Mutations in the m-AAA proteases AFG3L2 and SPG7 are causing isolated dominant optic atrophy.

OBJECTIVE: To improve the genetic diagnosis of dominant optic atrophy (DOA), the most frequently inherited optic nerve disease, and infer genotype-phenotype correlations. METHODS: Exonic sequences of 22 genes were screened by new-generation sequencing in patients with DOA who were investigated for ophthalmology, neurology, and brain MRI. RESULTS: We identified 7 and 8 new heterozygous pathogenic variants in SPG7 and AFG3L2. Both genes encode for mitochondrial matricial AAA (m-AAA) proteases, initially involved in recessive hereditary spastic paraplegia type 7 (HSP7) and dominant spinocerebellar ataxia 28 (SCA28), respectively. Notably, variants in AFG3L2 that result in DOA are located in different domains to those reported in SCA28, which likely explains the lack of clinical overlap between these 2 phenotypic manifestations. In comparison, the SPG7 variants identified in DOA are interspersed among those responsible for HSP7 in which optic neuropathy has previously been reported. CONCLUSIONS: Our results position SPG7 and AFG3L2 as candidate genes to be screened in DOA and indicate that regulation of mitochondrial protein homeostasis and maturation by m-AAA proteases are crucial for the maintenance of optic nerve physiology

Pathogenic <i>NR2F1</i> variants cause a developmental ocular phenotype recapitulated in a mutant mouse model.

Funder: National Institute of Health Research Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of OphthalmologyPathogenic NR2F1 variants cause a rare autosomal dominant neurodevelopmental disorder referred to as the Bosch-Boonstra-Schaaf Optic Atrophy Syndrome. Although visual loss is a prominent feature seen in affected individuals, the molecular and cellular mechanisms contributing to visual impairment are still poorly characterized. We conducted a deep phenotyping study on a cohort of 22 individuals carrying pathogenic NR2F1 variants to document the neurodevelopmental and ophthalmological manifestations, in particular the structural and functional changes within the retina and the optic nerve, which have not been detailed previously. The visual impairment became apparent in early childhood with small and/or tilted hypoplastic optic nerves observed in 10 cases. High-resolution optical coherence tomography imaging confirmed significant loss of retinal ganglion cells with thinning of the ganglion cell layer, consistent with electrophysiological evidence of retinal ganglion cells dysfunction. Interestingly, for those individuals with available longitudinal ophthalmological data, there was no significant deterioration in visual function during the period of follow-up. Diffusion tensor imaging tractography studies showed defective connections and disorganization of the extracortical visual pathways. To further investigate how pathogenic NR2F1 variants impact on retinal and optic nerve development, we took advantage of an Nr2f1 mutant mouse disease model. Abnormal retinogenesis in early stages of development was observed in Nr2f1 mutant mice with decreased retinal ganglion cell density and disruption of retinal ganglion cell axonal guidance from the neural retina into the optic stalk, accounting for the development of optic nerve hypoplasia. The mutant mice showed significantly reduced visual acuity based on electrophysiological parameters with marked conduction delay and decreased amplitude of the recordings in the superficial layers of the visual cortex. The clinical observations in our study cohort, supported by the mouse data, suggest an early neurodevelopmental origin for the retinal and optic nerve head defects caused by NR2F1 pathogenic variants, resulting in congenital vision loss that seems to be non-progressive. We propose NR2F1 as a major gene that orchestrates early retinal and optic nerve head development, playing a key role in the maturation of the visual system

Pathogenic NR2F1 variants cause a developmental ocular phenotype recapitulated in a mutant mouse model.

Pathogenic NR2F1 variants cause a rare autosomal dominant neurodevelopmental disorder referred to as the Bosch-Boonstra-Schaaf Optic Atrophy Syndrome. Although visual loss is a prominent feature seen in affected individuals, the molecular and cellular mechanisms contributing to visual impairment are still poorly characterized. We conducted a deep phenotyping study on a cohort of 22 individuals carrying pathogenic NR2F1 variants to document the neurodevelopmental and ophthalmological manifestations, in particular the structural and functional changes within the retina and the optic nerve, which have not been detailed previously. The visual impairment became apparent in early childhood with small and/or tilted hypoplastic optic nerves observed in 10 cases. High-resolution optical coherence tomography imaging confirmed significant loss of retinal ganglion cells with thinning of the ganglion cell layer, consistent with electrophysiological evidence of retinal ganglion cells dysfunction. Interestingly, for those individuals with available longitudinal ophthalmological data, there was no significant deterioration in visual function during the period of follow-up. Diffusion tensor imaging tractography studies showed defective connections and disorganization of the extracortical visual pathways. To further investigate how pathogenic NR2F1 variants impact on retinal and optic nerve development, we took advantage of an Nr2f1 mutant mouse disease model. Abnormal retinogenesis in early stages of development was observed in Nr2f1 mutant mice with decreased retinal ganglion cell density and disruption of retinal ganglion cell axonal guidance from the neural retina into the optic stalk, accounting for the development of optic nerve hypoplasia. The mutant mice showed significantly reduced visual acuity based on electrophysiological parameters with marked conduction delay and decreased amplitude of the recordings in the superficial layers of the visual cortex. The clinical observations in our study cohort, supported by the mouse data, suggest an early neurodevelopmental origin for the retinal and optic nerve head defects caused by NR2F1 pathogenic variants, resulting in congenital vision loss that seems to be non-progressive. We propose NR2F1 as a major gene that orchestrates early retinal and optic nerve head development, playing a key role in the maturation of the visual system

Etude multicentrique d'intervention nutritionnelle LipGene (effets de la qualité et de la quantité des acides gras alimentaires chez des sujets présentant un syndrome métabolique)

Le syndrome métabolique n'est pas une maladie spécifique, mais désigne plutôt une association de dysfonctionnements métaboliques modérés liés aux risques cardio-vasculaires: insulino-résistance, hyperglycémie, hyper-triglycéridémie, hypertension et excès de poids. L étude d intervention nutritionnelle LipGene est une étude européenne multicentrique menée sur une cohorte de 486 volontaires présentant un syndrome métabolique d après les critères de la NCEP-ATPIII. Le principal objectif de LipGene est d étudier l impact de la qualité et de la quantité des lipides alimentaires sur de nombreux paramètres liés à l insulino-résistance, principale composante du syndrome métabolique. Les volontaires ont été randomisés dans quatre régimes avec des teneurs variées d AGS, d AGMI, d AGPI et de glucides. L intervention nutritionnelle a duré 12 semaines et a permis d étudier les variations des profils glucidiques, lipidiques, des paramètres inflammatoires et du stress oxydant et les variations de marqueurs liés aux dysfonctions endothéliales. Une des originalités de cette étude est d avoir appliqué avec succès un modèle diététique unique à travers les huit centres européens participants. Le modèle de substitution alimentaire mis en place lors de l intervention nutritionnelle a permis une bonne compliance aux régimes et des objectifs d apports lipidiques et glucidiques atteints dans les 4 groupes de régimes. Après 12 semaines de régime, l état d insulino-résistance des volontaires SM n apparaît pas directement affecté par les 4 régimes mais les effets observés sur les marqueurs de l insulinorésistance semblent très dépendants de la composition lipidique des habitudes alimentaires de base. Nous avons confirmé l effet hypotriglycéridémiant des AGPI n-3 quand, en complément dans un régime pauvre en lipides mais hyperglucidiques, ces acides gras permettaient d atténuer l hypertriglycéridémie généralement observée avec ce type de régime sans supplémentation. Le profil lipidique des sujets SM et notamment leur métabolisme du cholestérol est affecté par les régimes riches en glucides même s ils sont pauvres en lipides. Les taux des marqueurs de l inflammation, de la coagulation ou encore du stress oxydant n ont pas été modifiés par l intervention nutritionnelle. La formation d une sous-cohorte Méditerranéenne a permis quelques études additionnelles. Parmi celles-ci, l étude du dysfonctionnement endothéliale a été réalisée par quantification des microparticules circulantes. Avant analyse de l intervention nutritionnelle sur ces taux de microparticules, il est intéressant de souligner l élévation de microparticules de diverses origines dans notre population SM comparée à une population contrôle ainsi que le lien de corrélation de ces microparticules avec un marqueur du stress oxydant.AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocSudocFranceF

Effects of 3-month Mediterranean-type diet on postprandial TAG and apolipoprotein B48 in the Medi-RIVAGE cohort

Objective: To determine the postprandial lipaemia response before and after intervention with healthy diets in the Medi-RIVAGE cohort of subjects with moderate risk factors of CVD. Design: One hundred and thirty-five adults (fifty-two men and eighty-three women) followed either a Mediterranean-type (MED) diet or a low-fat American Heart Association-type diet in a parallel design for 3 months. At entry and after 3 months, lipids, glucose and insulin were measured in the fasting samples; TAG and apolipoprotein B48 (ApoB48; a marker of intestinally derived chylomicrons) levels were measured in the fasting and postprandial samples after a standard test meal. Results: The MED diet only lowered (P 25 kg/m(2) showed reduced postprandial ApoB48. Men and women displayed comparable postprandial changes after dietary challenges. Conclusions: A MED diet appears efficient to improve postprandial lipaemia, a recently acknowledged CVD risk, in men and women at moderate cardiovascular risk

Ionic wind produced by a DC needle-to-plate corona discharge with a gap of 15 mm

International audienceThe goal of the present study is to better understand the electrohydrodynamic (EHD) phenomena occurring in 15 mm gap point-to-plate corona discharges supplied by positive and negative DC voltages, and to link them to the discharge regime. For that, discharge current measurements have been conducted and a 20 kHz Particle Image Velocimetry system has been used to characterize the ionic wind produced by the discharges. The main results are as follows: (a) the Townsend's law can always correctly interpolate the experimental I–V characteristics of a negative corona, even in presence of Trichel pulses, (b) in the case of a positive streamer discharge, the current does not follow the Townsend's law as it evolves in Vk with k  =  4 in the present study, (c) Indeed, the discharge current becomes higher than the Townsend's law when the glow-to-streamer regime transition occurs, (d) the ionic wind is unsteady, more especially in the case of a positive corona for which it seems that its velocity is pulsed at the same frequency than the streamer one, (e) when the positive high voltage is switched on, a strong streamer occurs at the end of the voltage rising (t  =  25 µs for  +6 kV), resulting in an over-velocity region upstream the head of the ionic wind jet that progresses in quiescent air toward the plate, (f) the topology of the time-averaged ionic wind is fully different compared to the one observed in a previous study where the gap was equal to 25 mm, (g) in the case of a negative corona, the ionic wind velocity is nearly constant in the electrode gap, (h) in the case of the positive corona, the results are even more surprising since the velocity is minimum at the tip and increases when one approaches the grounded plate, indicating that there is a significant space charge remained by the streamers in the second half of the inter-electrode region, (i) generally speaking, this study highlights that the spatio-temporal characteristics of the EHD force and the resulting ionic wind depend on the distribution of the space charge between both electrodes, the latter being linked to the voltage polarity, the discharge regime and the electrode gap

Quantification of trans-resveratrol and its metabolites in human plasma using ultra-high performance liquid chromatography tandem quadrupole-orbitrap mass spectrometry

International audienceTrans-resveratrol is a stilbene polyphenol with a large spectrum of biological activities. This is why it is widely studied in terms of activities, bioavailability and quantitation in different foods, beverages and biological matrices. Different analytical methods are employed for its quantitation. In this study a quadrupole-orbitrap tandem mass spectrometer coupled to a reverse phase ultra-high performance liquid chromatography is applied to a quantitation of trans-resveratrol and its metabolites trans-resveratrol-3-O-beta-D-glucuronide, trans-resveratrol-4'-O-beta-D-glucuronide, trans-resveratrol-3-O-sulfate, a,b-dihydroresveratrol, a,b-dihydroresveratrol-glucuronide, a,b-dihydroresveratrol-glucuronide-sulfate, a,b-dihydroresveratrol-sulfate, trans-resveratrol-3,5-O-beta-D-diglucuronide, trans-resveratrol-3,4'-O-D-beta-diglucuronide, trans-resveratrol-3-O-beta-D-glucuronide-sulfate and trans-resveratrol-4'-O-beta-D-glucuronide-sulfate in human plasma. MS/MS experiments coupled to a high resolving power and accurate mass measurements as well as the use of labeled internal standards enabled the achievement of linear calibration curves across the four orders of magnitude concentration ranges. The method was validated in terms of specificity and selectivity, accuracy and precision, sensitivity and matrix effect and can be now applied to pharmacokinetic studies or routine analysis. In addition, the application of quadrupole-orbitrap mass spectrometer to the quantitation of trans-resveratrol and its metabolites provides acquisition of full collision induced dissociation spectra of analyzed compounds giving place to the structural characterization and sensitivity and linear concentration ranges respecting the accuracy and precision, specificity and selectivity requirements