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1.
Clin Immunol ; 230: 108815, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34339843

RESUMO

Traumatic Brain Injury (TBI) is the most prevalent of all head injuries. Microglia play an essential role in homeostasis and diseases of the central nervous system. We hypothesize that microglia may play a beneficial or detrimental role in TBI depending on their state of activation and duration. In this study, we evaluated whether TBI results in a spatiotemporal change in microglia phenotype and whether it affects sensory-motor or learning and memory functions in male C57BL/6 mice. We used a panel of neurological and behavioral tests and a multi-color flow cytometry-based data analysis followed by unsupervised clustering to evaluate isolated microglia from injured brain tissue. We characterized several microglial phenotypes and their association with cognitive deficits. TBI results in a spatiotemporal increase in activated microglia that correlated negatively with spatial learning and memory at 35 days post-injury. These observations could define therapeutic windows and accelerate translational research to improve patient outcomes.


Assuntos
Lesões Encefálicas Traumáticas/complicações , Disfunção Cognitiva/etiologia , Microglia/fisiologia , Animais , Encéfalo/patologia , Encéfalo/fisiopatologia , Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas Traumáticas/psicologia , Disfunção Cognitiva/patologia , Disfunção Cognitiva/psicologia , Modelos Animais de Doenças , Citometria de Fluxo , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/classificação , Microglia/patologia , Modelos Neurológicos , Modelos Psicológicos , Dinâmica não Linear , Aprendizagem Espacial/fisiologia , Memória Espacial/fisiologia , Análise Espaço-Temporal , Pesquisa Médica Translacional
2.
Mult Scler Relat Disord ; 53: 103041, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34051694

RESUMO

OBJECTIVE: To explore prospectively through OCT the rate of retinal layer changes in relapsing-remitting multiple sclerosis patients followed up on fingolimod or interferon, as well as the treatments' differential effects on cognitive tests scores. METHODS: This prospective observational study enrolled 128 stable RRMS patients treated either with fingolimod (n = 71) or interferon (n = 56). Symbol-Digit Modality Test and retinal OCT scans were obtained at baseline and every 6 to 12 months. A subgroup of patients underwent expanded cognitive tests annually (Brief visual-spatial memory-total recall, BVMT-delayed recall, and Montreal Cognitive Assessment). Retinal-OCT scans were also obtained from 22 age- and sex-matched healthy controls. Mixed effects regression was used to study annualized changes in retinal layers and cognitive function, including differences between treatment groups. Correlations between annualized changes in retinal measurements and cognitive scores were also explored. RESULTS: Fingolimod treated patients showed no significant difference in the rate of thinning of all retinal layers when compared to healthy controls and had significantly less GCIPL thinning when compared to interferons. SDMT scores improved similarly among both RRMS treatment groups. However, interferon but not fingolimod treated patients had significant decline in MOCA and total recall scores. We also found correlations between the annualized change in GCIPL thickness and annualized change in MOCA scores, and similar correlations with annualized change in total recall scores. CONCLUSION: Fingolimod has a potential role in reducing retinal neurodegeneration in RRMS. Longitudinal OCT measures appear to be sensitive to changes in cognitive function and may be useful for monitoring neuroprotective therapies.


Assuntos
Cloridrato de Fingolimode , Esclerose Múltipla Recidivante-Remitente , Cognição , Cloridrato de Fingolimode/uso terapêutico , Humanos , Imunossupressores/efeitos adversos , Interferons , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Testes Neuropsicológicos
3.
Artigo em Inglês | MEDLINE | ID: mdl-34006621

RESUMO

OBJECTIVE: To investigate in a cross-sectional study the effect of serum-derived exosomes on primary human blood monocyte-derived macrophages (MDMs) comparing exosomes from healthy donors vs patients with relapsing-remitting multiple sclerosis in remission and in relapse and to assess whether the response correlates with exosomal Epstein-Barr virus (EBV) protein expression. METHODS: A total of 45 serum-derived exosome preparations were isolated from patients and healthy controls and verified for the expression of exosomal and EBV markers. MDMs were differentiated from monocytes for 7 days and incubated for 24 hours with exosomes, and then, cell supernatants were collected for cytokine measurement by cytometric bead array. Cells were immunophenotyped before and after differentiation. RESULTS: Serum-derived exosomes of patients with multiple sclerosis (MS) expressed higher levels of EBV proteins than healthy controls. Of interest, expression of EBV nuclear antigen EBNA1 and latent membrane proteins LMP1 and 2A was higher on exosomes derived from patients with active RRMS compared with healthy controls and stable patients. After data normalization, we observed that incubation with EBV(+) exosomes induced CXCL10 and CCL2 secretion by MDMs. MDMs differentiated from patients with active disease were better secretors of CXCL10 and other interferon-γ-inducible chemokines, including CCL2 and CXCL9, than MDMs from healthy and stable MS groups. MDMs from active patients had a higher frequency of a CD14(++) subset that correlated with the secreted CXCL10. CONCLUSION: Exosomes expressing EBV proteins correlate with disease activity and induce an inflammatory response in MDMs that is compounded by the origin of the responder cells.

4.
J Int Neuropsychol Soc ; : 1-10, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33563350

RESUMO

OBJECTIVE: Multiple sclerosis (MS) is often associated with cognitive deficits. Accurate evaluation of the MS patients' cognitive performance is essential for diagnosis and treatment recommendation. The Brief International Cognitive Assessment in Multiple Sclerosis (BICAMS), widely used cognitive testing battery, examines processing speed, verbal and visuospatial learning, and memory. Our study aims to examine the psychometric properties of an Arabic version of the BICAMS and to provide normative values in a Lebanese sample. METHOD: The BICAMS, comprised of the Symbol Digit Modalities Test (SDMT), Brief Visuospatial Memory Test-Revised (BVMT-R), and a newly developed verbal learning/memory test, the Verbal Memory Arabic Test (VMAT), were administered on healthy subjects and MS patients. The sample consisted of 180 healthy individuals, of whom 63 were retested after 2-3 weeks. Forty-three MS patients matched with 43 healthy subjects based on age, sex, and years of education were assessed. A sample of 10 MS patients was also examined on two occasions. Test-retest reliability and criterion-related validity were examined, and regression-based norms were derived. RESULTS: The test-retest correlations showed good evidence of reliability with coefficients ranging between 0.64 and 0.73 in the healthy sample, and between 0.43 and 0.92 in the MS sample. The BICAMS was able to discriminate between MS patients and matched healthy participants on the SDMT and BVMT-R. Normative data were comparable to other studies. CONCLUSIONS: This new Arabic version of the BICAMS shows initial good psychometric properties. While good evidence of VMAT's reliability was shown in the healthy participants, less test-retest reliability in this tool was seen in the MS group, and partial criterion-related validity was evident. This renders further examination of the VMAT. We provide regression-based norms for a Lebanese sample and encourage the use of this battery in both research and clinical settings.

6.
J Clin Exp Neuropsychol ; 42(5): 505-515, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32567997

RESUMO

BACKGROUND: Tests of verbal memory (list learning) are particularly useful for clinicians and researchers globally, yet there are no psychometrically robust tests that are built indigenously for Arabic-speaking populations, which comprise more than 370 million. OBJECTIVE: To develop a verbal memory Arabic test using a systematic procedure of item selection and then provide evidence of validity and reliability in an Arabic-speaking sample in Lebanon. METHOD: In study 1, we conducted a word prototypicality study (n = 77), and identified 932 words across 7 semantic categories. Following quantitative analyzes and qualitative judgments by an expert panel, we selected a sufficient number of words and categories, and constructed and piloted the items, instructions, and protocol for the Verbal Memory Arabic Test (VMAT). In study 2, we administered the VMAT on a community sample (n = 199; screened for depression and cognitive impairment) and patients with Multiple Sclerosis (n = 16). RESULTS: Scores decreased with age as expected, they discriminated well between healthy and clinical populations (matched on age, sex, and years of education), and showed acceptable consistency within items and across time. Conclusions: The VMAT is the first Arabic test developed indigenously. It can be used in clinical and research settings with Arabic-speaking populations to assess verbal learning.


Assuntos
Disfunção Cognitiva/diagnóstico , Testes de Memória e Aprendizagem/normas , Psicometria/normas , Aprendizagem Verbal , Adulto , Árabes , Disfunção Cognitiva/etiologia , Depressão/complicações , Feminino , Humanos , Líbano , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Projetos Piloto , Psicometria/instrumentação , Psicometria/métodos , Valores de Referência , Reprodutibilidade dos Testes , Aprendizagem Verbal/fisiologia
8.
J Steroid Biochem Mol Biol ; 200: 105628, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32061642

RESUMO

Multiple Sclerosis (MS) is often associated with low serum 25(OH)D levels, as well as cognitive dysfunctions. The relationship between 25(OH)D and the most commonly affected cognitive domain in MS; processing speed, is poorly explored. The purpose of this study is to: (1) assess the effect of serum 25(OH)D change on processing speed in MS, and (2) explore the relationship between serum 25(OH)D and brain volume changes in MS. A retrospective chart review was conducted, data from 299 patients were extracted (baseline), of whom 163 had follow-up measurements (after at least a 9-month interval). The Symbol Digits Modalities Test (SDMT) was used as a measure of processing speed. MRI data was available from 78 individuals at baseline, and 70 at follow-up. SDMT scores and brain volumes (Cerebellum (total, grey, and white), intracranial, Grey Matter (GM), and White Matter (WM)) were compared based on 25(OH)D levels and their changes towards follow-up. Results indicated that patients with deficient 25(OH)D levels had lower SDMT scores when compared to those with sufficient levels, and SDMT scores improved as a function of 25(OH)D. For MRI measures, only patients with sufficient 25(OH)D levels during both assessment periods had significant changes in intracranial and total cerebellum volumes. We conclude that 25(OH)D levels seem to have an effect on processing speed in MS, thus the importance of clinical monitoring and supplementation in this regard is reinforced.


Assuntos
Disfunção Cognitiva/sangue , Esclerose Múltipla/sangue , Vitamina D/sangue , Adulto , Encéfalo/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico por imagem , Testes Neuropsicológicos , Adulto Jovem
9.
Mult Scler Relat Disord ; 40: 101935, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31951861

RESUMO

'No evidence of disease activity' (NEDA) that has been identified as a potential outcome measure for the evaluation of DMTs effects. The concept has been adopted from other diseases such as cancer where treatment is intended to free the patient from the disease. Disease-free status has been substituted by NEDA in MS, since we are limited when it comes to fully evaluating the underlying disease. In general, NEDA, otherwise termed as NEDA-3, is defined by the lack of disease activity based on the absence of clinical relapses, disability progression with the expanded disability status score (EDSS), and radiological activity. Recently, brain atrophy, a highly predictive marker of disability progression, has been added as a fourth component (NEDA-4). The use of this composite allowed a more comprehensive assessment of the disease activity. Indeed, it has an important role in clinical trials as a secondary outcome in addition to primary endpoints. However, the evidence is insufficient regarding the ability of NEDA to predict future disability and treatment response. Moreover, combining different composites does not eliminate the limitation of each, therefore the use of NEDA in clinical routine is still not implemented. The aim of this review is first to report from the literature the available definitions of NEDA and its different variants, and second, evaluate the importance of its use as a surrogate marker to assess the efficacy of different DMTs.


Assuntos
Progressão da Doença , Fatores Imunológicos/farmacologia , Imageamento por Ressonância Magnética , Esclerose Múltipla , Avaliação de Resultados em Cuidados de Saúde , Índice de Gravidade de Doença , Humanos , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Esclerose Múltipla/fisiopatologia
10.
Small GTPases ; 11(1): 62-68, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-28609201

RESUMO

We recently showed that Tiam1 expression is induced in pro-inflammatory T helper 17 (Th17) cells differentiated with interleukin (IL)-6 and TGF-ß1, and together with Rac1 promote Th17 cell development and autoimmunity in a mouse model of multiple sclerosis. Here we found that STAT3 and Smad3, downstream transcription factors of IL-6 and TGF-ß1, respectively, play opposing roles in regulating Tiam1 transcription in CD4+ T-cells. While IL-6-STAT3 signaling promotes Tiam1 expression, TGF-ß1-Smad3 induces the opposite outcome. At the Tiam1 promoter, both STAT3 and Smad3 bind to the Tiam1 promoter in Th17 cells. However, STAT3 induces Tiam1 promoter activity whereas Smad3 competes with STAT3 and inhibits its activity. Our findings uncover the complexity of STAT3/Smad3 signaling in regulating Tiam1 expression and Th17 cells.

11.
Adv Exp Med Biol ; 1189: 233-265, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31758537

RESUMO

Inflammation plays an important role in the onset and progression of many neurological diseases. As the central nervous system (CNS) constitutes a highly specialized environment where immune activation can be detrimental, it is crucial to understand mechanisms by which the immune system is regulated during neurological diseases. The system of co-signaling pathways provides the immune system with the means to fine-tune immune responses by turning on and off immune cell activation. Studies of co-signaling molecules in neurological diseases and their animal models have highlighted the complexities of immune regulation within the CNS and the intricacies of the interplay between the different cells of the immune system and how they interact with the resident cells of the CNS. This complexity poses challenges when targeting co-signaling pathway to treat neurological diseases and may explain why no drugs targeting these pathways have been successfully developed this far. Here, we will review the current literature on some important co-signaling pathways in multiple sclerosis (MS), Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, and ischemic stroke to understand these pathways in mediating and controlling neuroinflammation.


Assuntos
Doenças do Sistema Nervoso , Transdução de Sinais , Doença de Alzheimer , Esclerose Amiotrófica Lateral , Animais , Isquemia Encefálica , Esclerose Múltipla , Doença de Parkinson
12.
Lancet Psychiatry ; 6(11): 961-966, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31327707

RESUMO

Although mental disorders are a leading cause of disability in the Arab region, which includes 5·54% of the global population, Arab countries produce only 1·0% of the global output of peer-reviewed publications in mental health research. Various stakeholders, including Arab mental health researchers, institutional and funding agency officials, and international research collaborators, convened to identify challenges faced by Arab mental health researchers and propose an evidence-informed call for action. Challenges identified include prevalent stigma and low awareness, conflict and war, scarce institutional and funding resources, inadequate publishing opportunities, insufficient training in mental health research, and shortage of reliable and valid assessment tools. The proposed action plan includes ways of addressing stigma and spreading awareness, increasing collaborative efforts, building research infrastructure, strengthening the mental health workforce, and translating research findings into a call to action on societal and governmental levels. The proposed action plan could provide a roadmap for Arab mental health researchers and research institutions, which might ultimately increase research productivity in the Arab region and close the gap between Arab countries and the rest of the world.


Assuntos
Árabes , Transtornos Mentais , Pesquisa , Humanos , Saúde Mental , Oriente Médio
13.
Mult Scler Relat Disord ; 34: 9-13, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31202959

RESUMO

BACKGROUND: Relapse rate in women with Multiple Sclerosis (MS) is reduced during pregnancy especially in the third trimester according to the previous studies. OBJECTIVES: To measure the annual relapse rate (ARR) in women with MS during pregnancy. METHODS: A retrospective study was conducted using prospectively collected data from two MS registries in Kuwait and Lebanon. Demographics, clinical characteristics including relapses, disease modifying therapies (DMTs) and their washout periods were extracted. The annual relapse rates pre and post pregnancies were compared and the relationship between relapses and prior use of different DMTs was assessed. RESULTS: Data of 164 pregnancies (132 MS patients) was reviewed. Mean age and disease duration at the time of pregnancy confirmation were 32.4 ±â€¯5.3 and 7.8 ±â€¯4.7 years respectively. Most patients (91.7%; n = 121) were on DMTs in the year prior to pregnancy. The pre-pregnancy ARR was 0.10 (95% CI: 0.04 - 0.13), which increased to 0.20 (95% CI: 0.13- 0.29) during pregnancy. Most relapses occurred either during the 1st (ARR = 0.24; 95% CI: 0.12 - 0.44) or 3rd (ARR = 0.32; 95%CI: 0.17 - 0.53) trimesters. Fingolimod (31.8%) and natalizumab (22.7%) were the most commonly prescribed DMTs in patients who sustained relapses during pregnancy. The mean washout period was significantly longer among subjects with relapses (9.3 ±â€¯6.6 vs. 2.5 ±â€¯3.9; p < 0.001) than those of without relapses. CONCLUSIONS: Relapse rate during pregnancy was higher than previous studies conducted in patients on platform therapies or untreated. Longer washout period prior to conception was associated with increased relapses especially in fingolimod and natalizumab treated patients.


Assuntos
Esclerose Múltipla/epidemiologia , Complicações na Gravidez/epidemiologia , Adulto , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Kuweit , Líbano , Esclerose Múltipla/terapia , Gravidez , Complicações na Gravidez/terapia , Estudos Prospectivos , Recidiva , Sistema de Registros , Estudos Retrospectivos , Risco
14.
Crit Rev Toxicol ; 49(3): 262-279, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30942117

RESUMO

Ever since gadolinium was found to deposit in the brain of patients with normal kidney function by Kanda et al. in 2014, several studies have been conducted to evaluate its effect on the patients' health. However, conflicting results were obtained regarding imaging in gadolinium retention. These finding were attributed to the chelating structure of the administered gadolinium-based contrast agent (GBCA): linear agents were found to accumulate in the dentate nucleus (DN) and the globus pallidus (GP) of subjects even after one dose. There are some contradictory results when assessing macrocyclic agents. In the following article, we review the basis of GBCAs characteristics and their side effects, as well as, the MRI studies that assessed the accumulation of gadolinium in the brain. Based on the results of several studies, in 2017, the European Medicine Agency requested the suspension of the marketing authorizations for three linear GBCAs: gadodiamide (Omniscan®), gadoversetamide (Optimark®) and gadopentate dimeglimine (Magnevist®) and limited the use of gadoxetate disodium (Primovist/Eovist®) and gadobenate dimeglumine (MultiHance®) to hepatic uptake for imaging poorly vascularized hepatic lesions. Accordingly, the FDA did not restrict GBCA use, but will continue to study their safety and urged clinicians to use these agents sparingly. All macrocyclic GBCAs continued however to be used as no available valid evidence linked them to brain gadolinium retention. Regardless of possible accumulation in the brain, there is no evidence to-date that gadolinium retention leads to any disease or disorders in subjects with normal renal function. Further investigations with long-term follow-up are needed.


Assuntos
Exposição Ambiental/estatística & dados numéricos , Gadolínio/toxicidade , Adulto , Encéfalo , Núcleos Cerebelares , Meios de Contraste , Feminino , Gadolínio/metabolismo , Gadolínio DTPA , Humanos , Imageamento por Ressonância Magnética , Masculino , Meglumina/análogos & derivados , Compostos Organometálicos
15.
Nat Commun ; 10(1): 217, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30644388

RESUMO

In demyelinating diseases including multiple sclerosis (MS), neural stem cells (NSCs) can replace damaged oligodendrocytes if the local microenvironment supports the required differentiation process. Although chitinase-like proteins (CLPs) form part of this microenvironment, their function in this differentiation process is unknown. Here, we demonstrate that murine Chitinase 3-like-3 (Chi3l3/Ym1), human Chi3L1 and Chit1 induce oligodendrogenesis. In mice, Chi3l3 is highly expressed in the subventricular zone, a stem cell niche of the adult brain, and in inflammatory brain lesions during experimental autoimmune encephalomyelitis (EAE). We find that silencing Chi3l3 increases severity of EAE. We present evidence that in NSCs Chi3l3 activates the epidermal growth factor receptor (EGFR), thereby inducing Pyk2-and Erk1/2- dependent expression of a pro-oligodendrogenic transcription factor signature. Our results implicate CLP-EGFR-Pyk2-MEK-ERK as a key intrinsic pathway controlling oligodendrogenesis.


Assuntos
Encefalomielite Autoimune Experimental/etiologia , Receptores ErbB/metabolismo , Lectinas/metabolismo , Células-Tronco Neurais/metabolismo , Oligodendroglia/metabolismo , beta-N-Acetil-Hexosaminidases/metabolismo , Animais , Proteína 1 Semelhante à Quitinase-3/metabolismo , Feminino , Células HEK293 , Hexosaminidases/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos
16.
J Immunol ; 202(5): 1373-1382, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30683697

RESUMO

Abatacept is a CTLA-4-Ig fusion protein that binds to the costimulatory ligands CD80 and CD86 and blocks their interaction with the CD28 and CTLA-4 receptors expressed by T cells, therefore inhibiting T cell activation and function. Abatacept has shown clinical efficacy in treating some autoimmune diseases but has failed to show clinical benefit in other autoimmune conditions. The reasons for these disparate results are not clear and warrant further investigation of abatacept's mode of action. Longitudinal specimens from the Immune Tolerance Network's A Cooperative Clinical Study of Abatacept in Multiple Sclerosis trial were used to examine the effects of abatacept treatment on the frequency and transcriptional profile of specific T cell populations in peripheral blood. We found that the relative abundance of CD4+ T follicular helper (Tfh) cells and regulatory T cells was selectively decreased in participants following abatacept treatment. Within both cell types, abatacept reduced the proportion of activated cells expressing CD38 and ICOS and was associated with decreased expression of genes that regulate cell-cycle and chromatin dynamics during cell proliferation, thereby linking changes in costimulatory signaling to impaired activation, proliferation, and decreased abundance. All cellular and molecular changes were reversed following termination of abatacept treatment. These data expand upon the mechanism of action of abatacept reported in other autoimmune diseases and identify new transcriptional targets of CD28-mediated costimulatory signaling in human regulatory T and Tfh cells, further informing on its potential use in diseases associated with dysregulated Tfh activity.


Assuntos
Abatacepte/farmacologia , Imunossupressores/farmacologia , Esclerose Múltipla/tratamento farmacológico , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Método Duplo-Cego , Humanos , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/patologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia
17.
Acad Radiol ; 26(10): e284-e291, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30527456

RESUMO

RATIONALE AND OBJECTIVES: Previous studies on possible accumulation of gadolinium-based contrast agents (GBCA) in the brain suggest that macrocyclic GBCA are less likely to accumulate than linear GBCA. However, conflicting results have been reported, especially in MS. The aim of this study is to investigate retrospectively the correlation between gadoterate-meglumine (macrocyclic GBCA) use and T1 signal intensity changes (SI) in the dentate nucleus and the GP on unenhanced T1-weighted images in a large cohort of MS patients. MATERIALS AND METHODS: Unenhanced T1-weighted images of 232 MS patients who previously received multiple intravenous administrations of 0.1 mmol/kg of gadoterate-meglumine were reviewed. The change in T1 SI ratios of dentate nucleus/central pons (DN/CP) and globus pallidus/centrum semiovale (GP/CSO) was calculated between the first and last MRIs and correlated with age, number of injections, time interval between MRIs, disease duration, activity, and therapy. RESULTS: DN/CP ratio showed no significant changes whereas the GP/CSO ratio showed a significant decrease (p < 0.0001) between the first and last MRIs. Multivariable analyses of both ratios, controlling for age, disease duration, and time interval between MRIs, showed no significant correlation between the number of gadolinium injections and the differences in DN/CP (standardized beta = -0.018, p = 0.811) or GP/CSO SI ratios (standardized beta = -0.049, p = 0.499). CONCLUSION: Repeated administration of gadoterate-meglumine in MS patients did not result in increased T1 SI in the DN or the GP. The significant decrease of GP/CSO ratio between the first and last MRIs is not due to gadolinium accumulation but rather to varying MR parameters.


Assuntos
Núcleos Cerebelares/diagnóstico por imagem , Meios de Contraste/administração & dosagem , Globo Pálido/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Meglumina/administração & dosagem , Esclerose Múltipla/diagnóstico por imagem , Compostos Organometálicos/administração & dosagem , Administração Intravenosa , Adolescente , Adulto , Idoso , Núcleos Cerebelares/metabolismo , Criança , Estudos de Coortes , Meios de Contraste/farmacocinética , Feminino , Globo Pálido/metabolismo , Humanos , Estudos Longitudinais , Masculino , Meglumina/farmacocinética , Pessoa de Meia-Idade , Compostos Organometálicos/farmacocinética , Estudos Retrospectivos , Adulto Jovem
18.
J Immunol Res ; 2018: 9084759, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30539030

RESUMO

Objective: To evaluate the efficacy and safety of rituximab in multiple sclerosis in a clinical practice setting. Methods: Clinical data for all adult patients with multiple sclerosis (MS) treated with off-label rituximab at a single MS center in Lebanon between March 2008 and April 2017 were retrospectively collected from medical charts. The main efficacy outcomes assessed were annualized relapse rate (ARR) and proportion of patients free from relapses, disability progression, or magnetic resonance imaging (MRI) activity. Results: A total of 89 rituximab-treated patients were included: 59 relapsing-remitting MS (RRMS) and 30 progressive MS (PMS). Patients were treated with 1000 or 2000 mg rituximab IV every 6-12 months for a mean duration of 22.2 ± 24.8 months. The subjects were 65.2% females with a mean age of 40.5 ± 12.3 years and a mean disease duration of 7.9 ± 6.2 years. During treatment, the ARR decreased from 1.07 at baseline to 0.11 in RRMS (p < 0.0001) and from 0.25 to 0.16 in PMS patients (p = 0.593). The mean Expanded Disability Status Scale (EDSS) remained unchanged in both RRMS and PMS patients. Between baseline and the last follow-up, the percent of patients free from any new MRI lesions increased from 18.6% to 92.6% in the RRMS group and from 43.3% to 82% in the PMS group. No evidence of disease activity (NEDA) was achieved in 74% of patients at 1 year of treatment. A total of 64 adverse events (AEs) (71.9%) were recorded with the most common being infusion-related reactions in 25.8% of patients, all mild in nature. Two of our rituximab-treated patients experienced serious AEs requiring surgical interventions: pyoderma gangrenosum vaginalis with perianal abscess and fistula and an increase in the size of a meningioma. No case of progressive multifocal leukoencephalopathy (PML) was detected. Conclusion: In our real-world cohort, rituximab was well-tolerated and effective in reducing relapse rate and disability progression in relapsing-remitting and progressive MS patients.


Assuntos
Encéfalo/patologia , Fatores Imunológicos/uso terapêutico , Esclerose Múltipla/dietoterapia , Rituximab/uso terapêutico , Adulto , Antígenos CD20/imunologia , Encéfalo/diagnóstico por imagem , Estudos de Coortes , Progressão da Doença , Feminino , Seguimentos , Humanos , Fatores Imunológicos/efeitos adversos , Reação no Local da Injeção/etiologia , Líbano , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Uso Off-Label , Estudos Retrospectivos , Rituximab/efeitos adversos
19.
Mult Scler Relat Disord ; 26: 96-102, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30243236

RESUMO

BACKGROUND: Prevention of long-term disability is the goal of therapeutic intervention in Relapsing Remitting MS (RRMS). The Bayesian Risk Estimate for MS at Onset (BREMSO) gives an individual risk score predicting disease evolution into Secondary Progressive MS (SPMS). We investigated whether BREMSO correlates with physical disability, cognitive dysfunction, and regional brain atrophy early in MS. METHODS: One hundred RRMS patients with at least two years of follow-up were enrolled. BREMSO score as well as Symbol Digit Modalities Test (SDMT) and Multiple Sclerosis Severity Score (MSSS), Timed 25-Foot Walk Test (T25-FW) and 9-Hole Peg Test (9-HPT), were assessed. Intracranial volume (ICV), subcortical gray matter structures and corpus callosum (CC) were automatically segmented on MRI images and their volumes measured. RESULTS: BREMSO score correlated negatively with SDMT at visit1 (ß = -0.33, p = 0.019), visit2 (ß = -0.34, p = 0.017) and visit3 (ß = -0.34, p = 0.014), and positively with MSSS at visit1 (r = 0.38, p = 0.006), visit2 (r = 0.47, p < 0.0001) and visit3 (r = 0.42, p = 0.002), but not with T25-FW and 9-HPT. BREMSO negatively correlated with CC volume at baseline (p < 0.03). No correlations were found with ICV and subcortical gray matter. CONCLUSIONS: BREMSO score at onset correlated with physical disability (MSSS), cognitive function (SDMT) and CC volume measurements in patients with early MS.


Assuntos
Disfunção Cognitiva/diagnóstico , Teste de Esforço , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Medição de Risco/estatística & dados numéricos , Índice de Gravidade de Doença , Adulto , Teorema de Bayes , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/fisiopatologia , Feminino , Seguimentos , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/complicações , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Medição de Risco/métodos
20.
Neurol Neuroimmunol Neuroinflamm ; 5(5): e491, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30175165

RESUMO

Objective: To identify circulating microRNAs (miRNAs) linked to disease, disease stage, and disability in MS across cohorts. Methods: Samples were obtained from the Comprehensive Longitudinal Investigation of Multiple Sclerosis (CLIMB, Boston, MA), EPIC (San Francisco, CA), AMIR (Beirut, Lebanon) as part of the SUMMIT consortium, and Stockholm Prospective Assessment of Multiple Sclerosis (Stockholm, Sweden) cohorts. Serum miRNA expression was measured using locked nucleic acid-based quantitative PCR. Four groups were compared: (1) MS vs healthy control (HC), (2) relapsing-remitting (RR) vs HC, (3) secondary progressive (SP) vs HC, and (4) RR vs SP. A Wilcoxon rank-sum test was used for the comparisons. The association between each miRNA and the Expanded Disability Status Scale (EDSS) score was assessed using the Spearman correlation coefficient. For each comparison, the p values were corrected for multiple comparisons using the approach of Benjamini and Hochberg to control the false discovery rate. Results: In the CLIMB cohort, 5 miRNAs (hsa-miR-484, hsa-miR-140-5p, hsa-miR-320a, hsa-miR-486-5p, and hsa-miR-320c) showed a significant difference between patients with MS and healthy individuals; among these, miR-484 remained significant after accounting for multiple comparisons (p = 0.01). When comparing RRMS with HCs, hsa-miR-484 showed a significant difference (p = 0.004) between the groups after accounting for multiple group comparisons. When SP and HC were compared, 6 miRNAs (hsa-miR-484, hsa-miR-140-5p, hsa-miR-142-5p, hsa-miR-320a, hsa-miR-320b, and hsa-miR-320c) remained significantly different after accounting for multiple comparisons. Disability correlation analysis with miRNA provided 4 miRNAs (hsa-miR-320a, hsa-miR-337-3p, hsa-miR-199a-5p, and hsa-miR-142-5p) that correlated with the EDSS during the internal reproducibility phase. Among these, hsa-miR-337-3p was the most statistically significant miRNA that negatively correlated with the EDSS in three of the MS cohorts tested. Conclusions: These findings further confirm the use of circulating serum miRNAs as biomarkers to diagnose and monitor disease status in MS. Classification of evidence: This study provides Class III evidence that levels of circulating miRNAs identify patients with MS.

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