Acute and late-onset optic atrophy due to a novel OPA1 mutation leading to a mitochondrial coupling defect

PurposeAutosomal dominant optic atrophy (ADOA, OMIM 165500), an inherited optic neuropathy that leads to retinal ganglion cell degeneration and reduced visual acuity during the early decades of life, is mainly associated with mutations in the OPA1 gene. Here we report a novel ADOA phenotype associated with a new pathogenic OPA1 gene mutation. Methods The patient, a 62-year-old woman, was referred for acute, painless, and severe visual loss in her right eye. Acute visual loss in her left eye occurred a year after initial presentation. MRI confirmed the diagnosis of isolated atrophic bilateral optic neuropathy. We performed DNA sequencing of the entire coding sequence and the exon/intron junctions of the OPA1 gene, and we searched for the mitochondrial DNA mutations responsible for Leber hereditary optic atrophy by sequencing entirely mitochondrial DNA. Mitochondrial respiratory chain complex activity and mitochondrial morphology were investigated in skin fibroblasts from the patient and controls. Results We identified a novel heterozygous missense mutation (c.2794C>T) in exon 27 of the OPA1 gene, resulting in an amino acid change (p.R932C) in the protein. This mutation, which affects a highly conserved amino acids, has not been previously reported, and was absent in 400 control chromosomes. Mitochondrial DNA sequence analysis did not reveal any mutation associated with Leber hereditary optic neuropathy or any pathogenic mutations. The investigation of skin fibroblasts from the patient revealed a coupling defect of oxidative phosphorylation and a larger proportion of short mitochondria than in controls. Conclusions The presence of an OPA1 mutation indicates that this sporadic, late-onset acute case of optic neuropathy is related to ADOA and to a mitochondrial energetic defect. This suggests that the mutational screening of the OPA1 gene would be justified in atypical cases of optic nerve atrophy with no evident cause

Hypoxia-activated genes from early placenta are elevated in preeclampsia, but not in Intra-Uterine Growth Retardation.

BACKGROUND: As a first step to explore the possible relationships existing between the effects of low oxygen pressure in the first trimester placenta and placental pathologies developing from mid-gestation, two subtracted libraries totaling 2304 cDNA clones were constructed. For achieving this, two reciprocal suppressive/subtractive hybridization procedures (SSH) were applied to early (11 weeks) human placental villi after incubation either in normoxic or in hypoxic conditions. The clones from both libraries (1440 hypoxia-specific and 864 normoxia-specific) were spotted on nylon macroarrays. Complex cDNAs probes prepared from placental villi (either from early pregnancy, after hypoxic or normoxic culture conditions, or near term for controls or pathological placentas) were hybridized to the membranes. RESULTS: Three hundred and fifty nine clones presenting a hybridization signal above the background were sequenced and shown to correspond to 276 different genes. Nine of these genes are mitochondrial, while 267 are nuclear. Specific expression profiles characteristic of preeclampsia (PE) could be identified, as well as profiles specific of Intra-Uterine Growth Retardation (IUGR). Focusing on the chromosomal distribution of the fraction of genes that responded in at least one hybridization experiment, we could observe a highly significant chromosomal clustering of 54 genes into 8 chromosomal regions, four of which containing imprinted genes. Comparative mapping data indicate that these imprinted clusters are maintained in synteny in mice, and apparently in cattle and pigs, suggesting that the maintenance of such syntenies is requested for achieving a normal placental physiology in eutherian mammals. CONCLUSION: We could demonstrate that genes induced in PE were also genes highly expressed under hypoxic conditions (P = 5 x 10(-5)), which was not the case for isolated IUGR. Highly expressed placental genes may be in syntenies conserved interspecifically, suggesting that the maintenance of such clusters is requested for achieving a normal placental physiology in eutherian mammals

Young People’s Views on Food Hygiene and Food Safety: A Multicentre Qualitative Study

Foodborne diseases are a global burden, are preventable, and young people are a key population for behaviour change as they gain autonomy. This study aimed to explore young people’s needs across several European countries in relation to learning about and implementing food hygiene and food safety. Qualitative focus groups and interviews were conducted in rural and city regions across England, France, Hungary and Portugal. Data were collected to attain data saturation, transcribed, thematically analysed, and mapped to the Theoretical Domains Framework. Twenty-five out of 84 schools approached (29.8%) participated, with data collected from 156 11–18-year-old students. Students had good knowledge of personal hygiene but did not always follow hygiene rules due to forgetfulness, lack of facilities or lack of concern for consequences. Students had limited understanding of foodborne microbes, underestimated the risks and consequences of foodborne illness and perceived the “home” environment as the safest. Young people preferred interactive educational methods. Addressing gaps in young people’s food safety knowledge is essential to improve their lack of concern towards foodborne illness and motivate them to follow food hygiene and safety behaviours consistently. Findings have been used to develop educational resources to address gaps in knowledge, skills, attitudes and beliefs.info:eu-repo/semantics/publishedVersio

HIV-1-infected patients from the French National Observatory experiencing virological failure while receiving enfuvirtide

Objectives We studied gp41 mutations associated with failing enfuvirtide salvage therapy. Methods This multicentre study involved patients with HIV-1 plasma viral load (pVL) > 5000 copies/mL after at least 3 months of uninterrupted enfuvirtide therapy and with plasma samples available at inclusion (T0), at initial enfuvirtide failure (T1) and at last follow-up visit during continued failing enfuvirtide therapy (T2). The HR-1 and HR-2 domains of the gp41 gene were sequenced at T0, T1 and T2. Results Ninety-nine patients were enrolled. At baseline, the median pVL and CD4 cell count were 5.1 log copies/mL and 72 cells/mm3, respectively. Based on the ANRS Resistance Group algorithm, the proportion of patients harbouring viruses with enfuvirtide resistance mutations increased significantly between T0 and T1. In the HR-1 domain, the V38A/M, Q40H, N42T, N43D and L45M mutations wereselected (P < 0.02). In the HR-2 domain, no mutations were significantly selected during the follow-up. None of the mutations was associated with a CD4 cell count increment. Conclusions Mutations selected during failing enfuvirtide salvage therapy are mainly located in the HR-1 domain of the gp41 gene, between codons 38 and 45. No mutations were associated with an increase in the CD4 cell coun

Simultaneous brain and cervical spinal cord MP2RAGE for T1 measurement: robustness and sensitivity for tissue modification assessment in multiple sclerosis in a multicenter context

International audienceIntroductionRecent optimisations of T1 quantification through magnetization‐prepared two rapidacquisition gradient echoes (MP2RAGE; Marques et al. 2010) allow to perform both brainand cervical spinal cord acquisitions simultaneously with good trade-off between acquisitiontime, robustness and accuracy (Rasoanandrianina et al. 2019; Forodighasemabadi et al.2021). This sequence is of particular interest to investigate tissue microstructuralmodifications in pathologies such as multiple sclerosis (MS) (Demortière et al. 2020;Mchinda et al, 2021). In order to spread out the use of the MP2RAGE sequence, weevaluated the reproducibility and variability in two different centres.MethodsThe data included in this work were collected in the context of the multicentric MSTRACTS(NCT04220814), OSV-IRM (NCT05107232) and T1-M3C-SEP (FLI-RE2) studies. Sixhealthy controls (HC; F/M: 4/2, mean age 38.9 years) were scanned 3 times each(separated sessions), in two different centres both equipped with 3T Siemens scanners(Prisma with 20 channels in centre 1, Vida with 64 channels in centre 2 ). Additionally 26 HC(centre 1/2: 20/6) were scanned one time (F/M: 19/7, mean age 39.2 years). The sameacquisition protocol was performed in both centres and included MP2RAGE and B1 mapacquisitions covering both brain and cervical spinal cord (cSC). The acquisition parameterswere previously described in (Rasoanandrianina et al. 2019; 4000ms TR, 243×300mm² FOV,176 slabs, 6/8 partial Fourier (PF) factor 0.9×0.9×1mm 3 voxel size, TI1/TI2 = 650/2000ms,ɑ1/ɑ2=4/5°, GRAPPA 2). After B1 correction (Massire et al. 2016), mean T1 values wereextracted in different regions including brain white matter (bWM), deep grey matter (dGM)and cortical grey matter (cGM; all computed using CAT12 [(Ashburner and Friston 2000)])and all cSC segments (computed using the SCT toolbox [(De Leener et al. 2017)]). Weevaluated the variability between centres and subjects using linear mixed-effects modelswith subject as random effect and centre as fixed effect. The coefficients of variation (CV)and the intraclass correlations (ICC) of between-session and between-participant variabilitieswere computed according to Combès et al. (2019). In order to interpret these results withrespect to potential application in MS pathology, we also reported exploratory analysesbased on the extraction of T1 values in the same regions for 5 MS patients (centre 1/2: 3/2,same acquisition protocol and image processing) without cSC lesions.ResultsFor the whole dataset collected in HC, the mean (and standard deviation) T1 values in thebrain were 1281.5 (28.8), 1176.5 (20) and 823.9 (21.1) ms for cGM,dGM, and bWM,respectively and were ranging from 921 (22.6) to 954 (30.5) ms over the 7 cSC segments(see Fig. 1)For the brain, we observed evidence of centre differences for the three regions (all p<.01).Nevertheless, the estimated differences between centres were low, ranging from 4.71 (bWM)to 25.31 (dGM) ms (ie. 0.57 to 1.98% of the mean). Between-participant CV were 2.1, 1.7and 1.8%, and between-session CV were 0.2, 2.2 and 0.5% for bWM cGM and dGM,respectively. Between-session ICC were .01, .61 and .06 for the same regions.For the SC, we observed evidence of centre differences for all vertebrae (all p<.05), exceptC4, C5 and C7 (p=.149, .163, .062, resp.). The estimated mean differences were also low,ranging from 9.6 (C5) to 20.2 (C1) ms (ie. 1.03 to 2.15%). To simplify the results, T1 valuesfrom C3 to C5 levels were averaged. In this region, between-participant andbetween-session CV were 1.5 and 1.6%, while between-session ICC was .53.MS patients showed a mean T1 value increase ranging from 19.5 (cGM) to 44.2 (dGM) msfor the brain, and from 14 (C7) to 122.7 (C3) ms for the cSC compared to the mean in allHC. Fig. 2 shows that, for each region, the majority of patients (coloured triangles) havehigher T1 values than the third quartile of HC.DiscussionOur results showed that, even if differences exist between the two centres, the variability islow, especially for bWM (0.57 %) and central cSC segments (1.03 %). Moreover, the T1variability is primarily explained by between-participant variability for the brain and by bothsession- and participant-variabilities for cSC. The differences between scanners were foundto be less important than the differences observed between HC and MS patients with nocSC lesions. Overall, our results highlight the multicenter robustness of simultaneous brainand cervical spinal cord acquisition and its potential for further applications in multicenter MSstudies to assess regional tissue impairment

Impact of lesion damages along the whole motor pathways on disability in multiple sclerosis

International audienceIntroduction: The anatomical substrate of motor disability in MS patients is not fully understood. Studyingthe distribution of corticospinal tracts (CST) lesions per side, from the brain to the end of the thoracic spinal cord (SC) couldprovide a better association with patient motor deficits evaluated per limb.Objectives: i) To describe lesion preferential location along the CST; ii) To investigate the association between CST lesionsand motor functional consequences, as measured using the EDSS, and the ASIA motor scores and electrophysiology (Centralmotor conduction time (CMCT)) per limb.Methods: 21 relapsing remitting MS (median EDSS=2.5) and 9 progressive MS patients (median EDSS=5.2) with clinicalpyramidal symptoms were scanned on a 3T Siemens MRI scanner. White matter lesions were segmented on 3D FLAIR for thebrain, on T2* for cervical SC and T2 for thoracic SC. For each patient, registration to an atlas was computed using Anima andSCT toolboxes. Lesion volume fraction along the CST (defined as "lesion volume along the CST"/"overall CST volume") wascalculated separately for the both sides on 3 regions: brain including brainstem, C1 to C7 (C1C7) and T1 to T10 (T1T10).Finally, the relationships between lesion volume fraction and the associated lateralized disability scores were assessed usingmultiple linear models, adjusting for age and disease duration.Results: In MS patients, lesion volume fraction was higher in the C1C7 portion compared to the brain and T1T10 portion (allp’s.6; all p’s<.005). Finally, we observed a mild positive association betweenlesion volume fraction in T1T10 and CMCT for inferior limbs on the left side (std-beta=.53; p=.02).Conclusions: CST damage is not homogeneous along the tract and predominates in the cervical portion. It has clearconsequences on motor conduction velocities measured using electrophysiology. Future work will include an assessment oflesion severity to better explain lesion consequences on motor disability

Impact of lesion damages along the whole motor pathways on disability in multiple sclerosis

International audienceIntroduction: The anatomical substrate of motor disability in MS patients is not fully understood. Studyingthe distribution of corticospinal tracts (CST) lesions per side, from the brain to the end of the thoracic spinal cord (SC) couldprovide a better association with patient motor deficits evaluated per limb.Objectives: i) To describe lesion preferential location along the CST; ii) To investigate the association between CST lesionsand motor functional consequences, as measured using the EDSS, and the ASIA motor scores and electrophysiology (Centralmotor conduction time (CMCT)) per limb.Methods: 21 relapsing remitting MS (median EDSS=2.5) and 9 progressive MS patients (median EDSS=5.2) with clinicalpyramidal symptoms were scanned on a 3T Siemens MRI scanner. White matter lesions were segmented on 3D FLAIR for thebrain, on T2* for cervical SC and T2 for thoracic SC. For each patient, registration to an atlas was computed using Anima andSCT toolboxes. Lesion volume fraction along the CST (defined as "lesion volume along the CST"/"overall CST volume") wascalculated separately for the both sides on 3 regions: brain including brainstem, C1 to C7 (C1C7) and T1 to T10 (T1T10).Finally, the relationships between lesion volume fraction and the associated lateralized disability scores were assessed usingmultiple linear models, adjusting for age and disease duration.Results: In MS patients, lesion volume fraction was higher in the C1C7 portion compared to the brain and T1T10 portion (allp’s.6; all p’s<.005). Finally, we observed a mild positive association betweenlesion volume fraction in T1T10 and CMCT for inferior limbs on the left side (std-beta=.53; p=.02).Conclusions: CST damage is not homogeneous along the tract and predominates in the cervical portion. It has clearconsequences on motor conduction velocities measured using electrophysiology. Future work will include an assessment oflesion severity to better explain lesion consequences on motor disability

Magnetization transfer imaging of the whole spinal cord in multiple sclerosis patients

International audienceContext: Magnetization transfer ratio (MTR) has shown promise to assess tissue microstructure modificationin MS patients. To date, such exploration has been limited to the brain and the cervical spinal cord (SC) portions of thecentral nervous system (CNS). Studying the MTR abnormalities in the whole SC could provide a better association withambulatory disability in MS patients.Objectives: i) to compare mean MTR values in MS patients and healthy controls (HC) according to the SC level; ii ) todescribe the link between MTR measurements at the cervical and thoracic SC levels; iii) to evaluate the link between MTRmeasures and disability according to the spinal cord level.Methods: 21 relapsing remitting MS (RRMS; median EDSS=2.5), 10 progressive MS patients (PMS; median EDSS=5.25) and13 HC were scanned on a 3T Siemens MRI scanner. The imaging protocol included 3 MT imaging acquisition slabs to coverthe whole SC. For each subject, MTR maps and vertebra labeling were computed using the SCT toolbox. MTR means werecomputed in semi-automatic delineated SC for the following vertebral levels: C4 to C6, T4 to T6, T9 to T10. Groupdifferences as well as correlations with lesions in the whole SC and EDSS were assessed controlling for age.Results: Evidence of group difference was only found in the cervical SC (C4C6; mean MTR=41.7pu, 39.4pu, 35.4pu for HC,RRMS and PMS resp.; p<.001). No evidence for group difference was found in the thoracic SC. A positive association wasfound between the mean MTR in the cervical SC and in the thoracic SC (r=.45, p=.01 for T4T6 and r=.54, p=.002 for T9T10)in MS patients. We observed negative associations between mean MTR in the cervical SC and the EDSS score (r=-.51,p=.004) and between mean MTR in the cervical SC and the SC lesion load (r=-.6, p<.001), while no clear evidence ofcorrelation was found between SC lesion load and EDSS score (r=.35; p=.084). No evidence of correlation was foundbetween mean MTR in the thoracic cord and EDSS score.Conclusions: The microstructural damage in the SC of MS patients seems to be predominant in the cervical SC and is linkedto the lesion load and the disability. In our sample data, the added value of exploring thoracic SC in addition to cervical SCusing MTR to explain disability in MS patients seems limited. Potential explanations could be the presence of highervariabilities in MTR measurement in the thoracic SC or the preferential location of MS lesions in the cervical SC

Impact of lesion damages along the whole motor pathways on disability in multiple sclerosis

International audienceIntroduction: The anatomical substrate of motor disability in MS patients is not fully understood. Studyingthe distribution of corticospinal tracts (CST) lesions per side, from the brain to the end of the thoracic spinal cord (SC) couldprovide a better association with patient motor deficits evaluated per limb.Objectives: i) To describe lesion preferential location along the CST; ii) To investigate the association between CST lesionsand motor functional consequences, as measured using the EDSS, and the ASIA motor scores and electrophysiology (Centralmotor conduction time (CMCT)) per limb.Methods: 21 relapsing remitting MS (median EDSS=2.5) and 9 progressive MS patients (median EDSS=5.2) with clinicalpyramidal symptoms were scanned on a 3T Siemens MRI scanner. White matter lesions were segmented on 3D FLAIR for thebrain, on T2* for cervical SC and T2 for thoracic SC. For each patient, registration to an atlas was computed using Anima andSCT toolboxes. Lesion volume fraction along the CST (defined as "lesion volume along the CST"/"overall CST volume") wascalculated separately for the both sides on 3 regions: brain including brainstem, C1 to C7 (C1C7) and T1 to T10 (T1T10).Finally, the relationships between lesion volume fraction and the associated lateralized disability scores were assessed usingmultiple linear models, adjusting for age and disease duration.Results: In MS patients, lesion volume fraction was higher in the C1C7 portion compared to the brain and T1T10 portion (allp’s.6; all p’s<.005). Finally, we observed a mild positive association betweenlesion volume fraction in T1T10 and CMCT for inferior limbs on the left side (std-beta=.53; p=.02).Conclusions: CST damage is not homogeneous along the tract and predominates in the cervical portion. It has clearconsequences on motor conduction velocities measured using electrophysiology. Future work will include an assessment oflesion severity to better explain lesion consequences on motor disability