Publications by authors named "Laurent Kremer"

210 Publications

Impact of Coronavirus Disease 2019 in a French Cohort of Myasthenia Gravis.

Neurology 2021 Feb 10. Epub 2021 Feb 10.

Referral Center for Neuromuscular Diseases and ALS, Timone University Hospital, Aix-Marseille University, Marseille, France.

Objective: To describe the clinical characteristics and outcomes of COVID-19 among patients with MG and identify factors associated with COVID-19 severity in MG patients.

Methods: The CO-MY-COVID registry was a multicenter, retrospective, observational cohort study conducted in neuromuscular referral centers and general hospitals of the FILNEMUS network (between March 1, 2020, and June 8, 2020), including MG patients with a confirmed or highly-suspected diagnosis of COVID-19. COVID-19 was diagnosed based on a polymerase chain reaction (PCR) test from a nasopharyngeal swab and/or SARS-CoV-2 serology, thoracic computed tomography (CT-scan), or typical symptoms. The main outcome was COVID-19 severity based on location of treatment/management (home, hospitalized in a medical unit, or in an intensive care unit). We collected information on demographic variables, general history, and risk factors for severe COVID-19. Multivariate ordinal regression models were used to identify factors associated with severe COVID-19 outcomes.

Results: Among 3,558 MG patients registered in the French database for rare disorders, 34 (0.96%) had COVID-19. The mean age at COVID-19 onset was 55.0 ±19.9 years (mean MG duration: 8.5 ± 8.5 years). By the end of the study period, 28 patients recovered from COVID-19, 1 remained affected, and 5 died. Only high Myasthenia Gravis Foundation of America (MGFA) class (≥IV) before COVID-19 was associated with severe COVID-19 (p=0.004); factors that were not associated included gender, MG duration, and medium MGFA classes (≤IIIb). The type of MG treatment had no independent effect on COVID-19 severity.

Conclusions: This registry-based cohort study shows that COVID-19 had a limited effect on most patients, and immunosuppressive medications and corticosteroids used for MG management are not risk factors for poorer outcomes. However, the risk of severe COVID-19 is elevated in patients with high MGFA classes [odds ratio: 102.6 (4.4; 2,371.9)]. These results are important for establishing evidence-based guidelines for the management of MG patients during the COVID-19 pandemic.
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http://dx.doi.org/10.1212/WNL.0000000000011669DOI Listing
February 2021

First line treatment failure: Predictive factors in a cohort of 863 Relapsing Remitting MS patients.

Mult Scler Relat Disord 2021 Feb 13;48:102686. Epub 2020 Dec 13.

CRC SEP, Montpellier University Hospital, INSERM, Univ Montpellier, Montpellier. Electronic address:

Background: The advent of new, potent, disease-modifying therapies has dramatically changed the management of multiple sclerosis (MS). Along with these possibilities, it is crucial to better recognize patients who are at risk of first line treatment (FLT) failure and switch to highly effective therapies (HET).

Objectives: To identify baseline prognostic factors associated with FLT failure in relapsing remitting MS (RR-MS) patients.

Methods: We included recently diagnosed RR-MS patients starting an FLT identified from 3 French MS centers databases. Baseline characteristics were included in a multivariable Cox analysis to identify the main factors associated with FLT failure.

Results: Eight hundred sixty-three patients were included. We observed an overall rate of treatment failure of 23.5%. The main baseline characteristics associated with treatment failure were age <26 years at treatment start (HR= 2.1, p<0.001), EDSS ≥2 (HR=2.1, p<0.001) and ≥2relapses in the previous year (HR=1.5, p=0.04). The association with the presence of gadolinium enhancement on MRI was not statistically significant. EDSS progression was only significantly associated with age at treatment start and treatment failure.

Conclusion: Our series demonstrates that some clinical and imaging factors are associated with treatment failure, and should be considered when planning treatment strategy in patients with recently diagnosed RR-MS.
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http://dx.doi.org/10.1016/j.msard.2020.102686DOI Listing
February 2021

A case of acute disseminate encephalomyelitis after SARS-CoV-2 related acute respiratory distress syndrome.

J Neuroradiol 2020 Nov 18. Epub 2020 Nov 18.

Division of Cardiovascular Medicine, University Hospital of Strasbourg, Strasbourg, France. Electronic address:

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http://dx.doi.org/10.1016/j.neurad.2020.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673217PMC
November 2020

Functional Characterization of the -Acetylmuramyl-l-Alanine Amidase, Ami1, from .

Cells 2020 11 4;9(11). Epub 2020 Nov 4.

Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, CNRS UMR 9004, CEDEX 5, 34293 Montpellier, France.

Peptidoglycan (PG) is made of a polymer of disaccharides organized as a three-dimensional mesh-like network connected together by peptidic cross-links. PG is a dynamic structure that is essential for resistance to environmental stressors. Remodeling of PG occurs throughout the bacterial life cycle, particularly during bacterial division and separation into daughter cells. Numerous autolysins with various substrate specificities participate in PG remodeling. Expression of these enzymes must be tightly regulated, as an excess of hydrolytic activity can be detrimental for the bacteria. In non-tuberculous mycobacteria such as , the function of PG-modifying enzymes has been poorly investigated. In this study, we characterized the function of the PG amidase, Ami1 from . An deletion mutant was generated and the phenotypes of the mutant were evaluated with respect to susceptibility to antibiotics and virulence in human macrophages and zebrafish. The capacity of purified Ami1 to hydrolyze muramyl-dipeptide was demonstrated in vitro. In addition, the screening of a 9200 compounds library led to the selection of three compounds inhibiting Ami1 in vitro. We also report the structural characterization of Ami1 which, combined with in silico docking studies, allows us to propose a mode of action for these inhibitors.
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http://dx.doi.org/10.3390/cells9112410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694207PMC
November 2020

Outcomes of coronavirus disease 2019 in patients with neuromyelitis optica and associated disorders.

Eur J Neurol 2020 Oct 26. Epub 2020 Oct 26.

Service de Neurologie and CIC INSERM 1434, CHU de Strasbourg, Strasbourg, France.

Background: Outcomes of coronavirus disease 2019 (COVID-19) in patients with neuromyelitis optica spectrum disorders (NMOSD) or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), often treated with immunosuppressive therapies, are still unknown.

Methods: We conducted a multicenter, retrospective, observational cohort study among all French expert centers for neuromyelitis optica and related disorders. Patients with NMOSD or MOGAD included in the study received a confirmed or highly suspected diagnosis of COVID-19 between 1 March 2020 and 30 June 2020. Main outcome was COVID-19 severity score assessed on a seven-point ordinal scale ranging from 1 (not hospitalized with no limitations on activities) to 7 (death).

Results: Fifteen cases (mean [SD] age: 39.3 [14.3] years, 11 female) were included. Five patients (33.3%) were hospitalized, all receiving rituximab. A 24-year-old patient with positive aquaporine-4 antibody, with obesity as comorbidity, needed mechanical ventilation. Outpatients were receiving anti-CD20 (5), mycophenolate mofetil (3) or azathioprine (3). They were younger (mean [SD] age: 37.0 [13.4] years), with a longer disease duration (mean [SD]: 8.3 [6.3] years) and had a lower expanded disability severity score (EDSS) score (median [range] EDSS: 2.5 [0-4]) relative to patients requiring hospitalization (mean [SD] age: 44.0 [16.4] years, mean [SD] disease duration: 5.8 [5.5] years, median [range] EDSS: 4 [0-6.5]).

Conclusions: COVID-19 outcome was overall favorable in this cohort. Larger international studies are needed to identify risk factors of severe COVID-19; however, we recommend personal protective measures to reduce risk of SARS-CoV-2 infection in this immunocompromised population.
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http://dx.doi.org/10.1111/ene.14612DOI Listing
October 2020

Design and synthesis of 4-Aminoquinoline-isoindoline-dione-isoniazid triads as potential anti-mycobacterials.

Bioorg Med Chem Lett 2020 11 24;30(22):127576. Epub 2020 Sep 24.

Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, Punjab, India. Electronic address:

A series of 4-aminoquinoline-isoindoline-dione-isoniazid triads were synthesized and assessed for their anti-mycobacterial activities and cytotoxicity. Most of the synthesized compounds exhibited promising activities against the mc6230 strain of M. tuberculosis with MIC in the range of 5.1-11.9 µM and were non-cytotoxic against Vero cells. The conjugates lacking either isoniazid or quinoline core in their structural framework failed to inhibit the growth of M. tuberculosis; thus, further strengthening the proposed design of triads in the present study.
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http://dx.doi.org/10.1016/j.bmcl.2020.127576DOI Listing
November 2020

The roles of tetraspanins in bacterial infections.

Cell Microbiol 2020 12 2;22(12):e13260. Epub 2020 Oct 2.

Centre National de la Recherche Scientifique UMR 9004, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, Montpellier, France.

Tetraspanins, a wide family composed of 33 transmembrane proteins, are associated with different types of proteins through which they arbitrate important cellular processes such as fusion, adhesion, invasion, tissue differentiation and immunological responses. Tetraspanins share a comparable structural design, which consists of four hydrophobic transmembrane domains with cytoplasmic and extracellular loops. They cooperate with different proteins, including other tetraspanins, receptors or signalling proteins to compose functional complexes at the cell surface, designated tetraspanin-enriched microdomains (TEM). Increasing evidences establish that tetraspanins are exploited by numerous intracellular pathogens as a doorway for entering and replicating within human cells. Although previous surveys focused mainly on viruses and parasites, it is now becoming clear that bacteria interact with tetraspanins, using TEM as a "gateway" to infection. In this review, we examine the biological functions of tetraspanins that are relevant to bacterial infective procedures and consider the available data that reveal how different bacteria benefit from host cell tetraspanins in infection and in the pathogenesis of diseases. We will also emphasise the stimulating potentials of targeting tetraspanins for preventing bacterial infectious diseases, using specific neutralising antibodies or anti-adhesion peptide-based therapies. Such innovative therapeutic opportunities may deliver alternatives for fighting difficult-to-manage and drug-resistant bacterial pathogens.
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http://dx.doi.org/10.1111/cmi.13260DOI Listing
December 2020

Structural analysis of the N-acetyltransferase Eis1 from Mycobacterium abscessus reveals the molecular determinants of its incapacity to modify aminoglycosides.

Proteins 2020 Aug 28. Epub 2020 Aug 28.

Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, CNRS UMR, Montpellier, France.

Enhanced intracellular survival (Eis) proteins belonging to the superfamily of the GCN5-related N-acetyltransferases play important functions in mycobacterial pathogenesis. In Mycobacterium tuberculosis, Eis enhances the intracellular survival of the bacilli in macrophages by modulating the host immune response and is capable to chemically modify and inactivate aminoglycosides. In nontuberculous mycobacteria (NTM), Eis shares similar functions. However, Mycobacterium abscessus, a multidrug resistant NTM, possesses two functionally distinct Eis homologues, Eis1 and Eis2 . While Eis2 participates in virulence and aminoglycosides resistance, this is not the case for Eis1 whose exact biological function remains to be determined. Herein, we show that overexpression of Eis1 in M. abscessus fails to induce resistance to aminoglycosides. To clarify why Eis1 is unable to modify this class of antibiotics, we solved its crystal structure bound to its cofactor, acetyl-CoA. The structure revealed that Eis1 has a typical homohexameric Eis-like organization. The structural analysis supported by biochemical approaches demonstrated that while Eis1 can acetylate small substrates, its active site is too narrow to accommodate aminoglycosides. Comparison with other Eis structures showed that an extended loop between strands 9 and 10 is blocking the access of large substrates to the active site and movement of helices 4 and 5 reduces the volume of the substrate-binding pocket to these compounds in Eis1 . Overall, this study underscores the molecular determinants explaining functional differences between Eis1 and Eis2 especially those inherent to their capacity to modify aminoglycosides.
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http://dx.doi.org/10.1002/prot.25997DOI Listing
August 2020

-Methylation of the Glycopeptidolipid Acyl Chain Defines Surface Hydrophobicity of and Macrophage Invasion.

ACS Infect Dis 2020 10 14;6(10):2756-2770. Epub 2020 Sep 14.

Centre National de la Recherche Scientifique UMR 9004, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, 1919 route de Mende, 34293 Montpellier, France.

, an emerging pathogen responsible for severe lung infections in cystic fibrosis patients, displays either smooth (S) or rough (R) morphotypes. The S-to-R transition is associated with reduced levels of glycopeptidolipid (GPL) production and is correlated with increased pathogenicity in animal and human hosts. While the structure of GPL is well established, its biosynthetic pathway is incomplete. In addition, the biological functions of the distinct structural parts of this complex lipid remain elusive. Herein, the gene encoding a putative -methyltransferase was deleted in the S variant. Subsequent biochemical and structural analyses demonstrated that methoxylation of the fatty acyl chain of GPL was abrogated in the mutant, and this defect was rescued upon complementation with a functional gene. In contrast, the introduction of derivatives mutated at residues essential for methyltransferase activity failed to complement GPL defects, indicating that encodes an -methyltransferase. Unexpectedly, phenotypic analyses showed that was more hydrophilic than its parental progenitor, as demonstrated by hexadecane-aqueous buffer partitioning and atomic force microscopy experiments with hydrophobic probes. Importantly, the invasion rate of THP-1 macrophages by was reduced by 50% when compared to the wild-type strain. Together, these results indicate that Fmt -methylates the lipid moiety of GPL and plays a substantial role in conditioning the surface hydrophobicity of as well as in the early steps of the interaction between the bacilli and macrophages.
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http://dx.doi.org/10.1021/acsinfecdis.0c00490DOI Listing
October 2020

CFTR Depletion Confers Hypersusceptibility to in a Zebrafish Model.

Front Cell Infect Microbiol 2020 17;10:357. Epub 2020 Jul 17.

Institut de Recherche en Infectiologie de Montpellier, Centre National de la Recherche Scientifique UMR 9004, Université de Montpellier, Montpellier, France.

The complex comprises several closely related species, causing pulmonary and extra-pulmonary infections. However, there is very limited knowledge about the disease pathogenesis involved in infections, particularly due to the lack of suitable animal models. Using the zebrafish model, we show that embryos are susceptible to infection in a dose-dependent manner. Furthermore, zebrafish embryos form granulomas from as early as 2 days post-infection, recapitulating critical aspects of mycobacterial pathogenesis observed in other pathogenic species. The formation of extracellular cords in infected embryos highlights a previously unknown pathogenic feature of . The formation of large corded structures occurs also during growth, suggesting that this is not a host-adapted stress mechanism deployed during infection. Moreover, transient macrophage depletion led to rapid embryo death with increased extracellular cords, indicating that macrophages are essential determinants of infection control. Importantly, morpholino depletion of the cystic fibrosis transmembrane conductance regulator () significantly increased embryo death, bacterial burden, bacterial cords and abscesses. There was a noticeable decrease in the number of -deficient infected embryos with granulomas as compared to infected controls, suggesting that loss of CFTR leads to impaired host immune responses and confers hypersusceptiblity to infection. Overall, these findings highlight the application of the zebrafish embryo to study and emphasizes previously unexplored aspects of disease pathogenesis of this significant mycobacterial species.
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http://dx.doi.org/10.3389/fcimb.2020.00357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396536PMC
July 2020

[New hopes for the treatment of persistent Mycobacterium abscessus infections?]

Med Sci (Paris) 2020 Aug-Sep;36(8-9):691-694. Epub 2020 Aug 21.

CNRS UMR 9004, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, 1919 route de Mende, 34293 Montpellier, France.

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http://dx.doi.org/10.1051/medsci/2020138DOI Listing
November 2020

Rifabutin Is Bactericidal against Intracellular and Extracellular Forms of Mycobacterium abscessus.

Antimicrob Agents Chemother 2020 10 20;64(11). Epub 2020 Oct 20.

Centre National de la Recherche Scientifique UMR 9004, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, Montpellier, France

is increasingly recognized as an emerging opportunistic pathogen causing severe lung diseases. As it is intrinsically resistant to most conventional antibiotics, there is an unmet medical need for effective treatments. Repurposing of clinically validated pharmaceuticals represents an attractive option for the development of chemotherapeutic alternatives against infections. In this context, rifabutin (RFB) has been shown to be active against and has raised renewed interest in using rifamycins for the treatment of pulmonary diseases. Here, we compared the and activity of RFB against the smooth and rough variants of , differing in their susceptibility profiles to several drugs and physiopathologial characteristics. While the activity of RFB is greater against rough strains than in smooth strains , suggesting a role of the glycopeptidolipid layer in susceptibility to RFB, both variants were equally susceptible to RFB inside human macrophages. RFB treatment also led to a reduction in the number and size of intracellular and extracellular mycobacterial cords. Furthermore, RFB was highly effective in a zebrafish model of infection and protected the infected larvae from -induced killing. This was corroborated by a significant reduction in the overall bacterial burden, as well as decreased numbers of abscesses and cords, two major pathophysiological traits in infected zebrafish. This study indicates that RFB is active against both and , further supporting its potential usefulness as part of combination regimens targeting this difficult-to-treat mycobacterium.
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http://dx.doi.org/10.1128/AAC.00363-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577168PMC
October 2020

Progressive multifocal leukoencephalopathy and sarcoidosis under interleukin 7: The price of healing.

Neurol Neuroimmunol Neuroinflamm 2020 09 11;7(5). Epub 2020 Aug 11.

From the Department of Clinical Immunology and Internal Medicine (A.G., V.G, Y.D., V.P., T.M., A.-S.K.), National Reference Center for Systemic Autoimmune Diseases (CNR RESO), Tertiary Center for Primary Immunodeficiency, Strasbourg University Hospital; Université de Strasbourg (A.G., M.S., V.G., Y.D., T.M., A.-S.K.), INSERM UMR - S1109; Université de Strasbourg (A.G., M.S., Y.D., C.L., Y.H., T.M., A.-S.K.), Faculty of Medicine; Virology Laboratory (M.S.), Strasbourg University Hospital; Université de Strasbourg (V.G.), Faculty of Pharmacy, Illkirch, France; Internal Medicine and Intensive Care (C.K.), Strasbourg University Hospital; Department of Dermatology (C.L.), Strasbourg University Hospital; Department of Neurology (L.K.), INSERM U1119, Biopathologie de La Myéline, Neuroprotection et Stratégies Thérapeutiques, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS); Université de Strasbourg (A.M., R.C.), INSERM UMR-S1109, GENOMAX Platform, Fédération Hospitalo-Universitaire OMICARE, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), LabEx TRANSPLANTEX; Department of Infectious Diseases (Y.H.), Strasbourg University Hospital; and Departement of Pneumology (S.H.), Strasbourg University Hospital, Strasbourg, France.

Objective: To report the association of JC virus infection of the brain (progressive multifocal encephalopathy [PML]) during the course of sarcoidosis and the challenging balance between immune reconstitution under targeted cytokine interleukin 7 (IL7) therapy for PML and immunosuppression for sarcoidosis.

Methods: Original case report including deep sequencing (whole-exome sequencing) to exclude a primary immunodeficiency (PID) and review of the literature of cases of PML and sarcoidosis.

Results: We report and discuss here a challenging case of immune reconstitution with IL7 therapy for PML in sarcoidosis in a patient without evidence for underling PID or previous immunosuppressive therapy.

Conclusions: New targeted therapies in immunology and infectiology open the doors of more specific and more specialized therapies for patients with immunodeficiencies, autoimmune diseases, or cancers. However, before instauration of these treatments, the risk of immune reconstitution inflammatory syndrome and potential exacerbation of an underlying disease must be considered. It is particularly true in case of autoimmune disease such as sarcoidosis or lupus.
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http://dx.doi.org/10.1212/NXI.0000000000000862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428361PMC
September 2020

Antibodies against the node of Ranvier: a real-life evaluation of incidence, clinical features and response to treatment based on a prospective analysis of 1500 sera.

J Neurol 2020 Dec 16;267(12):3664-3672. Epub 2020 Jul 16.

Timone Neuroscience Institute, UMR CNRS 7289, Aix-Marseille University, 13005, Marseille, France.

Introduction: IgG4 antibodies against neurofascin (Nfasc155 and Nfasc140/186), contactin (CNTN1) and contactin-associated protein (Caspr1) are described in specific subtypes of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Our objective was to assess, in a real-life practice, the incidence, the clinical features and the response to treatment of these forms of CIDP.

Methods: 1500 sera of patients suspected of having CIDP from France, Belgium and Switzerland were prospectively tested using a flow cytometry technique. The characteristics of patients with antibodies against the node of Ranvier were compared to 100 seronegative CIDP from our department.

Results: IgG4 antibodies against Nfasc155, CNTN1, and Caspr1 were, respectively, detected in 15 (prevalence 1%), 10 (0.7%) and 2 (0.2%) sera. Antibodies specific of the Nfasc140/186 were not detected. All subjects with antibodies against the node of Ranvier fulfilled diagnostic criteria for CIDP. CIDP with anti-Nfasc155 were younger, had more sensory ataxia and postural tremor than seronegative CIDP. CIDP with anti-CNTN1 had more frequent subacute onset and facial paralysis, commoner renal involvement with membranous glomerulonephritis and greater disability, than seronegative CIDP. CIDP with anti-Caspr1 had more frequent respiratory failure and cranial nerve involvement but not more neuropathic pain than seronegative CIDP. Intravenous immunoglobulins were ineffective in most seropositive patients. Rituximab produced dramatic improvement in disability and decreased antibodies titres in 13 seropositive patients (8 with anti-Nfasc155 and 5 with anti-CNTN1 antibodies).

Conclusions: Although rare, anti-paranodal antibodies are clinically valuable, because they are associated with specific phenotypes and therapeutic response.
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http://dx.doi.org/10.1007/s00415-020-10041-zDOI Listing
December 2020

Long-term effect of natalizumab in patients with RRMS: TYSTEN cohort.

Mult Scler 2020 Jul 9:1352458520936239. Epub 2020 Jul 9.

Department of Neurology, Centre Hospitalier Universitaire de Lille, Lille, France/Department of Neuroradiology, Centre Hospitalier Universitaire de Lille, Lille, France.

Background: Data are needed on long-term effect of natalizumab (NTZ) in relapsing-remitting multiple sclerosis (RRMS).

Objectives: To evaluate the time of onset of secondary progressive phase in patients with an RRMS treated with NTZ and to investigate predictive factors.

Methods: TYSTEN is an observational study. Patients starting NTZ between 2007 and 2012 were included and followed up until October 2018. Relapses, Expanded Disability Status Scale (EDSS) scores, and results of brain magnetic resonance imaging (MRI) were collected each year. Data were used to estimate the cumulative probability of several poor outcomes such as secondary progressive multiple sclerosis (SPMS) conversion, EDSS worsening, EDSS 4.0, and EDSS 6.0.

Results: 770 patients were included. The mean follow-up duration was 97 months and the mean time exposure to NTZ was 66 months. At 10 years, the cumulative probability of SPMS was 27.7%. Predictive factors for poor outcomes were a ⩾1-point increase in EDSS score from baseline, new T2 lesion or T1 gadolinium-enhancing lesion, the occurrence of relapse at 1 or 2 years and No Evidence of Disease Activity (NEDA-3; no relapse, no new T2 or T1 gadolinium-enhancing lesions, no progression) was a protective factor.

Conclusion: In our cohort of patients treated with NTZ, poor outcomes were infrequent and are driven by disease activity.
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http://dx.doi.org/10.1177/1352458520936239DOI Listing
July 2020

The TOTEM RRMS (Testosterone Treatment on neuroprotection and Myelin Repair in Relapsing Remitting Multiple Sclerosis) trial: study protocol for a randomized, double-blind, placebo-controlled trial.

Trials 2020 Jun 29;21(1):591. Epub 2020 Jun 29.

Centre d᾿Investigation Clinique INSERM 1434, Strasbourg, France.

Background: Central nervous system damage in multiple sclerosis (MS) is responsible for serious deficiencies. Current therapies are focused on the treatment of inflammation; however, there is an urgent need for innovative therapies promoting neuroregeneration, particularly myelin repair. It is demonstrated that testosterone can act through neural androgen receptors and several clinical observations stimulated an interest in the potential protective effects of testosterone treatment for MS. Here, we sought to demonstrate the effects of a testosterone supplementation in testosterone-deficient men with relapsing-remitting MS.

Methods/design: This report presents the rationale and methodology of TOTEM RRMS, a French, phase 2, multicenter, randomized, placebo-controlled, and double-blind trial, which aims to prevent the progression of MS in men with low testosterone levels by administration of testosterone undecanoate, who were kept under natalizumab (Tysabri®) to overcome the anti-inflammatory effect of testosterone. Forty patients will be randomized into two groups receiving either a testosterone treatment (Nebido®) or a matching placebo. The intervention period for each group will last 66 weeks (treatment will be injected at baseline, week 6, and then every 12 weeks). The main objective is to determine the neuroprotective and remyelinating effects of testosterone using tensor diffusion imaging techniques and thalamic atrophy analyses. As secondary objectives, impacts of the testosterone supplementation will be studied using other conventional and unconventional MRI parameters and with clinical outcomes.

Discussion: The action of testosterone is observed in different experimental autoimmune encephalomyelitis models and epidemiological studies in humans. However, despite several preclinical data and some small clinical trials in MS, clear evidence for a therapeutic effect of hormone therapy is still missing. Therefore, our goal is to demonstrate the effects of testosterone therapies in MS. As there is no effective treatment currently available on fatigue in MS, careful attention should also be paid to secondary endpoints: fatigue, cognitive functions, and other symptoms that may improve life quality. Assuming a positive outcome of the trial, this treatment could be considered as a new neuroprotective and remyelinating therapy in relapsing-remitting MS and could be applicable to other demyelinating diseases.

Trial Registration: ClinicalTrials.gov NCT03910738. Registered on 10 April 2019.
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http://dx.doi.org/10.1186/s13063-020-04517-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322908PMC
June 2020

Synthesis and evaluation of heterocycle structures as potential inhibitors of Mycobacterium tuberculosis UGM.

Bioorg Med Chem 2020 07 2;28(13):115579. Epub 2020 Jun 2.

Laboratoire Synthèse et Isolement de Molécules Bioactives (SIMBA, EA 7502), Université de Tours, Faculté de Pharmacie, Parc de Grandmont, 31 Avenue Monge, 37200 Tours, France. Electronic address:

In this study, we screen three heterocyclic structures as potential inhibitors of UDP-galactopyranose mutase (UGM), an enzyme involved in the biosynthesis of the cell wall of Mycobacterium tuberculosis. In order to understand the binding mode, docking simulations are performed on the best inhibitors. Their activity on Mycobacterium tuberculosis is also evaluated. This study made it possible to highlight an "oxazepino-indole" structure as a new inhibitor of UGM and of M. tuberculosis growth in vitro.
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http://dx.doi.org/10.1016/j.bmc.2020.115579DOI Listing
July 2020

Discovery of the first Mycobacterium tuberculosis MabA (FabG1) inhibitors through a fragment-based screening.

Eur J Med Chem 2020 Aug 18;200:112440. Epub 2020 May 18.

Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000, Lille, France. Electronic address:

Mycobacterium tuberculosis (M.tb), the etiologic agent of tuberculosis, remains the leading cause of death from a single infectious agent worldwide. The emergence of drug-resistant M.tb strains stresses the need for drugs acting on new targets. Mycolic acids are very long chain fatty acids playing an essential role in the architecture and permeability of the mycobacterial cell wall. Their biosynthesis involves two fatty acid synthase (FAS) systems. Among the four enzymes (MabA, HadAB/BC, InhA and KasA/B) of the FAS-II cycle, MabA (FabG1) remains the only one for which specific inhibitors have not been reported yet. The development of a new LC-MS/MS based enzymatic assay allowed the screening of a 1280 fragment-library and led to the discovery of the first small molecules that inhibit MabA activity. A fragment from the anthranilic acid series was optimized into more potent inhibitors and their binding to MabA was confirmed by F ligand-observed NMR experiments.
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http://dx.doi.org/10.1016/j.ejmech.2020.112440DOI Listing
August 2020

Guillain-Barré syndrome related to SARS-CoV-2 infection.

Neurol Neuroimmunol Neuroinflamm 2020 09 27;7(5). Epub 2020 May 27.

From the Service de Neurologie (K.B., P.V., L.K., J.-B.C., J.S.), Hôpitaux Universitaires de Strasbourg; Service de Neurologie (M.M.), Centre Hospitalo-Universitaire de Grenoble Alpes, La Tronche; Service de Neuroradiologie (S.B.), Hôpitaux Universitaires de Strasbourg; Institut de Biologie Structurale (IBS) (B.N., P.M.), Université de Grenoble Alpes, CEA, CNRS; Laboratoire de virologie (B.N., P.M.), Centre Hospitalo-Universitaire de Grenoble Alpes, La Tronche; Service d'Accueil des Urgences (F.B.), Hôpitaux Universitaires de Strasbourg; and Service de Réanimation Polyvalente Chirurgicale (A.G.), Centre Hospitalo-Universitaire de Grenoble Alpes, La Tronche, France.

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http://dx.doi.org/10.1212/NXI.0000000000000785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286648PMC
September 2020

Fast chemical force microscopy demonstrates that glycopeptidolipids define nanodomains of varying hydrophobicity on mycobacteria.

Nanoscale Horiz 2020 06 21;5(6):944-953. Epub 2020 Apr 21.

Louvain Institute of Biomolecular Science and Technology, UCLouvain, Croix du Sud, 4-5, bte L7.07.07, B-1348 Louvain-la-Neuve, Belgium.

Mycobacterium abscessus is an emerging multidrug-resistant bacterial pathogen causing severe lung infections in cystic fibrosis patients. A remarkable trait of this mycobacterial species is its ability to form morphologically smooth (S) and rough (R) colonies. The S-to-R transition is caused by the loss of glycopeptidolipids (GPLs) in the outer layer of the cell envelope and correlates with an increase in cording and virulence. Despite the physiological and medical importance of this morphological transition, whether it involves changes in cell surface properties remains unknown. Herein, we combine recently developed quantitative imaging (QI) atomic force microscopy (AFM) with hydrophobic tips to quantitatively map the surface structure and hydrophobicity of M. abscessus at high spatiotemporal resolution, and to assess how these properties are modulated by the S-to-R transition and by treatment with an inhibitor of the mycolic acid transporter MmpL3. We discover that loss of GPLs leads to major modifications in surface hydrophobicity, without any apparent change in cell surface ultrastructure. While R bacilli are homogeneously hydrophobic, S bacilli feature unusual variations of nanoscale hydrophobic properties. These previously undescribed cell surface nanodomains are likely to play critical roles in bacterial adhesion, aggregation, phenotypic heterogeneity and transmission, and in turn in virulence and pathogenicity. Our study also suggests that MmpL3 inhibitors show promise in nanomedicine as chemotherapeutic agents to interfere with the highly hydrophobic nature of the mycobacterial cell wall. The advantages of QI-AFM with hydrophobic tips are the ability to map chemical and structural properties simultaneously and at high resolution, applicable to a wide range of biosystems.
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http://dx.doi.org/10.1039/c9nh00736aDOI Listing
June 2020

Large Extracellular Cord Formation in a Zebrafish Model of Mycobacterium kansasii Infection.

J Infect Dis 2020 08;222(6):1046-1050

Institut de Recherche en Infectiologie de Montpellier, Centre National de la Recherche Scientifique UMR 9004, Université de Montpellier, Montpellier, France.

Mycobacterium kansasii is a slow-growing nontuberculous mycobacteria responsible for coinfections particularly in patients with human immunodeficiency virus. To date, our knowledge of M. kansasii infection has been hampered owing to the lack of an effective animal model to study pathogenesis. In the current study, we showed that the zebrafish embryo is permissive to M. kansasii infection, resulting in chronic infection and formation of granulomas. On macrophage depletion, we identified M. kansasii forms extracellular cords, resulting in acute infection and rapid larval death. These findings highlight the feasibility of zebrafish for studying M. kansasii pathogenesis and for the first time identify extracellular cords in this species.
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http://dx.doi.org/10.1093/infdis/jiaa187DOI Listing
August 2020

Efficacy of Bedaquiline, Alone or in Combination with Imipenem, against Mycobacterium abscessus in C3HeB/FeJ Mice.

Antimicrob Agents Chemother 2020 05 21;64(6). Epub 2020 May 21.

UVSQ, INSERM, Infection et Inflammation (U1173), Université Paris-Saclay, Montigny-le-Bretonneux, France.

lung infections remain difficult to treat. Recent studies have recognized the power of new combinations of antibiotics, such as bedaquiline and imipenem, although data have questioned this combination. We report that the efficacy of bedaquiline-imipenem combination treatment relies essentially on the activity of bedaquiline in a C3HeB/FeJ mice model of infection with a rough variant of The addition of imipenem contributed to clearing the infection in the spleen.
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http://dx.doi.org/10.1128/AAC.00114-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269509PMC
May 2020

Structure-Based Design and Synthesis of Piperidinol-Containing Molecules as New Inhibitors.

ChemistryOpen 2020 03 20;9(3):351-365. Epub 2020 Mar 20.

Univ. Lille, CNRS UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle 59000 Lille France.

Non-tuberculous mycobacterium (NTM) infections, such as those caused by , are increasing globally. Due to their intrinsic drug resistance, pulmonary infections are often difficult to cure using standard chemotherapy. We previously demonstrated that a piperidinol derivative, named PIPD1, is an efficient molecule both against and , the agent of tuberculosis, by targeting the mycolic acid transporter MmpL3. These results prompted us to design and synthesize a series of piperidinol derivatives and to determine the biological activity against . Structure-activity relationship (SAR) studies pointed toward specific sites on the scaffold that can tolerate slight modifications. Overall, these results identified FMD-88 as a new promising active analogue against . Also, we determined the pharmacokinetics properties of PIPD1 and showed that intraperitoneal administration of this compound resulted in promising serum concentration and an elimination half-life of 3.2 hours.
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http://dx.doi.org/10.1002/open.202000042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083170PMC
March 2020

Self-control of vitamin K production captured in the crystal.

J Biol Chem 2020 03;295(12):3771-3772

Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, CNRS UMR 9004, 34293 Montpellier, France

Menaquinone (MK) or vitamin K is an important metabolite that controls the redox/energy status of Although the major steps of MK biosynthesis have been delineated, the regulatory mechanisms of this pathway have not been adequately explored. Bashiri now demonstrate that MenD, catalyzing the first committed step of MK production, is allosterically inhibited by a downstream cytosolic metabolite in the MK biosynthesis pathway.
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http://dx.doi.org/10.1074/jbc.H120.013113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086030PMC
March 2020

The endogenous galactofuranosidase GlfH1 hydrolyzes mycobacterial arabinogalactan.

J Biol Chem 2020 04 27;295(15):5110-5123. Epub 2020 Feb 27.

Univ. Lille, CNRS, UMR8576 - UGSF - Unit[c33c]zpi;● de Glycobiologie Structurale et Fonctionnelle, F-59000 Lille, France

Despite impressive progress made over the past 20 years in our understanding of mycolylarabinogalactan-peptidoglycan (mAGP) biogenesis, the mechanisms by which the tubercle bacillus adapts its cell wall structure and composition to various environmental conditions, especially during infection, remain poorly understood. Being the central portion of the mAGP complex, arabinogalactan (AG) is believed to be the constituent of the mycobacterial cell envelope that undergoes the least structural changes, but no reports exist supporting this assumption. Herein, using recombinantly expressed mycobacterial protein, bioinformatics analyses, and kinetic and biochemical assays, we demonstrate that the AG can be remodeled by a mycobacterial endogenous enzyme. In particular, we found that the mycobacterial GlfH1 (Rv3096) protein exhibits exo-β-d-galactofuranose hydrolase activity and is capable of hydrolyzing the galactan chain of AG by recurrent cleavage of the terminal β-(1,5) and β-(1,6)-Galf linkages. The characterization of this galactosidase represents a first step toward understanding the remodeling of mycobacterial AG.
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http://dx.doi.org/10.1074/jbc.RA119.011817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7152746PMC
April 2020

Non-tuberculous mycobacteria and the rise of Mycobacterium abscessus.

Nat Rev Microbiol 2020 07 21;18(7):392-407. Epub 2020 Feb 21.

Institut de Recherche en Infectiologie de Montpellier, Centre National de la Recherche Scientifique UMR 9004, Université de Montpellier, Montpellier, France.

Infections caused by non-tuberculous mycobacteria (NTM) are increasing globally and are notoriously difficult to treat due to intrinsic resistance of these bacteria to many common antibiotics. NTM are diverse and ubiquitous in the environment, with only a few species causing serious and often opportunistic infections in humans, including Mycobacterium abscessus. This rapidly growing mycobacterium is one of the most commonly identified NTM species responsible for severe respiratory, skin and mucosal infections in humans. It is often regarded as one of the most antibiotic-resistant mycobacteria, leaving us with few therapeutic options. In this Review, we cover the proposed infection process of M. abscessus, its virulence factors and host interactions and highlight the commonalities and differences of M. abscessus with other NTM species. Finally, we discuss drug resistance mechanisms and future therapeutic options. Taken together, this knowledge is essential to further our understanding of this overlooked and neglected global threat.
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http://dx.doi.org/10.1038/s41579-020-0331-1DOI Listing
July 2020

Electrophysiological features of chronic inflammatory demyelinating polyradiculoneuropathy associated with IgG4 antibodies targeting neurofascin 155 or contactin 1 glycoproteins.

Clin Neurophysiol 2020 04 6;131(4):921-927. Epub 2020 Feb 6.

Referral Centre for Neuromuscular Diseases and ALS, La Timone hospital, Marseille, France; Aix-Marseille University, Timone Neuroscience Institute, UMR CNRS 7289, 13005 Marseille, France. Electronic address:

Objective: Chronic inflammatory demyelinating polyradiculoneuropathies (CIDP) with antibodies against neurofascin 155 (Nfasc155) or contactin-1 (CNTN1) have distinctive clinical features. Knowledge on their electrophysiological characteristics is still scarce. In this study, we are investigating whether these patients have specific electrophysiological characteristics.

Methods: The electrophysiological data from 13 patients with anti-Nfasc155 IgG4 antibodies, 9 with anti-CNTN1 IgG4 antibodies were compared with those of 40 consecutive CIDP patients without antibodies.

Results: All the patients with antibodies against Nfasc155 or CNTN1 fulfilled the EFNS/PNS electrodiagnostic criteria for definite CIDP. There was no electrophysiological difference between patients with anti-CNTN1 and anti-Nfasc155 antibodies. Nerve conduction abnormalities were heterogeneously distributed along nerves trunks and roots. They were more pronounced than in CIDP without antibodies. Motor conduction velocity on median nerve <24 m/s or motor velocity on ulnar nerve <26 m/s or motor distal latency on ulnar nerve >7.4 ms were predictive of positive antibodies against the node of Ranvier with a sensitivity of 59% and a specificity of 93%.

Conclusions: Marked conduction abnormalities may suggest the presence of positive antibodies against the node of Ranvier.

Significance: Anti-Nfasc155 and anti-CNTN1 antibodies target the the paranodal axo-glial domain but are associated with nerve conduction abnormalities mimicking a "demyelinating" neuropathy.
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http://dx.doi.org/10.1016/j.clinph.2020.01.013DOI Listing
April 2020

Synergistic Interactions of Indole-2-Carboxamides and β-Lactam Antibiotics against Mycobacterium abscessus.

Antimicrob Agents Chemother 2020 04 21;64(5). Epub 2020 Apr 21.

Centre National de la Recherche Scientifique UMR 9004, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, Montpellier, France

New drugs or therapeutic combinations are urgently needed against Previously, we demonstrated the potent activity of indole-2-carboxamides 6 and 12 against We show here that these compounds act synergistically with imipenem and cefoxitin and increase the bactericidal activity of the β-lactams against In addition, compound 12 also displays synergism with imipenem and cefoxitin within infected macrophages. The clinical potential of these new drug combinations requires further evaluation.
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http://dx.doi.org/10.1128/AAC.02548-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179587PMC
April 2020

Active Benzimidazole Derivatives Targeting the MmpL3 Transporter in .

ACS Infect Dis 2020 02 7;6(2):324-337. Epub 2020 Jan 7.

Centre National de la Recherche Scientifique UMR 9004, Institut de Recherche en Infectiologie de Montpellier (IRIM) , Université de Montpellier , 1919 route de Mende , 34293 Montpellier , France.

The prevalence of pulmonary infections due to nontuberculous mycobacteria such as has been increasing and surpassing tuberculosis (TB) in some industrialized countries. Because of intrinsic resistance to most antibiotics that drastically limits conventional chemotherapeutic treatment options, new anti- therapeutics are urgently needed against this emerging pathogen. Extensive screening of a library of benzimidazole derivatives that were previously shown to be active against led to the identification of a lead compound exhibiting very potent in vitro activity against a wide panel of clinical strains. Designated EJMCh-6, this compound, a 2-(2-cyclohexylethyl)-5,6-dimethyl-1-benzo[]imidazole), also exerted very strong activity against intramacrophage-residing . Moreover, the treatment of infected zebrafish embryos with EJMCh-6 was correlated with significantly increased embryo survival and a decrease in the bacterial burden as compared to those for untreated fish. Insights into the mechanism of action were inferred from the generation of spontaneous benzimidazole-resistant strains and the identification of a large set of missense mutations in MmpL3, the mycolic acid transporter in mycobacteria. Overexpression of the mutated alleles in a susceptible strain was associated with high resistance levels to EJMCh-6 and to other known MmpL3 inhibitors. Mapping the mutations conferring resistance on an MmpL3 three-dimensional homology model defined a potential EJMCh-6-binding cavity. These data emphasize a yet unexploited chemical structure class against with promising translational development for the treatment of lung diseases.
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http://dx.doi.org/10.1021/acsinfecdis.9b00389DOI Listing
February 2020

Frequency of myelin oligodendrocyte glycoprotein antibody in multiple sclerosis: A multicenter cross-sectional study.

Neurol Neuroimmunol Neuroinflamm 2020 03 13;7(2). Epub 2019 Dec 13.

From the Service de Neurologie (Á.C.-C., F.D.-D., S.V., R.M.), Sclérose en Plaques, Pathologies de La Myéline et Neuro-inflammation, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, France; Centre de Référence pour Les Maladies Inflammatoires Rares Du Cerveau et de La Moelle (MIRCEM) (Á.C.-C., F.D.-D., S.V., R.M.), Hôpital Neurologique Pierre Wertheimer Hospices Civils de Lyon, Lyon, France; Centre de Recherche en Neurosciences de Lyon (Á.C.-C., H.I., A.R., R.M.), U1028 INSERM, UMR5292 CNRS, Lyon, France; Département de Neurologie (N.C., L.K., J.D.S.), Centre Hospitalier Universitaire de Strasbourg, France; Biopathologie de La Myéline (N.C., J.D.S.), Neuroprotection et Stratégies Thérapeutiques, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, France; Centre D'investigation Clinique (N.C., J.D.S.), INSERM U1434, Centre Hospitalier Universitaire de Strasbourg, France; Centre de Recherche en Neurosciences de Lyon (F.R., R.C., S.V.), Observatoire Français de La Sclérose en Plaques, INSERM 1028 et CNRS UMR5292, Lyon, France; and Université Claude Bernard Lyon 1 (F.R., R.C., S.V.), F-69000 Lyon, France; Hospices Civils de Lyon, Lyon, France.

Objective: To address the frequency of myelin oligodendrocyte glycoprotein (MOG) antibody (Ab) in an unselected large cohort of adults with MS.

Methods: This is a cross-sectional study in 2 MS expert centers (Lyon and Strasbourg University Hospitals, France) between December 1, 2017, and June 31, 2018. Patients aged ≥18 years with a definite diagnosis of MS according to 2010 McDonald criteria were tested for MOG-Ab by using a cell-based assay (CBA) in Lyon and subsequently included. Positive samples were tested by investigators blinded to the first result with a second assay in a different laboratory (Barcelona, Spain) by using the same plasmid and secondary Ab.

Results: Serum samples from 685 consecutive patients with MS were analyzed for MOG-Ab. Median disease duration at sampling was 11.5 (interquartile range, 5.8-17.7) years, and 72% were women. Two (0.3%) patients resulted to be MOG-Ab-positive. The 2 patients were women aged 42 and 38 at disease onset and were diagnosed with secondary and primary progressive forms of MS, respectively. This positive result was confirmed by the CBA in Barcelona.

Conclusion: Our findings indicate that MOG-Ab are exceptional in MS phenotype, suggesting that the MOG-Ab testing should not be performed in typical MS presentation.
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http://dx.doi.org/10.1212/NXI.0000000000000649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943364PMC
March 2020