Myelin-associated glycoprotein activation triggers glutamate uptake by oligodendrocytes in vitro and contributes to ameliorate glutamate-mediated toxicity in vivo

Background: Myelin-associated glycoprotein (MAG) is a key molecule involved in the nurturing effect of myelin on ensheathed axons. MAG also inhibits axon outgrowth after injury. In preclinical stroke models, administration of a function-blocking anti-MAG monoclonal antibody (mAb) aimed to improve axon regeneration demonstrated reduced lesion volumes and a rapid clinical improvement, suggesting a mechanism of immediate neuroprotection rather than enhanced axon regeneration. In addition, it has been reported that antibody-mediated crosslinking of MAG can protect oligodendrocytes (OLs) against glutamate (Glu) overload by unknown mechanisms. Purpose: To unravel the molecular mechanisms underlying the protective effect of anti-MAG therapy with a focus on neuroprotection against Glu toxicity. Results: MAG activation (via antibody crosslinking) triggered the clearance of extracellular Glu by its uptake into OLs via high affinity excitatory amino acid transporters. This resulted not only in protection of OLs but also nearby neurons. MAG activation led to a PKC-dependent activation of factor Nrf2 (nuclear-erythroid related factor-2) leading to antioxidant responses including increased mRNA expression of metabolic enzymes from the glutathione biosynthetic pathway and the regulatory chain of cystine/Glu antiporter system xc− increasing reduced glutathione (GSH), the main antioxidant in cells. The efficacy of early anti-MAG mAb administration was demonstrated in a preclinical model of excitotoxicity induced by intrastriatal Glu administration and extended to a model of Experimental Autoimmune Encephalitis showing axonal damage secondary to demyelination. Conclusions: MAG activation triggers Glu uptake into OLs under conditions of Glu overload and induces a robust protective antioxidant response.Fil: Vivinetto, Ana Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Castañares, Clara Nicole. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Garcia Keller, Constanza. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; ArgentinaFil: Moyano, Ana Lis. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Cordoba. Instituto de Investigacion Medica Mercedes y Martin Ferreyra. Grupo Vinculado Centro de Investigacion En Medicina Traslacional Severo R. Amuchastegui - Cimetsa | Universidad Nacional de Cordoba. Instituto de Investigacion Medica Mercedes y Martin Ferreyra. Grupo Vinculado Centro de Investigacion En Medicina Traslacional Severo R. Amuchastegui - Cimetsa | Instituto de Investigacion Medica Mercedes y Martin Ferreyra. Instituto de Investigacion Medica Mercedes y Martin Ferreyra. Grupo Vinculado Centro de Investigacion En Medicina Traslacional Severo R. Amuchastegui - Cimetsa.; ArgentinaFil: Falcón, Cristian Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Palandri, Anabela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Rozés Salvador, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Rojas, Juan Ignacio. Centro de Esclerosis Múltiple de Buenos Aires; Argentina. Hospital Italiano; ArgentinaFil: Patrucco, Liliana. Hospital Italiano; Argentina. Centro de Esclerosis Múltiple de Buenos Aires; ArgentinaFil: Monferran, Clara Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Cancela, Liliana Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; ArgentinaFil: Cristiano, Edgardo. Centro de Esclerosis Múltiple de Buenos Aires; Argentina. Hospital Italiano; ArgentinaFil: Schnaar, Ronald L.. University Johns Hopkins; Estados UnidosFil: Lopez, Pablo H. H.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Psicología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentin

Brain atrophy in multiple sclerosis: therapeutic, cognitive and clinical impact

ABSTRACT Multiple sclerosis (MS) was always considered as a white matter inflammatory disease. Today, there is an important body of evidence that supports the hypothesis that gray matter involvement and the neurodegenerative mechanism are at least partially independent from inflammation. Gray matter atrophy develops faster than white matter atrophy, and predominates in the initial stages of the disease. The neurodegenerative mechanism creates permanent damage and correlates with physical and cognitive disability. In this review we describe the current available evidence regarding brain atrophy and its consequence in MS patients

Can you grow your supply chain without skills? The role of human resource management for better supply chain management in Latin America

PurposeIn line with the knowledge-based view of organizations, this paper aims to analyze how supply chain (SC) employees contribute to the creation of competitive advantage through knowledge acquisition and utilization activities. The authors consider SC employees' skills and competencies, their external network of relationships, their job satisfaction and company investments in training and test how they relate to SC-level outcomes (i.e. SC growth).Design/methodology/approachThe authors design a research model including the aforementioned variables, and the authors apply structural equation modeling (SEM) to survey data collected from 246 SC professionals in Latin America. The authors also use multi-group analysis to evaluate how the relationships between these variables change with different levels of company investment in training.FindingsThe results show that a broad professional network of relationships contributes to increasing the skills and competencies of SC professionals, which, in turn, impact job satisfaction and SC performance. This reinforces the value of investing in skilled human talent, who can contribute to knowledge acquisition, utilization, and, ultimately, to SC competitiveness. Companies that invest more in training to develop their SC employees benefit from stronger SC outcomes.Originality/valueThis study contributes to broadening the understanding of the impact of human resource management (HRM) on supply chain management (SCM). One of the added original foci of this research is the emphasis on developing countries where these HRM-to-SCM performance relationships have not been studied before.</jats:sec

Real-World Effectiveness and Safety of Fingolimod in Patients With Relapsing Remitting Multiple Sclerosis

Objectives The aim of this prospective observational postmarketing study was to evaluate fingolimod effectiveness in a real-world setting in Buenos Aires, Argentina. Methods Relapsing remitting multiple sclerosis patients who had been prescribed fingolimod owing to treatment failure and had at least greater than or equal to 24 months of follow-up were included during August 2013 and June 2018. Three-monthly clinical evaluations and 12-monthly magnetic resonance were performed. Demographic and clinical variables were described as well as the safety and the effectiveness outcomes that included the proportion of patients free from clinical relapses, from disability progression, from new or enlarging T2 or T1 gadolinium-enhancing lesions on annual magnetic resonance imaging, and from any disease activity during the follow-up. Results A total of 97 patients were included (68% female [n = 66]; mean ± SD age, 30 ± 10.5 years; mean ± SD disease duration, 6.5 ± 3.1 years; mean ± SD Expanded Disability Status Scale, 3.5 ± 1; mean ± SD fingolimod use, 30 ± 13 months [range, 18-56 months]). One hundred percent (97) used previous disease-modifying therapy, mainly interferons (87%; n = 84). Fourteen patients (14.4%) discontinued/withdrew fingolimod (10 owing to disease activity and 4 owing to tolerance and personal decisions). Eighty-two percent were free from clinical relapses, and 85% were free from disability progression; 75% of patients remained free from new or newly enlarging T2 lesions, and 78% of patients were free from gadolinium enhancing lesions. The proportion of patients free from any disease activity was 54%. Conclusions The effectiveness of fingolimod in a newly real-world setting was consistent with information provided from phase III clinical trials.Fil: Patrucco, Liliana. Hospital Italiano; ArgentinaFil: Cristiano, Edgardo. Hospital Italiano; ArgentinaFil: Sánchez, Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Miguez, Jimena. Hospital Italiano; ArgentinaFil: Rojas, Juan Ignacio. Hospital Italiano; Argentin

Structural sex differences at disease onset in multiple sclerosis patients

BACKGROUND: Male sex is associated with worsening disability and a more rapid progression of multiple sclerosis (MS). This study analysed structural sex differences in magnetic resonance images of the brain, comparing women whose disease started before and after the menopause with a control group of men. METHODS: This was a case control study in which female patients whose MS started before (Group 1) and after (Group 2) the menopause were included. The control group was matched by age, disease duration, Expanded Disability Status Scale and disease-modifying treatment. Patients were analysed according to demographic and clinical variables, as well as in terms of radiological measurements at disease onset and during the first 12 months of follow-up. These measurements included normalised total brain volume (NTBV), normalised cortical volume (NCV), normalised white matter volume, left and right hippocampus, the thalamus, brain stem volume, lesion load and percentage brain volume change. A linear regression model was used to analyse the data. RESULTS: A total of 97 patients were included: 53 in Group 1 (27 females) and 44 in Group 2 (22 females). In Group 1, we observed a reduction in brain volume in males compared with females at disease onset in NTBV (p = 0.01), NCV (p = 0.001) and brain stem volume (p = 0.01). We did not observe differences in Group 2 at disease onset in the brain volumes analysed. CONCLUSION: We observed structural sex differences in brain volume at disease onset in the pre-menopausal group. However, no structural differences were observed at disease onset between the sexes after the menopause had started.Fil: Rojas, Juan Ignacio. Hospital Italiano; ArgentinaFil: Sanchez, Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina. Hospital Italiano; ArgentinaFil: Patrucco, Liliana. Hospital Italiano; ArgentinaFil: Miguez, Jimena. Hospital Italiano; ArgentinaFil: Funes, Jorge. Hospital Italiano; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cristiano, Edgardo. Hospital Italiano; Argentin

Lower limb deep vein thrombosis in COVID-19 patients admitted to intermediate care respiratory units

COVID-19 has been associated with an increased risk of thrombotic events; however, the reported incidence of deep vein thrombosis varies depending, at least in part, on the severity of the disease. Aim of this prospective, multicenter, observational study was to investigate the incidence of lower limb deep vein thrombosis as assessed by compression ultrasound in consecutive patients admitted to three pulmonary medicine wards designated to care for patients with COVID-19 related pneumonia, with or without respiratory failure but not requiring admission to an intensive care unit. Consecutive patients admitted between March 27 and May 6, 2020 were enrolled. Patients were excluded if they were less than 18-year-old or if compression ultrasound could not be performed for any reason. Patients were assessed at admission (t0) and after 7 days (t1). Major and non-major clinically relevant bleedings were recorded. Sixty-eight patients were enrolled. Two were excluded due to anatomical abnormalities that prevented compression ultrasound; sixty patients were retested at (t1). All patients were started on antithrombotic prophylaxis, unless therapeutic anticoagulation was required. Deep vein thrombosis as assessed by compression ultrasound was observed in 2 patients (3%); one of them was later deemed to represent a previous episode. No new episodes were detected at t1. One major and 2 non-major clinically relevant bleedings were observed. In the setting of patients with COVID-related pneumonia not requiring admission to an intensive care unit, the incidence of deep vein thrombosis is low and our data support not screening asymptomatic patients