Multiple sclerosis New Drugs Review
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Lipids in multiple sclerosis: adverse lipid profiles, disability and disease progression, Clinical Lipidology, Future Medicine

Lipids in multiple sclerosis: adverse lipid profiles, disability and disease progression, Clinical Lipidology, Future Medicine | Multiple sclerosis New Drugs Review | Scoop.it

Evidence from the studies examined  suggests a negative impact of high TC, LDL and triglycerides on acute inflammatory activity, disease course in MS patients and a beneficial effect of higher HDL levels on MS, but without a significant effect on the risk of relapse. The fact that the lipid profile may be associated with MS disability, progression of disability and disease activity on MRI, but not with relapses may provide some insights as to how an adverse lipid profile may exert their effect. The prevalence of dyslipidemia and its association with disability progression is an indication that the serum lipid profile could be a potential target for reducing or modulating the rate of disability progression.

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Full TextClinical LipidologyVol. 9, No. 5, Pages 473-475 , DOI 10.2217/clp.14.41(doi:10.2217/clp.14.41)

 

Lipids in multiple sclerosis: adverse lipid profiles, disability and disease progressionPrudence Tettey & Ingrid AF van der MeiAuthor for correspondence: ingrid.vandermei@utas.edu.au

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Daclizumab (Biogen, Abbott) Review: Multiple sclerosis - Krishan Maggon

Daclizumab (Biogen, Abbott) Review: Multiple sclerosis - Krishan Maggon | Multiple sclerosis New Drugs Review | Scoop.it
Daclizumab is a humanized monoclonal antibody which targets the CD25 alpha subunit of the high affinity receptor and inhibits...
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Fingolimod vs. Interferon Beta-1a in Pediatric Multiple Sclerosis | NEJM

Fingolimod vs. Interferon Beta-1a in Pediatric Multiple Sclerosis | NEJM | Multiple sclerosis New Drugs Review | Scoop.it
The New England Journal of Medicine...

 

MS typically appears in young adulthood, but 3% to 5% of cases have an onset in early childhood or adolescence. No disease-modifying therapies have FDA approval for persons younger than 18 years of age. New research findings are summarized in a short video.

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Trial of Fingolimod versus Interferon Beta-1a in Pediatric Multiple Sclerosis | NEJM

Trial of Fingolimod versus Interferon Beta-1a in Pediatric Multiple Sclerosis | NEJM | Multiple sclerosis New Drugs Review | Scoop.it
Original Article from The New England Journal of Medicine — Trial of Fingolimod versus Interferon Beta-1a in Pediatric Multiple Sclerosis...
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B cells among factors leading to brain lesions in multiple sclerosis

B cells among factors leading to brain lesions in multiple sclerosis | Multiple sclerosis New Drugs Review | Scoop.it
A team of researchers has shown that in multiple sclerosis, it is not only specific T cells that cause inflammation and lesions in the brain. B cells, a different type of immune cell, also play a role.
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Trial of Fingolimod versus Interferon Beta-1a in Pediatric Multiple Sclerosis | NEJM

Trial of Fingolimod versus Interferon Beta-1a in Pediatric Multiple Sclerosis | NEJM | Multiple sclerosis New Drugs Review | Scoop.it
Abstract
BACKGROUND
Treatment of patients younger than 18 years of age with multiple sclerosis has not been adequately examined in randomized trials. We compared fingolimod with interferon beta-1a in this population.

METHODS
In this phase 3 trial, we randomly assigned patients 10 to 17 years of age with relapsing multiple sclerosis in a 1:1 ratio to receive oral fingolimod at a dose of 0.5 mg per day (0.25 mg per day for patients with a body weight of ≤40 kg) or intramuscular interferon beta-1a at a dose of 30 μg per week for up to 2 years. The primary end point was the annualized relapse rate.

RESULTS
Of a total of 215 patients, 107 were assigned to fingolimod and 108 to interferon beta-1a. The mean age of the patients was 15.3 years. Among all patients, there was a mean of 2.4 relapses during the preceding 2 years. The adjusted annualized relapse rate was 0.12 with fingolimod and 0.67 with interferon beta-1a (absolute difference, 0.55 relapses; relative difference, 82%; P<0.001). The key secondary end point of the annualized rate of new or newly enlarged lesions on T2-weighted magnetic resonance imaging (MRI) was 4.39 with fingolimod and 9.27 with interferon beta-1a (absolute difference, 4.88 lesions; relative difference, 53%; P<0.001). Adverse events, excluding relapses of multiple sclerosis, occurred in 88.8% of patients who received fingolimod and 95.3% of those who received interferon beta-1a. Serious adverse events occurred in 18 patients (16.8%) in the fingolimod group and included infection (in 4 patients) and leukopenia (in 2 patients). Six patients had convulsions. Serious adverse events occurred in 7 patients (6.5%) in the interferon beta-1a group and included infection (in 2 patients) and supraventricular tachycardia (in 1 patient).

CONCLUSIONS
Among pediatric patients with relapsing multiple sclerosis, fingolimod was associated with a lower rate of relapse and less accumulation of lesions on MRI over a 2-year period than interferon beta-1a but was associated with a higher rate of serious adverse events. Longer studies are required to determine the durability and safety of fingolimod in pediatric multiple sclerosis. (Funded by Novartis Pharma; PARADIGMS ClinicalTrials.gov number, NCT01892722.)
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Efficacy and safety of monoclonal antibody therapies for relapsing remitting multiple sclerosis: A network meta-analysis

Efficacy and safety of monoclonal antibody therapies for relapsing remitting multiple sclerosis: A network meta-analysis | Multiple sclerosis New Drugs Review | Scoop.it
Highlights
•The first NMA comparing the currently 4 licensed monoclonal antibodies for RRMS.
•Monoclonal antibody therapies were safe and effective compared with INFβ-1a or placebo.
•Natalizumab plus INFβ-1a and alemtuzumab performed best among all treatment regimens.
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Epigenetic modifications in brain and immune cells of multiple sclerosis patients - Kamilah Castro, Patrizia Casaccia, 2018

Epigenetic modifications in brain and immune cells of multiple sclerosis patients - Kamilah Castro, Patrizia Casaccia, 2018 | Multiple sclerosis New Drugs Review | Scoop.it
Abstract
Multiple sclerosis (MS) is a debilitating neurological disease whose onset and progression are influenced by the interplay of genetic and environmental factors. Epigenetic modifications, which include post-translational modification of the histones and DNA, are considered mediators of gene–environment interactions and a growing body of evidence suggests that they play an important role in MS pathology and could be potential therapeutic targets. Since epigenetic events regulate transcription of different genes in a cell type–specific fashion, we caution on the distinct functional consequences that targeting the same epigenetic modifications might have in distinct cell types. In this review, we primarily focus on the role of histone acetylation and DNA methylation on oligodendrocyte and T-cell function and its potential implications for MS. We find that decreased histone acetylation and increased DNA methylation in oligodendrocyte lineage (OL) cells enhance myelin repair, which is beneficial for MS, while the same epigenetic processes in T cells augment their pro-inflammatory phenotype, which can exacerbate disease severity. In conclusion, epigenetic-based therapies for MS may have great value but only when cellular specificity is taken into consideration.

Keywords Animal model, histone, DNA methylation, demyelination, remyelination, myelin
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Immunopathology of multiple sclerosis

Immunopathology of multiple sclerosis | Multiple sclerosis New Drugs Review | Scoop.it
This Review provides an insightful discussion on the current concepts in multiple sclerosis research, including genetic predisposition and environmental triggers, and explores the evolving link between inflammation and neurodegeneration. The authors highlight the clinical challenges and key questions that remain to be addressed.
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Neuro-Compass.education | A Multiple Sclerosis Online Resource

Neuro-Compass.education | A Multiple Sclerosis Online Resource | Multiple sclerosis New Drugs Review | Scoop.it
Neuro-Compass.education is a free, comprehensive, practical medical resource developed by healthcare professionals for healthcare professionals involved in the care of multiple sclerosis.
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Drug shows promise in slowing multiple sclerosis

Drug shows promise in slowing multiple sclerosis | Multiple sclerosis New Drugs Review | Scoop.it
Research appearing in the New England Journal of Medicine could herald a new treatment approach for individuals with multiple sclerosis (MS) if confirmed in future studies. The results of a clinical trial, which involved ...
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Dietary Inflammatory Index and clinical course of multiple sclerosis

Dietary Inflammatory Index and clinical course of multiple sclerosis | Multiple sclerosis New Drugs Review | Scoop.it

National Multiple Sclerosis Society. Relapsing-Remitting MS (RRMS). 2017. http://www.nationalmssociety.org/What-is-MS/Types-of-MS/Relapsing-remitting-MS. 35. Leary SM, Porter B, Thompson AJ. Multiple sclerosis: diagnosis

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UZH - B Cells Among Factors Leading to Brain Lesions in Multiple Sclerosis

UZH - B Cells Among Factors Leading to Brain Lesions in Multiple Sclerosis | Multiple sclerosis New Drugs Review | Scoop.it
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system. The body’s own immune cells attack and damage the layer that surrounds nerve cells in the brain and spinal cord, which impedes their ability to communicate with each other. The disease, which affects around 2.5 million people worldwide, is a common cause of disability in young adults and affects women particularly often. MS can lead to severe neurological disabilities such as sensory problems, pain and signs of paralysis. B cells activate T cells A team led by neurologist Roland Martin and immunologist Mireia Sospedra at the University of Zurich (UZH), the University Hospital Zurich (USZ) and researchers at the Karolinska Institute in Sweden has now discovered a key aspect in the pathogenesis of MS. “We were able to show for the first time that certain B cells – the cells of the immune system that produce antibodies – activate the specific T cells that cause inflammation in the brain and nerve cell lesions,” says Roland Martin, Director of the Clinical Research Priority Program Multiple Sclerosis at UZH. Novel MS drugs attack B cells Until recently, MS research had mainly focused on T cells, or T helper cells. They are the immune system’s “guardians”, which for example sound the alarm if the organism is infected with a virus or bacteria. In about one in a 1,000 people, the cells’ ability to distinguish between the body’s own and foreign structures becomes disturbed. The effect of this is that the misguided T cells start to attack the body’s own nerve tissue – the onset of MS. However, the T cells aren’t the sole cause of this. “A class of MS drugs called Rituximab and Ocrelizumab led us to believe that B cells also played an important part in the pathogenesis of the disease,” explains Roland Martin. These drugs eliminate B cells, which very effectively inhibits inflammation of the brain and flare-ups in patients. B cells’ “complicity” revealed The researchers established the role of B cells by using an experimental in-vitro system that allowed blood samples to be analyzed. The blood of patients with MS revealed increased levels of activation and cellular division among those T cells attacking the body’s myelin sheaths that surround nerve cells. This was caused by B cells interacting with the T cells. When the B cells were eliminated, the researchers found that it very effectively inhibited the proliferation of T cells. “This means that we can now explain the previously unclear mechanism of these MS drugs,” says Roland Martin. Activated T cells migrate to the brain Moreover, the team also discovered that the activated T cells in the blood notably included those that also occur in the brain in MS patients during flare-ups of the disease. It is suspected that they cause the inflammation. Further studies showed that these T cells recognize the structures of a protein that is produced by the B cells as well as nerve cells in the brain. After being activated in the peripheral blood, the T cells migrate to the brain, where they destroy nerve tissue. “Our findings not only explain how new MS drugs take effect, but also pave the way for novel approaches in basic research and therapy for MS,” concludes Roland Martin. Literature: Ivan Jelcic, Faiez Al Nimer, Jian Wang, Verena Lentsch, Raquel Planas, Ilijas Jelcic, Aleksandar Madjovski, Sabrina Ruhrmann, Wolfgang Faigle, Katrin Frauenknecht, Clemencia Pinilla, Radleigh Santos, Christian Hammer, Yaneth Ortiz, Lennart Opitz, Hans Grönlund, Gerhard Rogler, Onur Boyman, Richard Reynolds, Andreas Lutterotti, Mohsen Khademi, Tomas Olsson, Fredrik Piehl, Mireia Sospedra, and Roland Martin. Memory B Cells Activate Brain-Homing, Autoreactive CD4+ T Cells in Multiple Sclerosis. Cell. August 30, 2018. DOI: 10.1016/j.cell.2018.08.011
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Tryptophan and arginine catabolic enzymes and regulatory cytokines in clinically isolated syndrome and multiple sclerosis - Cha - 2018 - Clinical & Translational Immunology - Wiley Online Library

Tryptophan and arginine catabolic enzymes and regulatory cytokines in clinically isolated syndrome and multiple sclerosis - Cha - 2018 - Clinical & Translational Immunology - Wiley Online Library | Multiple sclerosis New Drugs Review | Scoop.it
Abstract Objectives Clinically isolated syndrome (CIS) is the earliest clinical episode in multiple sclerosis (MS). A study of circulating cells from patients with CIS may help us understand the transition to, and processes associated with, the development of MS. Methods As immune cell activity can be determined by flux through metabolic pathways, the mRNA expression of l‐tryptophan‐ and l‐arginine‐catabolising enzymes, indoleamine 2,3‐dioxygenase (IDO) 1 and IDO2 and arginase (ARG) 1 and ARG2, respectively, was compared between peripheral blood mononuclear cells (PBMCs) from healthy controls, and patients with CIS and definite MS. As one measure of cell function, cytokine mRNA levels were analysed directly ex vivo and in cells after culture for 4 h in the absence of regulatory factors in autologous serum. Results When measured directly ex vivo, the expression of IDO and ARG was greater in cells from patients with CIS and MS than cells from healthy controls. Although not linked to IDO and ARG expression, PBMCs from the CIS patients were characterised by low IL‐10 and TGFB mRNA levels and not by greater expression of proinflammatory cytokines. When the cells were cultured for 4 h without autologous serum, pro‐ and anti‐inflammatory cytokine mRNA levels positively correlated with IDO1 expression, and TGFB mRNA levels correlated with ARG1 expression. Conclusion Higher IDO and ARG expression in CIS and MS provides one sustained homeostatic mechanism to control MS‐associated inflammation. However, potent extrinsic mediators in serum may regulate immune cell function in CIS and associations between IDO, ARG and cytokine expression. Introduction The survival and activity of immune cells are determined in large part by flux through metabolic pathways, including those providing ATP interlinked with those providing the amino acids and nucleotides for protein and nucleic acid synthesis.1 For example, increasing l‐arginine (Arg) in activated T cells induces global metabolic changes including a shift from glycolysis to oxidative phosphorylation.2 Immune cells require amino acids for proliferation, and production of proinflammatory mediators. In turn, increased expression of the enzymes that catabolise amino acids such as l‐tryptophan (Trp) and l‐arginine (Arg) could limit the activity of inflammatory immune cells and restrict inappropriate autoimmune responses. Increased expression of these enzymes may not only reduce the supply of amino acids that limit immune cell survival, activation and expansion, but they would allow the production of multiple downstream metabolites such as the kynurenines and spermidine with proven immunomodulatory properties.3-5 The first and rate‐limiting enzymes in haematopoietic cells responsible for Trp metabolism are indoleamine 2,3‐dioxygenase (IDO)1 and IDO2. The third enzyme that catabolises Trp, tryptophan 2,3‐dioxygenase, is expressed mainly in the liver. Increased IDO expression associates with tolerogenic pathways because of Trp depletion and has been associated with the formation of tolerogenic dendritic cells and induction of T regulatory (Treg) cells.6, 7 Kynurenines are Trp metabolites that stimulate aryl hydrocarbon receptors and associated downstream immunoregulatory pathways.8, 9 Two arginases, arginase 1 and arginase 2 (ARG1 and ARG2), expressed by different genes catabolise Arg in myeloid cells (macrophages, dendritic cells) and activated T cells. ARG1 is principally cytosolic whilst ARG2 is expressed in mitochondria. ARG1 and ARG2 convert Arg to l‐ornithine and urea; the former molecule is a precursor for glutamic acid, proline and polyamine synthesis and helps to create an anti‐inflammatory environment conducive to tissue repair. Arg is also catabolised by a third enzyme, inducible NO synthase (NOS2), to produce NO and l‐citrulline. NO enhances the differentiation of monocytes to ‘classically activated’ macrophages whilst increased ARG1 expression has been linked with prohomeostatic ‘alternatively activated’ macrophages that do not produce NO.10, 11 Arg is required for the production of TNF‐α.12, 13 In T cells, ARG expression, by reducing Arg levels, reduces the metabolic fitness of the cells and reduces the generation of central memory‐like cells.2 In human peripheral blood cells from healthy individuals, approximately 70% of mRNA for IDO1 and ARG1 are expressed by CD14+ cells, 15% by CD4+ T cells, 10% by CD8+ T cells and 5% by B cells.14 A recent study from Argentina of patients with relapsing–remitting MS (mean duration of disease of 5.2 years) suggested that circulating blood cells of MS patients expressed reduced levels of IDO1 and ARG1.14 This would provide a proinflammatory environment with increased availability of Trp and Arg for the Th1‐ and Th17‐driven autoimmune responses associated with MS pathogenesis.15 In the study reported here, the focus was on expression of IDO and ARG during the MS disease course. PBMCs were studied from individuals with clinically isolated syndrome (CIS), the earliest clinical episode in MS, but their brain magnetic resonance imaging (MRI) results do not fulfil all criteria for diagnosis as MS. Levels of IDO and ARG mRNA were compared with those of cells from healthy controls (HCs), as well as patients with established MS. The aim was to determine whether changes in catabolic enzyme expression were a characteristic of the early form of disease, or reflected a later development in established MS. The effect of a potential immunomodulatory treatment, namely narrowband UVB phototherapy (311–312 nm),16, 17 on the expression of IDO and ARG by PBMCs was also examined. Associations between IDO and ARG expression and the function of the PBMCs were assessed by analysis of mRNA levels of genes encoding pro‐ and anti‐inflammatory cytokines. The effect of intrinsic or extrinsic determinants of IDO and ARG expression was examined by culture of PBMCs for 4 h in the absence of regulatory factors in autologous serum. This study identified changes in PBMCs from CIS patients that suggest lower expression of anti‐inflammatory cytokines precedes the expression of proinflammatory cytokines in the development of MS. Results mRNA levels of IDO1 and IDO2, and ARG1 and ARG2, are higher in cells from MS patients To establish whether there were differences in the expression of genes for IDO and ARG in PBMCs from HCs and CIS and MS patients, relative mRNA expression (normalised to ubiquitin‐conjugating enzyme E2 D2 [UBE2D2]) was compared. There were significantly higher levels of IDO1 and ARG2 mRNA in PBMCs from CIS patients relative to HCs. mRNA levels for all enzymes were significantly elevated further in cells from MS patients (Figure 1). The expression of the anti‐inflammatory cytokines, IL‐10 and TGFB, is lower in CIS As amino acid catabolism can modulate cytokine production and immune cell activity5, levels of mRNA for cytokine genes were assessed. Greater IL‐6 mRNA levels were detected in PBMCs from MS compared with CIS patients; however, no significant differences were observed for TNF or IL‐1B expression between the HC, CIS and MS groups (Figure 2). In contrast, in comparison with cells from HCs and MS patients, there was significantly less IL‐10 mRNA expression in cells from patients with CIS. There was significantly lower TGFB expression in cells from both CIS and MS patients compared with cells from HCs (Figure 2). When correlations between the expression of the proinflammatory and anti‐inflammatory cytokines and IDO and ARG were analysed, no associations were observed in PBMCs from the HC, CIS and MS groups, with the exception of a positive correlation between ARG1 and TGFB mRNA in cells from CIS patients (columns for PBMC ex vivo, Table 1). PBMC ex vivo PBMC culture (4 h, 37°C) HC n = 7 CIS n = 11 MS n = 8 HC n = 14 CIS n = 14 MS n = 8 IDO1 TNF 0.18 −0.28 −0.21 0.72 *** 0.89 *** 0.86 ** IL‐1B 0.32 −0.37 0.69 0.76 ** 0.63 * 0.79 * IL‐6 −0.04 0.09 0.12 0.69 ** 0.66 * 0.74 * COX2 nd nd nd 0.79 ** 0.84 *** 0.79 * IL‐10 −0.18 −0.33 0.55 0.60 * 0.62 * 0.76 * TGFB −0.07 0.33 0.00 0.86 *** 0.70 ** 0.31 ARG1 TNF −0.07 −0.21 −0.55 0.49 0.17 0.19 IL‐1B 0.21 −0.19 0.09 0.44 0.29 0.26 IL‐6 −0.25 −0.30 0.36 0.31 0.31 0.29 COX2 nd nd nd 0.52 0.62 * 0.38 IL‐10 −0.39 0.01 0.50 0.44 0.48 0.45 TGFB −0.27 0.64 * −0.14 0.58 * 0.82 *** 0.52 *P < 0.05; **P < 0.01; ***P < 0.001; nd, not done. Timing of recent demyelinating/inflammatory events and levels of serum 25(OH)D3 do not correlate with gene expression of IDO, ARG and cytokines To test whether recent demyelination and any associated inflammation led to the differences in catabolic enzyme and cytokine mRNA expression, their levels were tested for correlation with the days to venepuncture since CIS diagnosis or MS diagnosis/relapse. No significant correlations were observed for IDO and ARG; however, a weak positive correlation (P = 0.04) was detected for TNF and IL‐6 mRNA expression and days from CIS diagnosis to venepuncture (Supplementary table 1). As levels of TNF and IL‐6 mRNA in cells of CIS patients were generally low and not different to those of HCs, this result may reflect amounts measured in cells from two or three patients only (Figure 2). As immune cells may activate vitamin D for purposes of regulating catabolic enzyme and cytokine expression,18, 19 correlations were investigated between serum 25‐hydroxy vitamin D3 [25(OH)D3] and IDO, ARG and cytokine mRNA levels in PBMCs. No significant relationships were detected and because 25(OH)D levels change with season suggested no significant seasonal effects on the transcripts measured (Supplementary table 1). Alterations in gene expression of IDO, ARG and cytokines do not reflect changes in major cell subsets As higher IDO and ARG mRNA levels in CIS and MS patients may be because of a greater percentage of a major cell subset in patient PBMCs, correlations were sought between the relative mRNA expression levels of IDO and ARG and the frequency of CD3+CD4+ and CD3+CD8+ T cells, CD19+CD20+ B cells, CD3−CD56+ NK cells and CD14++ monocytes in PBMCs from HCs and CIS and MS patients. These subsets were chosen because they can represent more than 10% of circulating PBMCs in the groups under analysis and have been shown previously to express significant levels of IDO and ARG.14 No significant associations were observed with any cell population in the three blood donor groups suggesting the increase in IDO and ARG expression observed in CIS and MS was not linked to elevated numbers of a specific cell subset (data not shown). Furthermore, no relationships were observed between cytokine mRNA levels and a PBMC subset (data not shown). Correlations between IDO and ARG expression and numerically less frequent cell subsets were next analysed as those cells may not be expressing the detected enzyme mRNA but may regulate levels of expression by other cells. A positive relationship between the proportion of Treg cells and ARG1 and ARG2 mRNA levels was detected in HCs, but this relationship was not observed in CIS or MS patients (Supplementary table 2). The proportion of CD3−CD56hiCD16lo NK cells (representing approximately 10% NK cells) in PBMCs from CIS patients was associated with greater IDO1 mRNA levels (Supplementary table 2) but is of unknown meaning as this relationship was not detected for the higher IDO1 levels in cells from MS patients (Figure 1). In MS, the proportion of switched memory B cells inversely correlated with IDO1 and IDO2 mRNA expression; however, to our knowledge, a reduction of switched memory B cells has not been reported in MS (Supplementary table 2). These associations were detected, but their meaning remains elusive. No associations were detected with naïve B cells (CD19+CD20+CD27−IgD+CD38−CD24−/+), nonswitched memory B cells (CD19+CD20+CD27+IgD+), CD3−CD56lo CD16hi NK cells, CD14++CD16− classical monocytes, CD14++ CD16+ intermediate monocytes and CD14+ CD16++ nonclassical monocytes. There were some significant correlations between cytokine mRNA levels and the numerically minor cell subsets (Supplementary table 2). This may reflect indirect relationships and/or multiple testing and require further investigations before any conclusions can be drawn. Phototherapy stabilises ARG1 expression CIS patients (all participants in the PhoCIS trial)16, 17 donated blood again 3 months after their first venepuncture. There were no differences in the expression of IDO1, IDO2 and ARG2 mRNA in cells from the participants (Figure 3a, b and d). However, for cells from CIS patients not receiving phototherapy, the expression of ARG1 significantly increased at 3 months compared with their baseline sample (Figure 3c). This result supports higher ARG1 expression by PBMCs from those with MS and that the CIS patients studied were on a trajectory for conversion to MS (all CIS patients not receiving phototherapy converted to MS by 12 months of follow‐up).17 The increase after 3 months from baseline in ARG1 mRNA levels was not observed in the CIS patients that received phototherapy and suggested that the intervention may have stimulated pathways that stabilise ARG1 expression. There were no associations between mRNA for the catabolic enzymes and the cytokines after 3 months, or changes in cytokine mRNA levels between baseline and 3‐month samples (data not shown). IDO1 expression is regulated by extrinsic cues whilst ARG1 expression is intrinsic in MS Next, PBMCs were incubated for 4 h in medium containing low maintenance levels of Trp (0.02 mmol L−1) and Arg (1.15 mmol L−1) but no extracellular activation signals. It was proposed that mRNA levels after 4 h would reflect ongoing endogenous stimulation. The elevated mRNA levels of IDO1 in cells from CIS and MS patients were not detected in their PBMCs after 4 h culture (Figure 4a) and suggested that the increased IDO1 mRNA in cells ex vivo was stimulated by extrinsic cues. In contrast, higher ARG1 mRNA expression in cells from MS patients compared with that in cells from HCs was sustained after culture (Figure 4b). This is further demonstrated in Supplementary table 3, where a significant association was observed between ARG1, but not IDO1 mRNA levels, in cells directly ex vivo and after culture for 4 h. This result suggests an intrinsic change in PBMCs from MS patients for increased ARG1 expression. IDO1 expression is associated with the production of proinflammatory cytokines As no correlations were detected between mRNA levels of cytokine genes and mRNA of IDO and ARG in PBMCs directly ex vivo, associations were sought for PBMCs cultured without stimulation for 4 h. The proinflammatory mediators chosen for study were TNF, IL‐1B, IL‐6 and the enzyme, COX2. PBMCs from MS but not CIS patients expressed significantly higher levels of TNF and COX2 (Figure 5a and d). However, of the levels expressed, mRNA levels of TNF, IL‐1B, IL‐6 and COX2 in all groups of individuals studied, including HCs, positively and significantly correlated with IDO1 mRNA levels (columns for PBMC culture, Table 2). This supported the hypothesis of an association between IDO1 and cytokine expression, particularly when more cytokines may be expressed in MS. ARG1 mRNA did not correlate with mRNA of proinflammatory cytokines, only for COX2 mRNA and only in cells from CIS patients (Table 2). HC CIS MS n 18 17 8 Age in years 38 (26–61) 36 (26–54) 44 (18–54) Male/Female 8/10 7/10 3/5 Days to venepuncture from CIS or MS diagnosis by MRI – 37 (−1 to 119) 6 (0–22) Serum 25(OH)D3 in nmol L−1 nd 91.5 (43.7–135.6) 69.9 (40.8–108.2) nd, not determined. IDO1 expression correlates with IL‐10, but both IDO1 and ARG1 correlate with TGFB mRNA in cultured cells from HCs and CIS patients When mRNA levels for the anti‐inflammatory cytokines, IL‐10 and TGFB, were examined in cultured cells, significantly higher expression was detected for cells from MS patients only (Figure 5e and f). This did not match the pattern detected for PBMCs analysed ex vivo (Figure 2d and e), with the pattern of expression of TGFB mRNA being an inverse of that of cells ex vivo. For all three blood donor groups, mRNA levels of IL‐10 correlated significantly with IDO1 mRNA levels. For TGFB mRNA, correlations with IDO1 were detected only for HCs and CIS patients (columns for PBMC culture, Table 2). ARG1 mRNA levels associated only with TGFB mRNA in cells from HCs and CIS patients (columns for PBMC culture, Table 2). These correlations suggest that, in the absence of strong extrinsic regulators in vivo, the expression of both pro‐ and anti‐inflammatory cytokines and COX2 positively and significantly associated with the expression of IDO in PBMCs. Significant correlations with ARG1 mRNA expression were limited to TGFB. Discussion Greater cellular expression of IDO and ARG has been associated with a homeostatic or normalising response to cellular activation and with degradation of amino acids that would otherwise be available to increase a proinflammatory response. The PBMCs of the MS patients studied had no adverse dampening of the expression of IDO and ARG; such a block may otherwise contribute to disease pathogenesis. There was no correlation in PBMCs ex vivo from HCs and patients with CIS and MS between mRNA levels for IDO and ARG, and expression of pro‐ or anti‐inflammatory cytokine genes. However, there were differences in PBMC mRNA levels for the catabolic enzymes and for cytokines (independently of each other) according to patient disease stage. Emphasis was placed on measures of mRNA directly ex vivo because accurate measures of the translated protein, particularly cytokines which are not stored intracellularly, require culture of the cells in vitro. This study demonstrates the labile nature of cytokine and enzyme mRNA as they can change with cell incubation for 4 h under contrived in vitro conditions. This study confirms that mRNA levels best capture direct ex vivo expression. Greater percentages of a major cell type in PBMCs were not found to be responsible for higher mRNA levels of IDO and ARG in cells from CIS and MS patients. It remains possible that single or multiple cell subsets express increased levels of the enzymes. Both decreases14 and increases20 in ARG1 in monocytes from MS patients have been previously reported. Dysfunction in the pathway downstream of IDO in Trp metabolism has been implicated in MS pathogenesis,21 particularly when IDO‐expressing cells leave the circulation and enter the central nervous system. The kynurenines produced by Trp catabolism may be neuroprotective (kynurenic acid, picolinic acid) or neurotoxic (3‐hydroxykynurenine, quinolinic acid), with dysfunction suggested in MS by greater activity in pathways leading to production of neurotoxic mediators.22 With measurement of greater IDO1 mRNA in cells from patients with CIS, the present study suggests greater flux through the kynurenine pathway early in the MS disease course. Our study suggests that in CIS, lower IL‐10 and TGFB mRNA expression in PBMCs precedes any stimulation of proinflammatory cytokine expression. In cells ex vivo from the CIS patients, mRNA levels of the anti‐inflammatory cytokines, IL‐10 and TGFB, were significantly reduced compared with levels in HCs. There was no expression of the proinflammatory cytokines in CIS. It was only in cells from MS patients that significantly higher IL‐6 mRNA levels were detected. In the established MS patients, IL‐10 mRNA levels were also no longer different to those measured in cells from HCs and suggested a shifted balance towards a more inflammatory cytokine transcriptional signature. In a pattern different to that of IL‐10, mRNA levels for TGFB, already low in CIS individuals, were lower again in PBMCs from MS patients. Low levels of expression of tolerance‐inducing TGFB have been reported in experimental autoimmune encephalomyelitis, the murine model of neuroinflammation used to study MS, with increased expression after treatment with the disease modifier, fingolimod.23 Also, in PBMCs from patients with established disease, TNF mRNA levels are higher and IL‐10 and TGFB levels are lower during relapse, and this balance is inverted during stable disease.24 Cytokine and catabolic enzyme mRNA levels were re‐examined after culture of PBMCs for 4 h, a time frame that is generally longer than the half‐life of mRNA. A 4‐h culture period is also the time popularly used for sensitive detection of cytokines that have accumulated intracellularly after blocking their secretion through the endoplasmic reticulum.25 The differing levels of IL‐10 mRNA in cells ex vivo were not replicated and suggested that during culture, an important external modulating agent was not present. Further, the potency of the modulating agent was highlighted as cells from MS patients now expressed higher IL‐10 mRNA levels. The pattern of TGFB levels in cells from HCs, and CIS and MS patients was also different, further highlighting the strength of an extrinsic TGFB‐suppressive agent in vivo that was not present in culture. When the relationship between cytokine and IDO and ARG expression was reinvestigated after culture, IDO1 and ARG1 mRNA levels in PBMCs ex vivo from HCs and CIS patients did not correlate with levels measured after culture. In PBMCs from the MS patients where levels of expression were greater and associations more likely detected, the increased IDO1 mRNA expression was lost but the higher ARG1 mRNA levels were maintained in PBMCs after culture. This suggested that in the cells of MS patients, the higher IDO1 mRNA levels in PBMCs ex vivo were extrinsically determined but those of ARG1 mRNA levels were determined by intrinsic signals. For cultured cells from all blood donor groups, IDO1 mRNA significantly correlated with levels of TNF, IL‐1B, IL‐6, COX2, IL‐10 and TGFB mRNA (with the exception of TGFB in PBMCs from MS patients). For cultured cells from HCs and CIS (but not MS patients), ARG1 associated positively only with TGFB mRNA levels; this supported an ARG‐TGFB inter‐relationship with Treg induction (Table 2).26 However, in PBMCs from MS patients, this link may be impaired because of ARG1 intrinsic changes described above. Greater ARG1 expression in MS compared with CIS patients was confirmed when PBMCs from 15 patients with CIS were restudied 3 months after their first blood donation. In cells from those who did not receive phototherapy, the levels of expression of ARG1 increased, a rise not measured in PBMCs from those who underwent an 8‐week course of narrowband UVB phototherapy. As increases in ARG expression have been attributed to inflammatory signals,27, 28 narrowband UVB phototherapy may have reduced the expression of those signals. Our study does not support the reduced expression of IDO1 and ARG1 in PBMCs from Argentinian patients with clinically definite, relapsing–remitting MS.14 To explain differences in study outcomes, 62% of the Argentinian cohort were taking IFN‐β1α or glatiramer acetate. Our patients may be genetically different, and IDO and ARG expression may vary with activity or duration of MS. In the Argentinian study, culture of the blood cells also altered IDO1 and ARG1 expression. Increased ARG1 expression in PBMCs from MS patients is supported by a study of macrophages from the blood of disease‐modifying treatment (DMT)‐free patients with established MS.20 These cells expressed increased ARG1 in vitro, and they were more susceptible to activation with an enhanced ability, relative to macrophages from normal people, to skew towards inducible NOS‐ or ARG‐expressing cells in the presence of LPS or IL‐4, respectively.20 In summary, IDO1 and ARG2 mRNA levels were higher in cells from CIS patients relative to HCs. However, they had no association with the significantly lower regulatory cytokine mRNA levels in circulating PBMCs from those with CIS. Only after 4 h in culture, IDO1 expression associated with levels of both pro‐ and anti‐inflammatory cytokines, and ARG1 associated with TGFB mRNA, indicating potential catabolic enzyme–cytokine coregulation. This suggested removal of a suppressive regulator rather than intrinsic changes in the cells and highlights the complexity of regulating immune cells in CIS and MS, and the need to study external factors in serum that may have been produced by disease‐associated nonhaematopoietic cells. This study highlights that in patients with CIS and who are not yet diagnosed as MS, there are already changes to circulating haematopoietic cells that contribute to immune cell dysfunction. Methods Selection of donors of peripheral blood PBMCs were isolated from 17 individuals with CIS and eight with MS. The CIS patients (with clinical symptoms as detailed previously)17 donated blood within 120 days of confirmation of their first demyelinating event by MRI and were at high risk for MS conversion as their MRI satisfied Paty A or Paty B criteria.16, 17, 29 All CIS patients were participants in the PhoCIS trial,16, 17 with their baseline sample included in the present study. Seven of the eight patients with MS had recent clinical symptoms but their MRI showed a diagnosis of MS by 2010 McDonald criteria; that is, their cerebral and/or spinal cord MRI indicated that they had multiple demyelinating lesions separated in time and space.30 Despite subjective recollection of symptoms in past years, only one MS patient had been previously formally diagnosed with MS and that was 7 years before. Blood for PBMC isolation was drawn from that MS patient 20 days after a clinical relapse. At the time of venepuncture, all CIS and MS blood donors had not taken steroids for at least 1 month, or ever received a DMT. PBMCs were also isolated from 18 HCs with no history of autoimmune disease. The demographic data for the groups are displayed in Table 2. The study was approved by the Bellberry Human Research Ethics Committee (2014‐02‐083) and endorsed by the Human Research Ethics Office of the University of Western Australia (RA/4/1/6796). Informed consent was obtained from all blood donors. Narrowband UVB phototherapy intervention The CIS patients were randomly assigned into two groups as previously described.16, 17 One group received narrowband UVB phototherapy (wavelengths 311‐312 nm) 3 times per week for 8 weeks (24 exposures in total) to their full body.16, 17 Blood samples were again collected at 3 months and PBMCs isolated. Baseline and 3‐month paired blood samples were available for enzyme and cytokine mRNA analysis from 15 CIS participants (8 receiving phototherapy and 7 in the no phototherapy (i.e. control) group). The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12614000185662). Isolation of PBMCs for direct RNA isolation or cell culture Peripheral venous blood was collected into lithium heparin tubes (BD Vacutainer Systems, Plymouth, UK) and processed within 1‐2 h. PBMCs were isolated by density gradient centrifugation using Lymphoprep (Axis‐Sheild, Oslo, Norway) and cryopreserved in liquid nitrogen at 5‐10 × 106 cells mL−1 in 10% DMSO/FCS (Sigma‐Aldrich, St Louis, MO, USA) until analysis. Cryopreserved PBMCs were thawed, washed and resuspended at 106 cells mL−1 in RPMI 1640 medium (HyClone; GE Health Care Life Sciences, Logan, UT) supplemented with 10% FCS (HyClone), 5 μg mL−1 gentamicin, 2 mm l‐glutamine and 50 μm 2‐β‐mercaptoethanol (all from Sigma‐Aldrich). For ex vivo PBMC preparation, duplicate samples of 106 cells were pelleted (500 × g, 5 min), then homogenised in 500 μL TRIzol (Life Technologies, Carlsbad, CA) and incubated for 5 min to permit complete dissociation of nucleoproteins. Cell lysates were stored at −80°C until batch processing. For PBMC cultures, 106 cells mL−1 were incubated in medium (as above) at 37°C/5% CO₂ for 4 h. PBMCs were then pelleted, homogenised in TRIzol and stored as previously described. RNA extraction and cDNA synthesis To extract total RNA, a modified TRIzol/RNeasy Mini Kit (Qiagen, Hilden, Germany) protocol was utilised. Chloroform (100 μL; Merck Millipore, Darmstadt, Germany) was added to cell lysates, vigorously mixed and incubated for 2 min. The samples were separated by centrifugation (14 000 g, 5 min at 4°C) and the aqueous layer containing RNA transferred to a new tube and mixed with an equal volume of 70% ethanol. The solution was transferred to a RNeasy spin column and the protocol continued according to the manufacturer's instructions. RNA was quantitated using a Qubit 3.0 (Thermo Fisher Scientific, Waltham, MA), and the absorbance at 260:280 nm was used as a measure of purity (NanoDrop 2000 Spectrophotometer, Thermo Fisher Scientific). All RNA samples were standardised to a concentration of 25 ng μL−1 and reverse‐transcribed to cDNA with the iScript gDNA Clear cDNA Synthesis Kit (Bio‐Rad, Hercules, CA). Quantitative real‐time polymerase chain reaction Synthesised cDNA samples were diluted to 8 ng μL−1 (20 ng total RNA in 2.5 μL per reaction) and combined with 2× SsoAdvanced Universal Probes Supermix (Bio‐Rad), RNase‐free water and the following PrimerPCR Probes all fluorescently labelled with FAM (Bio‐Rad). For analysis of cells ex vivo, probes were for IDO1, IDO2, ARG1, ARG2, nitric oxide synthase 2 (NOS2), TNF, IL‐1B, IL‐6, IL‐10, transforming growth factor beta 1 (TGFB) and UBE2D2. For analysis of cultured cells, probes were for TNF, IL‐1B, IL‐6, IL‐10, TGFB, cyclooxygenase 2 (COX2), IDO1, ARG1 and UBE2D2. UBE2D2 was used as the housekeeping gene because in a comparison with seven other potential housekeeping genes, it was the most stably expressed gene in cell subsets from HCs and those with relapsing–remitting MS.31 All samples were loaded onto a 96‐well plate that contained a nonreverse transcriptase control and a no template control. An aliquot from a large cDNA preparation (frozen as multiple vials) was added to every plate for UBE2D2 measurement and used as a PCR quality control. Levels of PBMC mRNA were determined by RT–PCR performed on a ABI Prism 7900HT sequence detection system (Applied Biosystems, Foster City, CA) with the following cycling conditions: 95°C for 30 s, 40 cycles of amplification at 95°C for 15 s and 60°C for 1 min. Calculating relative gene expression The threshold cycle (CT) values were determined for all genes and exported from SDS software (Applied Biosystems). The CT cut‐off was set to 35 for all genes, and relative gene expression was determined by normalising to the housekeeping gene (ΔCT = gene of interest – UBE2D2). Normalised values of duplicate samples were then averaged and inversely transformed (2(−ΔCT)). Comparison of the PCR quality controls for 26 plates showed a maximum difference of 0.5 CT with a standard deviation of 0.1. All genes were detectable except for NOS2 which was subsequently excluded from analysis. In some samples, IDO2 was below the level of detection and a CT value of 35 was assigned for inclusion. T cell, B cell, NK cell and monocyte subset analysis, and vitamin D measurement The frequencies of major (CD4+ T cells, CD8+ T cells, B cells, NK cells and monocytes) and numerically minor cell subsets (Treg cells, naïve B cells, nonswitched memory B cells, switched memory B cells, CD56loCD16hi NK cells, CD56hiCD16lo NK cells, classical monocytes, intermediate monocytes and nonclassical monocytes) were assessed by flow cytometry in freshly isolated PBMCs from HCs and CIS and MS patients as previously reported.25, 32 Serum levels (25(OH)D3) were measured as previously described.33 Statistical analyses Statistical analyses were performed using SPSS Statistics v25 (IBM Corp., Armonk, NY), and figures were generated in GraphPad Prism v7 (GraphPad Software, La Jolla, CA). Nonparametric tests were conducted to determine statistical significance. Wilcoxon matched pairs tests were used to compare baseline and 3‐month results within groups, and Kruskal–Wallis and Mann–Whitney tests were used to compare results between blood donor groups. Correlation coefficients were calculated with Spearman's tests. P values < 0.05 were considered statistically significant. Conflict of interest The authors declare no conflict of interest. Acknowledgments This work was supported by the National Health and Medical Research Council of Australia (ID 1067209) and MS Western Australia. Drs AP Jones, S Trend and MJ Fabis‐Pedrini were supported by MS Western Australia and Professor RM Lucas by a National Health and Medical Research Council of Australia Senior Research Fellowship. We thank the willing CIS and MS patients who participated in this study without whom this study was not possible. Supporting Information References
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A new roadmap for repairing the damage of multiple sclerosis – Patient Talk

A new roadmap for repairing the damage of multiple sclerosis – Patient Talk | Multiple sclerosis New Drugs Review | Scoop.it
Research published today in the journal Nature provides new understanding about how drugs can repair damaged brain cells that cause disability in patients with multiple sclerosis. Led by researchers at Case Western Reserve University School of Medicine, the study suggests new drug targets and potent early-stage drug candidates could lead to regenerative medicines for multiple sclerosis and other debilitating neurological diseases. Multiple sclerosis, a chronic and progressive disease affecting millions worldwide, is characterized by damage to the protective sheath that surrounds nerve cells. Without this insulating layer, called myelin, nerve cells in the brain and spinal cord struggle to transmit electrical impulses. As a result, multiple sclerosis patients suffer progressive loss of motor skills, vision and balance. The new study describes how drugs work to replenish myelin destroyed by multiple sclerosis. While the brain is known to have some capacity to regenerate new myelin during the early stages of multiple sclerosis, this innate repair process is overwhelmed as the disease progresses. “Many labs, including at Case Western Reserve, had identified drug candidates that kickstart the formation of new myelin, but exactly how each of these molecules affected brain cell function wasn’t clear,” said Drew Adams, PhD, the Thomas F. Peterson, Jr. Professor of Novel Therapeutics and assistant professor of genetics and genome sciences at Case Western Reserve University School of Medicine. “We were shocked to find that almost all of these previously identified molecules share the ability to inhibit specific enzymes that help to make cholesterol. This insight reorients drug discovery efforts onto these novel, druggable targets.” This study builds on prior work by co-author Paul Tesar, PhD, the Dr. Donald and Ruth Weber Goodman Professor of Innovative Therapeutics and associate professor of genetics and genome sciences at Case Western Reserve University School of Medicine. In work reported in 2015 in Nature, Tesar identified a drug typically used to treat athlete’s foot, called miconazole, as a potent enhancer of new myelin. In the current study, teams led by Adams and Tesar demonstrated that miconazole enhanced myelin formation by inhibiting an enzyme used by brain stem cells to produce cholesterol. Subsequent experiments identified more than 20 new drugs that enhance myelin formation by inhibiting closely-related cholesterol-producing enzymes. Surprisingly, drugs identified previously by labs across the world as enhancing new myelin also inhibited these same enzymes. “The idea that almost all drug candidates that promote myelin repair inhibit the same enzyme targets represents a bold new paradigm for the field and may redirect the course of ongoing drug discovery efforts,” said Tesar. Normally, cellular pathways are crisscrossed, complex diagrams. But cholesterol biosynthesis is linear, said Adams, who is also a Mount Sinai Scholar. “There is only one way in, and one way out. So when you block enzymes in the cholesterol pathway, the metabolites simply accumulate.” In the Adams laboratory, lead authors Zita Hubler and Dharmaraja Allimuthu, PhD, could detect distinct cholesterol intermediaries as they accumulated, allowing them to pinpoint which enzymes were being blocked by which drugs. Notably, several drugs accelerated myelin repair in mouse models of multiple sclerosis. Mouse experiments were performed in collaboration with Robert H. Miller, PhD, the Vivian Gill Distinguished Research Professor and professor of anatomy and cell biology at the George Washington University School of Medicine and Health Sciences. To measure the formation of human myelin in the laboratory, the team used a new three-dimensional nerve cell culture model that closely mimics human brain tissue. Here too, the drug candidates promoted human myelin formation by blocking cholesterol pathway enzymes. A study describing this innovative model, developed in Tesar’s laboratory, was also published today in Nature Methods. “Together these studies provide new drug targets, new drug candidates, and new cholesterol pathway biomarkers to propel the development of medicines that can replenish lost myelin in patients with multiple sclerosis and related diseases,” said Adams. While clinical candidates based on this work are not expected to enter clinical trials until 2019, say the authors, the new understanding of myelin repair provides a promising new path toward novel, regenerative multiple sclerosis treatments. ### Adams, Tesar, and Miller collaborated with researchers from Ludwig-Maximilians University of Munich, Germany; Rice University; Leiden University Medical Center, Netherlands; and the Case Western Reserve University School of Medicine Department of Pediatrics for the study. Hubler, et. al. “Accumulation of 8,9-unsaturated sterols drives oligodendrocyte formation and remyelination.” Nature. This research was supported by grants from the National Institutes of Health, Conrad N. Hilton Foundation, and Mt. Sinai Health Care Foundation. Philanthropic support was generously provided by the Peterson, Fakhouri, Long, Goodman, Geller, Judge, and Weidenthal families. For more information about the Adams and Tesar laboratories, please visit: genetics.case.eduand tesarlab.case.edu. For more information about Case Western Reserve University School of Medicine, please visit: case.edu/medicine.
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The hippocampus in multiple sclerosis

The hippocampus in multiple sclerosis | Multiple sclerosis New Drugs Review | Scoop.it
Some of the clinical manifestations of multiple sclerosis, such as memory impairment
and depression, are, at least partly, related to involvement of the hippocampus. Pathological studies have shown extensive demyelination, neuronal damage, and synaptic abnormalities in the hippocampus of patients...
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Protein structures guide the design of a much-needed tool for neuroscience

Protein structures guide the design of a much-needed tool for neuroscience | Multiple sclerosis New Drugs Review | Scoop.it
The structures of anion-conducting channelrhodopsin proteins have been solved and used to develop a tool for optogenetics. Experts discuss what the structures tell us about ion conduction, and why the tool is needed.
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Cholinergic and purinergic systems: A key to multiple sclerosis? - ScienceDirect

Cholinergic and purinergic systems: A key to multiple sclerosis? - ScienceDirect | Multiple sclerosis New Drugs Review | Scoop.it
Highlights

Influence of cholinergic and purinergic systems in multiple sclerosis


Involvement of purinergic signaling in the sequence of events leading to MS/EAE


Cholinergic signaling could contribute to inflammatory and immune responses in MS.


Better understanding MS immune response can improve patient healthcare.


Interaction between the cholinergic and purinergic systems can be important in MS.
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The intestinal barrier in multiple sclerosis: implications for pathophysiology and therapeutics. - The Microbiome

The intestinal barrier in multiple sclerosis: implications for pathophysiology and therapeutics. - The Microbiome | Multiple sclerosis New Drugs Review | Scoop.it
PubMed ID: 29860380 Camara-Lemarroy CR, Metz L, Meddings JB, Sharkey KA, Wee Yong V Brain. Jul 2018. doi: 10.1093/brain/awy131 COMMENT: This review is focused on the role that the gut microbiome and the intestinal barrier could play in the pathophysiology of multiple sclerosis. In several works it has been reported that some gastrointestinal disorders with intestinal barrier breakdown show evidence of CNS demyelination, probably due to the impact on the functions of CNS microglia that the microbial organisms entering in the circulation provoke. The authors highlight the importance of the intestinal barrier and the mucosal immune cells in the brain-gut axis and describe this host-microbiome interface as a crucial zone of interaction between immune cells and microbial cells: In this review, we describe the intestinal barrier as the physical and functional zone of interaction between the luminal microbiome and the host. Besides its essential role in the regulation of homeostatic processes, the intestinal barrier contains the gut mucosal immune system, a guardian of the integrity of the intestinal tract and the whole organism. Barrier-stabilizing strategies of treatment for multiple esclerosis as probiotics and stabilizers of tight junctions are discussed along the review and proposed as new therapeutic possibilities for multiple esclerosis.   Contributor Raquel Tobes
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B-cell composition in the blood and cerebrospinal fluid of multiple sclerosis patients treated with dimethyl fumarate

B-cell composition in the blood and cerebrospinal fluid of multiple sclerosis patients treated with dimethyl fumarate | Multiple sclerosis New Drugs Review | Scoop.it
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NICE reject ocrelizumab for people with primary progressive MS | Multiple Sclerosis Society UK

NICE reject ocrelizumab for people with primary progressive MS | Multiple Sclerosis Society UK | Multiple sclerosis New Drugs Review | Scoop.it
NICE have decided not to recommend ocrelizumab for primary progressive MS.Take action to...
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Neurofilaments as biomarkers in neurological disorders

Neurofilaments as biomarkers in neurological disorders | Multiple sclerosis New Drugs Review | Scoop.it
Key points
Neuronal damage and loss are the pathological substrates of permanent disability in various acute and chronic neurological disorders.

Levels of neurofilament proteins increase in cerebrospinal fluid (CSF) and in the blood upon neuroaxonal damage.

First-generation (immunoblot) and second-generation (enzyme-linked immunosorbent assay) neurofilament assays captured only the tip of the iceberg in disease.

Third-generation (electrochemiluminescence) and fourth-generation (single-molecule array) assays permit highly sensitive, longitudinal detection of blood neurofilament levels even in mild disease and in healthy controls.

Multicentre studies are underway to consolidate neurofilaments as biomarkers that reflect brain tissue damage, enabling longitudinal monitoring of disease activity and drug effects in clinical trials in neurological diseases.
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Multiple Sclerosis | NEJM

Multiple Sclerosis | NEJM | Multiple sclerosis New Drugs Review | Scoop.it
Multiple sclerosis affects more than 2 million people worldwide and is currently incurable. A number of interventions to modify the course of multiple sclerosis have been developed that offer new insight into disease mechanisms.
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B cells among factors leading to brain lesions in multiple sclerosis | EurekAlert! Science News

B cells among factors leading to brain lesions in multiple sclerosis | EurekAlert! Science News | Multiple sclerosis New Drugs Review | Scoop.it
A team of researchers from UZH and USZ has shown that in multiple sclerosis, it is not only specific T cells that cause inflammation and lesions in the brain. B cells, a different type of immune cell, also play a role.
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Study suggests potential of new therapy for progressive multiple sclerosis

Study suggests potential of new therapy for progressive multiple sclerosis | Multiple sclerosis New Drugs Review | Scoop.it
NIH-funded trial offers hope for disease with limited treatment options.
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Pharmacological treatment for memory disorder in multiple sclerosis - He, D - 2013 | Cochrane Library

Pharmacological treatment for memory disorder in multiple sclerosis - He, D - 2013 | Cochrane Library | Multiple sclerosis New Drugs Review | Scoop.it
Cochrane Database of Systematic Reviews Abstract available in Background This is an update of the Cochrane review "Pharmacologic treatment for memory disorder in multiple sclerosis" (first published in The Cochrane Library 2011, Issue 10). Multiple sclerosis (MS) is a chronic immune‐mediated, inflammatory, demyelinating, neurodegenerative disorder of the central nervous system (CNS) and can cause both neurological and neuropsychological disability. Both demyelination and axonal and neuronal loss are believed to contribute to MS‐related cognitive impairment. Memory disorder is one of the most frequent cognitive dysfunctions and presents a considerable burden to people with MS and to society due to the negative impact on function. A number of pharmacological agents have been evaluated in many existing randomised controlled trials for their efficacy on memory disorder in people with MS but the results were not consistent. Objectives To assess the absolute and comparative efficacy, tolerability and safety of pharmacological treatments for memory disorder in adults with MS. Search methods We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Trials Register (24 July 2013), PsycINFO (January 1980 to 26 June 2013) and CBMdisc (1978 to 24 June 2013), and checked reference lists of identified articles, searched some relevant journals manually, registers of clinical trials and published abstracts of conference proceedings. Selection criteria All double‐blind, randomised controlled parallel trials on pharmacological treatment versus placebo or one or more pharmacological treatments in adults with MS who had at least mild memory impairment (at 0.5 standard deviations below age‐ and sex‐based normative data on a validated memory scale). We placed no restrictions regarding dose, route of administration and frequency; however, we only included trials with an administration duration of 12 weeks or greater. Data collection and analysis Two review authors independently assessed trial quality and extracted data. We discussed disagreements and resolved them by consensus among review authors. We contacted principal investigators of included studies for additional data or confirmation. Main results We included seven randomised controlled trials (RCTs) involving 625 people mostly with relapsing‐remitting, secondary‐progressive and primary‐progressive MS, evaluating the absolute efficacy of donepezil, ginkgo biloba, memantine and rivastigmine versus placebo in improving memory performance with diverse assessment scales. Overall, clinical and methodological heterogeneities existed across these studies. Moreover, most of them had methodological limitations on non‐specific selections of targeted sample, non‐matched variables at baseline or incomplete outcome data (high attrition bias). Only the two studies on donepezil had clinical and methodological homogeneity and relatively low risks for bias. One RCT evaluating estriol versus placebo is currently ongoing. We could not carry out a meta‐analysis due to the heterogeneities across studies and the high attrition bias.

 

 

 

 

 

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Ocrelizumab: A Review in Multiple Sclerosis

Ocrelizumab: A Review in Multiple Sclerosis | Multiple sclerosis New Drugs Review | Scoop.it
Abstract
Ocrelizumab (Ocrevus®) is a humanized anti-CD20 monoclonal antibody approved for the treatment of adults with relapsing multiple sclerosis (RMS) or primary progressive multiple sclerosis (PPMS). In the two identically designed, 96-week OPERA I and II trials in patients with RMS, ocrelizumab significantly reduced annualized relapse rates versus interferon β-1a. In the ≥ 120-week ORATORIO trial in patients with PPMS, ocrelizumab significantly reduced the risk of ≥ 12-week confirmed disability progression relative to placebo. These primary endpoint results were supported by a number of secondary outcomes, including disease activity in the brain assessed by magnetic resonance imaging. Ocrelizumab was generally well tolerated in these studies, with infusion-related reactions and infections being the most common adverse events, which were mostly mild to moderate in severity. In summary, ocrelizumab is a novel high-efficacy disease-modifying therapy for RMS that is more effective than interferon β-1a and also a valuable new treatment option for delaying progression in early PPMS. It offers a convenient once every 6 months treatment regimen, with no need for routine monitoring.
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