Interplay between neuromodulator-induced switching of short-term plasticity at sensorimotor synapses in the neonatal rat spinal cord

In the present study, we investigated the modulation of short-term depression (STD) at synapses between sensory afferents and rat motoneurons by serotonin, dopamine and noradrenaline. STD was elicited with trains of 15 stimuli at 1, 5 and 10 Hz and investigated using whole-cell voltage-clamp recordings from identified motoneurons in the neonatal rat spinal cord in vitro . STD was differentially modulated by the amines. Dopamine was effective at all stimulation frequencies, whereas serotonin affected STD only during 5 and 10 Hz stimulus trains and noradrenaline during 1 and 5 Hz trains. Dopamine and serotonin homogenized the degree of depression observed with the different stimulation modalities, in contrast to noradrenaline, which amplified the rate differences. The different modulatory profiles observed with the amines were partly due to GABAergic interneuron activity. In the presence of GABA_A and GABA_B receptor antagonists, the rate and/or kinetics of STD did not vary with the stimulation frequency in contrast to the control condition, and noradrenaline failed to alter either synaptic amplitude or STD, suggesting indirect actions. Dopamine and serotonin strongly decreased STD and converted depression to facilitation at 5 and 10 Hz during the blockade of the GABAergic receptors in 50% of the neurons tested. Altogether, these results show that STD expressed at sensorimotor synapses in the neonatal rat not only is a function of the frequency of afferent firing but also closely depends on the neuromodulatory state of these connections, with a major contribution from GABAergic transmission.     

Repeated KI Prophylaxis in Case of Prolonged Exposure to Iodine Radioisotopes: Pharmacokinetic Studies in Adult Rats

Purpose

To propose a new and effective dose regimen for stable potassium iodide (KI) repeated prophylaxis in case of prolonged exposure to radioactive iodine.

Methods

The pharmacokinetics of iodine was determined in rats by compartmental analyses after intravenous and oral administrations of the optimal dose of 1 mg/kg KI, which was previously selected in a dose-effect study. The thyroid protection against iodine-125 incorporation was followed during 24 h after a single oral dosing of KI. A repeated KI prophylaxis was modeled using initial estimates of iodine pharmacokinetic parameters.

Results

A dose regimen consisting in administrations of 1 mg/kg daily for 8 days was selected and studied. Plasma iodine concentrations predicted by simulation were verified by experimental data and varied after the third dose of KI between 174 and 1190 μg/l. The inhibition study of iodine-125 binding in the thyroid as a function of the time showed that the protection effect of KI could be correlated to stable iodine plasma concentrations. Hence, a theoretical decrease in iodine-125 thyroid uptake from 63 to 88% could be achieved in a 24 h-interval between two KI doses.

Conclusion

Given the satisfactory levels of thyroid protection, this dose regimen could be envisaged in order to extent KI indications for repeated prophylaxis.

     

The relationship between spatial attention and saccades in the frontoparietal network of the monkey

Spatial attention bears a remarkable resemblance to saccadic eye movements from both a behavioural and a neurophysiological point of view. In this review, we examine the contributions of two cortical areas, namely the lateral intraparietal area (LIP) and frontal eye field (FEF), to saccades and attention and discuss the possible interactions between these two areas. Based on the results of electrophysiological studies and on inactivation studies performed in the macaque monkey, we propose that LIP is mainly involved in salience representation and an attentional selection mechanism that underlies saccade guidance, at least when two objects or locations are in competition in the visual environment. In contrast, we suggest that FEF is involved in coding and triggering saccadic eye movements, as well as in coding the location of attention or the attentional shifts. However, these two functions subserved by the FEF are dissociable at a neuronal level. Saccade planning and attentional selection are intimately coupled from a behavioural point of view but correspond to distinct functional operations.     

Molecular imaging of membrane interfaces reveals mode of beta-glucosidase activation by saposin C

Acid beta-glucosidase (GCase) is a soluble lysosomal enzyme responsible for the hydrolysis of glucose from glucosylceramide and requires activation by the small nonenzymatic protein saposin C (sapC) to gain access to the membrane-embedded glycosphingolipid substrate. We have used in situ atomic force microscopy (AFM) with simultaneous confocal and epifluorescence microscopies to investigate the interactions of GCase and sapC with lipid bilayers. GCase binds to sites on membranes transformed by sapC, and enzyme activity occurs at loci containing both GCase and sapC. Using FRET, we establish the presence of GCase/sapC and GCase/product contacts in the bilayer. These data support a mechanism in which sapC locally alters regions of bilayer for subsequent attack by the enzyme in stably bound protein complexes.     

Assessment of Cardiac Risk before Aortic Reconstruction: Noninvasive Work-up Using Clinical Examination, Exercise Testing, and Dobutamine Stress Echocardiography versus Routine Coronary Arteriography

In this prospective study we evaluated the efficacy of a battery of noninvasive tests including clinical evaluation (CE), exercise testing (ET), and dobutamine stress echocardiography (DSE) for assessment of cardiac risk in 90 patients indicated for aortic reconstruction. As the gold-standard reference technique, coronary arteriography was performed in each patient after noninvasive evaluation. The sensitivity of CE was low (61%). ET proved to be more sensitive (71.4%) and highly specific (95.8%) but feasibility (77%) and diagnostic accuracy (42%) were low. DSE demonstrated acceptable sensitivity (78%) and specificity (75.5%) with high feasibility (94.5%) and diagnostic accuracy (100%). None of the four patients with false negative ET results and only one of seven with false-negative DSE required coronary bypass. On the basis of these findings we conclude that a combination of CE and ET with DES, if necessary, can reliably assess cardiac risk before aortic reconstruction. Noninvasive assessment is a reliable alternative to routine coronary arteriography.     

Myocardial uptake of thallium-201 diethyldithiocarbamate (201TI-DDC) in cultured heart cells and in humans

We assessed the feasibility of SPECT imaging with ²⁰¹Tl-diethyldithiocarbamate (²⁰¹Tl-DDC), a new cerebral blood flow tracer with little redistribution, expecting to observe less extensive redistribution than with ²⁰¹Tl-chloride. Myocardial sections were obtained in three patients presenting with documented coronary artery disease and injected at peak exercise with 100 MBq ²⁰¹Tl-DDC. In two patients there was a clear redistribution phenomenon at four h after injection. In cultured myocardial cells of newborn rats, the uptake and washout of ²⁰¹Tl-chloride and ²⁰¹Tl-DDC were compared. The ²⁰¹Tl-DDC uptake was lower than ²⁰¹Tl-chloride (transmembrane gradients were respectively 89±10 and 4.1±0.2, mean±sem, n=14, P<0.001). After 2 h washout in a Tl free medium, the retention of ²⁰¹Tl-chloride in the cells was 4% vs 19% for ²⁰¹Tl-DDC. It is concluded that although myocardial imaging is feasible with ²⁰¹Tl-DDC, this agent redistributes significantly with time.     

Are the effects of training on fat metabolism involved in the improvement of performance during high-intensity exercise?

The objective of the present study was to relate changes in certain muscle characteristics and indicators of metabolism in response to endurance training to the concomitant changes in time to exhaustion (T_lim) at a work rate corresponding to maximal oxygen uptake Eight healthy sedentary subjects pedalled on a cycle ergometer 2 h a day, 6 days a week, for 4 weeks. Training caused increases in O_2peak (by 8%), T_lim (from 299±23 s before to 486±63 s after training), citrate synthase and 3-hydroxyl-acyl-CoA dehydrogenase (HAD) activities (by 54% and 16%, respectively) and capillary density (by 31%). Decreases in activity of lactate dehydrogenase (LDH) and muscle type of LDH (by 24% and 28%, respectively) and the phosphofructokinase/citrate synthase ratio (by 37%) were also observed. Respiratory exchange ratio (RER) tended to be lower (P<0.1) at all relative work rates after training while the corresponding ventilation rates ( E) were unchanged. At the same absolute work rate, RER and E were lower after training (P<0.05). The improvement of T_lim with training was related to the increases in HAD activity (r=0.91, P=0.0043), and to the decreases in RER calculated for Pa_peak (r=0.71, P=0.0496). The present results suggest that the training-induced adaptations in fat metabolism might influence T_lim at a work rate corresponding to O_2peak and stimulate the still debated and incompletely understood role of fat metabolism during short high-intensity exercise     

Tolerability and pharmacokinetics of non-fixed and fixed combinations of artesunate and amodiaquine in Malaysian healthy normal volunteers

Objective  There is limited pharmacokinetic data available for the combination artesunate + amodiaquine, which is used widely to treat uncomplicated malaria. This study examines the bioavailability and tolerability of a fixed (200 mg artesunate + 540 mg amodiaquine) and loose (200 mg + 612 mg) combination with a 2×2 cross-over design in 24 healthy volunteers. Methods  Parent compounds and metabolites [dihydroartemisinin (DHA) and desethylamodiaquine (DEAQ)] were measured by high-performance liquid chromatography–electrochemical detection, and the area under the curve (AUC)_0-t and C_max were compared by an analysis of variance (ANOVA) based on geometric least square means using the Schuirmann two one-sided test. Results  The AUC_0-t for total DHA and DEAQ were 1522 ± 633 and 30021 ± 14211 ng h/ml for the fixed products and 1688 ± 767 and 40261 ± 19824 ng h/ml (mean ± standard deviation) for the loose products. The ANOVA showed no statistical differences except for sequence effect for DHA. The values obtained with the fixed product were within the 125% bioequivalent limits but extend below the 80% bioequivalence limits. Conclusion  Both combinations were well tolerated and had comparable pharmacokinetic profiles; differences are unlikely to be clinically relevant. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Multidisciplinary European low dose initiative: an update of the MELODI program

Abstract

Purpose: This paper provides an update and summary on the organization of European research in the field of low dose risk and radiation protection. To address declining resources and competence in radiation protection and related research across European countries, a High Level and Expert Group (HLEG) was established in 2007. The HLEG identified key policy and scientific questions to be addressed through a strategic research agenda for low dose radiation risk. This initiated the establishment of a European Research Platform, called MELODI (Multidisciplinary European Low Dose Research Initiative). Dr Bill Morgan closely followed the European low dose programme and chaired the international Advisory Boards of DoReMi Network of Excellence and the MELODI platform.

Conclusion: The MELODI research platform is dedicated to low dose ionizing radiation risk. In 2010, MELODI was founded as a registered association with 15 members. As of September 2016, the association´s membership increased to 46. A major activity of MELODI is the establishment and updating of a long-term Strategic Research Agenda (SRA) for research on low dose risk in Europe. The SRA is intended to guide the priorities for national and European research programmes and the preparation of competitive calls at the European level. A key priority for radiation protection research is to improve health risk estimates for exposures corresponding to the dose limits for occupational exposures and to reference levels for the exposure of the population in emergency situations.     

Influence of two pedalling rate conditions on mechanical output and physiological responses during all-out intermittent exercise

The purpose of this study was to investigate the effect of two cycling velocities on power output and concomitant metabolic and cardiorespiratory responses to repeated all-out exercises. Mean power output (P _m), total work (W _tot), total oxygen consumption (VO_2tot) and blood lactate accumulation (Δ[La]_b) were evaluated in 13 male subjects who performed two series of twelve 5-s bouts of sprint cycling. Recovery periods of 45-s were allowed between trials. One series was executed at optimal velocity (V _opt: velocity for greatest power) and the other one at 50% V _opt (0.5V _opt). Velocities obtained in these conditions were V_opt=116.6 (4.7) rpm; 0.5V_opt=60.6 (4.9) rpm. After a phase of adaptation in oxygen uptake in the first part of the series, the data from the 6th to the 12th sprint were as follows: P _m, 924.6 (73.9) versus 689.2 (61.8) W; W _tot, 29.95 (4.14) versus 22.04 (3.17) kJ; VO_2tot, 12.80 (1.36) versus 10.58 (1.37) l; Δ[La]_b, 2.72 (1.22) versus 0.64 (0.79) mmol.l⁻¹, respectively (P<0.001). Both W _tot and VO_2tot were consistently higher at optimal velocity (+21 and +35.8%, respectively). The present findings demonstrate that during intermittent short-term all-out exercise requiring maximal activation, the energy turnover is not necessarily maximal. It depends on muscle contraction velocity. The increase, lower than expected, in metabolic response from 0.5V _opt to V _opt suggests also that mechanical efficiency is higher at V _opt. Electronic Publication