Babuty D.,CHRU Tours
Journal of Pharmacological and Toxicological Methods | Year: 2013
Introduction: Power spectral analysis of heart rate variability is a tool known to provide information of interest on the autonomic control of heart rate in human. However, its use and its conditions of application and interpretation for safety purposes are not well defined for cardiovascular safety pharmacology studies. Likewise, data of power spectral analysis of heart rate variability in cynomolgus monkeys, a species often appropriate for use as second non rodent species in preclinical safety programmes, are not available. This study was designed to evaluate the relevance of this biomarker in this non human primate species, and to compare results with those from beagle dogs under the conditions of safety evaluation studies. Methods: Power spectral analysis of heart rate variability was performed on data collected in both species by telemetry following a standard design for cardiovascular safety pharmacology studies. Various pharmacological agents were tested in order to compare the profile of responses in both species after modifying the autonomic nervous balance. Results: Heart rate variability in cynomolgus monkeys is mainly driven by the parasympathetic nervous system as in beagle dogs although vagal tone is less than in dogs. Power spectral analysis of heart rate variability allows detection of interaction with the autonomic nervous system in both species in all investigated situations, i.e. sympatholytic/sympathomimetic and parasympatholytic/parasympathomimetic drug induced effects. However, due to species difference in the autonomic control of heart rate, cynomolgus monkeys are likely to be more sensitive than beagle dogs for assessment of sympatholytic properties. Discussion: This study confirms that power spectral analysis of heart rate variability from data derived from ECG recordings in telemetry studies is applicable in cardiovascular safety pharmacology studies and may provide relevant information about possible interaction with the autonomic nervous system when new drug entities are evaluated in either species. However, interspecies differences in autonomic control must be taken into account when interpreting possible drug effects. © 2013 Elsevier Inc.
Ferro F.,French Institute of Health and Medical Research |
Ouille A.,Montpellier University |
Tran T.-A.,French Institute of Health and Medical Research |
Fontanaud P.,Montpellier University |
And 4 more authors.
PLoS ONE | Year: 2012
Background and purpose: In some pathological conditions carnitine concentration is high while in othersitis low.In bothcases,cardiac arrhythmiascan occur and lead to sudden cardiac death. It has been proposed that in ischaemia, acylcarnitine (acyl-CAR), but not carnitine, is involved in arrhythmiasthrough modulation of ionic currents. We studied the effects of acyl-CARs on hERG, KIR2.1 and Kv7.1/minKchannels (channels responsible for IKR, IK1 and IKS respectively). Experimental approach: HEK293 cells stably expressing hERG, KIR2.1 or Kv7.1/minK were studied using the patch clamp technique. Free carnitine (CAR) and acyl-CAR derivatives from medium- (C8 and C10) and long-chain (C16 and C18:1) fatty acids were applied intra- and extracellularly at different concentrations. Forstudies onhERG, C16 and C18:1 free fatty acid were also used. Key results: Extracellular long-chain (LCAC), but not medium-chain, acyl-CAR,induced an increase of IhERG amplitude associated with a dose-dependent speeding of deactivation kinetics. They had no effect on KIR2.1 or Kv7.1/minK currents.Computer simulations of these effects wereconsistent with changes in action potential profile. Conclusions and applications: Extracellular LCAC tonically regulates IhERG amplitude and kineticsunder physiological conditions. This modulation maycontribute tothe changes in action potential duration thatprecede cardiac arrhythmias in ischaemia, diabetes and primary systemic carnitine deficiency. © 2012 Ferro et al.
PubMed | University of Bordeaux 1, CHU Rouen, Paris-Sorbonne University, APHP and 5 more.
Type: Journal Article | Journal: Clinical genetics | Year: 2016
Otopalatodigital spectrum disorders (OPDSD) include OPD syndromes types 1 and type 2 (OPD1, OPD2), Melnick-Needles syndrome (MNS), and frontometaphyseal dysplasia (FMD). These conditions are clinically characterized by variable skeletal dysplasia associated in males, with extra-skeletal features including brain malformations, cleft palate, cardiac anomalies, omphalocele and obstructive uropathy. Mutations in the FLNA gene have been reported in most FMD and OPD2 cases and in all instances of typical OPD1 and MNS. Here, we report a series of 10 fetuses and a neonatally deceased newborn displaying a multiple congenital anomalies syndrome suggestive of OPDSD and in whom we performed FLNA analysis. We found a global mutation rate of 44%. This series allows expanding the clinical and FLNA mutational spectrum in OPDSD. However, we emphasize difficulties to correctly discriminate OPDSD based on clinical criteria in fetuses due to the major overlap between these conditions. Molecular analyses may help pathologists to refine clinical diagnosis according to the type and the location of FLNA mutations. Discriminating the type of OPDSD is of importance in order to improve the genetic counseling to provide to families.
PubMed | CHRU Tours, Center hospitalier Lyon Sud and University of Lyon
Type: Journal Article | Journal: Virchows Archiv : an international journal of pathology | Year: 2016
The DICER1 gene encodes an endoribonuclease involved in the production of mature microRNAs which regulates gene expression through several mechanisms. Carriers of germline DICER1 mutations are predisposed to a rare cancer syndrome, the DICER1 syndrome. Pleuropulmonary blastoma is the most frequent lesion seen in this syndrome. Thyroid abnormalities are also a common finding, essentially concerning multinodular goiter. However, differentiated thyroid carcinoma is infrequently seen in such pedigrees. In addition to germline DICER1 mutations, specific somatic mutations have been identified in the DICER1 RNase IIIb catalytic domain in several tumor types, including ovarian Sertoli-Leydig cell tumors. We report two cases of differentiated thyroid carcinoma associated with ovarian Sertoli-Leydig cell tumor and with a heterozygous DICER1 gene mutation, occurring in two unrelated young girls without pleuropulmonary blastoma. Both thyroid carcinomas showed an E1813 mutation in exon 25 while the ovarian tumors harboured a somatic mutation in E1705 in exon 24 and a D1709 mutation in exon 25. Our observations confirm that the occurrence of an ovarian Sertoli-Leydig cell tumor with a thyroid carcinoma is highly suggestive of a DICER1 syndrome. We contend that the possibility of a relationship between sporadic thyroid carcinoma in young patients and somatic DICER1 gene mutation needs further investigation.
PubMed | CHRU Tours, Service Of Pharmacologie Clinique Center Regional Of Pharmacovigilance, French Institute of Health and Medical Research and University of Tours
Type: Journal Article | Journal: Respiratory medicine | Year: 2014
Amiodarone-induced pulmonary toxicity (APT) is a serious adverse event that can lead to death. The aims of our study are to determine factors associated with mortality and to describe outcome and sequelae of patients with APT.Forty-six patients with APT were divided into two groups according to survival at day 90 for a clinical, functional, biological and radiological comparaison. We then evaluated the evolution of 15 survivors at a median of three months [1-6 months] and/or 12 months [8-36 months].Mortality of APT at day 90 was 37% (17 patients) and was linked to the speed of onset of symptoms and a high HRCT alveolar score. Angiotensin system antagonist treatment was prescribed significantly more in the survival group (p = 0.042, HR 0.34 (95% CI 0.12-0.96)). In surviving patients, dyspnea, vital capacity and HRCT alveolar score improved significantly while HRCT fibrosis score deteriorated gradually during the first six months. At the end of the study, all the surviving patients presented functional and/or radiological sequelae.Severity of APT is linked to the extent and speed of onset of pulmonary damage. After the initial episode, the patients who survived improved slowly but with persistent sequelae.