ROLE OF EPSTEIN-BARR VIRUS IN THE PATHOGENESIS OF MULTIPLE SCLEROSIS

Multiple sclerosis (MS) is a chronic pathology of the central nervous system, characterized by inflammation, demyelination, and neurodegeneration. The prevalence and incidence rates of MS are on the rise worldwide. What causes MS is unknown. However, it is widely accepted that MS occurs in genetically susceptible individuals exposed to certain environmental factors. Sero-epidemiological data suggest a strong association between Epstein-Barr virus (EBV) and MS. EBV is one of the commonest viruses in the human population with ~90% global seropositivity. EBV infects naïve B cells and immortalizes them. While some postmortem studies have shown EBV in MS lesions, others have failed to reach similar observation. Variation in technical approaches and sample size could be the reason for reported inconsistencies. Thus, we have assessed the hypothesis that EBV may enter the MS brain and contribute to disease pathogenesis. Four objectives were highlighted in this thesis: to investigate EBV presence in MS brain using a large sample size, quantify EBV viral load in brain tissues, determine the possible route of virus entry to the brain, and determine viral gene expression in MS brain. In a case-control design, 122 MS and non-MS cases were studied and compared. Formalin stored brain coronal slices were received from Rocky Mountain MS Centre, US. DNA extraction was optimized and PCR amplification of EBV BamHI was performed to determine EBV presence/ absence in the brain. EBV viral load was quantified in infected cases using qPCR. Localization of infected cells was achieved using EBER in situ hybridization, and viral gene expression was determined using immunohistochemistry. The phenotype of EBV infected cells was characterized using immunohistochemistry for cellular markers. EBV DNA has been detected in 90% MS and 24% non-MS cases. EBV infected cells were more prevalent in brain parenchyma than in meninges, expressing latent EBNA1 and lytic BZLF1. EBV-infected cells were likely to have a B lymphocyte phenotype. We concluded that EBV differential presence in the MS brain reflected a pathogenic contribution to MS. Further studies are warranted to determine the mechanism of EBV involvement in M

ROLE OF EBV IN NEUROINFLAMMATION: IMPLICATIONS FOR MULTIPLE SCLEROSIS PATHOGENESIS

Multiple sclerosis (MS) is a demyelinating disease of the CNS with unknown cause. Individuals who are genetically predisposed and exposed to specific environmental factors have an increased risk of developing MS. Epstein-Barr virus (EBV) infection is linked to MS development, according to a large body of seroepidemiological and pathological evidence. EBV is a ubiquitous human herpesvirus that typically produces silent infection but can also cause a wide range of illnesses. A large cohort of MS and non-MS control cases has been previously examined and revealed the prevalent presence of EBV in MS. However, the role of the virus in the disease is unclear. The main objective of this research was to understand the viral dynamics in vivo and the consequences of peripheral infection on the CNS. To this end, a novel rabbit model of EBV, which produces latent infection comparable to the persistent infection in human carriers, was used in this study. The present dissertation contains (1) human study and (2) animal study for correlation of the results. In the human study, EBV-positive MS cases were examined for histopathological changes. In the animal study, EBV was injected intravenously in one group of animals, and PBS was injected in the control group, with and without immunosuppression. Histopathological changes and viral dynamics were evaluated in the peripheral blood, spleen, brain, and spinal cord, using molecular and histopathology techniques. A number of important aspects of EBV infection were revealed. Peripheral EBV infection led to CNS infection and promoted neuroinflammation in the form of immune aggregates. EBV infected B cells were most likely the source of CNS infection. The immune aggregates were more prevalent in immunosuppressed animals and consisted of focal accumulation of macrophages surrounded by reactive astrocytes and dispersed B and T lymphocytes. The center of aggregates exhibited signs of myelin destruction. Moreover, studying EBV infection over time revealed that the peak in viral load in the periphery and CNS corresponded to an increase in the occurrence of cellular aggregates in the brain. Additionally, altered expression of viral latent transcripts correlated with upregulation of several proinflammatory cytokines in the periphery and the CNS. Increased expression of IL- 6 at the mRNA and protein level in the brain was associated with neuroinflammation. Finally, several similarities and differences were observed between the pathology in EBV positive MS cases and EBV infected rabbit CNS. Several cellular key players contributed to both pathologies, however, the extent of infiltration of these cells and their distribution differed between the two. This work establishes the first direct in vivo evidence for the role of peripheral EBV infection in CNS pathology, and demonstrates the utility of a novel model for dissecting viral mechanisms involved in the development of EBV- associated diseases including MS

Epstein-Barr Virus in Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system in which the body’s immune system is abnormally directed towards the myelin sheaths covering the nerve fibers. What triggers the neuroinflammation and autoimmune destruction of the myelin sheaths remains unknown. However, it is widely accepted that susceptibility depends on a combination of genetic and environmental factors and their interactions. With little chance of influencing genetic predisposition, the importance of identifying risk factors which could be modulated to either prevent the on-set of MS or to ameliorate the course of the disease, is an attractive alternative. An accumulating body of evidence, including our own recent study involving over 1000 MS and non-MS samples, indicates that Epstein-Barr virus (EBV), a common herpesvirus, could be involved. In this chapter, we review the studies linking EBV to MS and propose an explanation by which this common virus could be involved in the pathogenesis of MS

Analyse des mouvements 3D en temps réel pour un dispositif médical destiné au maintien de l'indépendance fonctionnelle des personnes âgées à domicile

We propose in this manuscript a realtime3D movement analysis system for inhomefunctionalabilities assessment in aged adults. As a first step, the purpose is to maintain the functionalindependence of this population and to allow an earlier detection of a motor decompensation inorder to facilitate a rehabilitation process. To quantify the equilibrium quality of a subject, webuilt a system using the Kinect sensor in order to analyze a simple clinical test validated in geriatricrehabilitation: the Timed Up and Go (TUG). Three experiments conducted in heterogeneousenvironments (laboratory, day hospital and home) showed good measurement reliability of theidentified parameters. In particular, they allow to assign a motor control note indicating themotor frailty. Then, we proposed a video processing chain to increase the robustness of theanalysis of the various TUG phases: automatic detection of the sitting posture, patientsegmentation and three body joints extraction. The results of this work allow us to considerseveral perspectives. First, we believe conduct experiments on a larger population in order toconfirm the system reliability. Then, various technical and ergonomic improvements would benecessary to facilitate general public use. Finally, it would be interesting to extend the proposedmethodology for other clinical test to prolong the autonomy at home.Dans ce manuscrit, nous proposons un système d'analyse automatique des mouvements 3D entemps réel permettant l'évaluation des capacités fonctionnelles chez les personnes âgées àdomicile. Dans un premier temps, l'objectif est de contribuer à maintenir l'indépendancefonctionnelle de cette population et permettre une détection précoce d'une décompensationmotrice pour faciliter une démarche de rééducation. Pour quantifier la qualité d'équilibre d'unsujet en temps réel, nous avons conçu un système en utilisant le capteur Kinect et permettantd'analyser un test clinique simple et validé en rééducation gériatrique: le Timed Up and Go (TUG).Trois expériences, réalisées dans des environnements hétérogènes (laboratoire, hôpital de jouret domicile) ont montré une bonne fiabilité de la mesure des paramètres identifiés. Ellespermettent notamment d'attribuer une note de contrôle moteur indiquant la fragilité motrice.Dans un second temps, nous avons proposé une chaîne de traitement vidéo permettantd'augmenter la robustesse d'analyse de différentes phases du TUG : détection automatique de laposition assise, segmentation du patient et extraction de 3 articulations du corps. Les résultats deces travaux nous permettent d'envisager plusieurs perspectives. Tout d'abord, nous pensonseffectuer des expérimentations sur une population plus large afin de confirmer la fiabilité dusystème. Puis, différentes améliorations techniques et ergonomiques seraient nécessaires pourfaciliter l'utilisation grand public. Enfin, il serait intéressant d'étendre la méthodologie proposéepour d'autres tests cliniques en vue de prolonger l'autonomie à domicile

Epstein-Barr Virus and miRNAs: Partners in Crime in the Pathogenesis of Multiple Sclerosis?

MicroRNAs (miRNAs) are small non-coding RNAs that modulate gene expression post transcriptionally. In healthy individuals, miRNAs contribute to maintaining gene expression homeostasis. However, the level of miRNAs expressed is markedly altered in different diseases, including multiple sclerosis (MS). The impact of such changes is being investigated, and thought to shape the immune system into the inflammatory autoimmune phenotype. Much is yet to be learned about the contribution of miRNAs in the molecular pathology of MS. Epstein-Barr virus (EBV) infection is a major risk factor for the development of MS. EBV encodes more than 40 miRNAs, most of which have been studied in the context of EBV associated cancers. These viral miRNAs regulate genes involved in cell apoptosis, antigen presentation and recognition, as well as B cell transformation. If EBV infection contributes to the pathology of MS, it is plausible that EBV miRNAs may be involved. Unfortunately, there are limited studies addressing how EBV miRNAs are involved in the pathogenesis of MS. This review summarizes what has been reported regarding cellular and viral miRNA profiles in MS and proposes possible interactions between the two in the development of MS

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021. Methods: The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk–outcome pairs. Pairs were included on the basis of data-driven determination of a risk–outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk–outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk–outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws. Findings: Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7–9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4–9·2]), smoking (5·7% [4·7–6·8]), low birthweight and short gestation (5·6% [4·8–6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8–6·0]). For younger demographics (ie, those aged 0–4 years and 5–14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9–27·7]) and environmental and occupational risks (decrease of 22·0% [15·5–28·8]), coupled with a 49·4% (42·3–56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9–21·7] for high BMI and 7·9% [3·3–12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6–1·9) for high BMI and 1·3% (1·1–1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4–78·8) for child growth failure and 66·3% (60·2–72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP). Interpretation: Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions