Understanding Autoimmune Mechanisms in Multiple Sclerosis Using Gene Expression Microarrays: Treatment Effect and Cytokine-related Pathways

Multiple sclerosis (MS) is a central nervous system disease in which activated autoreactive T-cells invade the blood brain barrier and initiate an inflammatory response that leads to myelin destruction and axonal loss. The etiology of MS, as well as the mechanisms associated with its unexpected onset, the unpredictable clinical course spanning decades, and the different rates of progression leading to disability over time, remains an enigma. We have applied gene expression microarrays technology in peripheral blood mononuclear cells (PBMC) to better understand MS pathogenesis and better target treatment approaches. A signature of 535 genes were found to distinguish immunomodulatory treatment effects between 13 treated and 13 untreated MS patients. In addition, the expression pattern of 1109 gene transcripts that were previously reported to significantly differentiate between MS patients and healthy subjects were further analyzed to study the effect of cytokine-related pathways on disease pathogenesis. When relative gene expression for 26 MS patients was compared to 18 healthy controls, 30 genes related to various cytokine-associated pathways were identified. These genes belong to a variety of families such as interleukins, small inducible cytokine subfamily and tumor necrosis factor ligand and receptor. Further analysis disclosed seven cytokine-associated genes within the immunomodulatory treatment signature, and two cytokine-associated genes SCYA4 (small inducible cytokine A4) and FCAR (Fc fragment of IgA, CD89) that were common to both the MS gene expression signature and the immunomodulatory treatment gene expression signature. Our results indicate that cytokine-associated genes are involved in various pathogenic pathways in MS and also related to immunomodulatory treatment effects

A personalized, intense physical rehabilitation program improves walking in people with multiple sclerosis presenting with different levels of disability: A retrospective cohort

Copyright © 2015 Kalron et al.Background: People with multiple sclerosis (PwMS) endure walking limitations. To address this restriction, various physical rehabilitation programs have been implemented with no consensus regarding their efficacy. Our objective was to report on the efficacy of an integrated tailored physical rehabilitation program on walking in people with multiple sclerosis categorized according to their level of neurological disability. Methods: Retrospective data were examined and analyzed. Specifically, data obtained from all patients who participated in the Multiple Sclerosis Center's 3 week rehabilitation program were extracted for in depth exploration. The personalized rehabilitation program included three major components modified according to the patient's specific impairments and functional needs: (a) goal directed physical therapy (b) moderately intense aerobic exercise training on a bicycle ergometer and (c) aquatic therapy chiefly oriented to body structures appropriate to movement. Gait outcome measurements included the 10 meter, 20 meter, Timed up and go and 2 minute walking tests measured pre and post the rehabilitation program. Three hundred and twelve people with relapsing-remitting multiple sclerosis were included in the final analysis. Patients were categorized into mild (n = 87), moderate (n = 104) and severely (n = 121) disabled groups. Results: All clinical walking outcome measurements demonstrated statistically significant improvements, however, only an increase in the 2 minute walking test was above the minimal clinical difference value. The moderate and severe groups considerably improved compared to the mild gait disability group. Mean change scores (%) of the pre-post intervention period of the 2 minute walking test were 19.0 (S.E. = 3.4) in the moderate group, 16.2 (S.E. = 5.4) in the severe group and 10.9 (S.E. = 2.3) in the mild gait disability group. Conclusions: We presented comprehensive evidence verifying the effects of an intense goal-directed physical rehabilitation program on ambulation in people with multiple sclerosis presenting with different neurological impairment levels

New Precision Orbits of Bright Double-Lined Spectroscopic Binaries. I: RR Lyncis, 12 Bootis, and HR 6169

Radial velocities from the 2.1 m telescope at McDonald Observatory supplemented with radial velocities from the coude' feed telescope at KPNO provide new precise orbits for the double-lined spectroscopic binaries RR Lyn (A3/A8/A6), 12 Boo (F8IV), and HR 6169 (A2V). We derive orbital dimensions and minimum masses with accuracies of 0.06 to 0.9 %. The three systems, which have V magnitudes of 5.54, 4.83, and 6.42, respectively, are all sufficiently bright that they are easily within the grasp of modern optical interferometers and so afford the prospect, when our spectroscopic observations are complemented by interferometric observations, of fully-determined orbits, precise masses, and distances. In the case of RR Lyn, which is also a detached eclipsing binary with a well-determined orbital inclination, we are able to determine the semimajor axis of the relative orbit, a = 29.32 +/- 0.04 Rsun, primary and secondary radii of 2.57 +/- 0.02 Rsun and 1.59 +/- 0.03 Rsun, respectively; and primary and secondary masses of 1.927 +/- 0.008 Msun and 1.507 +/- 0.004 Msun, respectively. Comparison of our new systemic velocity determination, gamma = -12.03 +/- 0.04 km/s, with an earlier one, gamma = -11.61 +/- 0.30 km/s, shows no evidence of any change in the systemic velocity in the 40 years separating the two measurements, a null result that neither confirms nor contradicts the presence of the low-mass third component proposed by Khaliullin & Khaliullina (2002). Our spectroscopic orbit of 12 Boo is more precise that that of Boden et al. (2005), but confirms their results about this system. Our analysis of HR 6169 has produced a major improvement in its orbital elements. The minimum masses of the primary and secondary are 2.20 +/- 0.01 and 1.64 +/- 0.02 Msun, respectively.Comment: To appear in the May A

Supplementary Material for: Radiological Disease Activity in Secondary Progressive Multiple Sclerosis

Introduction: MRI activity is less frequent among secondary progressive multiple sclerosis (SPMS) patients. In the current study, we aimed to identify SPMS patients with higher radiological disease activity (RDA) and determine their clinical characteristics. Methods: We evaluated the occurrence of RDA in SPMS patients followed at the Sheba Multiple Sclerosis Center between January 1, 2015, and December 31, 2020. All patients underwent brain and spinal cord MRI examinations as a routine follow-up unrelated to clinical disease activity. Patients were subdivided into RDA and non-RDA MRI groups based on the presence of active gadolinium-enhancing T1 lesions and/or new/enlarging T2 lesions. Demographic variables and disease-related data were compared. Results: One hundred consecutive SPMS patients, 74 females, median age of 50 years, disease duration of 19.5 years, and neurological disability by the Expanded Disability Status Scale (EDSS) score of 6.0, were included in the study. The RDA group comprised 35 patients (35%), of them 65.7% (n = 23) exhibited only brain MRI activity, 22.8% (n = 8) only spinal cord MRI activity, and 11.4% (n = 4) had both. Patients in the RDA group were diagnosed at a younger mean (SD) age of 28.2 (8.9) versus 33.7 (10.1) years and were younger with a mean (SD) age of 47.8 (9.9) versus 53.4 (10.1) years, as compared with the non-RDA group. No significant differences were found in relation to disease duration, EDSS, exposure to immunomodulatory treatments, and duration of immunomodulatory treatments. Conclusions: RDA unrelated to clinical symptomatology was more frequent in a subgroup of young SPMS patients

Intravenous immunoglobulin treatment following the first demyelinating event suggestive of multiple sclerosis: A randomized, double-blind, placebo-controlled trial

Intravenously administered immunoglobulin (IVIg) treatment has been reported to be beneficial in the treatment of patients with relapsing-remitting multiple sclerosis. The goal of this study was to evaluate the effect of IVIg treatment in patients after the first neurological event suggestive of demyelinative disease. The authors conducted a randomized, placebo-controlled, double-blind study in 91 patients enrolled within the first six weeks of neurological symptoms. All patients had an abnormal MRI. Patients were randomly assigned to receive IVIg treatment (2-g/kg loading dose) or placebo, with boosters (0.4 g/kg) given once every six weeks for one year. Neurological and clinical assessments were done every three months, and brain magnetic resonance imaging was performed at baseline and the end of the study (one year).The cumulative probability of developing clinically definite multiple sclerosis was significantly lower in the IVIg treatment group compared with the placebo group (rate ratio, 0.36 [95% confidence interval, 0.15-0.88]; P = .03). Patients in the IVIg treatment group had a significant reduction in the volume and number of T2-weighted lesions and in the volume of gadolinium-enhancing lesions as compared with the placebo group (P = .01, P = .01, and P = .03, respectively). Treatment was well tolerated, compliance was high, and incidence of adverse effects did not differ significantly between groups. The authors conclude that IVIg treatment for the first year from onset of the first neurological event, suggestive of demyelinative disease, significantly lowers the incidence of a second attack and reduces disease activity as measured by brain magnetic resonance imaging

Natalizumab plus interferon beta-1a for relapsing multiple sclerosis

.AbstractBackgroundInterferon beta is used to modify the course of relapsing multiple sclerosis. Despiteinterferon beta therapy, many patients have relapses. Natalizumab, an α4 integrinantagonist, appeared to be safe and effective alone and when added to interferonbeta-1a in preliminary studies.MethodsWe randomly assigned 1171 patients who, despite interferon beta-1a therapy, hadhad at least one relapse during the 12-month period before randomization to receivecontinued interferon beta-1a in combination with 300 mg of natalizumab (589patients) or placebo (582 patients) intravenously every 4 weeks for up to 116 weeks.The primary end points were the rate of clinical relapse at 1 year and the cumulativeprobability of disability progression sustained for 12 weeks, as measured by theExpanded Disability Status Scale, at 2 years.ResultsCombination therapy resulted in a 24 percent reduction in the relative risk of sustaineddisability progression (hazard ratio, 0.76; 95 percent confidence interval, 0.61to 0.96; P = 0.02). Kaplan–Meier estimates of the cumulative probability of progressionat two years were 23 percent with combination therapy and 29 percent withinterferon beta-1a alone. Combination therapy was associated with a lower annualizedrate of relapse over a two-year period than was interferon beta-1a alone (0.34vs. 0.75, P<0.001) and with fewer new or enlarging lesions on T2-weighted magneticresonance imaging (0.9 vs. 5.4, P<0.001). Adverse events associated with combinationtherapy were anxiety, pharyngitis, sinus congestion, and peripheral edema.Two cases of progressive multifocal leukoencephalopathy, one of which was fatal,were diagnosed in natalizumab-treated patients.ConclusionsNatalizumab added to interferon beta-1a was significantly more effective than interferonbeta-1a alone in patients with relapsing multiple sclerosis. Additional researchis needed to elucidate the benefits and risks of this combination treatment.(ClinicalTrials.gov number, NCT00030966.