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Despite the fact that PolyUnsaturated Fatty Acids (PUFA) are generally accepted to be good for health, the mechanisms of their bona fide benefits still remain elusive. PUFA are particularly enriched in the membrane Phospholipids (PLs) of selective organs, among which skeletal muscles and the cardiovascular system are prime examples. The fatty acid composition of PLs is known to regulate crucial membrane properties, including rigidity, elasticity and plasticity. Since muscle cells undergo repeated cycles of elongation and relaxation and are constantly exposed to mechanical stress, we postulated in the present study that PUFA-containing PLs could be central players for muscle cell adaptation to mechanical constraints. By a combination of in cellulo and in silico approaches, we show that PUFA, and particularly the ω-3 DocoHexaenoic Acid (DHA), regulate important properties of the plasma membrane that improve muscle cell resilience to mechanical constraints. Thanks to their unique property to contortionate within the bilayer plane, they facilitate the formation of Vacuole-like dilation (VLD) which, in turn, reduce membrane stress and avoid cell breakage under mechanical constraints.

International audience; Historically, double or triple hit lymphoma (DHL and THL) have poor outcomes with conventional chemotherapy, but there is currently no guideline. We report the French experience in managing DHL and THL in first line using collective data on both survival and tolerance. All consecutive patients with newly diagnosis of large B-cell lymphoma with MYC, BCL2, and/or BCL6 rearrangements, as determined by FISH between January 2013 and April 2019 were included. Based on the eligibility criteria, 160 patients were selected among the 184 patients identified. With a median follow-up of 32 months, 2- and 4-year progression free survival (PFS) rates were 40% and 28% with R-CHOP compared with 57% and 52% with intensive chemotherapy (P = .063). There was no difference in overall survival (OS). For advanced stages, PFS was significantly longer with intensive chemotherapy than with R-CHOP (P = .029). There was no impact of autologous stem cell transplantation among patient in remission. For patients with central nervous system (CNS) involvement, the 2-year PFS and OS rate was 21% and 39%, vs 57% and 75% without CNS disease (P = .007 and P < .001). By multivariate analysis, elevated IPI score and CNS disease were strongly and independently associated with a poorer survival, whereas treatment was not significantly associated with OS. This is the largest series reporting the treatment of DHL and THL in Europe. The PFS was significantly longer with an intensive regimen for advanced stage, but no difference in OS, supporting the need for a prospective randomized trial.

International audience; BACKGROUND: Obinutuzumab monotherapy has shown promising efficacy in mantle cell lymphoma. We aimed to investigate the activity of obinutuzumab plus DHAP (dexamethasone, high-dose cytarabine, and cisplatin), measured by minimal residual disease quantitative (q)PCR status in the bone marrow after four cycles. METHODS: LyMa-101 was a prospective, open-label, single-arm, phase 2 trial. Participants were enrolled from 28 hospitals in France. Newly diagnosed patients with mantle cell lymphoma (aged 18 to

Summary The human temporomandibular joint (TMJ) is involved in vital functions such as feeding and talking, while its disorder prevalence is reported to be between 5% and 12%. Functional evaluation using quantitative motion analysis tools is interesting in order to better understand normal and abnormal TMJ behavior. But, for the same mandibular displacement, left and right condyles will most certainly give different motion representation: both condyles showing a different shape and volume, being most of the time asymmetric and highly individual. This study performs quantification on relative left and right condyle orientation and position using the spatial location of palpated anatomical landmarks (ALs) and anatomical frames (AFs), on three-dimensional (3D) models created from computerized tomography (CT) performed on 94 mandibles from Universite Libre de Bruxelles bone repository, and magnetic resonance imaging (MRI) performed on 11 living subjects. Our aim was to gather as much data as possible on the morphological aspect of the condyle's orientation asymmetry within the same mandible, in order to better address the difference of motion representation that will be observed for the right and left condyles in further kinematic studies.

The balance within phospholipids (PLs) between saturated fatty acids and monounsaturated or polyunsaturated fatty acids is known to regulate the biophysical properties of cellular membranes. As a consequence, in many cell types, perturbing this balance alters crucial cellular processes, such as vesicular budding and the trafficking/function of membrane-anchored proteins. The worldwide spread of the Western diet, which is highly enriched in saturated fats, has been clearly correlated with the emergence of a complex syndrome known as metabolic syndrome (MetS). MetS is defined as a cluster of risk factors for cardiovascular diseases, type 2 diabetes and hepatic steatosis; however, no clear correlations have been established between diet-induced fatty acid redistribution within cellular PLs and the severity/chronology of the symptoms associated with MetS or the function of the targeted organs. To address this issue, in this study we analyzed PL remodeling in rats exposed to a high-fat/high-fructose diet (HFHF) over a 15-week period. PL remodeling was analyzed in several organs, including known MetS targets. We show that fatty acids from the diet can redistribute within PLs in a very selective manner, with phosphatidylcholine being the preferred sink for this redistribution. Moreover, in the HFHF rat model, most organs are protected from this redistribution, at least during the early onset of MetS, at the expense of the liver and skeletal muscles. Interestingly, such a redistribution correlates with clear-cut alterations in the function of these organs. This article has an associated First Person interview with the first author of the paper., Summary: In rats, a high-fat diet induces the selective distribution of fatty acids within phosphatidylcholine in the liver and muscles, in a manner that correlates with organ dysfunction. The cardiovascular system appears to be protected under these conditions.

We examined the understanding of emotional speech by deaf children with cochlear implant (CI). Thirty deaf children with CI and 60 typically developing controls (matched on chronological age or hearing age) performed a computerized task featuring emotional prosody, either embedded in a discrepant context or without any context at all. Across the task conditions, the deaf participants with CI scored lower on the prosody-bases responses than their peers matched on chronological age or hearing age. Additionally, we analyzed the effect of age on determining correct prosody-based responses and we found that hearing age was a predictor of the accuracy of prosody-based responses. We discuss these findings with respect to delay in prosody and intermodal processing. Future research should aim to specify the nature of the cognitive processes that would be required to process prosody.

The balance within phospholipids (PL) between Saturated Fatty Acids (SFA) and mono- or poly-Unsaturated Fatty Acids (UFA), is known to regulate the biophysical properties of cellular membranes. As a consequence, perturbating this balance alters crucial cellular processes in many cell types, such as vesicular budding and the trafficking/function of membrane-anchored proteins. The worldwide spreading of the Western-diet, which is specifically enriched in saturated fats, has been clearly correlated with the emergence of a complex syndrome, known as the Metabolic Syndrome (MetS), which is defined as a cluster of risk factors for cardiovascular diseases, type 2 diabetes and hepatic steatosis. However, no clear correlations between diet-induced fatty acid redistribution within cellular PL, the severity/chronology of the symptoms associated to MetS and the function of the targeted organs, particularly in the early onset of the disease, have been established. In an attempt to fill this gap, we analyzed in the present study PL remodeling in rats exposed during 15 weeks to a High Fat/High Fructose diet (HFHF) in several organs, including known MetS targets. We show that fatty acids from the diet can distribute within PL in a very selective way, with PhosphatidylCholine being the preferred sink for this distribution. Moreover, in the HFHF rat model, most organs are protected from this redistribution, at least during the early onset of MetS, at the exception of the liver and skeletal muscles. Interestingly, such a redistribution correlates with clear-cut alterations in the function of these organs.

WOS:000373250400012; International audience; The effects of weakly absorbing material coating on soot have attracted considerable research attention in recent years due to the significant influence of such coating on soot radiative properties and the large differences predicted by different numerical models. Soot aggregates were first numerically generated using the diffusion limited cluster aggregation algorithm to produce fractal aggregates formed by log-normally distributed polydisperse spherical primary particles in point-touch. These aggregates were then processed by adding a certain amount of primary particle overlapping and necking to simulate the soot morphology observed from transmission electron microscopy images. After this process, a layer of WAM coating of different thicknesses was added to these more realistic soot aggregates. The radiative properties of these coated soot aggregates over the spectral range of 266-1064 nm were calculated by the discrete dipole approximation (DDA) using the spectrally dependent refractive index of soot for four aggregates containing N-p =1, 20, 51 and 96 primary particles. The considered coating thicknesses range from 0% (no coating) up to 100% coating in terms of the primary particle diameter. Coating enhances both the particle absorption and scattering cross sections, with much stronger enhancement to the scattering one, as well as the asymmetry factor and the single scattering albedo. The absorption enhancement is stronger in the UV than in the visible and the near infrared. The simple corrections to the Rayleigh-Debye-Gans fractal aggregates theory for uncoated soot aggregates are found not working for coated soot aggregates. The core-shell model significantly overestimates the absorption enhancement by coating in the visible and the near infrared compared to the DDA results of the coated soot particle. Treating an externally coated soot aggregate as an aggregate formed by individually coated primary particles significantly underestimates the absorption enhancement by coating in the visible and the near infrared. Crown Copyright (C) 2015 Published by Elsevier Ltd. All rights reserved.

[Figure][1] An allegedly 15-year-old male was seen at the emergency unit on 1 January 2018 for cold sweats, hyperthermia, cough, and fatigue occurring for 1 week. This Senegalese migrant had traveled across Libya and Italy before arriving in France 11 weeks before, where he resided in a

In this paper, we present some first attempt to measure graded suspension of sands in an alpine river. It is a real challenge to measure gradedsuspensions of sands in such dynamic rivers. Specific measurements of the graded suspension in the middle of a secondary channel were attempted using a sampler that allows simultaneous sampling at three different elevations (5 cm, 10 cm, and 20 cm) above the bed. Very large concentrations (up to C = 40 g/l) of fine sediments in suspension were measured during a dam reservoir flushing event. It included large amounts of sand (from 10 to 60% of the measured concentration). A substantial graded suspension of sand was measured even for relatively low velocities. Sand fluxes estimates for varying bed shear stresses during the event are discussed. In particular, based on the measured bed shear stress, a semi-empirical formula developed for sand suspension is applied to test its ability to predict sand flux in alpine rivers. The sensibility of such formula to the grain size is very high whereas large uncertainties exist in the measurement (d50 varies from 0.1 to 0.3 mm depending on the sample), which makes its application difficult at the moment.

Recently, a new population of resident cardiac stem cells (CSCs) positive for the W8B2 marker has been identified. These CSCs are considered to be an ideal cellular source to repair myocardial damage after infarction. However, the electrophysiological profile of these cells has not been characterized yet. We first establish the conditions of isolation and expansion of W8B2+ CSCs from human heart biopsies using a magnetic sorting system followed by flow cytometry cell sorting. These cells display a spindle-shaped morphology, are highly proliferative, and possess self-renewal capacity demonstrated by their ability to form colonies. Besides, W8B2+ CSCs are positive for mesenchymal markers but negative for hematopoietic and endothelial ones. RT-qPCR and immunostaining experiments show that W8B2+ CSCs express some early cardiac-specific transcription factors but lack the expression of cardiac-specific structural genes. Using patch clamp in the whole-cell configuration, we show for the first time the electrophysiological signature of BKCa current in these cells. Accordingly, RT-PCR and western blotting analysis confirmed the presence of BKCa at both mRNA and protein levels in W8B2+ CSCs. Interestingly, BKCa channel inhibition by paxilline decreased cell proliferation in a concentration-dependent manner and halted cell cycle progression at the G0/G1 phase. The inhibition of BKCa also decreased the self-renewal capacity but did not affect migration of W8B2+ CSCs. Taken together, our results are consistent with an important role of BKCa channels in cell cycle progression and self-renewal in human cardiac stem cells.

WOS:000357543800021; International audience; There is a strong interest in accurately modelling the radiative properties of soot aggregates (also known as black carbon particles) emitted from combustion systems and fires to gain improved understanding of the role of black carbon to global warming. This study conducted a systematic investigation of the effects of overlapping and necking between neighbouring primary particles on the radiative properties of soot aggregates using the discrete dipole approximation. The degrees of overlapping and necking are quantified by the overlapping and necking parameters. Realistic soot aggregates were generated numerically by constructing overlapping and necking to fractal aggregates formed by point-touch primary particles simulated using a diffusion-limited cluster aggregation algorithm. Radiative properties (differential scattering, absorption, total scattering, specific extinction, asymmetry factor and single scattering albedo) were calculated using the experimentally measured soot refractive index over the spectral range of 266-1064 nm for 9 combinations of the overlapping and necking parameters. Overlapping and necking affect significantly the absorption and scattering properties of soot aggregates, especially in the near UV spectrum due to the enhanced multiple scattering effects within an aggregate. By using correctly modified aggregate properties (fractal dimension, prefactor, primary particle radius, and the number of primary particle) and by accounting for the effects of multiple scattering, the simple Rayleigh-Debye-Gans theory for fractal aggregates can reproduce reasonably accurate radiative properties of realistic soot aggregates. (C) 2015 Elsevier Ltd. All rights reserved.

Seven new adociaquinone derivatives, xestoadociaquinones A (1a), B (1b), 14-carboxy-xestoquinol sulfate (2) and xestoadociaminals A–D (3a, 3c, 4a, 4c), together with seven known compounds (5–11) were isolated from an Indonesian marine sponge Xestospongia sp. Their structures were elucidated by extensive 1D and 2D NMR and mass spectrometric data. All the compounds were evaluated for their potential inhibitory activity against eight different protein kinases involved in cell proliferation, cancer, diabetes and neurodegenerative disorders as well as for their antioxidant and antibacterial activities.

Several therapeutic agents targeting HGF/MET signaling are under clinical development as single agents or in combination, notably with anti-EGFR therapies in non–small cell lung cancer (NSCLC). However, despite increasing data supporting a link between MET, irradiation, and cancer progression, no data regarding the combination of MET-targeting agents and radiotherapy are available from the clinic. S49076 is an oral ATP-competitive inhibitor of MET, AXL, and FGFR1-3 receptors that is currently in phase I/II clinical trials in combination with gefitinib in NSCLC patients whose tumors show resistance to EGFR inhibitors. Here, we studied the impact of S49076 on MET signaling, cell proliferation, and clonogenic survival in MET-dependent (GTL16 and U87-MG) and MET-independent (H441, H460, and A549) cells. Our data show that S49076 exerts its cytotoxic activity at low doses on MET-dependent cells through MET inhibition, whereas it inhibits growth of MET-independent cells at higher but clinically relevant doses by targeting Aurora B. Furthermore, we found that S49076 improves the antitumor efficacy of radiotherapy in both MET-dependent and MET-independent cell lines in vitro and in subcutaneous and orthotopic tumor models in vivo. In conclusion, our study demonstrates that S49076 has dual antitumor activity and can be used in combination with radiotherapy for the treatment of both MET-dependent and MET-independent tumors. These results support the evaluation of combined treatment of S49076 with radiation in clinical trials without patient selection based on the tumor MET dependency status. Mol Cancer Ther; 16(10); 2107–19. ©2017 AACR.

We present a case of a non-provoked fatal shark attack on a 15-year old male kitesurfer in New Caledonia. The victim lost his board and was pulled by the sail along the water surface in a reef passage when a shark attacked. The shark inflicted at least two bites on the left leg, including a severe one around the knee, resulting in a quick hypovolemic shock that was fatal. The analysis of one of these bites indicated that a 2.8 m TL (est. length) tiger shark was responsible for this attack. The features of the attack are consistent with those of a predator response to a surface feeding stimulus.

International audience; Agelanthus dodoneifolius is one of the medicinal plants used in African pharmacopeia and traditional medicine for the treatment of cardiovascular diseases. A chemical analysis has identified one of the active principles: Dodoneine (Ddn). It is a new dihydropyranone which exerts hypotensive and vasorelaxant effects on rat. Since the mechanism of the hypotensive effect is unknown, we performed a variety of preclinical and mechanistic studies to characterize the specific cardiac effect of Ddn at tissue (ex-vivo) and cellular levels (in-vitro) in order to determine a molecular target. Ddn effects were evaluated in an isolated rat heart preparation using Langendorff retrograde perfusion and then, the effects of Ddn were characterized in freshly dissociated cardiac ventricular myocytes using the whole-cell patch-clamp configuration. Ex-vivo, Ddn produced a dose-dependent negative inotropic effect with an IC50 value of 10 µM without changed heart rate. 100 µM Ddn decreased left ventricular developed pressure of about 40%. In isolated cardiac myocytes, Ddn reduced I(Ca),L density of about 30% with an IC50 value estimated at 3 µM. Ddn did not change current-voltage relation but it shifted the inactivation curve toward negative potentials and modified the half inactivation potentials. Furthermore, Ddn induced a phasic-dependent blocking on ICa,L. This study demonstrates that the hypotensive property of dodoneine is likely associated with a negative inotropic effect and the blockade of the L-type calcium channels.

International audience; To improve the optical diagnostics of soot particles and gain an increased comprehension of the soot formation and aging mechanisms requires a better understanding of the soot refractive index. The present study evaluated the refractive index of soot generated by a miniCAST, an ethylene diffusion flame, and a PALAS GFG by interpreting specific extinction measurements in the near-UV spectrum with the help of an improved RDG-FA theory. Soot's morphology, size distribution, and bulk densities were determined and taken into account for the inversion process. Findings indicate that absorption and scattering capacities of the considered soot were strongly dependent on the amount of organic or volatile carbons and the degree of graphitization of the carbon atoms in the primary sphere (amorphous to graphitic arrangement). The proposed speciation of particles according to these properties is based on the spectral dependence of the determined refractive index for three reference aerosols representative of organic, amorphous, and ordered soot particles. Results show that by combining the refractive indices of these three aerosols it is possible to explain the high variability of most of the optical properties of soot, paving the way for a simple optical technique that permits the speciation of soot particles. (C) 2016 Elsevier Ltd. All rights reserved.

Abexinostat, an oral pan-histone deacetylase inhibitor (HDACi), was evaluated in patients with advanced solid tumours in two single agent phase I studies (PCYC-402 and CL1-78454-002). In PCYC-402 study testing four different administration schedules, the maximum tolerated dose (MTD) was established at 75 mg/m(2) BID (twice daily) and the recommended dose at 60 mg/m(2) BID regardless of the schedule tested. The dose limiting toxicity (DLT), consistently observed across all these schedules, was reversible thrombocytopenia. The CL1-78454-002 study was initially investigating an additional schedule of 14 days on/7 days off. While testing two first cohorts, thrombocytopenia was observed without reaching DLT. To address this issue, a pharmacokinetic/pharmacodynamic (PK/PD) model was used to predict the optimal schedule allowing higher doses with minimal thrombocytopenia. Several administration schedules were simulated using this model. A 4 days on/3 days off schedule was associated with the smallest platelet decrease. Accordingly, the CL1-78454-002 study was amended. After reaching MTD1 (75 mg/m(2) BID) with the initial schedule, subsequent cohorts received abexinostat on a revised schedule of 4 days on/3 days off, starting at one dose level below MTD1 (60 mg/m(2) BID). As expected, the dose-escalation continued for two more dose levels beyond MTD1. The MTD2 reached for this optimised schedule was 105 mg/m(2) BID and the recommended dose 90 mg/m(2) BID. In conclusion, early understanding of toxicities and PK determination allowed us to build a PK/PD model of thrombocytopenia, which predicted the optimal administration schedule. This optimised schedule is currently used in the trials in solid tumours with abexinostat.

IF (2,26); International audience; Aim of the study: Effects of the different fractions obtained by partition of ethanolic extract (EE) of Agelanthus dodoneifolius through column chromatography were investigated on rat blood pressure and aortic relaxation and compared to those observed in the presence of crude EE. Materials and methods: The acute hypotensive activity of EE, fractions and dodoneine, administrated intravenously, was evaluated in anaesthetized rats using the invasive method of blood pressure recording. Bioassay-guided fractionation using rat aorta pre-contracted by norepinephrine to monitor the relaxant activity led to the isolation of dodoneine. Results: In normotensive rats, injection of EE (0.01–10 mg/kg) produced a dose-dependent decrease in both systolic and diastolic blood pressure without any significant change in heart rate. In a similar way, the EE (0.001–3 mg/mL) caused relaxation of rat pre-contracted aorta in a concentration-dependent manner. Fractionation of the EE afforded 14 fractions, F1–F14, that were tested on rat precontracted aortic rings. At the concentration level of 1 mg/mL, a maximum relaxation effect was observed for fractions F2–F5. F4 was the most effective to elicit a concentration-dependent relaxation effect with an ED50 = 160±1.1 g/mL (n = 5) and to decreased systolic and diastolic control pressure by 56.9% and 81.6% respectively. F4 contains most of the dihydropyranone dodoneine, with 93% of the sample mass. Dodoneine separated from this fraction was also able to decrease both systolic and diastolic arterial pressure by 32.5% and 38.7% at 100g/kg, respectively. Conclusion: For the first time, this study demonstrates the hypotensive property of the dodoneine present in Agelanthus dodoneifolius.

Resume Introduction La difficulte d’utilisation d’un collyre est un facteur de mauvaise observance des patients limitant l’efficacite therapeutique. L’objectif de cette etude etait d’evaluer la maniabilite et l’acceptabilite globale d’un collyre a base de timolol en flacon Abak® nouvelle generation (collyre multidose non conserve) par rapport a celles des autres modes d’administration (collyres multidoses conserves ou unidoses) chez des patients traites pour un glaucome ou une hypertonie oculaire. Methodes Etude transversale, retrospective et multicentrique impliquant 41 ophtalmologistes repartis sur toute la France. Les patients devaient avoir ete traites par le collyre en flacon Abak® nouvelle generation depuis au moins deux mois, suite au remplacement d’un autre collyre β-bloquant. La maniabilite et l’acceptabilite du flacon Abak® nouvelle generation par rapport au conditionnement utilise precedemment ont ete evaluees par un questionnaire rempli par l’ophtalmologiste. Resultats Les patients ont ete quasi unanimes concernant la maniabilite du flacon Abak® nouvelle generation : ouverture facile rapportee par 96,5 % des patients, prise en main aisee pour 96,0 % et sortie des gouttes facile pour 91,1 %. Sur tous ces criteres et de maniere globale, les patients ont prefere le flacon Abak® nouvelle generation par rapport au conditionnement precedent. Ces resultats ont ete confirmes chez les patients les plus âges. Conclusion Le flacon Abak® nouvelle generation a presente une acceptabilite superieure a celle des flacons multidoses conserves ou en unidoses. Sa maniabilite et l’absence de conservateur, qui laisse presager une meilleure tolerance locale, sont favorables a une meilleure observance therapeutique chez les patients traites au long cours.

International audience; Previous studies of preverbal development have highlighted the recurrent difficulties experienced by deaf children in acquiring knowledge of the social rules and social skills pertaining to discourse. We expected cochlear implants in children with bilateral profound deafness to improve their use of verbal language, so that their communication skill profile resembled that of younger, hearing children. Using conversation samples taken from videos recorded every 6 months over a 2-year period, we monitored the development of communication skills in a group of 18 prelingually profoundly deaf children (mean implantation age, 3 years and 5 months). Results corroborated our hypothesis that the overall communication performances of children with cochlear implants improve, both quantitatively and qualitatively, as early as the first year post-implantation.; Il ressort de travaux antérieurs que les enfants sourds ont des difficultés à s’approprier les conventions et règles implicites régissant l’utilisation du langage. De ce fait, la pose d’un implant cochléaire, permettant à des enfants atteints de surdité profonde d’accéder au langage verbal, devrait se traduire par un recours plus systématique au langage verbal. Par ailleurs nous faisons l’hypothèse que les actes de langage devraient progressivement tendre vers les profils présentés par les enfants entendants plus jeunes. Dix-huit enfants prélinguaux implantés (moyenne d’âge à l’implantation : 3 ; 5) ont été filmés, tous les six mois pendant deux ans. Les résultats obtenus sont en adéquation avec les hypothèses posées, dès la première année, les enfants tirent profit de la pose d’un implant cochléaire; les échanges conversationnels médiatisés par le langage verbal s’intensifient dès la première année suivant l’implantation ; de la même façon la répartition des actes de langage se modifie.

Objectives With more children receiving cochlear implants during infancy, there is a need for validated assessments of pre-verbal and early verbal auditory skills. The LittlEARS® Auditory Questionnaire is presented here as the first module of the LittlEARS® test battery. The LittlEARS® Auditory Questionnaire was developed and piloted to assess the auditory behaviour of normal hearing children and hearing impaired children who receive a cochlear implant or hearing aid prior to 24 months of age. This paper presents results from two studies: one validating the LittlEARS® Auditory Questionnaire on children with normal hearing who are German speaking and a second validating the norm curves found after adaptation and administration of the questionnaire to children with normal hearing in 15 different languages. Methods Scores from a group of 218 German and Austrian children with normal hearing between 5 days and 24 months of age were used to create a norm curve. The questionnaire was adapted from the German original into English and then 15 other languages to date. Regression curves were found based on parental responses from 3309 normal hearing infants and toddlers. Curves for each language were compared to the original German validation curve. Results The results of the first study were a norm curve which reflects the age-dependence of auditory behaviour, reliability and homogeneity as a measure of auditory behaviour, and calculations of expected and critical values as a function of age. Results of the second study show that the regression curves found for all the adapted languages are essentially equal to the German norm curve, as no statistically significant differences were found. Conclusions The LittlEARS® Auditory Questionnaire is a valid, language-independent tool for assessing the early auditory behaviour of infants and toddlers with normal hearing. The results of this study suggest that the LittlEARS® Auditory Questionnaire could also be very useful for documenting children's progress with their current amplification, providing evidence of the need for implantation, or highlighting the need for follow-up in other developmental areas.

(IF : 5,246); International audience; The present work is aimed at identifying and characterizing, at a molecular and functional level, new ionic conductances potentially involved in the excitation–secretion coupling and proliferation of cardiac ventricular fibroblasts. Among potassium channel transcripts which were screened by high-throughput real-time PCR, SUR2 and Kir6.1 mRNAs were found to be the most abundant in ventricular fibroblasts. The corresponding proteins were not detected by western blot following 5 days of cell culture, but had appeared at 7 days, increasing with extended cell culture duration as the fibroblasts differentiated into myofibroblasts. Using the inside-out configuration of the patch-clamp technique, single potassium channels could be recorded. These had properties similar to those reported for SUR2/Kir6.1 channels, i.e. activation by pinacidil, inhibition by glibenclamide and activation by intracellular UDP. As already reported for this molecular signature, they were insensitive to intracellular ATP. In the whole-cell configuration, these channels have been shown to be responsible for a glibenclamide-sensitive macroscopic potassium current which can be activated not only by pinacidil, but also by nanomolar concentrations of the sphingolipid sphingosine- 1-phosphate (S1P). The activation of this current resulted in an increase in cell proliferation and a decrease in IL-6 secretion, suggesting it has a functional role in situations where S1P increases. Overall, this work demonstrates for the first time that SUR2/Kir6.1 channels represent a significant potassium conductance in ventricular fibroblasts which may be activated in physio-pathological conditions and which may impact on fibroblast proliferation and function.

Genistein is a tyrosine kinase inhibitor which interferes with the activity of several ionic channels either by altering modulatory phosphorylating processes or by direct binding. In whole-cell conditions, genistein induces a partial inhibition of the pacemaker (If) current recorded in cardiac sinoatrial and ventricular myocytes. We investigated the mechanism of action of genistein (50 μM) on the If current in whole-cell, cell-attached, and inside-out configurations, and the measured fractional inhibitions were similar: 26.6, 27.2, and 33.6%, respectively. When ATP was removed from the whole-cell pipette solution no differences were revealed in the effect of the drug when compared to metabolically active cells. Genistein fully maintained its blocking ability even when herbimycin, a tyrosine kinase inhibitor, was added to the whole-cell ATP-free pipette solution. Genistein-induced block was independent of the gating state of the channel and did not display voltage or current dependence; this independence distinguishes genistein from all other f-channel blockers. When inside-out experiments were performed to test for a direct interaction with the channel, genistein, superfused on the intracellular side of the membrane, decreased the maximal If conductance, and slightly shifted the current–activation curve to the left. Furthermore, the effect of genistein was independent of cAMP modulation. We conclude that, in addition to its tyrosine kinase-inhibitory properties, genistein also blocks If by directly interacting with the channel, and thus cannot be considered a valuable pharmacological tool to investigate phosphorylation-dependent modulatory pathways of the If current and of cardiac rhythm. British Journal of Pharmacology (2006) 147, 36–44. doi:10.1038/sj.bjp.0706433

As reported for cyclic nucleotide-gated channels in sensory neurons, we investigated the action of Ca 2+ –calmodulin and calmodulin antagonist (W7) on the apparent affinity of pacemaker ( I f ) channels for cAMP. In this study, we used the patch-clamp technique in inside–out macro-patch configuration in rabbit sino-atrial cells. Intracellular calmodulin perfusion had no effect on f-channel activity and did not change the cAMP-induced I f activation shift. Nevertheless, W7 decreased maximal conductance and induced a voltage shift of the current activation curve towards negative potentials. W7 did not modify the positive shift caused by cAMP, and cAMP did not prevent the effects of W7. Contrary to the cyclic nucleotide-gated channel, the f-channel is not directly modulated by Ca 2+ –calmodulin. The data suggest that W7 alters the voltage-dependent properties of I f independent of cAMP binding. This agent opens the pathway for a new family of bradycardic drugs.

The fraction of glucose passing through glycolysis that is oxidized is low in hypertrophied hearts, a pattern of glucose use associated with poor postischemic contractile function. We tested the hypothesis that trimetazidine, a partial 3-ketoacyl coenzyme A thiolase inhibitor, would stimulate glucose oxidation and, thereby, improve fractional glucose oxidation and postischemic function of hypertrophied hearts. Function, glycolysis, and oxidation of glucose, lactate, and palmitate were measured before and after global no-flow ischemia in isolated working hearts from sham-operated (control) and aortic-constricted (hypertrophied) male Sprague-Dawley rats in the presence or absence of 1 microM trimetazidine. Heart function was significantly improved by trimetazidine after ischemia, but only in hypertrophied hearts, with function improving to values in untreated control hearts. This effect occurred in association with relatively minor changes in oxidative metabolism. However, trimetazidine reduced glycolysis by approximately 30% but did so only in hypertrophied hearts, an unexpected novel action of this agent that resulted in a larger fractional oxidation of glucose, effectively normalizing it in hypertrophied hearts. Thus, trimetazidine normalizes postischemic function and fractional glucose oxidation in hypertrophied hearts, mainly by reducing glycolysis. These data extend the potential usefulness of trimetazidine and provide support for its use as a means to improve postischemic function of pressure overload hypertrophied hearts.

The present study investigated the tolerance of the isolated rat heart to ischemia-reperfusion after administration of trimetazidine (TMZ) at different experimental phases, as well as the possible involvement of p38 MAPK and JNKs in this response. Isolated rat hearts were perfused in Langendorff mode. Untreated hearts after stabilization (S) were subjected to 20 min of zero-flow global ischemia (I) and 45 min of reperfusion (R), (NORM), n = 9. TMZ (10(-5) M) was administered (in the perfusate): a) only at S phase, (TMZ-STAB), n = 8, b) only at R, (TMZ-REP), n = 8 and c) during both S and R, (TMZ-STAB+REP), n = 8. Recovery of left ventricular developed pressure at 45 min of R (Rec) was significantly higher in TMZ-STAB and TMZ-STAB+REP and LDH release was lower in TMZ-STAB+REP and TMZ-STAB than NORM, [1153.2 (121.0) and 1152.1 (86.8) vs 1573.5 (138.2), P < 0.05]. TMZ induced cardioprotection did not involve p38 MAPK and JNKs. Phospho-p38 MAPK and JNKs levels after I/R were not changed with TMZ treatment. In TMZ-REP, Rec and LDH release were similar to NORM, but the rate of functional recovery (ratio of Rec at 10 min of R to Rec) was 86.7% (13.3) for TMZ-REP vs 53.8% (7.7) for NORM, P < 0.05. This effect was associated with decreased myocardial lactate content early at reperfusion. In conclusion, preischemic administration of TMZ protects against I/R injury while TMZ given only at reperfusion accelerates recovery of function without reducing the extent of injury.

In cardiac hypertrophy, both excessive enlargement of cardiac myocytes (CMs) and progressive fibrosis are known to occur simultaneously. To investigate the nature of interactions between ventricular CMs and cardiac fibroblasts (CFs) in these conditions, we have established a "dedifferentiated model" of adult murine CMs in coculture with CFs. In such a model, which is recognized to study cardiac cell hypertrophy in vitro, dedifferentiated CMs in culture and in coculture were characterized by immunopositive staining to ANP (atrial natriuretic peptide) and beta-myosin heavy chain (beta-MHC). The results confirm that ANP secretion by CMs was significantly increased during the cultures. The increase size of cultured CMs was significantly higher in CM/CF cocultures than in CM cultures which was also observed when CMs were cultured with fibroblast conditioned medium (FCM). In addition, fibroblast proliferation studies showed that CMs favored fibroblast adhesion and/or growth at the beginning of the coculture and fibroblast proliferation throughout the time course of the coculture. Furthermore, a significant level of interleukin-6 (IL-6) production was detected by ELISA in CM/CF cocultures. A similar higher increase was observed when CMs were cultured in the presence of FCM. These results demonstrate that CFs enhance myocyte hypertrophy and that CMs regulate fibroblast adhesion and/or proliferation, suggesting a paracrine interaction between CMs and CFs which could involve IL-6.

Objectives: Recent in vivo and in vitro studies in animals have demonstrated that cytokines of the IL-6 family are involved in cardiac hypertrophy and in protection of cardiomyocytes against apoptosis. The present study aims to analyse the capacity of human atrial cardiac cells (i.e., cardiomyocytes and fibroblasts) to display the gp130 receptor subunit, and to evaluate its functionality. Methods: Twenty human atrial biopsies were used for immunohistochemistry, in situ hybridisation, and western blot analysis or dissociated for isolation and primary culture of cardiac cells. Results: Fibroblasts present in tissue or maintained in primary culture clearly express gp130 whereas the signal in cardiomyocytes is weaker. Culture of cardiac cells with a gp130 agonist antibody enhances atrial natriuretic peptide (ANP), β myosin heavy chain (β-MHC) expression in cardiomyocytes, and significantly increases the cell surface area (μm2). This process could involve STAT3 (signal transducer and activator of transcription 3) phosphorylation. Conclusions: These results demonstrate that gp130 activation in human cardiac cells leads to cardiomyocyte hypertrophy. We discuss several hypotheses on the role of IL-6-type cytokines on cardiomyocyte functions.

Summary Introduction The bronchogenic cyst is a rare congenital malformation of the tracheobronchial tree. Ectopic bronchogenic cysts are extremely rare; they usually develop at the cervical level. This cyst is characterized by the presence of respiratory epithelium. Observation A 5-year-old child was referred to maxillofacial surgery consultation because a right bronchial cyst was suspected. The radiological assessment suggested a thyroglossal tract cyst. The anatomopathological examination confirmed the cyst and lead to the final diagnosis of a dysembryoplastic bronchogenic cyst. Discussion A bronchogenic cyst is rarely found at the cervical level. When this is the case, its embryological origin and management may be discussed. The preoperative diagnosis may be complex with no clinical or non-specific symptomatology. A complete excision of the lesion must be performed to reduce the risk of recurrence and malignant transformation.

International audience; Cardiac fibroblasts are an integral part of the myocardial tissue and contribute to its remodelling. This study characterises for the first time the calcium-dependent chloride channels (CaCC) in the plasma membrane of primary human atrial cardiac fibroblasts by means of the iodide efflux and the patch clamp methods. The calcium ionophore A23187 and Angiotensin II (Ang II) activate a chloride conductance in cardiac fibroblasts that shares pharmacological similarities with calcium-dependent chloride channels. This chloride conductance is depressed by RNAi-mediated selective Anoctamine 1 (ANO1) but not by Anoctamine 2 (ANO2) which has been revealed as CaCC and is inhibited by the selective ANO1 inhibitor, T16inh-A01. The effect of Ang II on anion efflux is mediated through AT1 receptors (with an EC50 = 13.8 ± 1.3 nM). The decrease of anion efflux by calphostin C and bisindolylmaleimide I (BIM I) suggests that chloride conductance activation is dependent on PKC. We conclude that ANO1 contributes to CaCC current in human cardiac fibroblasts and that this is regulated by Ang II acting via the AT1 receptor pathway.

EBV-related nasopharyngeal carcinomas (NPCs) still raise serious therapeutic problems. The therapeutic potential of the histone-deacetylase (HDAC) inhibitor Abexinostat was investigated using 5 preclinical NPC models including 2 patient-derived xenografts (C15 and C17). The cytotoxicity of Abexinostat used either alone or in combination with cis-platin or irradiation was assessed in vitro by MTT and clonogenic assays using 2 EBV-negative (CNE1 and HONE1) and 3 EBV-positive NPC models (C15, C17 and C666-1). Subsequently, the 3 EBV-positive models were used under the form of xenografts to assess the impact of systemic treatments by Abexinostat or combinations of Abexinostat with cis-platin or irradiation. Several cell proteins known to be affected by HDAC inhibitors and the small viral non-coding RNA EBER1 were investigated in the treated tumors. Synergistic cytotoxic effects of Abexinostat combined with cis-platin or irradiation were demonstrated in vitro for each NPC model. When using xenografts, Abexinostat by itself (12.5 mg/kg, BID, 4 days a week for 3 weeks) had significant anti-tumor effects against C17. Cooperative effects with cis-platin (2 mg/kg, IP, at days 3, 10 and 17) and irradiation (1 Gy) were observed for the C15 and C17 xenografts. Simultaneously two types of biological alterations were induced in the tumor tissue, especially in the C17 model: a depletion of the DNA-repair protein RAD51 and a stronger in situ detection of the small viral RNA EBER1. Overall, these results support implementation of phase I/II clinical trials of Abexinostat for the treatment of NPC. A depletion of RAD51 is likely to contribute to the cooperation of Abexinostat with DNA damaging agents. Reduction of RAD51 combined to enhanced detection of EBER 1 might be helpful for early assessment of tumor response.

Increased levels of the physiological amino acid homocysteine (Hcy) are considered a risk factor for vascular disease. Hyperhomocysteinemia causes an intense remodelling of the extracellular matrix in arterial walls, particularly an elastolysis involving metalloproteinases. We investigated the activation of the latent elastolytic metalloproteinase proMMP-2 (72 kDa) by Hcy. Hcy was proved to exert a dual effect, activating proMMP-2 at low molar ratio (MR 10:1) and inhibiting active MMP2 at high molar ratio (MR > 1000:1). Methionine and the disulphide homocystine did not activate nor inhibit MMP-2, showing that the activation as well as the inhibition requires the thiol group to be free. The activation of proMMP-2 by Hcy is in accordance with the "cysteine-switch" mechanism, but occurs without further autoproteolysis of the enzyme molecule. In contrast with Hcy, the other physiological thiol compounds cysteine and reduced glutathione did not activate proMMP-2. These results suggest that the direct activation of proMMP2 by Hcy could be one of the mechanisms involved in the extracellular matrix deterioration in hyperhomocysteinemia-associated arteriosclerosis.

The stiffness tensor of a balanced composite material is described by six coefficients. Four of them are measured by means of a non-contact technique consisting of the focusing of a pulsed laser in one side of the sample. A laser interferometric probe is used on the other side to detect the acoustic wave fronts. These devices are associated with a specific oven that allows the transmission of the optical beams. The four coefficients are measured for various temperatures, increasing by steps up to the glass transition temperature. The sensitivity of the measurement is convenient to detect the stiffness coefficient changes which show the anisotropy of the changes of material properties induced by temperature.

Ultrasonic waves are generated through a composite material by means of a noncontact technique. It uses a Nd:Yag LASER for the generation and an interferometric probe for the detection of acoustic waveforms. From a suitable set of experimental data, an inversion scheme is used for the recovering of four stiffness coefficients. They characterize the elasticity in a principal plane of symmetry of the material which exhibits an orthorhombic symmetry. The measurements are performed at various temperatures, elevated by steps up to 300°C for two specimen. The sensitivity of the method appears convenient to measure the temperature induced stiffness changes. The anisotropic degradation of the material properties are then pointed out.

Aberrant activity of the receptor tyrosine kinases MET, AXL, and FGFR1/2/3 has been associated with tumor progression in a wide variety of human malignancies, notably in instances of primary or acquired resistance to existing or emerging anticancer therapies. This study describes the preclinical characterization of S49076, a novel, potent inhibitor of MET, AXL/MER, and FGFR1/2/3. S49076 potently blocked cellular phosphorylation of MET, AXL, and FGFRs and inhibited downstream signaling in vitro and in vivo. In cell models, S49076 inhibited the proliferation of MET- and FGFR2-dependent gastric cancer cells, blocked MET-driven migration of lung carcinoma cells, and inhibited colony formation of hepatocarcinoma cells expressing FGFR1/2 and AXL. In tumor xenograft models, a good pharmacokinetic/pharmacodynamic relationship for MET and FGFR2 inhibition following oral administration of S49076 was established and correlated well with impact on tumor growth. MET, AXL, and the FGFRs have all been implicated in resistance to VEGF/VEGFR inhibitors such as bevacizumab. Accordingly, combination of S49076 with bevacizumab in colon carcinoma xenograft models led to near total inhibition of tumor growth. Moreover, S49076 alone caused tumor growth arrest in bevacizumab-resistant tumors. On the basis of these preclinical studies showing a favorable and novel pharmacologic profile of S49076, a phase I study is currently underway in patients with advanced solid tumors. Mol Cancer Ther; 12(9); 1749–62. ©2013 AACR.

Aqueous-ethanolic extract ofCassia alata(AECal) and its derived fractions obtained through liquid-liquid fractionation were evaluated for their bronchorelaxant, genotoxic, and antigenotoxic effects. Contractile activity of rats’ tracheas in the presence of tested materials, as well as its modifications with different inhibitors and blockers, was isometrically recorded. The antigenotoxic potential of AECal was evaluated on cyclophosphamide- (CP-) induced genotoxicity in the rat. Animals were pretreated with the extract, then liver comet assay was performed. AECal and its chloroformic fractions (CF-AECal) relaxed the contraction induced by Ach, but both were significantly less potent in inhibiting contraction induced by KCl (30 mM; 80 mM). Propranolol, indomethacin, L-NAME, methylene blue, and glibenclamide did not modify the relaxant effect of CF-AECal. TEA altered the response of trachea to CF-AECal. CF-AECal caused a rightward shift without affecting theEmaxin cumulative concentration-response curves of Ach only at low concentrations. In animals pretreated with the extract, the percentage of CP-induced DNA damage decreased. Our results suggest that (1) muscarinic receptors contribute at least in part to the relaxant effects of CF-AECal; (2) CF-AECal interferes with membrane polarization; and (3) AECal is not genotoxicin vivoand contains chemopreventive phytoconstituents offering protection against CP-induced genotoxicity.

1. The effect of the bradycardic agent S 16257 on the main ionic mechanisms of diastolic depolarization in sinoatrial node cells isolated from rabbit heart, was investigated by the patch-clamp technique in whole-cell and macro-patch recordings. 2. In whole-cell conditions, S 16257 induced a marked exponential use-dependent blockade of the hyperpolarization-activated I(f) current, without shift of the voltage range of its activation curve. The rate of block increased with the drug concentration. The IC50 for the block of I(f) was 2.8 x 10(-6) M. 3. A similar use-dependent decline of I(f) was obtained with 3 microM S 16257, in cell-attached and in inside out macro-patch configurations, suggesting that the bradycardic agent interacts with I(f) channels from the inside of the cell. 4. A high concentration of S 16257 (10 microM) had no detectable effect on T-type calcium current and slightly decreased L-type calcium current (-18.12 +/- 0.66%), without significant use-dependent blockade. 5. S 16257 had no effect on the delayed outward potassium current Ik at 3 microM and slightly decreased it only at high concentrations, -16.3 +/- 1.2% at 10 microM. In contrast, zatebradine, another bradycardic agent, reduced I k by 20.3 +/- 2.5% at 3 microM. 6. In conclusion, S 16257 may lower heart rate without significant negative inotropic action. In comparison with zatebradine, S 16257 had less effect on Ik suggesting less prolongation of repolarization time.

The current produced by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (termed I f, cardiac pacemaker “funny” current, and I h in neurons) is also considered a “pacemaker current” because it plays a key role in controlling the rhythmic activity of cardiac pacemaker cells and spontaneously firing neurons. The pacemaker current is an inward current activated by voltage hyperpolarization and modulated by intracellular cAMP. Voltage-dependent opening of these pacemaker channels is directly regulated by the binding of cAMP. The f-channels are encoded by four genes (HCN1–4) and are widely expressed throughout the heart and central nervous system. This article summarizes the structure, function, and regulation of these channels. Because of their relevance to cardiac pacemaker activity, f-channels are a natural target of drugs aimed at the pharmacological control of heart rate. In this regard, several agents developed for their capacity to selectively reduce heart rate act by specifically inhibiting f-channel function. Related compounds that could potentially be used for the treatment of diseases such as angina and heart failure are also discussed.

The mechanism of the action of acetylcholine (ACh) on the L-type calcium current (ICa,L) was examined using a whole-cell voltage-clamp technique in single sino-atrial myocytes from the rabbit heart. ACh depressed basal ICa,L at concentrations in the range 0.05-10 microM, without previous beta-adrenergic stimulation. The ACh-induced reduction of ICa,L was reversed by addition of atropine, indicating that muscarinic receptors mediate it. Incubation of cells with a solution containing pertussis toxin led to abolition of the ACh effect, suggesting that this effect is mediated by G proteins activated by muscarinic receptors. Dialysis of cells with protein kinase inhibitor or 5'-adenylyl imidodiphosphate, inhibitors of the cAMP-dependent protein kinase, decreased basal ICa,L by about 85% and suppressed the effect of ACh. The ACh effect was also absent in cells dialysed with a non-hydrolysable analogue of cAMP, 8-bromo-cAMP. The results suggest that, in basal conditions, a large part of the L-type calcium channels should be phosphorylated by protein kinase A stimulated by a high cAMP level correlated with a high adenylate cyclase activity. The depressing effect of ACh on ICa,L may occur via inhibition of the high basal adenylate cyclase activity leading to a decrease of cAMP-dependent protein kinase stimulation and thus to a dephosphorylation of calcium channels.

Cochlear implants help children with severe hearing difficulties achieve access to verbal language. We possess evidence of the capacities of perception and discrimination skills as well as knowledge relating to the development of verbal productions and intelligibility. In contrast, little work has been undertaken concerning the spontaneous use of language by children with implants in interactions with their friends and family. At the same time, the high level of variability observed in the language acquisition speed profiles has led us to consider the role of a number of variables. We hypothesized that the insertion of an implant and the consequent access to sound information should be followed by an increase in the number of different words used in spontaneous play interaction. The latter follows a different developmental process correlating to the age of the child at implantation, to the type of communication mode used before implantation, to the school integration level in a normal hearing environment (thus relating to the demands made on a verbal communication mode), and to the sex of the child. 38 pre-lingually deaf children (mean age: 3;08) using cochlear implants were filmed at regular intervals over a period of a year. Results tend to show that only school integration in a hearing environment seems to be a determining factor with regard to the development of lexical diversity in deaf children who have received implants. The demands made by age group peers seem to favor the use of verbal language and cause it to develop at a faster rate. L’implant cochléaire permet à des enfants atteints de surdité profonde, l’accès au langage verbal. Nous disposons actuellement de données sur les stratégies de traitement de l’information sonore, en revanche peu de travaux portent sur l’usage spontané du langage de l’enfant implanté avec son entourage. Par ailleurs, la forte variabilité observée dans les profils de vitesse d’acquisition du langage nous a menés à nous interroger sur le rôle de plusieurs variables. Nous avons supposé quela pose d’un implant et donc l’accès aux informations sonores, devrait s’accompagner d’une augmentation du nombre de mots différents utilisés au cours des interactions. Cette augmentation progressive de la diversité lexicale devrait s’effectuer selon des parcours de développement différenciés qui seraient indexés sur l’âge de l’enfant à l’implantation, le mode de communication privilégié avant l’implantation (communication orale vs signée), le type de scolarisation (intégration dans un milieu entendant vs école spécialisée) ainsi que le sexe de l’enfant. 38 enfants sourds (moyenne d’âge : 3 ;08 ans) prélinguaux implantés ont été filmés, à intervalle régulier, pendant une année. Les résultats tendent à montrer que l’intégration scolaire des enfants sourds implantés, en milieu entendant serait déterminante dans le développement de la diversité lexicale et l’usage spontané du langage verbal. De tels résultats semblent indiquer que les sollicitations des pairs favoriseraient l’usage du langage verbal et participeraient de ce fait à une maîtrise plus rapide d’une plus grande richesse lexicale.

WOS:000259308400018; International audience; [No abstract]

(IF : 4,868); International audience; The spontaneous activity of cardiac tissue originates in specialized pacemaker cells in the sino-atrial node that generate autonomous rhythmic electrical impulses. A number of regions in the brain are also able to generate spontaneous rhythmic activity to control and regulate important physiological functions. The generation of pacemaker potentials relies on a complex interplay between different types of currents carried by cation channels. Among these currents, the hyperpolarization-activated current (termed I(f), cardiac pacemaker "funny" current, and I(h) in neurons) is the major component contributing to the initiation of cardiac and neuronal excitability and to the modulation of this excitability by neurotransmitters and hormones. I(f) is an inward current activated by hyperpolarization of the membrane potential and by intracellular cyclic nucleotides such as cAMP. The identification at the end of the 1990s of a family of mammalian genes that encode for four Hyperpolarization-activated Cyclic Nucleotide-gated channels, HCN1-4, has made analysis of the location of these channels and the study of their biophysical properties an obtainable goal. As a result, specific agents have been developed for their ability to selectively reduce heart rate by lowering cardiac pacemaker activity where f-channels are their main natural target. These drugs include alinidine, zatebradine, cilobradine, ZD-7288 and ivabradine. Recent data indicate that pharmacological tools such as W7 and genistein, which have been used to identify some intracellular pathways involved in ionic channel modulation, also have the ability to inhibit I(f) directly. This opens new perspectives for the future development of other specific rhythm-lowering agents.