We report the case of a young woman with multiple sclerosis who discontinued natalizumab twice and experienced a severe relapse following each natalizumab withdrawal. The first relapse was ...successfully treated by intravenous methylprednisolone (IVMP). In contrast the second relapse was unresponsive to IVMP. Subsequent treatment by plasma exchanges (PLEX) was followed by a dramatic neurological worsening. This case suggests that PLEX after natalizumab discontinuation may increase relapse severity.
Recent advances in neuroimaging have simplified the diagnostic criteria of multiple sclerosis. Indeed, the diagnosis of multiple sclerosis could be obtained during the first bout of disease flare, ...very early in the disease course. This is particularly important to shorten the diagnostic delay as early treatment may limit the occurrence of late irreversible disabilities. At the same time, major therapeutic advances have been obtained and new drugs that are well tolerated and more effective, despite the possible rare but potentially severe side effects are been developed. This article reviews the modern diagnostic and therapeutic strategies in multiple sclerosis in accordance with the recent obtained advances.
Les progrès récents de la neuro-imagerie ont permis de simplifier les critères du diagnostic de la sclérose en plaques (SEP) qui peut être aujourd’hui porté dès le premier épisode clinique ...c’est-à-dire très précocement dans la maladie. Cette course à la précocité du diagnostic est motivée par l’hypothèse qu’un traitement précoce permettrait d’éviter l’apparition ultérieure d’un handicap irréversible. Parallèlement à cette possibilité de diagnostic précoce, de grandes avancées ont été accomplies dans le domaine thérapeutique avec l’arrivée de nouvelles molécules, bien tolérées, plus efficaces mais présentant des risques d’effets indésirables rares mais potentiellement graves. Cet article propose de discuter à la lumière de ces récentes avancées, la stratégie diagnostique et thérapeutique actuelle dans le domaine de la SEP.
Recent advances in neuroimaging have simplified the diagnostic criteria of multiple sclerosis. Indeed, the diagnosis of multiple sclerosis could be obtained during the first bout of disease flare, very early in the disease course. This is particularly important to shorten the diagnostic delay as early treatment may limit the occurrence of late irreversible disabilities. At the same time, major therapeutic advances have been obtained and new drugs that are well tolerated and more effective, despite the possible rare but potentially severe side effects are been developed. This article reviews the modern diagnostic and therapeutic strategies in multiple sclerosis in accordance with the recent obtained advances.
Multiple sclerosis (MS) is a dys-immune disease of the central nervous system with highly variable and unpredictable long-term outcome.
In the early 1970s association between HLA alleles and MS was ...established. Very recently, the power of Genome Wide Association Studies (GWAS) enabled the identification of several loci involved in immune functions as genetic risk factors in MS. Recent data suggest that common genetic variations might modulate the clinical phenotype of MS through a regulation of key pathophysiological pathways.
Identification of modifier genes might offer an opportunity to explore new relevant therapeutic targets and early prognostic markers. To date, studies of modifier genes in MS are numerous but results are still unclear. This research field may now benefit from large cohorts of patients available for association studies.
In this context, we propose a review of epidemiological and association studies of genetic modifying effect in MS.
La sclérose en plaques (SEP) est une affection dysimmunitaire touchant le système nerveux central dont la sévérité est extrêmement hétérogène, largement imprévisible.
L’influence de facteurs génétiques sur la susceptibilité de la SEP a été découverte au début des années 1970 avec l’identification du rôle du locus HLA. Très récemment, grâce à la puissance des études « Genome wide », de nombreux loci modulant le fonctionnement du système immunitaire ont été associés au risque de développer cette affection. De nombreuses données épidémiologiques suggèrent que le cours évolutif de la SEP pourrait être influencé par des facteurs génétiques modulant les voies physiopathologiques clés de la maladie.
L’identification de ces gènes modificateurs offre ainsi une opportunité majeure d’identifier de nouvelles cibles thérapeutiques et des marqueurs précoces du pronostic individuel à long terme. Les études portant sur l’association entre polymorphismes génétiques et phénotype de la SEP sont nombreuses mais leurs résultats ne sont pas clairs. Dans un proche avenir, ce champ de recherche va bénéficier des larges cohortes de patients constituées pour l’étude des gènes de susceptibilité.
Dans ce contexte, nous proposons une revue générale des données épidémiologiques et des études d’associations concernant l’effet modificateur des facteurs génétiques.
Proteins and enzymes for commercial use are often dried in order to extend their shelf lives. This study examined the effects of disaccharides (sucrose and trehalose), polymers (dextran and ...maltodextrin) and disaccharide–polymer mixtures on the stability of subtilisin, a common industrial laundry detergent enzyme, during drying and during subsequent storage in dried solids containing perborate, a laundry detergent additive that hydrolyzes to form hydrogen peroxide in the presence of water. Subtilisin is susceptible to oxidation by hydrogen peroxide at a partially buried methionine residue, which results in loss of catalytic activity. Two drying methods were compared: spray coating and lyophilization. During both drying methods, the presence of a disaccharide, which can hydrogen bond to subtilisin in the place of lost water, was necessary to inhibit dehydration-induced unfolding of subtilisin. Dehydration-induced unfolding was assessed by second-derivative IR spectroscopy. However, even in the samples in which the protein’s secondary structure was perturbed, the protein refolded to the native conformation and exhibited full activity upon rehydration. None of the additives protected Met222 from oxidation during storage of the initially dry protein formulations at 37
°C and 20 or 75% relative humidity under oxidizing conditions. In contrast, the two additional methionine residues in the enzyme, Met119 and Met175, which are deeply buried in the interior of the protein, remained unmodified during storage of the dried formulations and became oxidized only if the enzyme was completely unfolded in aqueous solution.
Heavy chain fragments of botulinum neurotoxin serotypes A and B are being developed as a bivalent vaccine for botulism. To potentiate the immune response, an aluminum containing adjuvant will be ...formulated with the two antigens. The adsorption mechanisms of each antigen to aluminum phosphate and aluminum hydroxide adjuvants were studied. The adsorption of the serotype A antigen to each adjuvant, and the serotype B antigen to aluminum phosphate adjuvant, is dependent on electrostatic attractive forces. The serotype A antigen is basic, and pretreatment with phosphate anions is required for favorable adsorption conditions to aluminum hydroxide adjuvant. In contrast, the serotype B antigen displays a high affinity to aluminum hydroxide adjuvant even when the two species possess the same charge. It is proposed that the serotype B antigen is adsorbed to aluminum hydroxide adjuvant by a ligand exchange mechanism.
The conformational stabilization of proteins by sucrose has been previously attributed to a preferential exclusion mechanism. The present study links this mechanism to stability against a chemical ...degradation pathway for subtilisin. Oxidation of a methionine residue adjacent to the active site to the sulfoxide form compromises subtilisin's enzymatic activity. In the presence of hydrogen peroxide and borate buffer, a borate–hydrogen peroxide complex binds to subtilisin's active site prior to the formation of methionine sulfoxide. Sucrose decreases the oxidation rate by limiting the accessibility of the complex to the methionine at the partially buried active site. The stabilization mechanism of sucrose is based on shifting the equilibrium of transiently expanding native conformations of subtilisin to favor the most compact states. Enzymatic parameter determination (kcat, KM) and hydrogen–deuterium exchange measurements confirm the limited conformational mobility of the enzyme in the presence of sucrose. Further support for limited mobility as the cause of oxidation inhibition by sucrose comes from the findings that neither viscosity nor possible interactions of sucrose with hydrogen peroxide, hydroxyl radicals, or borate can adequately explain the inhibition. The volume exclusion of sucrose from subtilisin is used to estimate the extent by which the native state of subtilisin must expand in solution to allow oxidation. The surface area of the oxidation-competent state is ca. 3.9% greater than that of the native state.
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