Publications by authors named "Catherine Larochelle"

48 Publications

Response to correspondence on "Reproducibility of CRISPR-Cas9 methods for generation of conditional mouse alleles: a multi-center evaluation".

Authors:
Channabasavaiah B Gurumurthy Aidan R O'Brien Rolen M Quadros John Adams Pilar Alcaide Shinya Ayabe Johnathan Ballard Surinder K Batra Marie-Claude Beauchamp Kathleen A Becker Guillaume Bernas David Brough Francisco Carrillo-Salinas Wesley Chan Hanying Chen Ruby Dawson Victoria DeMambro Jinke D'Hont Katharine Dibb James D Eudy Lin Gan Jing Gao Amy Gonzales Anyonya Guntur Huiping Guo Donald W Harms Anne Harrington Kathryn E Hentges Neil Humphreys Shiho Imai Hideshi Ishii Mizuho Iwama Eric Jonasch Michelle Karolak Bernard Keavney Nay-Chi Khin Masamitsu Konno Yuko Kotani Yayoi Kunihiro Imayavaramban Lakshmanan Catherine Larochelle Catherine B Lawrence Lin Li Volkhard Lindner Xian-De Liu Gloria Lopez-Castejon Andrew Loudon Jenna Lowe Loydie Jerome-Majeweska Taiji Matsusaka Hiromi Miura Yoshiki Miyasaka Benjamin Morpurgo Katherine Motyl Yo-Ichi Nabeshima Koji Nakade Toshiaki Nakashiba Kenichi Nakashima Yuichi Obata Sanae Ogiwara Mariette Ouellet Leif Oxburgh Sandra Piltz Ilka Pinz Moorthy P Ponnusamy David Ray Ronald J Redder Clifford J Rosen Nikki Ross Mark T Ruhe Larisa Ryzhova Ane M Salvador Sabrina Shameen Alam Radislav Sedlacek Karan Sharma Chad Smith Katrien Staes Lora Starrs Fumihiro Sugiyama Satoru Takahashi Tomohiro Tanaka Andrew Trafford Yoshihiro Uno Leen Vanhoutte Frederique Vanrockeghem Brandon J Willis Christian S Wright Yuko Yamauchi Xin Yi Kazuto Yoshimi Xuesong Zhang Yu Zhang Masato Ohtsuka Satyabrata Das Daniel J Garry Tino Hochepied Paul Thomas Jan Parker-Thornburg Antony D Adamson Atsushi Yoshiki Jean-Francois Schmouth Andrei Golovko William R Thompson K C Kent Lloyd Joshua A Wood Mitra Cowan Tomoji Mashimo Seiya Mizuno Hao Zhu Petr Kasparek Lucy Liaw Joseph M Miano Gaetan Burgio

Genome Biol 2021 Apr 7;22(1):99. Epub 2021 Apr 7.

Department of Immunology and Infectious Disease, the John Curtin School of Medical Research, The Australian National University, Canberra, Australia.

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http://dx.doi.org/10.1186/s13059-021-02320-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025318PMC
April 2021

A single BNT162b2 mRNA dose elicits antibodies with Fc-mediated effector functions and boost pre-existing humoral and T cell responses.

bioRxiv 2021 Mar 18. Epub 2021 Mar 18.

The standard dosing of the Pfizer/BioNTech BNT162b2 mRNA vaccine validated in clinical trials includes two doses administered three weeks apart. While the decision by some public health authorities to space the doses because of limiting supply has raised concerns about vaccine efficacy, data indicate that a single dose is up to 90% effective starting 14 days after its administration. We analyzed humoral and T cells responses three weeks after a single dose of this mRNA vaccine. Despite the proven efficacy of the vaccine at this time point, no neutralizing activity were elicited in SARS-CoV-2 naïve individuals. However, we detected strong anti-receptor binding domain (RBD) and Spike antibodies with Fc-mediated effector functions and cellular responses dominated by the CD4 T cell component. A single dose of this mRNA vaccine to individuals previously infected by SARS-CoV-2 boosted all humoral and T cell responses measured, with strong correlations between T helper and antibody immunity. Neutralizing responses were increased in both potency and breadth, with distinctive capacity to neutralize emerging variant strains. Our results highlight the importance of vaccinating uninfected and previously-infected individuals and shed new light into the potential role of Fc-mediated effector functions and T cell responses in vaccine efficacy. They also provide support to spacing the doses of two-vaccine regimens to vaccinate a larger pool of the population in the context of vaccine scarcity against SARS-CoV-2.
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http://dx.doi.org/10.1101/2021.03.18.435972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987016PMC
March 2021

The IL-27/IL-27R axis is altered in CD4 and CD8 T lymphocytes from multiple sclerosis patients.

Clin Transl Immunology 2021 5;10(3):e1262. Epub 2021 Mar 5.

Department of Neurosciences Université de Montréal and CRCHUM Montreal QC Canada.

Objectives: Pro- and anti-inflammatory properties have been attributed to interleukin-27 (IL-27). Nevertheless, the impact of this cytokine on chronic inflammatory diseases such as multiple sclerosis (MS) remains ill-defined. We investigated the biology of IL-27 and its specific receptor IL-27Rα in MS patients.

Methods: Levels of IL-27 and its natural antagonist (IL-27-Rα) were measured by ELISA in biological fluids. CD4 and CD8 T lymphocytes were isolated from untreated relapsing-remitting MS patients and healthy donors. Transcriptome-wide analysis compared T-cell subsets stimulated or not with IL-27. Expression of the IL-27Rα, key immune factors, STAT phosphorylation and cytokine production was assessed by flow cytometry.

Results: We observed elevated levels of IL-27 in the serum and cerebrospinal fluid of MS patients compared with controls. Moreover, we show that specific IL-27-mediated effects on T lymphocytes are reduced in MS patients including the induction of PD-L1. IL-27-triggered STAT3 signalling pathway is enhanced in CD4 and CD8 T lymphocytes from MS patients. Elevated IL-27Rα levels in serum from MS patients are sufficient to impair the capacity of IL-27 to act on immune cells. We demonstrate that shedding of IL-27Rα by activated CD4 T lymphocytes from MS patients contributes to the increased IL-27Rα peripheral levels and consequently can dampen the IL-27 responsiveness.

Conclusion: Our work identifies several mechanisms that are altered in the IL-27/IL-27R axis in MS patients, especially in T lymphocytes. Our results underline the importance of characterising the biology of cytokines in human patients prior to design new therapeutics.
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http://dx.doi.org/10.1002/cti2.1262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934284PMC
March 2021

The impact of iron-biofortified bean adoption on bean productivity, consumption, purchases and sales.

World Dev 2021 Mar;139:105260

Virginia Tech, Department of Agricultural and Applied Economics, 250 Drillfield Drive, 315 Hutcheson Hall, Blacksburg, VA 24061, United States.

Staple food crops tend to be low in micronutrients; therefore, individuals whose diets rely heavily on them can suffer from micronutrient deficiency. Biofortification addresses this issue through the breeding of staple crops that are micronutrient-dense and high yielding. One such crop is iron-biofortified beans. Ten iron-biofortified bean varieties were released between 2010 and 2012 in Rwanda, a country with high rates of bean production and consumption, to address iron deficiency. This study evaluates the effect of the most widely adopted of these varieties, RWR2245, on household yield, land cultivated under beans, bean consumption, purchases, and sales. Because the adoption decision could be endogenous, we use a control function approach to quantify the impacts of adoption. RWR2245 provides a yield gain of 20%-49% over traditional bush bean varieties. In our preferred model specification, we find that over a 12-month period, growing RWR2245 for at least one out of two annual growing seasons increases the length of time beans are consumed from own production by 0.64 months (19-20 days), reduces the length of time beans are purchased for consumption by 0.73 months (22-23 days), and increases the probability of selling beans by 12%. Adoption can thus improve household nutrition via two channels: primarily by increasing iron intake via substituting biofortified harvested beans for less nutrient-dense beans from the market, and additionally by increasing household income that can be spent on nutritious foods through the reduction in bean purchases and increased likelihood of selling beans. Moreover, the sale of iron-biofortified beans implies the availability of iron-dense food in markets, also benefiting households that purchase beans. These findings are promising for the continued adoption of iron-biofortified beans in Rwanda and elsewhere and provide evidence that biofortified crops are an effective investment for nutrition, food security, and poverty reduction.
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http://dx.doi.org/10.1016/j.worlddev.2020.105260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871334PMC
March 2021

Identification of SARS-CoV-2-specific immune alterations in acutely ill patients.

J Clin Invest 2021 Feb 26. Epub 2021 Feb 26.

Department of Neurosciences, CRCHUM University of Montreal, Montreal, Canada.

Dysregulated immune profiles have been described in symptomatic SARS-CoV-2-infected patients. Whether the reported immune alterations are specific to SARS-CoV-2 infection or also triggered by other acute illnesses remains unclear. We performed flow cytometry analysis on fresh peripheral blood from a consecutive cohort of i) patients hospitalized with acute SARS-CoV-2 infection; ii) patients of comparable age/sex hospitalized for other acute disease (SARS-CoV-2 negative); and iii) healthy controls. Using both data-driven and hypothesis-driven analyses, we found several dysregulations in immune cell subsets (e.g., decreased proportion of T cells) that are similarly associated with acute SARS-CoV-2 infection and non-COVID-19 related acute illnesses. In contrast, we identified specific differences in myeloid and lymphocyte subsets that are associated with SARS-CoV-2 status (e.g., elevated proportion of ICAM-1+ mature/activated neutrophils, ALCAM+ monocytes, and CD38+CD8+ T cells). A subset of SARS-CoV-2-specific immune alterations correlated with disease severity, disease outcome at 30 days and mortality. Our data provide an understanding of the immune dysregulation that are specifically associated with SARS-CoV-2 infection among acute care hospitalized patients. Our study lays the foundation for the development of specific biomarkers to stratify SARS-CoV-2+ patients at risk of unfavorable outcome and uncover candidate molecules to investigate from a therapeutic perspective.
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http://dx.doi.org/10.1172/JCI145853DOI Listing
February 2021

Major role of IgM in the neutralizing activity of convalescent plasma against SARS-CoV-2.

Cell Rep 2021 03 10;34(9):108790. Epub 2021 Feb 10.

Centre de recherche du CHUM, Montréal, QC H2X 0A9, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, QC H2X 0A9, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada. Electronic address:

Characterization of the humoral response to SARS-CoV-2, the etiological agent of COVID-19, is essential to help control the infection. The neutralization activity of plasma from patients with COVID-19 decreases rapidly during the first weeks after recovery. However, the specific role of each immunoglobulin isotype in the overall neutralizing capacity is still not well understood. In this study, we select plasma from a cohort of convalescent patients with COVID-19 and selectively deplete immunoglobulin A, M, or G before testing the remaining neutralizing capacity of the depleted plasma. We find that depletion of immunoglobulin M is associated with the most substantial loss of virus neutralization, followed by immunoglobulin G. This observation may help design efficient antibody-based COVID-19 therapies and may also explain the increased susceptibility to SARS-CoV-2 of autoimmune patients receiving therapies that impair the production of immunoglobulin M (IgM).
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http://dx.doi.org/10.1016/j.celrep.2021.108790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874916PMC
March 2021

Clearance of intracellular tau protein from neuronal cells via VAMP8-induced secretion.

J Biol Chem 2020 12;295(51):17827-17841

Research Center of the University of Montreal Hospital (CRCHUM), Montréal, Canada; Département de Neurosciences, Faculté de Médecine, Université de Montréal, Montréal, Canada. Electronic address:

In Alzheimer's disease (AD), tau, a microtubule-associated protein (MAP), becomes hyperphosphorylated, aggregates, and accumulates in the somato-dendritic compartment of neurons. In parallel to its intracellular accumulation in AD, tau is also released in the extracellular space, as revealed by its increased presence in cerebrospinal fluid (CSF). Consistent with this, recent studies, including ours, have reported that neurons secrete tau, and several therapeutic strategies aim to prevent the intracellular tau accumulation. Previously, we reported that late endosomes were implicated in tau secretion. Here, we explore the possibility of preventing intracellular tau accumulation by increasing tau secretion. Using neuronal models, we investigated whether overexpression of the vesicle-associated membrane protein 8 (VAMP8), an R-SNARE found on late endosomes, could increase tau secretion. The overexpression of VAMP8 significantly increased tau secretion, decreasing its intracellular levels in the neuroblastoma (N2a) cell line. Increased tau secretion by VAMP8 was also observed in murine hippocampal slices. The intracellular reduction of tau by VAMP8 overexpression correlated to a decrease of acetylated tubulin induced by tau overexpression in N2a cells. VAMP8 staining was preferentially found on late endosomes in N2a cells. Using total internal reflection fluorescence (TIRF) microscopy, the fusion of VAMP8-positive vesicles with the plasma membrane was correlated to the depletion of tau in the cytoplasm. Finally, overexpression of VAMP8 reduced the intracellular accumulation of tau mutants linked to frontotemporal dementia with parkinsonism and α-synuclein by increasing their secretion. Collectively, the present data indicate that VAMP8 could be used to increase tau and α-synuclein clearance to prevent their intracellular accumulation.
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http://dx.doi.org/10.1074/jbc.RA120.013553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762943PMC
December 2020

Age-related injury responses of human oligodendrocytes to metabolic insults: link to BCL-2 and autophagy pathways.

Commun Biol 2021 Jan 4;4(1):20. Epub 2021 Jan 4.

Neuroimmunology Unit, Montreal Neurological Institute and Department of Neurology and Neurosurgery, McGill University, 3801 University Street, Montreal, QC, H3A 2B4, Canada.

Myelin destruction and oligodendrocyte (OL) death consequent to metabolic stress is a feature of CNS disorders across the age spectrum. Using cells derived from surgically resected tissue, we demonstrate that young (
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http://dx.doi.org/10.1038/s42003-020-01557-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782481PMC
January 2021

Interleukin-15 enhances proinflammatory T-cell responses in patients with MS and EAE.

Neurol Neuroimmunol Neuroinflamm 2021 01 15;8(1). Epub 2020 Dec 15.

From the Department of Neurosciences (C. Laurent, G.D., M.-L.C., A.C.M., N.F.-k., M.G., P.D., A.P., C. Larochelle, N.A.), Université de Montréal and CRCHUM; and MS-CHUM Clinic (M.G., P.D., A.P., C. Larochelle), Québec, Canada.

Objective: We posit that interleukin-15 (IL-15) is a relevant contributor to MS pathobiology as this cytokine is elevated in the CNS and periphery of patients with MS. We aim to investigate (1) the impact of IL-15 on T lymphocytes from patients with MS and (2) the in vivo role of IL-15 using the experimental autoimmune encephalomyelitis (EAE) mouse model.

Methods: We compared the impact of IL-15 on T lymphocytes obtained from untreated patients with MS (relapsing-remitting, secondary progressive, and primary progressive) to cells from age/sex-matched healthy controls (HCs) using multiparametric flow cytometry and in vitro assays. We tested the effects of peripheral IL-15 administration after EAE disease onset in C57BL/6 mice.

Results: IL-15 triggered STAT5 signaling in an elevated proportion of T cells from patients with MS compared with HCs. This cytokine also enhanced the production of key proinflammatory cytokines (interferon γ, granulocyte-macrophage colony-stimulating factor [GM-CSF], IL-17, and tumor necrosis factor) by T cells from both MS and controls, but these effects were more robust for the production of IL-17 and GM-CSF in T-cell subsets from patients with MS. At the peak of EAE disease, the proportion of CD4 and CD8 T cells expressing CD122, the key signaling IL-15 receptor chain, was enriched in the CNS compared with the spleen. Finally, peripheral administration of IL-15 into EAE mice after disease onset significantly aggravated clinical scores and increased the number of inflammatory CNS-infiltrating T cells long term after stopping IL-15 administration.

Conclusions: Our results underscore that IL-15 contributes to the amplification of T-cell inflammatory properties after disease onset in both MS and EAE.
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http://dx.doi.org/10.1212/NXI.0000000000000931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745728PMC
January 2021

Increased frequency of proinflammatory CD4 T cells and pathological levels of serum neurofilament light chain in adult drug-resistant epilepsy.

Epilepsia 2021 01 2;62(1):176-189. Epub 2020 Nov 2.

Research Center of the University of Montreal Hospital Center, Montreal, QC, Canada.

Objective: Adult drug-resistant epilepsy (DRE) is associated with significant morbidity. Infiltration of immune cells is observed in DRE epileptic foci; however, the relation between DRE and the peripheral immune cell compartment remains only partially understood. We aimed to investigate differences in immune cell populations, cytokines, and neurodegenerative biomarkers in the peripheral blood of subjects with epilepsy versus healthy controls, and in DRE compared to well-controlled epilepsy (WCE).

Methods: Peripheral blood mononuclear cells and serum from >120 age- and sex-matched adults suffering from focal onset epilepsy and controls were analyzed by multipanel flow cytometry, multiplex immunoassays, and ultrasensitive single molecule array.

Results: Using a data-driven analytical approach, we identified that CD4 T cells in the peripheral blood are present in a higher proportion in DRE patients. Moreover, we observed that the frequency of CD4 T cells expressing proinflammatory cytokines interleukin (IL)-17A, IL-22, tumor necrosis factor, interferon-γ, and granulocyte-macrophage colony-stimulating factor, but not anti-inflammatory cytokines IL-10 and IL-4, is elevated in the peripheral blood of DRE subjects compared to WCE. In parallel, we found that Th17-related circulating proinflammatory cytokines are elevated, but Th2-related cytokine IL-4 is reduced, in the serum of epilepsy and DRE subjects. As Th17 cells can exert neurotoxicity, we measured levels of serum neurofilament light chain (sNfL), a marker of neuronal injury. We found significantly elevated levels of sNfL in DRE compared to controls, especially among older individuals.

Significance: Our data support that DRE is associated with an expansion of the CD4 Tcell subset in the peripheral blood and with a shift toward a proinflammatory Th17/Th1 CD4 Tcell immune profile. Our results further show that pathological levels of sNfL are more frequent in DRE, supporting a potential neurodegenerative component in adult DRE. With this work, we provide evidence for novel potential inflammatory and degenerative biomarkers in DRE.
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http://dx.doi.org/10.1111/epi.16742DOI Listing
January 2021

Association of Sustained Immunotherapy With Disability Outcomes in Patients With Active Secondary Progressive Multiple Sclerosis.

JAMA Neurol 2020 Jul 27. Epub 2020 Jul 27.

Clinical Outcomes Research Unit (CORe), Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.

Importance: It is unclear whether relapses and disease-modifying therapies are associated with the rate of disability accumulation in patients with secondary progressive multiple sclerosis (SPMS).

Objective: To examine the association of relapses with the rate of disability accumulation in patients with SPMS and to assess whether treatment before or during the secondary progressive phase can slow the progression of disability accumulation.

Design, Setting, And Participants: In this observational cohort study, patient data were prospectively collected from the MSBase international registry between January 1, 1995, and February 1, 2018. Among 53 680 patients in the MSBase registry, 4997 patients with SPMS (using the Lorscheider definition) were identified. Of those, 1621 patients were eligible for study inclusion based on sufficient follow-up before and after the onset of SPMS. Data were analyzed from November 15, 2017, to January 13, 2020.

Exposures: The association between disability accumulation and several clinical and demographic variables, including relapses and exposure to immunotherapy, was evaluated.

Main Outcomes And Measures: Two outcomes were analyzed as measures of disability accumulation during SPMS: the rate of disability accumulation during the secondary progressive phase (change relative to the reference population of patients with MS and absolute change) and the risk of becoming wheelchair dependent. A third outcome, the cumulative risk of experiencing confirmed disability progression events, was used for a secondary analysis. Outcomes were evaluated using multivariable mixed models (ie, linear and Cox models).

Results: Of 1621 patients eligible for inclusion, 1103 patients (68.0%) were female, with a mean (SD) age at MS onset of 33.9 (10.6) years. A total of 661 patients (40.8%) experienced superimposed relapses during SPMS. Therapy receipt and relapses during early relapsing-remitting MS were not associated with disability accumulation during the secondary progressive phase. Higher relapse rates during the secondary progressive disease stage were associated with an increased risk of becoming wheelchair dependent (hazard ratio [HR], 1.87; 95% CI, 1.17-3.00; P = .009). Among patients who experienced superimposed relapses during SPMS, greater receipt of disease-modifying therapies was significantly associated with a reduced rate of disability progression and a lower risk of becoming wheelchair dependent.

Conclusions And Relevance: In this study, the rate of disability progression after the onset of SPMS was not associated with the early disease course and treatment decisions. Relapses during SPMS were associated with accelerated disability progression and represent an accessible treatment target. Disease-modifying therapy was associated with improvements in disability outcomes among patients with active relapses during SPMS. The study's results suggest that inflammatory disease activity remains a substantial yet modifiable component of SPMS.
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http://dx.doi.org/10.1001/jamaneurol.2020.2453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385679PMC
July 2020

Disability outcomes of early cerebellar and brainstem symptoms in multiple sclerosis.

Mult Scler 2021 Apr 15;27(5):755-766. Epub 2020 Jun 15.

CORe, Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia; Department of Neurology, The Royal Melbourne Hospital, Melbourne, VIC, Australia.

Background: Cerebellar and brainstem symptoms are common in early stages of multiple sclerosis (MS) yet their prognostic values remain unclear.

Objective: The aim of this study was to investigate long-term disability outcomes in patients with early cerebellar and brainstem symptoms.

Methods: This study used data from MSBase registry. Patients with early cerebellar/brainstem presentations were identified as those with cerebellar/brainstem relapse(s) or functional system score ⩾ 2 in the initial 2 years. Early pyramidal presentation was chosen as a comparator. Andersen-Gill models were used to compare cumulative hazards of (1) disability progression events and (2) relapses between patients with and without early cerebellar/brainstem symptoms. Mixed effect models were used to estimate the associations between early cerebellar/brainstem presentations and expanded disability status scale (EDSS) scores.

Results: The study cohort consisted of 10,513 eligible patients, including 2723 and 3915 patients with early cerebellar and brainstem symptoms, respectively. Early cerebellar presentation was associated with greater hazard of progression events (HR = 1.37,  < 0.001) and EDSS (β = 0.16,  < 0.001). Patients with early brainstem symptoms had lower hazard of progression events (HR = 0.89,  = 0.01) and EDSS (β = -0.06,  < 0.001). Neither presentation was associated with changes in relapse risk.

Conclusion: Early cerebellar presentation is associated with unfavourable outcomes, while early brainstem presentation is associated with favourable prognosis. These presentations may be used as MS prognostic markers and guide therapeutic approach.
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http://dx.doi.org/10.1177/1352458520926955DOI Listing
April 2021

Frailty in ageing persons with multiple sclerosis.

Mult Scler 2021 Apr 27;27(4):613-620. Epub 2020 May 27.

Clinique de Sclérose en plaques du Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada/Department of Neurosciences, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada.

Background: Recent progress in multiple sclerosis (MS) management has contributed to a greater life expectancy in persons with MS. Ageing with MS comes with unique challenges and bears the potential to greatly affect quality of life and socioeconomic burden.

Objectives: To compare frailty in ageing persons with multiple sclerosis (pwMS) and controls; to correlate frailty with MS clinical characteristics.

Methods: PwMS and controls over 50 years old were recruited in a cross-sectional study. Two validated frailty measures were assessed: the frailty index and the Fried's phenotype. Several multiple linear regressions accounting for demographic and clinical characteristics were performed.

Results: Eighty pwMS (57 females, mean age 58.5 ± 6 years old) and 37 controls (24 females, mean age 61 ± 6.5 years old) were recruited. Multivariable analysis identified significantly higher frailty index in pwMS (0.21 ± 0.12 vs 0.11 ± 0.08, p < 0.0001). Similarly, according to Fried's phenotype, a significantly higher percentage of pwMS were frail compared to controls (28% vs 8%). In pwMS, frailty index was independently associated with expanded disability status scale (EDSS), comorbidities, education level and disease duration.

Conclusion: Our results suggest that frailty can be routinely assessed in pwMS. Increased frailty in MS patients suggests that, along with MS therapeutics, a tailored multidisciplinary approach of ageing pwMS is needed.
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http://dx.doi.org/10.1177/1352458520923945DOI Listing
April 2021

From Baló's concentric sclerosis to multiple sclerosis: a series of 6 patients.

Mult Scler Relat Disord 2020 Jul 4;42:102078. Epub 2020 May 4.

Clinique de Sclérose en plaques du Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), and department of Neurosciences, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.

Introduction: Baló's concentric sclerosis (BCS) is a rare CNS disorder characterized by alternating bands of demyelination on MRI. One of the main issues is its relationship with multiple sclerosis (MS).

Objectives: To describe 6 BCS patients. To review the risk of developing MS in BCS patients.

Methods: We retrospectively recorded clinical and radiological findings of 6 BCS patients and performed a review of the literature.

Results: Six patients (5 women) with a mean age of 25 years old were included. Main symptoms were hemiparesis/hemihypoesthesia. On MRI, two patients had a single BCS lesion and four had additional MS-like lesions. Alternating bands were usually more visible on DWI. A patient had reduced central perfusion and SWI hypointensity suggestive of a central vein. Oligoclonal bands were identified in 5/6 patients. After 7 years of follow-up, all patients achieved MS criteria with mild disability (mean EDSS 1.75; 0-4). Our literature review included 65 BCS patients from 30 studies: although CSF oligoclonal bands and the presence of additional MS lesions were associated with subsequent relapses, this was not significant.

Discussion/conclusion: Our series allows a detailed MRI description in BCS and gives a new insight into BCS evolution and its strong relationship with MS.
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http://dx.doi.org/10.1016/j.msard.2020.102078DOI Listing
July 2020

Timing of high-efficacy therapy for multiple sclerosis: a retrospective observational cohort study.

Lancet Neurol 2020 04 18;19(4):307-316. Epub 2020 Mar 18.

CORe, Department of Medicine, University of Melbourne, Melbourne, VIC, Australia; Department of Neurology, Royal Melbourne Hospital, Melbourne, VIC, Australia. Electronic address:

Background: High-efficacy therapies in multiple sclerosis are traditionally used after unsuccessful treatment with first-line disease modifying therapies. We hypothesised that early commencement of high-efficacy therapy would be associated with reduced long-term disability. We therefore aimed to compare long-term disability outcomes between patients who started high-efficacy therapies within 2 years of disease onset with those who started 4-6 years after disease onset.

Methods: In this retrospective international observational study, we obtained data from the MSBase registry and the Swedish MS registry, which prospectively collect patient data that are specific to multiple sclerosis as part of routine clinical care. We identified adult patients (aged ≥18 years) with relapsing-remitting multiple sclerosis, with at least 6 years of follow-up since disease onset, and who started the high-efficacy therapy (rituximab, ocrelizumab, mitoxantrone, alemtuzumab, or natalizumab) either 0-2 years (early) or 4-6 years (late) after clinical disease onset. We matched patients in the early and late groups using propensity scores calculated on the basis of their baseline clinical and demographic data. The primary outcome was disability, measured with the Expanded Disability Status Score (EDSS; an ordinal scale of 0-10, with higher scores indicating increased disability), at 6-10 years after disease onset, assessed with a linear mixed-effects model.

Findings: We identified 6149 patients in the MSBase registry who had been given high-efficacy therapy, with data collected between Jan 1, 1975, and April 13, 2017, and 2626 patients in the Swedish MS Registry, with data collected between Dec 10, 1997, and Sept 16, 2019. Of whom, 308 in the MSBase registry and 236 in the Swedish MS registry were eligible for inclusion. 277 (51%) of 544 patients commenced therapy early and 267 (49%) commenced therapy late. For the primary analysis, we matched 213 patients in the early treatment group with 253 in the late treatment group. At baseline, the mean EDSS score was 2·2 (SD 1·2) in the early group and 2·1 (SD 1·2) in the late group. Median follow-up time for matched patients was 7·8 years (IQR 6·7-8·9). In the sixth year after disease onset, the mean EDSS score was 2·2 (SD 1·6) in the early group compared with 2·9 (SD 1·8) in the late group (p<0·0001). This difference persisted throughout each year of follow-up until the tenth year after disease onset (mean EDSS score 2·3 [SD 1·8] vs 3·5 [SD 2·1]; p<0·0001), with a difference between groups of -0·98 (95% CI -1·51 to -0·45; p<0·0001, adjusted for proportion of time on any disease-modifying therapy) across the 6-10 year follow-up period.

Interpretation: High-efficacy therapy commenced within 2 years of disease onset is associated with less disability after 6-10 years than when commenced later in the disease course. This finding can inform decisions regarding optimal sequence and timing of multiple sclerosis therapy.

Funding: National Health and Medical Research Council Australia and MS Society UK.
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http://dx.doi.org/10.1016/S1474-4422(20)30067-3DOI Listing
April 2020

Very high-dose methylprednisolone for treatment of nivolumab-induced limbic encephalitis: A case report.

J Oncol Pharm Pract 2020 Sep 17;26(6):1538-1543. Epub 2020 Feb 17.

Department of Pharmacy, Centre hospitalier de l'Universite de Montreal, Montreal, Canada.

Introduction: Nivolumab is a programmed death 1 (PD-1) inhibitor approved by the Food and Drug Administration (FDA) for the treatment of eight different cancers including metastatic melanoma. Immune checkpoint blockade may lead to a range of neurologic immune-related adverse events (irAEs) with severity varying from mild to life-threatening, including encephalitis.

Case Report: We describe a case of a 68-year-old man who developed alteration in mental status, physical weakness and fatigue after nine cycles of nivolumab 3 mg/kg every two weeks. These symptoms were compatible with a clinical diagnosis of autoimmune limbic encephalitis, although no specific antibodies were detected and the initial MRI was normal.

Management And Outcome: The patient received intravenous methylprednisolone 1 g daily for 5 days, which was then converted to a maintenance dose of oral prednisone. The patient made a full clinical recovery but relapsed clinically upon steroid tapering, while hypersignal in the left mesial temporal suggestive of limbic encephalitis was observed on repeated MRI.

Discussion: Because of the prevailing usage of nivolumab in many cancer protocols, this case highlights the importance of rapidly recognising neurological impairment in patients treated with nivolumab and of initiating very high doses of corticosteroids.
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http://dx.doi.org/10.1177/1078155220904147DOI Listing
September 2020

Methionine Metabolism Shapes T Helper Cell Responses through Regulation of Epigenetic Reprogramming.

Cell Metab 2020 02;31(2):250-266.e9

Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada; Metabolic and Nutritional Programming, Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA. Electronic address:

Epigenetic modifications on DNA and histones regulate gene expression by modulating chromatin accessibility to transcription machinery. Here we identify methionine as a key nutrient affecting epigenetic reprogramming in CD4 T helper (Th) cells. Using metabolomics, we showed that methionine is rapidly taken up by activated T cells and serves as the major substrate for biosynthesis of the universal methyl donor S-adenosyl-L-methionine (SAM). Methionine was required to maintain intracellular SAM pools in T cells. Methionine restriction reduced histone H3K4 methylation (H3K4me3) at the promoter regions of key genes involved in Th17 cell proliferation and cytokine production. Applied to the mouse model of multiple sclerosis (experimental autoimmune encephalomyelitis), dietary methionine restriction reduced the expansion of pathogenic Th17 cells in vivo, leading to reduced T cell-mediated neuroinflammation and disease onset. Our data identify methionine as a key nutritional factor shaping Th cell proliferation and function in part through regulation of histone methylation.
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http://dx.doi.org/10.1016/j.cmet.2020.01.006DOI Listing
February 2020

Diagnosis and management of secondary-progressive multiple sclerosis: time for change.

Neurodegener Dis Manag 2019 12 26;9(6):301-317. Epub 2019 Nov 26.

University of Montreal Research Centre, Montreal, QC H9S 1A9, Canada.

Identifying the transition of relapsing-remitting multiple sclerosis (MS) to the secondary-progressive MS form remains a clinical challenge due to the gradual nature of the transition, superimposed relapses, the heterogeneous course of disease among patients and the absence of validated biomarkers and diagnostic tools. The uncertainty associated with the transition makes clinical care challenging for both patients and physicians. The emergence of new disease-modifying treatments for progressive MS and the increasing emphasis of nonpharmacological strategies mark a new era in the treatment of progressive MS. This article summarizes challenges in diagnosis and management, discusses novel treatment strategies and highlights the importance of establishing a clear diagnosis and instituting an interdisciplinary management plan in the care of patients with progressive MS.
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http://dx.doi.org/10.2217/nmt-2019-0024DOI Listing
December 2019

Reproducibility of CRISPR-Cas9 methods for generation of conditional mouse alleles: a multi-center evaluation.

Authors:
Channabasavaiah B Gurumurthy Aidan R O'Brien Rolen M Quadros John Adams Pilar Alcaide Shinya Ayabe Johnathan Ballard Surinder K Batra Marie-Claude Beauchamp Kathleen A Becker Guillaume Bernas David Brough Francisco Carrillo-Salinas Wesley Chan Hanying Chen Ruby Dawson Victoria DeMambro Jinke D'Hont Katharine M Dibb James D Eudy Lin Gan Jing Gao Amy Gonzales Anyonya R Guntur Huiping Guo Donald W Harms Anne Harrington Kathryn E Hentges Neil Humphreys Shiho Imai Hideshi Ishii Mizuho Iwama Eric Jonasch Michelle Karolak Bernard Keavney Nay-Chi Khin Masamitsu Konno Yuko Kotani Yayoi Kunihiro Imayavaramban Lakshmanan Catherine Larochelle Catherine B Lawrence Lin Li Volkhard Lindner Xian-De Liu Gloria Lopez-Castejon Andrew Loudon Jenna Lowe Loydie A Jerome-Majewska Taiji Matsusaka Hiromi Miura Yoshiki Miyasaka Benjamin Morpurgo Katherine Motyl Yo-Ichi Nabeshima Koji Nakade Toshiaki Nakashiba Kenichi Nakashima Yuichi Obata Sanae Ogiwara Mariette Ouellet Leif Oxburgh Sandra Piltz Ilka Pinz Moorthy P Ponnusamy David Ray Ronald J Redder Clifford J Rosen Nikki Ross Mark T Ruhe Larisa Ryzhova Ane M Salvador Sabrina Shameen Alam Radislav Sedlacek Karan Sharma Chad Smith Katrien Staes Lora Starrs Fumihiro Sugiyama Satoru Takahashi Tomohiro Tanaka Andrew W Trafford Yoshihiro Uno Leen Vanhoutte Frederique Vanrockeghem Brandon J Willis Christian S Wright Yuko Yamauchi Xin Yi Kazuto Yoshimi Xuesong Zhang Yu Zhang Masato Ohtsuka Satyabrata Das Daniel J Garry Tino Hochepied Paul Thomas Jan Parker-Thornburg Antony D Adamson Atsushi Yoshiki Jean-Francois Schmouth Andrei Golovko William R Thompson K C Kent Lloyd Joshua A Wood Mitra Cowan Tomoji Mashimo Seiya Mizuno Hao Zhu Petr Kasparek Lucy Liaw Joseph M Miano Gaetan Burgio

Genome Biol 2019 08 26;20(1):171. Epub 2019 Aug 26.

Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, the Australian National University, Canberra, Australia.

Background: CRISPR-Cas9 gene-editing technology has facilitated the generation of knockout mice, providing an alternative to cumbersome and time-consuming traditional embryonic stem cell-based methods. An earlier study reported up to 16% efficiency in generating conditional knockout (cKO or floxed) alleles by microinjection of 2 single guide RNAs (sgRNA) and 2 single-stranded oligonucleotides as donors (referred herein as "two-donor floxing" method).

Results: We re-evaluate the two-donor method from a consortium of 20 laboratories across the world. The dataset constitutes 56 genetic loci, 17,887 zygotes, and 1718 live-born mice, of which only 15 (0.87%) mice contain cKO alleles. We subject the dataset to statistical analyses and a machine learning algorithm, which reveals that none of the factors analyzed was predictive for the success of this method. We test some of the newer methods that use one-donor DNA on 18 loci for which the two-donor approach failed to produce cKO alleles. We find that the one-donor methods are 10- to 20-fold more efficient than the two-donor approach.

Conclusion: We propose that the two-donor method lacks efficiency because it relies on two simultaneous recombination events in cis, an outcome that is dwarfed by pervasive accompanying undesired editing events. The methods that use one-donor DNA are fairly efficient as they rely on only one recombination event, and the probability of correct insertion of the donor cassette without unanticipated mutational events is much higher. Therefore, one-donor methods offer higher efficiencies for the routine generation of cKO animal models.
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http://dx.doi.org/10.1186/s13059-019-1776-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709553PMC
August 2019

High dose vitamin D exacerbates central nervous system autoimmunity by raising T-cell excitatory calcium.

Brain 2019 09;142(9):2737-2755

Institute of Neuropathology, University Medical Center, Göttingen, Germany.

Poor vitamin D status is associated with a higher relapse rate and earlier disability in multiple sclerosis. Based on these associations, patients with multiple sclerosis are frequently supplemented with the vitamin D precursor cholecalciferol, although it is unclear whether this regimen is of therapeutic benefit. To model consequences of this common practice, mice were fed for more than 3 months with a low, medium or high dose of cholecalciferol, representative of vitamin D deficiency, modest and disproportionally high supplementation, respectively, in patients with multiple sclerosis. Compared to vitamin D-deprived mice, its moderate supplementation reduced the severity of subsequent experimental autoimmune encephalomyelitis, which was associated with an expansion of regulatory T cells. Direct exposure of murine or human T cells to vitamin D metabolites inhibited their activation. In contrast, mice with 25-(OH) vitamin D levels above 200 nmol/l developed fulminant experimental autoimmune encephalomyelitis with massive CNS infiltration of activated myeloid cells, Th1 and Th17 cells. When dissecting this unexpected outcome, we observed that high, but not medium dose vitamin D had caused mild hypercalcaemia, which rendered T cells more prone to pro-inflammatory activation. Exposing murine or human T cells to equivalent calcium concentrations in vitro enhanced its influx, triggering activation, upregulation of pro-inflammatory gene products and enhanced transmigration across a blood-brain barrier model. These findings suggest that vitamin D at moderate levels may exert a direct regulatory effect, while continuous high dose vitamin D treatment could trigger multiple sclerosis disease activity by raising mean levels of T-cell excitatory calcium.
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http://dx.doi.org/10.1093/brain/awz190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736324PMC
September 2019

Assessing the risk of multiple sclerosis disease-modifying therapies.

Expert Rev Neurother 2019 07 26;19(7):695-706. Epub 2019 Jun 26.

c Neurology , Centre Hospitalier de l'Université de Montréal (CHUM) , Montreal , Quebec , Canada.

: The number of immunomodulatory options approved for multiple sclerosis has increased over the past years, resulting in a better control of the disease. Depending on disease activity, neurologists can now propose treatments with different levels of efficacy, from injectable and oral treatments with modest efficacy, to highly active immunosuppressants. Nevertheless, this gain in efficacy has come with an increase in the global burden of treatment-related adverse events. : The authors have reviewed extensively the existing literature to gain insight into the adverse events associated with disease modifying therapies, so as to help neurologists choose the right treatment for their patients. The authors classified and summarized the adverse events based on frequency, severity and relevance. : As the number and diversity of adverse events is expected to increase, careful surveillance of patients under treatment will be even more important. The characteristics of the MS population, i.e. mainly young women of childbearing age, who will remain treated for decades, and the need for serial administration of distinct treatments with different mechanisms of action highlights the importance of a comprehensive risk-benefit assessment.
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http://dx.doi.org/10.1080/14737175.2019.1627201DOI Listing
July 2019

Distinct Function-Related Molecular Profile of Adult Human A2B5-Positive Pre-Oligodendrocytes Versus Mature Oligodendrocytes.

J Neuropathol Exp Neurol 2019 06;78(6):468-479

Neuroimmunology Unit, Montreal Neurological Institute, McGill University.

Remyelination in the human CNS is ascribed to progenitor cells rather than previously myelinating oligodendrocytes (OLs). The ganglioside-recognizing antibody A2B5 has been used to isolate putative progenitor cells, whose in vitro features resemble cells labeled as "pre-oligodendrocytes." Here, we compare the transcriptional profiles of adult human brain-derived A2B5 antibody-selected cells (A+) after initial isolation (day in vitro (DIV1)) and after DIV6, with nonselected (A-) cells (mature OLs), with regard to their differentiation state and functional properties. While a number of previously recognized progenitor associated genes, specifically PTPRZ1 and PDGFRα, were upregulated in the A2B5+ population, a number of such genes were comparably expressed in the mature OLs, as were mature myelin genes. Additional progenitor-related genes were upregulated in the A+ population. We show that A2B5+ cells have greater capacity to ensheath nanofibers, a model of myelination potential; consistent with this, ingenuity pathway analysis indicated that A+ cells had upregulated expression of genes within cell growth and cell signaling pathways. Differential expression of cell death/survival pathways complements previous functional studies showing their increased susceptibility to metabolic stress. At DIV6, we observed significantly fewer differentially expressed genes; suggestive of cell maturation occurring in vitro, indicating the complexity in comparing in vitro and in situ cell properties.
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http://dx.doi.org/10.1093/jnen/nlz026DOI Listing
June 2019

Promoting rapid and sustained adoption of biofortified crops: What we learned from iron-biofortified bean delivery approaches in Rwanda.

Food Policy 2019 Feb;83:271-284

HarvestPlus/International Food Policy Research Institute, c/o IFPRI, 1201 Eye St., NW, Washington, DC 20005-3915, USA.

Micronutrient deficiencies, also known as hidden hunger, affect two billion people worldwide, curtailing their ability to lead healthy, productive lives. Biofortified staple crops, bred to be rich in micronutrient content, are a cost-effective and scalable solution to alleviating micronutrient deficiency, particularly among rural households who consume what they produce. Delivery of biofortified planting material in Rwanda began in 2012, and it is important to learn from the efforts undertaken to date to inform the design of higher impact - lower cost delivery strategies for scaling up these crops. In this paper, we use a nationally representative household survey of bean producers and delivery data from seven consecutive seasons and apply duration analysis to estimate the impact of different delivery approaches on household time to adoption, disadoption and readoption of iron-biofortified beans in Rwanda. Proximity to formal delivery via sales of small packets of planting material quickens adoption and readoption, while delivery of larger quantities of planting material to small-scale producers within a village slows disadoption of iron-biofortified beans. Informal dissemination within social networks and access to extension are also major drivers of rapid adoption. In addition, households whose main decision maker for bean production is a woman, has some formal education, and more years of experience growing beans disadopt iron-biofortified beans more slowly than other households. These findings provide evidence that current efforts to promote iron-biofortified crops have been successful and are expected to inform future development of sustainable and cost-effective delivery models for biofortified crops in Rwanda and elsewhere.
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http://dx.doi.org/10.1016/j.foodpol.2018.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6472331PMC
February 2019

CD70 defines a subset of proinflammatory and CNS-pathogenic T1/T17 lymphocytes and is overexpressed in multiple sclerosis.

Cell Mol Immunol 2019 07 11;16(7):652-665. Epub 2019 Jan 11.

Department of Neuroscience, Faculty of Medicine, Université de Montréal, and Centre de Recherche du CHUM (CRCHUM), Montréal, QC, H2X0A9, Canada.

CD70 is the unique ligand of CD27 and is expressed on immune cells only upon activation. Therefore, engagement of the costimulatory CD27/CD70 pathway is solely dependent on upregulation of CD70. However, the T cell-intrinsic effect and function of human CD70 remain underexplored. Herein, we describe that CD70 expression distinguishes proinflammatory CD4 T lymphocytes that display an increased potential to migrate into the central nervous system (CNS). Upregulation of CD70 on CD4 T lymphocytes is induced by TGF-β1 and TGF-β3, which promote a pathogenic phenotype. In addition, CD70 is associated with a T1 and T17 profile of lymphocytes and is important for T-bet and IFN-γ expression by both T helper subtypes. Moreover, adoptive transfer of CD70CD4 T lymphocytes induced less severe experimental autoimmune encephalomyelitis (EAE) disease than transfer of WT CD4 T lymphocytes. CD70CD4 T lymphocytes are found in the CNS during acute autoimmune inflammation in humans and mice, highlighting CD70 as both an immune marker and an important costimulator of highly pathogenic proinflammatory T1/T17 lymphocytes infiltrating the CNS.
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http://dx.doi.org/10.1038/s41423-018-0198-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804668PMC
July 2019

EGFL7 - a potential therapeutic target for multiple sclerosis?

Expert Opin Ther Targets 2018 11 17;22(11):899-902. Epub 2018 Oct 17.

b Department of Neurosciences , Centre de recherche du centre hospitalier de l'Université de Montréal (CRCHUM) , Montréal (Québec) , Canada.

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http://dx.doi.org/10.1080/14728222.2018.1535595DOI Listing
November 2018

Toward a Shared-Care Model of Relapsing-Remitting Multiple Sclerosis: Role of the Primary Care Practitioner.

Can J Neurol Sci 2018 05;45(3):304-312

9Montreal Neurological Hospital,Montreal,Quebec,Canada.

The objective of this study was to develop a shared-care model to enable primary-care physicians to participate more fully in meeting the complex, multidisciplinary healthcare needs of patients with multiple sclerosis (MS).

Design: The design consisted of development of consensus recommendations and a shared-care algorithm.

Participants: A working group of 11 Canadian neurologists involved in the management of patients with MS were included in this study.

Main Message: The clinical management of patients with multiple sclerosis is increasing in complexity as new disease-modifying therapies (DMTs) become available, and ongoing safety monitoring is required. A shared-care model that includes primary care physicians is needed. Primary care physicians can assist in the early detection of MS of individuals presenting with neurological symptoms. Additional key roles for family physicians are health promotion, symptom management, and safety and relapse monitoring of DMT-treated patients. General principles of health promotion include counseling MS patients on maintaining a healthy lifestyle; performing standard screening measures; and identifying and treating comorbidities. Of particular importance are depression and anxiety, which occur in >20% of MS patients. Standard work-ups and treatments are needed for common MS-related symptoms, such as fatigue, pain, bladder dysfunction, sexual dysfunction, spasticity, and sleep disorders. Ongoing safety monitoring is required for patients receiving specific DMTs. Multiple sclerosis medications are generally contraindicated during pregnancy, and patients should be counseled to practice effective contraception.

Conclusions: Multiple sclerosis is a complex, disabling illness, which, similar to other chronic diseases, requires ongoing multidisciplinary care to meet the evolving needs of patients throughout the clinical course. Family physicians can play an invaluable role in maintaining general health, managing MS-related symptoms and comorbidities, monitoring for treatment-related adverse effects and MS relapses, and coordinating allied health services to ensure continuity of care to meet the complex and evolving needs of MS patients through the disease course. RÉSUMÉ: Élaborer un modèle de soins partagés dans les cas de sclérose en plaques récurrente-rémittente. Objectif: Élaborer un modèle de soins partagés afin de permettre aux médecins de première ligne de mieux répondre aux besoins complexes et multidisciplinaires de patients atteints de la sclérose en plaques (SP). Conception : Recommandations résultant d'un consensus et élaboration d'un algorithme en matière de soins partagés.

Participants: Un groupe de travail formé de onze neurologues canadiens impliqués dans la prise en charge de patients atteints de la SP. Message-clé : La prise en charge clinique de patients atteints de la SP est de plus en plus complexe dans la mesure où des médicaments modificateurs de l'évolution de la maladie (MMSP) deviennent accessibles et où un suivi permanent en matière de sécurité est nécessaire. Soulignons aussi qu'un modèle de soins partagés incluant les médecins de première ligne est nécessaire. Ces professionnels peuvent permettre un dépistage plus rapide de la SP chez des individus présentant des symptômes neurologiques. Ils peuvent aussi jouer un rôle de premier plan en matière de promotion de la santé, de soulagement des symptômes et de suivi de patients traités avec des MMSP en ce qui a trait à leur sécurité et à de possibles rechutes. Parmi les principes généraux de promotion de la santé, on peut inclure les suivants : offrir aux patients atteints de la SP des conseils leur permettant de maintenir de saines habitudes de vie ; adopter des mesures de dépistage standards ; identifier et traiter les comorbidités. À cet égard, l'anxiété et la dépression sont d'une importance particulière et sont fréquemment signalées (> 20 %) chez les patients atteints de SP. Des démarches d'investigation et des traitements standards sont nécessaires dans le cas des symptômes courants reliés à la SP, par exemple de la fatigue, des douleurs, une dysfonction vésicale, des dysfonctions sexuelles, de la spasticité et des troubles du sommeil. On l'a dit, un suivi permanent s'impose dans le cas de patients bénéficiant d'un traitement spécifique avec des MMSP. Les médicaments associés à la SP sont généralement contre-indiqués durant la grossesse de sorte qu'on devrait conseiller aux patients d'adopter des méthodes de contraception efficaces.

Conclusions: La SP est une maladie complexe et invalidante qui, à l'instar d'autres maladies chroniques, exige des soins multidisciplinaires continus afin de répondre, en lien avec un tableau clinique précis, aux besoins en constante évolution des patients. Les médecins de première ligne peuvent jouer un rôle irremplaçable à plusieurs égards : dans le maintien d'une bonne santé ; le suivi et le soulagement des symptômes et des comorbidités reliés à la SP ; le suivi des rechutes et des effets indésirables associés aux traitements. N'oublions pas non plus la coordination des services paramédicaux afin d'assurer, durant l'évolution de la SP, une continuité des soins répondant aux besoins complexes et en constante évolution des patients atteints de cette maladie.
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http://dx.doi.org/10.1017/cjn.2018.7DOI Listing
May 2018

EGFL7 reduces CNS inflammation in mouse.

Nat Commun 2018 02 26;9(1):819. Epub 2018 Feb 26.

Department of Neurology, Focus Program Translational Neuroscience (FTN), Research Center Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.

Extracellular matrix (ECM) proteins secreted by blood-brain barrier (BBB) endothelial cells (ECs) are implicated in cell trafficking. We discovered that the expression of ECM epidermal growth factor-like protein 7 (EGFL7) is increased in the CNS vasculature of patients with multiple sclerosis (MS), and in mice with experimental autoimmune encephalomyelitis (EAE). Perivascular CD4 T lymphocytes colocalize with ECM-bound EGFL7 in MS lesions. Human and mouse activated T cells upregulate EGFL7 ligand αvβ3 integrin and can adhere to EGFL7 through integrin αvβ3. EGFL7-knockout (KO) mice show earlier onset of EAE and increased brain and spinal cord parenchymal infiltration of T lymphocytes. Importantly, EC-restricted EGFL7-KO is associated with a similar EAE worsening. Finally, treatment with recombinant EGFL7 improves EAE, reduces MCAM expression, and tightens the BBB in mouse. Our data demonstrate that EGFL7 can limit CNS immune infiltration and may represent a novel therapeutic avenue in MS.
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http://dx.doi.org/10.1038/s41467-018-03186-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827652PMC
February 2018