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INTRODUCTION: Diet in people with multiple sclerosis (pcMS) is of interest due to its potential benefit. The objective is to evaluate the changes in eating habits in pcEM, their opinion, sources of information, perception of effect and quality of current diet. METHODS: Cross-sectional observational study based on an online survey. The pcEM were convened by a patient association (ALCEM). Demographic, disease, and dietary change data were collected. Diet quality was assessed with the modified Cardiovascular Diet Questionnaire-2 (CDQ-2). RESULTS: Two hundred and eight pcEM, 82% women, age: 41.5 (± 10.9), 47% reported changes in diet, of these 52% maintained an omnivorous diet (vs. 85% p>0.01), 14% gluten-free, 9% ketogenic/low carbohydrate, 5% lacto-ovo vegetarian, 4% pescetarian. The percentage of overweight was lower, and the quality of the diet was better (more fruits and vegetables, less saturated fat, more unsaturated fat) among those who modified their diet compared to those who did not (CDQ-2: 10.2(7.6) vs. 3.9(6.5) p<0.01), including in those who remained omnivores (CDQ-2: 8.1(6.7) vs. 4.1(6.1) p<0. 01). The 83% maintained the change, with 92% perceiving positive results. Main source of information: Doctor or nutritionist: 39%. There was discordance between the information received from the treating neurologists and their own opinion and expectations. DISCUSSION: The pcEM made changes in their eating habits, resulting in healthy eating, although only 40% had their doctor or nutritionist as an informant. More studies on the topic and a multidisciplinary approach are necessary.

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Introducción: La alimentación en personas con esclerosis múltiple (pcEM) reviste interés por su potencial beneficio. El objetivo es evaluar los cambios en hábitos alimentarios en pcEM, su opinión, fuentes de información, percepción de efecto y calidad de alimentación actual. Métodos: Estudio observacional transversal basado en una encuesta online. Las pcEM fueron convocadas por una asociación de pacientes (ALCEM). Se recolectaron datos demográficos, de la enfermedad y del cambio en la dieta. La calidad de la alimentación se evaluó con el Cuestionario de Dieta Cardiovascular-2 modificado (CDQ-2). Resultados: Doscientos ocho pcEM, 82% mujeres, edad: 41.5 (± 10.9), 47% refirieron cambios en la alimentación, de éstos el 52% mantiene dieta omnívora (vs. 85% p>0.01), 14% libre de gluten, 9% cetogénica/ baja en hidratos de carbono, 5% ovolactovegetariana, 4% pescetariana. El porcentaje de sobrepeso fue menor y la calidad de dieta fue mejor (más frutas y verduras, menos grasas saturadas, más grasas insaturadas) entre los que modificaron su dieta comparados con los que no (CDQ-2: 10.2(7.6) vs. 3.9(6.5) p<0.01), inclusive en los que se mantuvieron omnívoros (CDQ-2: 8.1(6.7) vs. 4.1(6.1) p<0.01). 83% mantuvo el cambio, con percepción de resultados positivos en 92%. Fuente de información principal: Médico o nutricionista: 39%. Hubo discordancia entre la información que reciben de los neurólogos tratantes y la opinión propia y expectativas. Discusión: Las pcEM realizaron cambios en sus hábitos alimentarios, resultando en alimentación saludable, aunque solo un 40% tuvo como informante a su médico o nutricionista. Son necesarios más estudios sobre el tema y un abordaje multidisciplinario.

Asunto(s)

Conducta Alimentaria , Esclerosis Múltiple , Humanos , Femenino , Estudios Transversales , Adulto , Masculino , Persona de Mediana Edad , Encuestas y Cuestionarios

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Progressive multiple sclerosis (PMS) represents the worsening phase of the disease by accumulative neurodegeneration and disability, mainly refractory to current treatments. The therapeutic options remain challenging based partially on the lack of understanding of the pathogenic mechanisms but also because the early dogma was centered on neuroinflammation, overshadowing the critical role of the tissue repair process. The tissue repair target should necessarily start early in disease development and PMS should combine anti-inflammatory and neuroprotective therapeutic strategies. Increasing preclinical evidence, together with the new era of omics applied on frozen human brain tissue, shed light on some ligand receptors axis, such as GAS6/TYRO3 and PROS1/AXL required to dampen inflammation, promote tissue repair and engage remyelination, at the early stages of multiple sclerosis (MS) as a critical step in preventing or stopping neurodegeneration. Here, we will discuss those receptor/ligand pairs that could be targetable for therapeutic intervention in progressive MS disease. Significance Statement The aim for PMS should be to combine anti-inflammatory and neuroprotective therapeutic strategies based on early intervention. The TYRO3, AXL, and MERTK (TAM) signaling axis, particularly GAS6/TYRO3 and PROS1/AXL, which are involved in tempering inflammation, promoting tissue repair, and engaging remyelination, could significantly benefit patients at the early PMS.

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BACKGROUND: Leukocyte telomere length (LTL) shortens with age and may be related to multiple sclerosis (MS). OBJECTIVE: We hypothesize that chronologically young people with MS (pwMS) with short LTL behave similarly to older MS subjects. METHODS: Prospective 2-year study including two cohorts of young (18-35 years) and elderly (⩾50 years) pwMS with similar disease duration. Physical and cognitive evaluation, 3 T brain magnetic resonance imaging (MRI) and retinal nerve fiber layer (RNFL) measurement by optical coherence tomography were performed. LTL was measured by quantitative polymerase chain reaction assay. RESULTS: Around 105 patients were included, 57 young and 48 elderly. LTL was shorter in older patients (0.61 versus 0.57, p = 0.0081) and in males (female, 0.60; male, 0.59; p = 0.01335). For every 10-year increase in age, LTL was 0.02 U shorter. In elderly, LTL correlated with disease duration (p = 0.05), smoking (p = 0.03), Expanded Disability Status Scale (EDSS; p = 0.004), 9HPT (p = 0.00007), high-efficacy therapies (p = 0.001), brain lesion volume (BLV) (p = 0.011), and number of T2 lesions (p = 0.01). In young patients, LTL did not correlate with clinical or radiological variables. For every 0.1 U shorter LTL, gray matter volume decreased 1.75 cm3 and white matter volume 1.78 cm3. CONCLUSION: LTL correlated with disability and BLV in elderly. Besides LTL shortening, other variables should be considered as mechanisms of neurodegeneration that might be involved in aging pwMS.

Asunto(s)

Esclerosis Múltiple , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Adulto Joven , Adolescente , Anciano , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/patología , Esclerosis Múltiple/genética , Estudios Prospectivos , Biomarcadores , Imagen por Resonancia Magnética , Telómero , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Leucocitos/patología , Tomografía de Coherencia Óptica , Acortamiento del Telómero , Envejecimiento/patología

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Background: Multiple sclerosis (MS) is an inflammatory chronic autoimmune and neurodegenerative disorder of the brain and spinal cord, resulting in loss of motor, sensorial, and cognitive function. Among the non-pharmacological interventions for several brain conditions, photobiomodulation (PBM) has gained attention in medical society for its neuroprotective effects. We systematically reviewed the effects of PBM on MS. Methods: We conducted a systematic search on the bibliographic databases (PubMed and ScienceDirect) with the keywords based on MeSH terms: PBM, low-level laser therapy, multiple sclerosis, autoimmune encephalomyelitis, demyelination, and progressive multiple sclerosis. Data search was limited from 2012 to July 2024. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The initial systematic search identified 126 articles. Of these, 68 articles were removed by duplicity and 50 by screening. Thus, 8 studies satisfied the inclusion criteria. Results: The reviewed studies showed that PBM modulates brain markers linked to inflammation, oxidative stress, and apoptosis. Improvements in motor, sensorial, and cognitive functions in MS patients were also observed after PBM therapy. No study reported adverse effects of PBM. Conclusion: These findings suggest the potential of PBM as a promising non-pharmacological intervention for the management of MS, although further research is needed to standardize PBM protocols and assess its long-term effects.

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INTRODUCTION: Cladribine was approved for Multiple Sclerosis (MS) in our country in 2018. A previous study by our group showed that its use among high efficacy therapies options has been increasing along the years. OBJECTIVE: to analyze the cladribine use trend across time since its approval. METHOD: A retrospective cohort study was performed. People with MS (pwMS) treated with cladribine were included. Two periods were defined: P1 = 2018 - 2020 and P2 = 2021 - 2023. A comparative analysis was carry out between P1 and P2 to assess the trend of use, clinical/demographic characteristics, and effectiveness. RESULTS: One hundred ninety- seven people with MS (pwMS) were included, mean EDSS: 2.2 ± 3.08, 72.6% female, mean age: 35.2 ± 9 years, mean disease duration: 6.6 ± 5.6 years, mean time lapse under cladribine: 26.1 ± 12.4 months. Regarding patient profile, we found significant differences between P1 and P2 in the MS evolution (p = 0.001) and EDSS ( p = 0.018) prior to initiation of cladribine. In the individualized analysis by year, we found a decrease in relapse number in the year prior to starting cladribine (p = 0.02). A higher proportion of No Evidence of Disease Activity (NEDA) was found in patients treated at P2 compared to those treated at P1 (p < 0.001). CONCLUSION: An earlier use of cladribine achieved a significant increase in reaching NEDA. This learning curve in the use of cladribine allows a better identification of the candidate patient and influences the treatment effectiveness.

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Introduction: There are no reports in LATAM related to longitudinal humoral and cellular response to adenovirus based COVID-19 vaccines in people with Multiple Sclerosis (pwMS) under different disease modifying therapies (DMTs) and neutralization of the Omicron and Wuhan variants of SARS-COV-2. Methods: IgG anti- SARS-COV-2 spike titer were measured in a cohort of 101 pwMS under fingolimod, dimethyl fumarate, cladribine and antiCD20, as well as 28 healthy controls (HC) were measured 6 weeks after vaccination with 2nd dose (Sputnik V or AZD1222) and 3nd dose (homologous or heterologous schedule). Neutralizing capacity was against Omicron (BA.1) and Wuhan (D614G) variants and pseudotyped particles and Cellular response were analyzed. Results: Multivariate regression analysis showed anti-cd20 (ß= -,349, 95% CI: -3655.6 - -369.01, p=0.017) and fingolimod (ß=-,399, 95% CI: -3363.8 - -250.9, p=0.023) treatments as an independent factor associated with low antibody response (r2 adjusted=0.157). After the 2nd dose we found a correlation between total and neutralizing titers against D614G (rho=0.6; p<0.001; slope 0.8, 95%CI:0.4-1.3), with no differences between DMTs. Neutralization capacity was lower for BA.1 (slope 0.3, 95%CI:0.1-0.4). After the 3rd dose, neutralization of BA.1 improved (slope: 0.9 95%CI:0.6-1.2), without differences between DMTs. A fraction of pwMS generated anti-Spike CD4+ and CD8+ T cell response. In contrast, pwMS under antiCD20 generated CD8+TNF+IL2+ response without differences with HC, even in the absence of humoral response. The 3rd dose significantly increased the neutralization against the Omicron, as observed in the immunocompetent population. Discussion: Findings regarding humoral and cellular response are consistent with previous reports.

Asunto(s)

Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacunas contra la COVID-19 , COVID-19 , Inmunosupresores , Esclerosis Múltiple , SARS-CoV-2 , Humanos , Masculino , Femenino , Inmunosupresores/uso terapéutico , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , SARS-CoV-2/inmunología , Persona de Mediana Edad , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/tratamiento farmacológico , COVID-19/inmunología , COVID-19/prevención & control , Adulto , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/sangre , Argentina , Adenoviridae/genética , Adenoviridae/inmunología , Inmunidad Humoral , Glicoproteína de la Espiga del Coronavirus/inmunología

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Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system with unknown etiology, resulting in various impairments that necessitate continuous rehabilitation to enhance functionality, quality of life, and motor function, including through Virtual Reality (VR) therapy. Comparing tasks in virtual environments and their potential skill transfer to real-world settings could aid in optimizing treatment programs to improve motor performance in individuals with MS. This study aimed to determine whether practicing acquisition and retention phases using two distinct interfaces (concrete-Touch Screen or abstract-Kinect system) affects performance in a subsequent task using a different interface (transfer phase). A randomized clinical trial was conducted with 56 volunteers with MS and 41 controls. Participants engaged in a computer game where they burst as many bubbles as possible within 10 s per attempt. After the acquisition and retention phases, all participants switched interfaces (e.g., those using Kinect switched to Touchscreen and vice versa). Significant performance improvements were observed in both groups during the acquisition phase, which were maintained in the retention phase. Although the abstract interface was more challenging for both groups, only the MS group that practiced with the abstract interface successfully transferred their improvements to the concrete interface. Thus, despite the increased difficulty of the abstract task during practice, it led to better performance transfer when required to complete a subsequent concrete task, suggesting that abstract devices may be beneficial in clinical practice for improving motor function in people with MS.

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BACKGROUND: Interactions between genetic and environmental variables contribute to the autoimmune inflammatory process in multiple sclerosis (MS). Elevated homocysteine levels, and vitamin D, vitamin B12, and folate deficiencies are some of the environmental factors associated with the pathogenesis of MS. Considering that the relationship between MTHFR 677C>T (rs1801133) genetic variant, homocysteine, and folate in patients with MS remains unclear and that their role were not extensively explored in the clinical course of the disease, we investigated whether this variant and plasma homocysteine and folate levels are associated with MS susceptibility, disability, disability progression, and inflammatory biomarkers. METHODS: The case-control study included 163 patients with MS categorized using the Expanded Disability Status Scale (EDSS) as mild (EDSS<3) and moderate/high (EDSS≥3) disability, and 226 healthy controls (HC). Disability progression was evaluated using Multiple Sclerosis Severity Score (MSSS) and the MTHFR 677C>T variant was genotyped using real time polymerase chain reaction. The plasma levels of some inflammatory biomarkers were determined. Two new composed scores were proposed: the first, namely as inflammatory activity index (IAI), was entered as a latent vector extracted from the macrophage M1 + T helper (Th)1 + Th17 + Th2 + T regulatory (Treg) cytokines, + tumor necrosis factor (TNF)-α+ soluble TNF receptor (sTNFR)-1 + sTNFR2. The second score, namely MS-severity index was entered as a latent vector extracted from the EDSS + MSSS scores + MS diagnosis. RESULTS: Patients with MS showed higher homocysteine and folate than controls (p < 0.001); homocysteine, and the M1, Th1, Th17, and Th2 Treg cytokine values were different between the three study groups and increased from HC to MS patients with mild disability and to MS patients with moderate/high disability (p < 0.0001). The levels of TNF-α and their soluble receptors sTNFR1 and sTNFR2 were higher in MS patients with EDSS≥3 than in the two other groups (EDSS<3 and HC) (p < 0.001). There was no association between the MTHFR 677 C > T genotypes and MS susceptibility, disability and disability progression (p > 0.05). Moreover, 21.8 % of the disability variance was explained by age, IAI and C-reactive protein (CRP) (all positively associated); 10.9 % of the disability progression variance was predicted by IAI and CRP (both positively) and 25-hydroxyvitamin D (negatively), whereas 54.4 % of the severity index (MS-EDSS-MSSS) was explained by the regression on age, IAI, homocysteine, folate, and CRP (all positively), and adiponectin, body mass index, and 25-hydroxyvitamin D (all negatively), female sex, and the MTHFR 677 TT genotype. In patients and controls, 16.6 % of the variance in the homocysteine was explained by the MTHFR 677 TT genotype and age (both positively), folate (negatively) and male sex. CONCLUSION: The MTHFR 677C>T variant has an indirect effect on the increase in disability in patients with MS, which also depends on factors such as age, sex, ad folate status.

Asunto(s)

Progresión de la Enfermedad , Predisposición Genética a la Enfermedad , Homocisteína , Metilenotetrahidrofolato Reductasa (NADPH2) , Esclerosis Múltiple , Humanos , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Femenino , Masculino , Adulto , Homocisteína/sangre , Estudios de Casos y Controles , Esclerosis Múltiple/genética , Esclerosis Múltiple/sangre , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Ácido Fólico/sangre , Índice de Severidad de la Enfermedad

RESUMEN

Multiple sclerosis (MS) is a chronic inflammatory autoimmune neurological disease characterized by the recurrent appearance of demyelinating lesions and progressive disability. Currently, there are multiple disease-modifying treatments, however, there is a significant need to develop new therapeutic targets, especially for the progressive forms of the disease. This review article provides an overview of the most recent studies aimed at understanding the inflammatory processes that are activated in response to the accumulation of kynurenine pathway (KP) metabolites, which exacerbate an imbalance between immune system cells (e.g., Th1, Th2, and T reg) and promote the release of pro-inflammatory interleukins that modulate different mechanisms: membrane-receptors function; nuclear factors expression; and cellular signals. Together, these alterations trigger cell death mechanisms in brain cells and promote neuron loss and axon demyelination. This hypothesis could represent a remarkable approach for disease-modifying therapies for MS. Here, we also provide a perspective on the repositioning of some already approved drugs involved in other signaling pathways, which could represent new therapeutic strategies for MS treatment.

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Revealing unknown cues that regulate oligodendrocyte progenitor cell (OPC) function in remyelination is important to optimise the development of regenerative therapies for multiple sclerosis (MS). Platelets are present in chronic non-remyelinated lesions of MS and an increase in circulating platelets has been described in experimental autoimmune encephalomyelitis (EAE) mice, an animal model for MS. However, the contribution of platelets to remyelination remains unexplored. Here we show platelet aggregation in proximity to OPCs in areas of experimental demyelination. Partial depletion of circulating platelets impaired OPC differentiation and remyelination, without altering blood-brain barrier stability and neuroinflammation. Transient exposure to platelets enhanced OPC differentiation in vitro, whereas sustained exposure suppressed this effect. In a mouse model of thrombocytosis (Calr+/-), there was a sustained increase in platelet aggregation together with a reduction of newly-generated oligodendrocytes following toxin-induced demyelination. These findings reveal a complex bimodal contribution of platelet to remyelination and provide insights into remyelination failure in MS.

Asunto(s)

Plaquetas , Diferenciación Celular , Células Precursoras de Oligodendrocitos , Remielinización , Animales , Células Precursoras de Oligodendrocitos/fisiología , Remielinización/fisiología , Ratones , Plaquetas/fisiología , Encefalomielitis Autoinmune Experimental/patología , Ratones Endogámicos C57BL , Esclerosis Múltiple/patología , Modelos Animales de Enfermedad , Oligodendroglía/fisiología , Femenino

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Multiple sclerosis is a chronic inflammatory disease of the central nervous system characterized by autoimmune destruction of the myelin sheath, leading to irreversible and progressive functional deficits in patients. Pre-clinical studies involving the use of neural stem cells (NSCs) have already demonstrated their potential in neuronal regeneration and remyelination. However, the exclusive application of cell therapy has not proved sufficient to achieve satisfactory therapeutic levels. Recognizing these limitations, there is a need to combine cell therapy with other adjuvant protocols. In this context, extracellular vesicles (EVs) can contribute to intercellular communication, stimulating the production of proteins and lipids associated with remyelination and providing trophic support to axons. This study aimed to evaluate the therapeutic efficacy of the combination of NSCs and EVs derived from oligodendrocyte precursor cells (OPCs) in an animal model of multiple sclerosis. OPCs were differentiated from NSCs and had their identity confirmed by gene expression analysis and immunocytochemistry. Exosomes were isolated by differential ultracentrifugation and characterized by Western, transmission electron microscopy and nanoparticle tracking analysis. Experimental therapy of C57BL/6 mice induced with experimental autoimmune encephalomyelitis (EAE) were grouped in control, treated with NSCs, treated with OPC-derived EVs and treated with a combination of both. The treatments were evaluated clinically using scores and body weight, microscopically using immunohistochemistry and immunological profile by flow cytometry. The animals showed significant clinical improvement and weight gain with the treatments. However, only the treatments involving EVs led to immune modulation, changing the profile from Th1 to Th2 lymphocytes. Fifteen days after treatment revealed a reduction in reactive microgliosis and astrogliosis in the groups treated with EVs. However, there was no reduction in demyelination. The results indicate the potential therapeutic use of OPC-derived EVs to attenuate inflammation and promote recovery in EAE, especially when combined with cell therapy.

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Background: Cladribine shows efficacy in multiple sclerosis (MS), but Latin American (LATAM) real-world data is limited, despite potential sociodemographic variations. Objective: Investigate baseline characteristics and clinical response in highly active MS patients in Mexico, identifying predictors of early treatment response. Method: A multicenter cohort study analyzed retrospective data from individuals with "highly active" MS in the Cladribine Patient Support Program across 11 Mexican clinics. Criteria included one-year prior treatment with another disease-modifying treatment and recent relapse with specific MRI findings. Primary outcomes focused on achieving NEDA-3 status after 12 months. Results: In the follow-up, 67.5% maintained NEDA-3 status. Baseline EDSS scores decreased significantly from 1.50 to 1.00 (p = 0.011), with no confirmed disability worsening. No significant differences were observed between NEDA-3 achievers and non-achievers in demographic and clinical variables. No severe adverse events were reported. Conclusion: Cladribine showed early and effective control of active MS in Mexican patients, demonstrating a secure profile with minimal adverse events. This study provides valuable real-world evidence in the LATAM context.

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This study aimed to evaluate the efficacy of the ethanolic extract of Anadenanthera colubrina in modulating the immune response in the Experimental Autoimmune Encephalomyelitis (EAE) model. The ethanolic extract of the dried bark was analyzed by ESI (+) Orbitrap-MS to obtain a metabolite profile, demonstrating a wide variety of polyphenols, such as flavonoids and phenolic acids. Various parameters were evaluated, such as clinical signs, cytokines, cellular profile, and histopathology in the central nervous system (CNS). The ethanolic extract of A. colubrina demonstrated significant positive effects attenuating the clinical signs and pathological processes associated with EAE. The beneficial effects of the extract treatment were evidenced by reduced levels of pro-inflammatory cytokines, such as IL1ß, IL-6, IL-12, TNF, IFN-γ, and a notable decrease in several cell profiles, including CD8+, CD4+, CD4+IFN-γ, CD4+IL-17+, CD11c+MHC-II+, CD11+CD80+, and CD11+CD86+ in the CNS. In addition, histological analysis revealed fewer inflammatory infiltrates and demyelination sites in the spinal cord of mice treated with the extract compared to the control model group. These results showed, for the first time, that the ethanolic extract of A. colubrina exerts a modulatory effect on inflammatory processes, improving clinical signs in EAE, in the acute phase of the disease, which could be further explored as a possible therapeutic alternative.

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Multiple sclerosis (MS) is a chronic and degenerative disease that impacts central nervous system (CNS) function. One of the major characteristics of the disease is the presence of regions lacking myelin and an oxidative and inflammatory environment. TGF-ß1 and Nrf2 proteins play a fundamental role in different oxidative/inflammatory processes linked to neurodegenerative diseases such as MS. The evidence from different experimental settings has demonstrated a TGF-ß1-Nrf2 signaling crosstalk under pathological conditions. However, this possibility has not been explored in experimental models of MS. Here, by using the cuprizone-induced demyelination model of MS, we report that the in vivo pharmacological blockage of the TGF-ß1 receptor reduced Nrf2, catalase, and TGFß-1 protein levels in the demyelination phase of cuprizone administration. In addition, ATP production, locomotor function and cognitive performance were diminished by the treatment. Altogether, our results provide evidence for a crosstalk between TGF-ß1 and Nrf2 signaling pathways under CNS demyelination, highlighting the importance of the antioxidant cellular response of neurodegenerative diseases such as MS.

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Multiple Sclerosis (MS) is a debilitating disease that severely affects the central nervous system (CNS). Apart from neurological symptoms, it is also characterized by neuropsychiatric comorbidities, such as anxiety and depression. Phosphodiesterase-5 inhibitors (PDE5Is) such as Sildenafil and Tadalafil have been shown to possess antidepressant-like effects, but the mechanisms underpinning such effects are not fully characterized. To address this question, we used the EAE model of MS, behavioral tests, immunofluorescence, immunohistochemistry, western blot, and 16 S rRNA sequencing. Here, we showed that depressive-like behavior in Experimental Autoimmune Encephalomyelitis (EAE) mice is due to neuroinflammation, reduced synaptic plasticity, dysfunction in glutamatergic neurotransmission, glucocorticoid receptor (GR) resistance, increased blood-brain barrier (BBB) permeability, and immune cell infiltration to the CNS, as well as inflammation, increased intestinal permeability, and immune cell infiltration in the distal colon. Furthermore, 16 S rRNA sequencing revealed that behavioral dysfunction in EAE mice is associated with changes in the gut microbiota, such as an increased abundance of Firmicutes and Saccharibacteria and a reduction in Proteobacteria, Parabacteroides, and Desulfovibrio. Moreover, we detected an increased abundance of Erysipelotrichaceae and Desulfovibrionaceae and a reduced abundance of Lactobacillus johnsonii. Surprisingly, we showed that Tadalafil likely exerts antidepressant-like effects by targeting all aforementioned disease aspects. In conclusion, our work demonstrated that anxiety- and depressive-like behavior in EAE is associated with a plethora of neuroimmune and gut microbiota-mediated mechanisms and that Tadalafil exerts antidepressant-like effects probably by targeting these mechanisms. Harnessing the knowledge of these mechanisms of action of Tadalafil is important to pave the way for future clinical trials with depressed patients.

Asunto(s)

Ansiolíticos , Antidepresivos , Eje Cerebro-Intestino , Depresión , Encefalomielitis Autoinmune Experimental , Inhibidores de Fosfodiesterasa 5 , Tadalafilo , Animales , Femenino , Ratones , Ansiolíticos/administración & dosificación , Antidepresivos/administración & dosificación , Autoinmunidad/efectos de los fármacos , Eje Cerebro-Intestino/efectos de los fármacos , Depresión/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/inmunología , Microbioma Gastrointestinal/efectos de los fármacos , Ratones Endogámicos C57BL , Inhibidores de Fosfodiesterasa 5/administración & dosificación , Tadalafilo/administración & dosificación

RESUMEN

Objective. This study was conducted with the aim of the effect of team members teaching design (TMTD) vs. regular Lectures method on the self-efficacy of the multiple sclerosis patients. Methods. This research is a randomized controlled trial study. In this study, 48 multiple sclerosis persons of members of Jahrom MS Society participated. The persons were selected by simple random sampling and then divided into three groups of: TMTD (n=16), regular lecture method (n=16), and control (n=16), by random allocation method. In the intervention groups, six training sessions were held twice a week; control group did not receive education. Data was collected by the MS self-efficacy questionnaire of Rigby et al. in the before, immediately and one month after the intervention. Results. Patients in three intervention and control groups were similar in terms of demographic variables. The results of the repeated measurement test before, immediately and one month after the intervention showed that the mean of the all dimensions of self-efficacy in two intervention groups had increased significantly (p<0.05). While these changes were not significant in the control group (p ≥ 0.05). Also, there was a significant difference in the mean of the all dimensions of self-efficacy between the intervention groups of TMTD and regular lectures. Conclusion. Based on the findings, TMTD compared to regular lectures method had a more significant effect on improving the self-efficacy of multiple sclerosis patients. Therefore, it is recommended that nursing use this educational approach to increase patients' self-efficacy.

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Objetivo. Determinar el efecto del diseño de la enseñanza colaborativa de los miembros del equipo (En inglés: Team Members Teaching Design -TMTD) frente al método de las clases regulares sobre la autoeficacia de los pacientes con esclerosis múltiple (EM).Métodos. Ensayo controlado aleatorizado realizado con la participación de 48 personas con esclerosis múltiple afiliados a la Sociedad de Esclerosis Múltiple de Jahrom (Iran), que fueron seleccionados por muestreo aleatorio simple y luego asignados en forma randomizada en tres grupos, dos de intervención: TMTD (n=16) y método de clases regulares (n=16), y un grupo control (n=16). En los grupos de intervención se impartieron seis sesiones educativas (dos por semana); mientras que el grupo control no recibió educación. Se empleó el cuestionario de autoeficacia en EM de Rigby et al. en los momentos: antes, inmediatamente después de terminada la intervención y un mes de finalizada la misma.Resultados. Los pacientes de los tres grupos de intervención y control eran similares en cuanto a variables demográficas. Los resultados de la prueba de medidas repetidas antes, inmediatamente y un mes después de la intervención mostraron que la media de todas las dimensiones de autoeficacia en los dos grupos de intervención había aumentado significativamente (p<0.05). Mientras que estos cambios no fueron significativos en el grupo de control (p ≥ 0.05). Además, hubo una diferencia significativa en la media de todas las dimensiones de autoeficacia entre los grupos de intervención de TMTD y clases regulares, siendo mayor en TMTD. Conclusión. El TMTD comparado con el método de clases regulares, tuvo un mejor efecto en el aumento de la autoeficacia de los pacientes con EM. Por lo tanto, se sugiere a enfermería utilizar este enfoque educativo para aumentar la autoeficacia de los pacientes.

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Objetivo. Determinar o efeito do desenho de ensino colaborativo dos membros da equipe (em inglês: Team Members Teaching Design -TMTD) comparado ao método de aulas regulares na autoeficácia de pacientes com esclerose múltipla (EM). Métodos. Ensaio controlado randomizado realizado com a participação de 48 pessoas com esclerose múltipla afiliadas à Sociedade de Esclerose Múltipla de Jahrom (Irã), que foram selecionadas por amostragem aleatória simples e depois distribuídas aleatoriamente em três grupos, dois grupos de intervenção: TMTD (n=16 ) e método de aula regular (n=16), e um grupo controle (n=16). Foram ministradas seis sessões educativas nos grupos de intervenção (duas por semana); enquanto o grupo de controle não recebeu educação. Foi utilizado o questionário de autoeficácia em SM de Rigby et al. nos momentos: antes, imediatamente após o término da intervenção e um mês após seu término. Resultados. Os pacientes dos três grupos intervenção e controle foram semelhantes em termos de variáveis demográficas. Os resultados do teste de medidas repetidas antes, imediatamente e um mês após a intervenção mostraram que a média de todas as dimensões da autoeficácia nos dois grupos de intervenção aumentou significativamente (p<0.05). Embora essas alterações não tenham sido significativas no grupo controle (p ≥ 0.05). Além disso, houve diferença significativa na média de todas as dimensões de autoeficácia entre os grupos de intervenção TMTD e aulas regulares, sendo maior no TMTD. Conclusão. O TMTD comparado ao método de aula regular teve melhor efeito no aumento da autoeficácia dos pacientes com EM. Portanto, sugere-se que a enfermagem utilize essa abordagem educativa para aumentar a autoeficácia dos pacientes.

Asunto(s)

Humanos , Masculino , Femenino , Lectura , Autoeficacia , Esclerosis Múltiple , Autocuidado , Educación , Extremidades

RESUMEN

BACKGROUND: Multiple sclerosis (MS) is an irreversible progressive CNS pathology characterized by the loss of myelin (i.e. demyelination). The lack of myelin is followed by a progressive neurodegeneration triggering symptoms as diverse as fatigue, motor, locomotor and sensory impairments and/or bladder, cardiac and respiratory dysfunction. Even though there are more than fourteen approved treatments for reducing MS progression, there are still no cure for the disease. Thus, MS research is a very active field and therefore we count with different experimental animal models for studying mechanisms of demyelination and myelin repair, however, we still lack a preclinical MS model assembling demyelination mechanisms with relevant clinical-like signs. RESULTS: Here, by inducing the simultaneous demyelination of both callosal and cerebellar white matter fibers by the double-site injection of lysolecithin (LPC), we were able to reproduce CNS demyelination, astrocyte recruitment and increases levels of proinflammatory cytokines levels along with motor, locomotor and urinary impairment, as well as cardiac and respiratory dysfunction, in the same animal model. Single site LPC-injections either in corpus callosum or cerebellum only, fails in to reproduce such a complete range of MS-like signs. CONCLUSION: We here report that the double-site LPC injections treatment evoke a complex MS-like mice model. We hope that this experimental approach will help to deepen our knowledge about the mechanisms of demyelinated diseases such as MS.

Asunto(s)

Cerebelo , Cuerpo Calloso , Enfermedades Desmielinizantes , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Esclerosis Múltiple , Animales , Esclerosis Múltiple/patología , Cuerpo Calloso/patología , Cerebelo/patología , Enfermedades Desmielinizantes/patología , Enfermedades Desmielinizantes/inducido químicamente , Ratones , Masculino , Lisofosfatidilcolinas , Citocinas/metabolismo , Vaina de Mielina/patología

RESUMEN

Background: Multiple Sclerosis (MS) is a common neurological disease among white populations of European origin. Frequencies among Latin Americans continue to be studied, however, epidemiologic, and clinical characterization studies lack from Central American and Caribbean countries. Ethnicity in these countries is uniformly similar with a prevalent Mestizo population. Methods and results: Data from January 2014 to December 2019 from Guatemala, El Salvador, Honduras, Nicaragua, Costa Rica, Panama, Dominican Republic, and Aruba on demographic, clinical, MRI and phenotypic traits were determined in coordinated studies: ENHANCE, a population-based, retrospective, observational study on incidence and clinical characteristics, and from the subgroup with MS national registries (Aruba, Dominican Republic, Honduras, and Panama), data on prevalence, phenotypes and demographics. Expanded Disability Status Scale (EDSS), and therapeutic schemes were included. ENHANCE data from 758 patients disclosed 79.8% of Mestizo ethnicity; 72.4% female; median age at onset 31.0 years and 33.2 at diagnosis. The highest incidence rate was from Aruba, 2.3-3.5 × 100,000 inhabitants, and the lowest, 0.07-0.15 × 100,000, from Honduras. Crude prevalence rates per 100,000 inhabitants fluctuated from 27.3 (Aruba) to 1.0 (Honduras). Relapsing MS accounted for 87.4% of cases; EDSS <3.0 determined in 66.6% (mean disease duration: 9.1 years, SD ± 5.0); CSF oligoclonal bands 85.7%, and 87% of subjects hydroxyvitamin D deficient. Common initial therapies were interferon and fingolimod. Switching from interferon to fingolimod was the most common escalation step. The COVID-19 pandemic affected follow-up aspects of these studies. Conclusion: This is the first study providing data on frequencies and clinical characteristics from 8 countries from the Central American and Caribbean region, addressing MS as an emergent epidemiologic disorder. More studies from these areas are encouraged.

RESUMEN

This study aims to evaluate and compare cellular therapy with human Wharton's jelly (WJ) mesenchymal stem cells (MSCs) and neural precursors (NPs) in experimental autoimmune encephalomyelitis (EAE), a preclinical model of Multiple Sclerosis. MSCs were isolated from WJ by an explant technique, differentiated to NPs, and characterized by cytometry and immunocytochemistry analysis after ethical approval. Forty-eight rats were EAE-induced by myelin basic protein and Freund's complete adjuvant. Forty-eight hours later, the animals received intraperitoneal injections of 250 ng/dose of Bordetella pertussis toxin. Fourteen days later, the animals were divided into the following groups: a. non-induced, induced: b. Sham, c. WJ-MSCs, d. NPs, and e. WJ-MSCs plus NPs. 1 × 105. Moreover, the cells were placed in a 10 µL solution and injected via a stereotaxic intracerebral ventricular injection. After ten days, the histopathological analysis for H&E, Luxol, interleukins, and CD4/CD8 was carried out. Statistical analyses demonstrated a higher frequency of clinical manifestation in the Sham group (15.66%) than in the other groups; less demyelination was seen in the treated groups than the Sham group (WJ-MSCs, p = 0.016; NPs, p = 0.010; WJ-MSCs + NPs, p = 0.000), and a lower cellular death rate was seen in the treated groups compared with the Sham group. A CD4/CD8 ratio of <1 showed no association with microglial activation (p = 0.366), astrocytes (p = 0.247), and cell death (p = 0.577) in WJ-MSCs. WJ-MSCs and NPs were immunomodulatory and neuroprotective in cellular therapy, which would be translated as an adjunct in demyelinating diseases.

Asunto(s)

Encefalomielitis Autoinmune Experimental , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Esclerosis Múltiple , Animales , Encefalomielitis Autoinmune Experimental/terapia , Encefalomielitis Autoinmune Experimental/patología , Ratas , Esclerosis Múltiple/terapia , Esclerosis Múltiple/patología , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Humanos , Femenino , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Células-Madre Neurales , Modelos Animales de Enfermedad , Gelatina de Wharton/citología

RESUMEN

Multiple sclerosis (MS) is the most common acquired inflammatory and demyelinating disease in adults. The conventional diagnostic of MS and the follow-up of inflammatory activity is based on the detection of hyperintense foci in T2 and fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) and lesions with brain-blood barrier (BBB) disruption in the central nervous system (CNS) parenchyma. However, T2/FLAIR hyperintense lesions are not specific to MS and the MS pathology and inflammatory processes go far beyond focal lesions and can be independent of BBB disruption. MRI techniques based on the magnetic susceptibility properties of the tissue, such as T2*, susceptibility-weighted images (SWI), and quantitative susceptibility mapping (QSM) offer tools for advanced MS diagnostic, follow-up, and the assessment of more detailed features of MS dynamic pathology. Susceptibility-weighted techniques are sensitive to the paramagnetic components of biological tissues, such as deoxyhemoglobin. This capability enables the visualization of brain parenchymal veins. Consequently, it presents an opportunity to identify veins within the core of multiple sclerosis (MS) lesions, thereby affirming their venocentric characteristics. This advancement significantly enhances the accuracy of the differential diagnostic process. Another important paramagnetic component in biological tissues is iron. In MS, the dynamic trafficking of iron between different cells, such as oligodendrocytes, astrocytes, and microglia, enables the study of different stages of demyelination and remyelination. Furthermore, the accumulation of iron in activated microglia serves as an indicator of latent inflammatory activity in chronic MS lesions, termed paramagnetic rim lesions (PRLs). PRLs have been correlated with disease progression and degenerative processes, underscoring their significance in MS pathology. This review will elucidate the underlying physical principles of magnetic susceptibility and their implications for the formation and interpretation of T2*, SWI, and QSM sequences. Additionally, it will explore their applications in multiple sclerosis (MS), particularly in detecting the central vein sign (CVS) and PRLs, and assessing iron metabolism. Furthermore, the review will discuss their role in advancing early and precise MS diagnosis and prognostic evaluation, as well as their utility in studying chronic active inflammation and degenerative processes.