Electrical stimulation induces propagated colonic contractions in an experimental model.

BACKGROUND: Direct colonic electrical stimulation may prove to be a treatment option for specific motility disorders such as chronic constipation. The aim of this study was to provoke colonic contractions using electrical stimulation delivered from a battery-operated device. METHODS: Electrodes were inserted into the caecal seromuscular layer of eight anaesthetized pigs. Contractions were induced by a neurostimulator (Medtronic 3625). Caecal motility was measured simultaneously by video image analysis, manometry and a technique assessing colonic transit. RESULTS: Caecal contractions were generated using 8-10 V amplitude, 1000 micros pulse width, 120 Hz frequency for 10-30 s, with an intensity of 7-15 mA. The maximal contraction strength was observed after 20-25 s. Electrical stimulation was followed by a relaxation phase of 1.5-2 min during which contractions propagated orally and aborally over at least 10 cm. Spontaneous and stimulated caecal motility values were significantly different for both intraluminal pressure (mean(s.d.) 332(124) and 463(187) mmHg respectively; P < 0.001, 42 experiments) and movement of contents (1.6(0.9) and 3.9(2.8) mm; P < 0.001, 40 experiments). CONCLUSION: Electrical stimulation modulated caecal motility, and provoked localized and propagated colonic contractions.

Teaching Video NeuroImages: Micronystagmus of oculopalatal tremor.

Three months after brainstem hemorrhage, MRI revealed a hyperintense lesion of the left inferior olivary nucleus of a 45-year-old man (figure). The patient was completely asymptomatic, but exhibited oculopalatal tremor (OPT), rhythmic palatal oscillations, and small-amplitude vertical pendular nystagmus of the right eye, best visualized on fundus examination (see video).

Combining chromosomal arm status and significantly aberrant genomic locations reveals new cancer subtypes.

Many types of tumors exhibit characteristic chromosomal losses or gains, as well as local amplifications and deletions. Within any given tumor type, sample specific amplifications and deletions are also observed. Typically, a region that is aberrant in more tumors, or whose copy number change is stronger, would be considered as a more promising candidate to be biologically relevant to cancer. We sought for an intuitive method to define such aberrations and prioritize them. We define V, the "volume" associated with an aberration, as the product of three factors: (a) fraction of patients with the aberration, (b) the aberration's length and (c) its amplitude. Our algorithm compares the values of V derived from the real data to a null distribution obtained by permutations, and yields the statistical significance (p-value) of the measured value of V. We detected genetic locations that were significantly aberrant, and combine them with chromosomal arm status (gain/loss) to create a succinct fingerprint of the tumor genome. This genomic fingerprint is used to visualize the tumors, highlighting events that are co-occurring or mutually exclusive. We apply the method on three different public array CGH datasets of Medulloblastoma and Neuroblastoma, and demonstrate its ability to detect chromosomal regions that were known to be altered in the tested cancer types, as well as to suggest new genomic locations to be tested. We identified a potential new subtype of Medulloblastoma, which is analogous to Neuroblastoma type 1.

Differentially phased leaf growth and movements in Arabidopsis depend on coordinated circadian and light regulation.

In contrast to vastly studied hypocotyl growth, little is known about diel regulation of leaf growth and its coordination with movements such as changes in leaf elevation angle (hyponasty). We developed a 3D live-leaf growth analysis system enabling simultaneous monitoring of growth and movements. Leaf growth is maximal several hours after dawn, requires light, and is regulated by daylength, suggesting coupling between growth and metabolism. We identify both blade and petiole positioning as important components of leaf movements in Arabidopsis thaliana and reveal a temporal delay between growth and movements. In hypocotyls, the combination of circadian expression of PHYTOCHROME INTERACTING FACTOR4 (PIF4) and PIF5 and their light-regulated protein stability drives rhythmic hypocotyl elongation with peak growth at dawn. We find that PIF4 and PIF5 are not essential to sustain rhythmic leaf growth but influence their amplitude. Furthermore, EARLY FLOWERING3, a member of the evening complex (EC), is required to maintain the correct phase between growth and movement. Our study shows that the mechanisms underlying rhythmic hypocotyl and leaf growth differ. Moreover, we reveal the temporal relationship between leaf elongation and movements and demonstrate the importance of the EC for the coordination of these phenotypic traits.

cGMP-dependent protein kinase type I is implicated in the regulation of the timing and quality of sleep and wakefulness.

Many effects of nitric oxide (NO) are mediated by the activation of guanylyl cyclases and subsequent production of the second messenger cyclic guanosine-3',5'-monophosphate (cGMP). cGMP activates cGMP-dependent protein kinases (PRKGs), which can therefore be considered downstream effectors of NO signaling. Since NO is thought to be involved in the regulation of both sleep and circadian rhythms, we analyzed these two processes in mice deficient for cGMP-dependent protein kinase type I (PRKG1) in the brain. Prkg1 mutant mice showed a strikingly altered distribution of sleep and wakefulness over the 24 hours of a day as well as reductions in rapid-eye-movement sleep (REMS) duration and in non-REM sleep (NREMS) consolidation, and their ability to sustain waking episodes was compromised. Furthermore, they displayed a drastic decrease in electroencephalogram (EEG) power in the delta frequency range (1-4 Hz) under baseline conditions, which could be normalized after sleep deprivation. In line with the re-distribution of sleep and wakefulness, the analysis of wheel-running and drinking activity revealed more rest bouts during the activity phase and a higher percentage of daytime activity in mutant animals. No changes were observed in internal period length and phase-shifting properties of the circadian clock while chi-squared periodogram amplitude was significantly reduced, hinting at a less robust oscillator. These results indicate that PRKG1 might be involved in the stabilization and output strength of the circadian oscillator in mice. Moreover, PRKG1 deficiency results in an aberrant pattern, and consequently a reduced quality, of sleep and wakefulness, possibly due to a decreased wake-promoting output of the circadian system impinging upon sleep.

Real-time, in vivo intracellular recordings of caterpillar-induced depolarization waves in sieve elements using aphid electrodes.

Plants propagate electrical signals in response to artificial wounding. However, little is known about the electrophysiological responses of the phloem to wounding, and whether natural damaging stimuli induce propagating electrical signals in this tissue. Here, we used living aphids and the direct current (DC) version of the electrical penetration graph (EPG) to detect changes in the membrane potential of Arabidopsis sieve elements (SEs) during caterpillar wounding. Feeding wounds in the lamina induced fast depolarization waves in the affected leaf, rising to maximum amplitude (c. 60 mV) within 2 s. Major damage to the midvein induced fast and slow depolarization waves in unwounded neighbor leaves, but only slow depolarization waves in non-neighbor leaves. The slow depolarization waves rose to maximum amplitude (c. 30 mV) within 14 s. Expression of a jasmonate-responsive gene was detected in leaves in which SEs displayed fast depolarization waves. No electrical signals were detected in SEs of unwounded neighbor leaves of plants with suppressed expression of GLR3.3 and GLR3.6. EPG applied as a novel approach to plant electrophysiology allows cell-specific, robust, real-time monitoring of early electrophysiological responses in plant cells to damage, and is potentially applicable to a broad range of plant-herbivore interactions.

In vivo administration of a lentiviral vaccine targets DCs and induces efficient CD8(+) T cell responses.

The present study evaluates the potential of third-generation lentivirus vectors with respect to their use as in vivo-administered T cell vaccines. We demonstrate that lentivector injection into the footpad of mice transduces DCs that appear in the draining lymph node and in the spleen. In addition, a lentivector vaccine bearing a T cell antigen induced very strong systemic antigen-specific cytotoxic T lymphocyte (CTL) responses in mice. Comparative vaccination performed in two different antigen models demonstrated that in vivo administration of lentivector was superior to transfer of transduced DCs or peptide/adjuvant vaccination in terms of both amplitude and longevity of the CTL response. Our data suggest that a decisive factor for efficient T cell priming by lentivector might be the targeting of DCs in situ and their subsequent migration to secondary lymphoid organs. The combination of performance, ease of application, and absence of pre-existing immunity in humans make lentivector-based vaccines an attractive candidate for cancer immunotherapy.

Origin of the relative afferent pupillary defect in optic tract lesions.

OBJECTIVE: To determine the percent decussation of pupil input fibers in humans and to explain the size and range of the log unit relative afferent pupillary defect (RAPD) in patients with optic tract lesions. DESIGN: Experimental study. PARTICIPANTS AND CONTROLS: Five patients with a unilateral optic tract lesion. METHODS: The pupil response from light stimulation of the nasal hemifield, temporal hemifield, and full field of each eye of 5 patients with a unilateral optic tract lesion was recorded using computerized binocular infrared pupillography. Six stimulus light intensities, separated by 0.5-log unit steps, were used; 12 stimulus repetitions were given for each stimulus condition. MAIN OUTCOME MEASURES: For each stimulus condition, the pupil response of each eye was characterized by plotting the mean pupil contraction amplitude as a function of stimulus light intensity. The percentage of decussating afferent pupillomotor input fibers was calculated from the ratio of the maximal pupil contractions elicited from each eye. The RAPD was determined pupillographically from full-field stimulation to each eye. RESULTS: In all patients, the pupil response from the functioning temporal hemifield ipsilateral to the tract lesion was greater than that from the functioning contralateral nasal hemifield. This temporal-nasal asymmetry increased with increasing stimulus intensity and was similar in hemifield and full-field stimuli, eventually saturating at maximal light intensity. The log unit RAPD did not correlate with the estimated percentage of decussating pupil fibers, which ranged from 54% to 67%. CONCLUSIONS: In patients with a unilateral optic tract lesion, the pupillary responses from full-field stimulation to each eye are the same as comparing the functioning temporal field with the functioning nasal field. The percentage of decussating fibers is reflected in the ratio of the maximal pupil contraction amplitudes resulting from stimulus input between the two eyes. The RAPD that occurs in this setting reflects the difference in light sensitivity between the intact temporal and nasal hemifields. Its magnitude does not correlate with the difference in the number of crossed and uncrossed axons, but its sidedness contralateral to the side of the optic tract lesion is consistent with the greater percentage of decussating pupillomotor input.

Endothelin-1 does not mediate the endothelium-dependent hypoxic contractions of small pulmonary arteries in rats.

Various pulmonary artery preparations in vitro demonstrate sustained endothelium-dependent contractions upon hypoxia. To determine whether endothelin-1 could mediate this phenomenon, we examined the effect of bosentan, a new antagonist of both the ETA and ETB subtypes of the endothelin receptor. Small (300 pm) pulmonary arteries from rats were mounted on a myograph, precontracted with prostaglandin F2 alpha and exposed to hypoxia (PO2, 10 to 15 mm Hg, measured on-line) for 45 min. Endothelium-intact control rings exhibited a biphasic response, with a transient initial vasoconstriction (phase 1) followed by a second slowly developing sustained contraction (phase 2). Expressed in percent of the maximal response to 80 mmol/L KCl, the amplitudes of phase 1 (peak tension) and 2 (tension after 45 min of hypoxia) averaged 37 +/- 12% and 17 +/- 14%, respectively (n = 11). In endothelium-denuded rings, phase 1 persisted while the amplitude of phase 2 was reduced to 2 +/- 12% (p < 0.05, n = 8), showing the endothelium dependence of this contraction. Neither phase was significantly decreased in rings treated with 10(-5) mmol/L bosentan (38 +/- 15% and 17 +/- 12%, respectively, n = 6). The PO2 threshold for onset of hypoxic contraction was not significantly different among these three groups and averaged 32 +/- 24 mm Hg. In a separate experiment, we assessed the inhibitory effect of 10(-5) mol/L bosentan on the response to 10(-8) mol/L endothelin-I. Rings treated for 45 min with 10(-8) mol/L endothelin-1 alone exhibited a maximal contraction of 75 +/- 27% (n = 6). This was reduced to 4 +/- 17% (p < 0.01, n = 6) in rings treated with both 10(-8) mol/L endothelin-1 and 10(-5) mol/L bosentan. We conclude that complete blockade of all endothelin receptor subtypes has no effect on either endothelium-dependent or -independent hypoxic contractions in this preparation. This suggests that endothelial factors other than endothelin-I mediate the acute hypoxic contractions of small pulmonary arteries in the rat.

Cross-frequency coupling in EEG revealed by adaptive oscillation tracking.

Introduction: Neuronal oscillations have been the focus of increasing interest in the neuroscientific community, in part because they have been considered as a possible integrating mechanism through which internal states can influence stimulus processing in a top-down way (Engel et al., 2001). Moreover, increasing evidence indicates that oscillations in different frequency bands interact with one other through coupling mechanisms (Jensen and Colgin, 2007). The existence and the importance of these cross-frequency couplings during various tasks have been verified by recent studies (Canolty et al., 2006; Lakatos et al., 2007). In this study, we measure the strength and directionality of two types of couplings - phase-amplitude couplings and phase-phase couplings - between various bands in EEG data recorded during an illusory contour experiment that were identified using a recently-proposed adaptive frequency tracking algorithm (Van Zaen et al., 2010). Methods: The data used in this study have been taken from a previously published study examining the spatiotemporal mechanisms of illusory contour processing (Murray et al., 2002). The EEG in the present study were from a subset of nine subjects. Each stimulus was composed of 'pac-man' inducers presented in two orientations: IC, when an illusory contour was present, and NC, when no contour could be detected. The signals recorded by the electrodes P2, P4, P6, PO4 and PO6 were averaged, and filtered into the following bands: 4-8Hz, 8-12Hz, 15-25Hz, 35-45Hz, 45-55Hz, 55-65Hz and 65-75Hz. An adaptive frequency tracking algorithm (Van Zaen et al., 2010) was then applied in each band in order to extract the main oscillation and estimate its frequency. This additional step ensures that clean phase information is obtained when taking the Hilbert transform. The frequency estimated by the tracker was averaged over sliding windows and then used to compare the two conditions. Two types of cross-frequency couplings were considered: phase-amplitude couplings and phase-phase couplings. Both types were measured with the phase locking value (PLV, Lachaux et al., 1999) over sliding windows. The phase-amplitude couplings were computed with the phase of the low frequency oscillation and the phase of the amplitude of the high frequency one. Different coupling coefficients were used when measuring phase-phase couplings in order to estimate different m:n synchronizations (4:3, 3:2, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1 and 9:1) and to take into account the frequency differences across bands. Moreover, the direction of coupling was estimated with a directionality index (Bahraminasab et al., 2008). Finally, the two conditions IC and NC were compared with ANOVAs with 'subject' as a random effect and 'condition' as a fixed effect. Before computing the statistical tests, the PLV values were transformed into approximately normal variables (Penny et al., 2008). Results: When comparing the mean estimated frequency across conditions, a significant difference was found only in the 4-8Hz band, such that the frequency within this band was significantly higher for IC than NC stimuli starting at ~250ms post-stimulus onset (Fig. 1; solid line shows IC and dashed line NC). Significant differences in phase-amplitude couplings were obtained only when the 4-8 Hz band was taken as the low frequency band. Moreover, in all significant situations, the coupling strength is higher for the NC than IC condition. An example of significant difference between conditions is shown in Fig. 2 for the phase-amplitude coupling between the 4-8Hz and 55-65Hz bands (p-value in top panel and mean PLV values in the bottom panel). A decrease in coupling strength was observed shortly after stimulus onset for both conditions and was greater for the condition IC. This phenomenon was observed with all other frequency bands. The results obtained for the phase-phase couplings were more complex. As for the phase-amplitude couplings, all significant differences were obtained when the 4-8Hz band was considered as the low frequency band. The stimulus condition exhibiting the higher coupling strength depended on the ratio of the coupling coefficients. When this ratio was small, the IC condition exhibited the higher phase-phase coupling strength. When this ratio was large, the NC condition exhibited the higher coupling strength. Fig. 3 shows the phase-phase couplings between the 4-8Hz and 35-45Hz bands for the coupling coefficient 6:1, and the coupling strength was significantly higher for the IC than NC condition. By contrast, for the coupling coefficient 9:1 the NC condition gave the higher coupling strength (Fig. 4). Control analyses verified that it is not a consequence of the frequency difference between the two conditions in the 4-8Hz band. The directionality measures indicated a transfer of information from the low frequency components towards the high frequency ones. Conclusions: Adaptive tracking is a feasible method for EEG analyses, revealing information both about stimulus-related differences and coupling patterns across frequencies. Theta oscillations play a central role in illusory shape processing and more generally in visual processing. The presence vs. absence of illusory shapes was paralleled by faster theta oscillations. Phase-amplitude couplings were decreased more for IC than NC and might be due to a resetting mechanism. The complex patterns in phase-phase coupling between theta and beta/gamma suggest that the contribution of these oscillations to visual binding and stimulus processing are not as straightforward as conventionally held. Causality analyses further suggest that theta oscillations drive beta/gamma oscillations (see also Schroeder and Lakatos, 2009). The present findings highlight the need for applying more sophisticated signal analyses in order to establish a fuller understanding of the functional role of neural oscillations.

Post-switching beta synchronization reveals concomitant sensory reafferences and active inhibition processes

It is known that post-movement beta synchronization (PMBS) is involved both in active inhibition and in sensory reafferences processes. The aim of this study was examine the temporal and spatial dynamics of the PMBS involved during multi-limb coordination task. We investigated post-switching beta synchronization (assigned PMBS) using time-frequency and source estimations analyzes. Participants (n = 17) initiated an auditory-paced bimanual tapping. After a 1500 ms preparatory period, an imperative stimulus required to either selectively stop the left while maintaining the right unimanual tapping (Switch condition: SWIT) or to continue the bimanual tapping (Continue condition: CONT). PMBS significantly increased in SWIT compared to CONT with maximal difference within right central region in broad-band 14âeuro"30 Hz and within left central region in restricted-band 22âeuro"26 Hz. Source estimations localized these effects within right pre-frontal cortex and left parietal cortex, respectively. A negative correlation showed that participants with a low percentage of errors in SWIT had a large PMBS amplitude within right parietal and frontal cortices. This study shows for the first time simultaneous PMBS with distinct functions in different brain regions and frequency ranges. The left parietal PMBS restricted to 22âeuro"26 Hz could reflect the sensory reafferences of the right hand tapping disrupted by the switching. In contrast, the right pre-frontal PMBS in a broad-band 14âeuro"30 Hz is likely reflecting the active inhibition of the left hand stopped. Finally, correlations between behavioral performance and the magnitude of the PMBS suggest that beta oscillations can be viewed as a marker of successful active inhibition.

Développement de l'interprétation quantitative de la sismique réflexion lacustre : application de l'AVO aux sédiments quaternaires dans le lac Léman

Résumé Des développements antérieurs, au sein de l'Institut de Géophysique de Lausanne, ont permis de développer des techniques d'acquisition sismique et de réaliser l'interprétation des données sismique 2D et 3D pour étudier la géologie de la région et notamment les différentes séquences sédimentaires du Lac Léman. Pour permettre un interprétation quantitative de la sismique en déterminant des paramètres physiques des sédiments la méthode AVO (Amplitude Versus Offset) a été appliquée. Deux campagnes sismiques lacustres, 2D et 3D, ont été acquises afin de tester la méthode AVO dans le Grand Lac sur les deltas des rivières. La géométrie d'acquisition a été repensée afin de pouvoir enregistrer les données à grands déports. Les flûtes sismiques, mises bout à bout, ont permis d'atteindre des angles d'incidence d'environ 40˚ . Des récepteurs GPS spécialement développés à cet effet, et disposés le long de la flûte, ont permis, après post-traitement des données, de déterminer la position de la flûte avec précision (± 0.5 m). L'étalonnage de nos hydrophones, réalisé dans une chambre anéchoïque, a permis de connaître leur réponse en amplitude en fonction de la fréquence. Une variation maximale de 10 dB a été mis en évidence entre les capteurs des flûtes et le signal de référence. Un traitement sismique dont l'amplitude a été conservée a été appliqué sur les données du lac. L'utilisation de l'algorithme en surface en consistante a permis de corriger les variations d'amplitude des tirs du canon à air. Les sections interceptes et gradients obtenues sur les deltas de l'Aubonne et de la Dranse ont permis de produire des cross-plots. Cette représentation permet de classer les anomalies d'amplitude en fonction du type de sédiments et de leur contenu potentiel en gaz. L'un des attributs qui peut être extrait des données 3D, est l'amplitude de la réflectivité d'une interface sismique. Ceci ajoute une composante quantitative à l'interprétation géologique d'une interface. Le fond d'eau sur le delta de l'Aubonne présente des anomalies en amplitude qui caractérisent les chenaux. L'inversion de l'équation de Zoeppritz par l'algorithme de Levenberg-Marquardt a été programmée afin d'extraire les paramètres physiques des sédiments sur ce delta. Une étude statistique des résultats de l'inversion permet de simuler la variation de l'amplitude en fonction du déport. On a obtenu un modèle dont la première couche est l'eau et dont la seconde est une couche pour laquelle V P = 1461 m∕s, ρ = 1182 kg∕m3 et V S = 383 m∕s. Abstract A system to record very high resolution (VHR) seismic data on lakes in 2D and 3D was developed at the Institute of Geophysics, University of Lausanne. Several seismic surveys carried out on Lake Geneva helped us to better understand the geology of the area and to identify sedimentary sequences. However, more sophisticated analysis of the data such as the AVO (Amplitude Versus Offset) method provides means of deciphering the detailed structure of the complex Quaternary sedimentary fill of the Lake Geneva trough. To study the physical parameters we applied the AVO method at some selected places of sediments. These areas are the Aubonne and Dranse River deltas where the configurations of the strata are relatively smooth and the discontinuities between them easy to pick. A specific layout was developed to acquire large incidence angle. 2D and 3D seismic data were acquired with streamers, deployed end to end, providing incidence angle up to 40˚ . One or more GPS antennas attached to the streamer enabled us to calculate individual hydrophone positions with an accuracy of 50 cm after post-processing of the navigation data. To ensure that our system provides correct amplitude information, our streamer sensors were calibrated in an anechoic chamber using a loudspeaker as a source. Amplitude variations between the each hydrophone were of the order of 10 dB. An amplitude correction for each hydrophone was computed and applied before processing. Amplitude preserving processing was then carried out. Intercept vs. gradient cross-plots enable us to determine that both geological discontinuities (lacustrine sediments/moraine and moraine/molasse) have well defined trends. A 3D volume collected on the Aubonne river delta was processed in order ro obtain AVO attributes. Quantitative interpretation using amplitude maps were produced and amplitude maps revealed high reflectivity in channels. Inversion of the water bottom of the Zoeppritz equation using the Levenberg-Marquadt algorithm was carried out to estimate V P , V S and ρ of sediments immediately under the lake bottom. Real-data inversion gave, under the water layer, a mud layer with V P = 1461 m∕s, ρ = 1182 kg∕m3 et V S = 383 m∕s.

Molar substitution and C2/C6 ratio of hydroxyethyl starch: influence of blood coagulation

Résumé Cette étude a démontré l'effet individuel sur la coagulation sanguine humaine des deux principales caractéristiques de la molécule d'hydroxyéthylamidon (HES) : la substitution molaire et le rapport C2/C6. L'analyse par thrombélastographe (TEG®) indique que la molécule de HES dont la substitution molaire est de 0.42 et le rapport C2/C6 de 2.7 a le moins d'effet sur la coagulation sanguine chez l'être humain. Objectifs de l'étude Le développement d'hydroxyéthylamidons (HES) qui ont à la fois peu d'impact sur la coagulation sanguine et une longue persistance intravasculaire est d'un grand intérêt clinique. Une précédente étude in vitro a démontré qu'une solution de HES de haut poids moléculaire et de bas degré de substitution molaire ne compromettait pas plus la coagulation sanguine qu'une solution HES de poids moléculaire moyen (1). La présente étude examine l'effet individuel de la substitution molaire et du rapport C2/C6 d'une solution de HES de haut poids moléculaire (700 kDa) sur la coagulation sanguine. Matériel et méthode Nous avons prélevé du sang chez 30 adultes en bonne santé; le sang a été mélangé avec 6 solutions de HES qui diffèrent par leur degré de substitution molaire (0.42 et 0.51) et leur rapport C2/C6 (2.7, 7 et 14) à trois degrés de dilution : 20%, 40% et 60%. Les échantillons ont ensuite été analysés par thrombélastographe. Les données ont été étudiées par analyse de variance à trois voies pour mesures répétées sur une voie (dilution). Résultats Plus la substitution molaire est élevée, plus la coagulation sanguine est compromise et ce concernant tous les paramètres du TEG® (tous les p sont < à 0.05). La solution HES avec le rapport C2/C6 le plus bas a l'effet le moins prononcé sur le temps r (p<0.001), l'angle α (p=0.003) et l'Index de Coagulation CI (p<0.001) ; on n'a pas observé d'effet sur le temps k (p=0.513) et l'amplitude maximale (p=0.699) concernant ce paramètre. Conclusion L'analyse par thrombélastographe révèle qu'une molécule de HES avec une substitution molaire de 0.42 et un rapport C2/C6 de 2.7 a un effet minimal sur la coagulation sanguine humaine in vitro.

Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain.

Peripheral neuropathic pain is a disabling condition resulting from nerve injury. It is characterized by the dysregulation of voltage-gated sodium channels (Navs) expressed in dorsal root ganglion (DRG) sensory neurons. The mechanisms underlying the altered expression of Navs remain unknown. This study investigated the role of the E3 ubiquitin ligase NEDD4-2, which is known to ubiquitylate Navs, in the pathogenesis of neuropathic pain in mice. The spared nerve injury (SNI) model of traumatic nerve injury-induced neuropathic pain was used, and an Nav1.7-specific inhibitor, ProTxII, allowed the isolation of Nav1.7-mediated currents. SNI decreased NEDD4-2 expression in DRG cells and increased the amplitude of Nav1.7 and Nav1.8 currents. The redistribution of Nav1.7 channels toward peripheral axons was also observed. Similar changes were observed in the nociceptive DRG neurons of Nedd4L knockout mice (SNS-Nedd4L-/-). SNS-Nedd4L-/- mice exhibited thermal hypersensitivity and an enhanced second pain phase after formalin injection. Restoration of NEDD4-2 expression in DRG neurons using recombinant adenoassociated virus (rAAV2/6) not only reduced Nav1.7 and Nav1.8 current amplitudes, but also alleviated SNI-induced mechanical allodynia. These findings demonstrate that NEDD4-2 is a potent posttranslational regulator of Navs and that downregulation of NEDD4-2 leads to the hyperexcitability of DRG neurons and contributes to the genesis of pathological pain.

Deciphering neuron-glia compartmentalization in cortical energy metabolism.

Energy demand is an important constraint on neural signaling. Several methods have been proposed to assess the energy budget of the brain based on a bottom-up approach in which the energy demand of individual biophysical processes are first estimated independently and then summed up to compute the brain's total energy budget. Here, we address this question using a novel approach that makes use of published datasets that reported average cerebral glucose and oxygen utilization in humans and rodents during different activation states. Our approach allows us (1) to decipher neuron-glia compartmentalization in energy metabolism and (2) to compute a precise state-dependent energy budget for the brain. Under the assumption that the fraction of energy used for signaling is proportional to the cycling of neurotransmitters, we find that in the activated state, most of the energy ( approximately 80%) is oxidatively produced and consumed by neurons to support neuron-to-neuron signaling. Glial cells, while only contributing for a small fraction to energy production ( approximately 6%), actually take up a significant fraction of glucose (50% or more) from the blood and provide neurons with glucose-derived energy substrates. Our results suggest that glycolysis occurs for a significant part in astrocytes whereas most of the oxygen is utilized in neurons. As a consequence, a transfer of glucose-derived metabolites from glial cells to neurons has to take place. Furthermore, we find that the amplitude of this transfer is correlated to (1) the activity level of the brain; the larger the activity, the more metabolites are shuttled from glia to neurons and (2) the oxidative activity in astrocytes; with higher glial pyruvate metabolism, less metabolites are shuttled from glia to neurons. While some of the details of a bottom-up biophysical approach have to be simplified, our method allows for a straightforward assessment of the brain's energy budget from macroscopic measurements with minimal underlying assumptions.