overall survival (HR 0 center dot 51, P = 0 center dot 0018). Induction therapy with dexamethasone did not improve EFS compared to prednisolone. Remarkably, intensification of central nervous system (CNS)-directed therapy in trial 58951 resulted in fewer bone marrow relapses, while the incidence of CNS relapses remained low. In summary, we showed that adequate asparaginase therapy, intensified induction treatment and intensification of CNS-directed chemotherapy can result in an improvement of outcome in T-ALL patients with good prephase response and initial WBC counts <100 x 10(9)/l, representing approximately 50% of T-ALL patients