Objective
The objective of this study was to evaluate the implementation of NGS within the French mitochondrial network, MitoDiag, from targeted gene panels to whole exome sequencing (WES) or whole ...genome sequencing (WGS) focusing on mitochondrial nuclear‐encoded genes.
Methods
Over 2000 patients suspected of Primary Mitochondrial Diseases (PMD) were sequenced by either targeted gene panels, WES or WGS within MitoDiag. We described the clinical, biochemical, and molecular data of 397 genetically confirmed patients, comprising 294 children and 103 adults, carrying pathogenic or likely pathogenic variants in nuclear‐encoded genes.
Results
The cohort exhibited a large genetic heterogeneity, with the identification of 172 distinct genes and 253 novel variants. Among children, a notable prevalence of pathogenic variants in genes associated with oxidative phosphorylation (OXPHOS) functions and mitochondrial translation was observed. In adults, pathogenic variants were primarily identified in genes linked to mtDNA maintenance. Additionally, a substantial proportion of patients (54% (42/78) and 48% (13/27) in children and adults, respectively), undergoing WES or WGS testing displayed PMD mimics, representing pathologies that clinically resemble mitochondrial diseases.
Interpretation
We reported the largest French cohort of patients suspected of PMD with pathogenic variants in nuclear genes. We have emphasized the clinical complexity of PMD and the challenges associated with recognizing and distinguishing them from other pathologies, particularly neuromuscular disorders. We confirmed that WES/WGS, instead of panel approach, was more valuable to identify the genetic basis in patients with “possible” PMD and we provided a genetic testing flowchart to guide physicians in their diagnostic strategy.
Abstract Understanding breast cancer survivors’ perspectives is critical to personalizing endocrine therapy (ET) in the adjuvant setting. A nationwide survey among breast cancer survivors was ...proposed in France, in collaboration with patient advocacy organizations, to assess their perspectives on personalizing ET and developing dedicated informative tools. This survey explored patients’ preferences regarding ET intake schedule, formulation, presentation (color, taste, shape, size, design, and packaging), combination with agents targeting ET-related adverse events, and a mobile application to support them during ET. Of the 1103 individuals who started the survey, 939 (85.1%) were eligible for enrollment and completed the survey. The majority of the participants considered that a personalized ET should take into consideration the intake schedule ( n = 974, 90.7%) and swallowable tablet formulation ( n = 606, 64.5%), without a preference for ET presentation ( n = 619; 65.9%). The majority of the participants expressed a willingness to participate in a potential clinical trial evaluating the combination of ET with agents targeting ET-related adverse events at the start of ET ( n = 752, 80.1%) or in the case of major ET-related adverse events ( n = 778, 82.8%). The primary considerations were to have an uncompromised ET efficacy and a guaranteed reduction of adverse events. Last, a dedicated mobile application was considered helpful by 665 participants (70.8%). Informative tools should focus on the recommendations for dealing with adverse events ( n = 593, 63.2%), the impact on the patient’s daily life ( n = 515, 54.9%), benefits ( n = 504, 53.7%), and adverse events ( n = 494, 52.6%) of ET. This survey paves the way for multimodal strategies that can include a personalized ET (e.g., ET in combination with agents targeting ET-related adverse events) and dedicated mobile applications to ultimately improve adherence.
This article discusses the uncertainty about water quality in the Province of Chacabuco (Santiago Metropolitan Region) in Chile, a region marked by very strong pressure on the resource, both natural ...(drought) and anthropogenic (urban growth, agricultural intensification, industrialisation, and mining activity). Our main objective was, through an interdisciplinary research approach, to understand how the uncertainty concerning the state of hydro systems becomes central in the social representations of the inhabitants, since there is no consensus amongst regional stakeholders about environmental impacts nor is there evidence of pollution. By cross-referencing geochemical data on water quality and the inhabitants’ discourse on the resource, we identified those factors that create uncertainty about water resources: institutional lack of knowledge of the state of the resource, scientific difficulties in understanding the functioning of the hydro system, water and ground quality data that are difficult to interpret given the persistent drought, and the inhabitants’ distrust of data producers, in a context of planned regulatory zoning of polluting activities in the area. We also show the negative effects that the lack of trustworthy information has on the daily lives of local communities living near industrial infrastructures: anxiety, health concerns, and mistrust of drinking water, even though it is potable.
Alzheimer's disease (AD) is characterized by intracerebral accumulations of extracellular amyloid-β (Aβ) plaques and intracellular tau pathology that spread in the brain. Three types of tau lesions ...occur in the form of neuropil threads, neurofibrillary tangles, and neuritic plaques i.e. tau aggregates within neurites surrounding Aβ deposits. The cascade of events linking these lesions and synaptic or memory impairments are still debated. Intracerebral infusion of human AD brain extracts in Aβ plaque-bearing mice that do not overexpress pathological tau proteins induces tau pathologies following heterotopic seeding of mouse tau protein. There is however little information regarding the downstream events including synaptic or cognitive repercussions of tau pathology induction in these models. In the present study, human AD brain extracts (AD
) and control-brain extracts (Ctrl
) were infused into the hippocampus of Aβ plaque-bearing APP
/PS1
mice. Memory, synaptic density, as well as Aβ plaque and tau aggregate loads, microgliosis, astrogliosis at the inoculation site and in connected regions (perirhinal/entorhinal cortex) were evaluated 4 and 8 months post-inoculation. AD
inoculation produced the following effects: (i) memory deficit; (ii) increased Aβ plaque deposition in proximity to the inoculation site; (iii) tau pathology induction; (iv) appearance of neuropil threads and neurofibrillary tangles next to the inoculation site with a spreading to connected regions. Neuritic plaque pathology was detected in both AD
- and Ctrl
-inoculated animals but AD
inoculation increased the severity close to and at distance of the inoculation site. (v) Finally, AD
inoculation reduced synaptic density in the vicinity to the inoculation site and in connected regions as the perirhinal/entorhinal cortex. Synaptic impairments were correlated with increased severity of neuritic plaques but not to other tau lesions or Aβ lesions, suggesting that neuritic plaques are a culprit for synaptic loss. Synaptic density was also associated with microglial load.
•A multiple HS/GC–MS measurement of residual EO present in sterilized plastic samples is proposed.•The quantification of EO is done, according to the ISO 10993-7 standard, adding EO amounts extracted ...for each repeated extractions.•The specificity of the detection of EO regarding acetaldehyde (structural isomer of EO) which may be formed from EO is ensured.•Extraction conditions to maximize the amount of extractible EO are given for different type of plastics.•A method validation and an inter-laboratory reproducibility study had been performed for COC samples.•Results obtained for 70 medical devices controlled during a market survey are reported.
This manuscript, based on the ISO 10993-7 approach, describes a multiple HS-GC measurement of residual EO present in sterilized plastic samples. The quantification of EO is done, according to the ISO standard, by addition of EO amounts extracted for each repeated extraction. During the method development, the specificity of the detection of EO regarding acetaldehyde (structural isomer of EO) which may be formed from EO has been ensured and different tests were performed to check a possible influence of the sample preparation. Assays to maximize EO extraction were performed for different materials (Cyclo-olefine Copolymer (COC), Cyclo-olefine Polymer (COP), Silicon, Polyurethane (PUR)) changing extraction temperatures and times for the headspace and the pre-thermal treatment. Results highlight that depending on the material, EO can be more or less retained and thus thermal extraction conditions to maximize the amount of extractible EO from plastics may change accordingly. For COC syringes a validation according to ICH guidelines and an inter-laboratories study were performed. The method has been used for a market survey of EO sterilized medical devices, results obtained are reported in this manuscript.
Amyloid-β (Aβ) pathology transmission has been described in patients following iatrogenic exposure to compounds contaminated with Aβ proteins. It can induce cerebral Aβ angiopathy resulting in brain ...hemorrhages and devastating clinical impacts. Iatrogenic transmission of tau pathology is also suspected but not experimentally proven. In both scenarios, lesions were detected several decades after the putatively triggering medico-surgical act. There is however little information regarding the cognitive repercussions in individuals who do not develop cerebral hemorrhages. In the current study, we inoculated the posterior cingulate cortex and underlying corpus callosum of young adult primates (Microcebus murinus) with either Alzheimer's disease or control brain extracts. This led to widespread Aβ and tau pathologies in all of the Alzheimer-inoculated animals following a 21-month-long incubation period (n = 12) whereas none of the control brain extract-inoculated animals developed such lesions (n = 6). Aβ deposition affected almost all cortical regions. Tau pathology was also detected in Aβ-deposit-free regions distant from the inoculation sites (e.g. in the entorhinal cortex), while some regions adjacent, but not connected, to the inoculation sites were spared (e.g. the occipital cortex). Alzheimer-inoculated animals developed cognitive deficits and cerebral atrophy compared to controls. These pathologies were induced using two different batches of Alzheimer brain extracts. This is the first experimental demonstration that tau can be transmitted by human brain extracts inoculations in a primate. We also showed for the first time that the transmission of widespread Aβ and tau pathologies can be associated with cognitive decline. Our results thus reinforce the need to organize a systematic monitoring of individuals who underwent procedures associated with a risk of Aβ and tau iatrogenic transmission. They also provide support for Alzheimer brain-inoculated primates as relevant models of Alzheimer pathology.
Inherited chromosomally integrated (ici) human herpes virus 6 (HHV-6) is estimated to occur in 0.6-2.7% of people worldwide. HHV-6 comprises two distinct species: HHV-6A and HHV-6B. Both HHV-6A and ...HHV-6B integration have been reported. Several drugs are capable of activating iciHHV-6 in tissues, the consequences of which are poorly understood. We report herein a case of a woman with iciHHV-6A+ and iciHHV-6B+, who developed ulipristal acetate (a selective progesterone receptor modulator)-induced fulminant hepatic failure that required liver transplantation. We confirmed the presence of ~one copy per cell of both HHV-6A and HHV-6B DNA in her hair follicles using multiplex HHV-6A/B real-time PCR and demonstrated the Mendelian inheritance of both iciHHV-6A and iciHHV-6B in her family members over three generations. Because of the rarity of this presentation, we discuss herein the possible links between reactivated HHV-6 from iciHHV-6A and/or iciHHV-6B and adverse drug reactions, suggesting that iciHHV-6 could be screened before the introduction of any hepatotoxic drugs to exclude HHV-6 active disease or combined idiosyncratic drug-induced liver injury in these patients.
Intracellular protein aggregates are common pathological hallmarks of many neurodegenerative disorders, and a defect in axonal transport is also incriminated. Here, we studied intra‐axonal abnormal ...protein aggregation and axonopathy by using immunohistochemistry and electron microscopy on peripheral nerve biopsies from 12 patients with chronic axonal peripheral neuropathy (PN) of unknown etiology. Among these patients, three had idiopathic Parkinson's disease (PD). Intra‐axonal ubiquitin aggregates were more numerous in the patients with PD. Intra‐axonal aggregates of tau AT8 were found in five patients without PD. Phosphorylated α‐synuclein aggregation was absent in all cases, while intra‐axonal colocalization of 14‐3‐3 β and ubiquitin was observed in two PD cases. Electron microscopy revealed enlarged axons crowded with organelles in six cases, including the three patients with PD, thus attesting a slowing of the axoplasmic flux. The number of ubiquitin aggregates was correlated with features of reduced axonal flux, while no such correlation was found for tau and 14‐3‐3 β. Age did not correlate with the number of tau, ubiquitin, and 14‐3‐3 aggregates. Thus, both ubiquitin and/or abnormal tau intra‐axonal aggregates may be found in chronic axonal PN. Ubiquitin aggregates might reduce the axonal flux or result from a disease producing slowing of axonal transport.
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