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Background: People with multiple sclerosis (MS) present varying degrees of disability throughout their disease course. The Multiple Sclerosis Severity Score (MSSS) and the Age-Related Multiple Sclerosis Severity Score (ARMSSS) adjust the Expanded Disability Status Scale (EDSS) according to disease duration and age, respectively. These measures could be useful for quantifying MS severity and as health outcome indicators for benchmarking in population-based settings. The aim of this study was to describe the severity of MS in our health district using the MSSS and ARMSSS and to assess their consistency over time. Methods: This population-based study included patients from our health district who were diagnosed with MS according to the 2010 McDonald criteria, had a disease duration of at least one year and were followed up in our MS unit. Sex, age at onset, disease duration, clinical course, age and irreversible EDSS at the last follow-up visit were collected, and the MSSS and ARMSSS were calculated at two time points: 2017 and 2020. Results: One hundred seventy-seven patients were included in 2017, and 208 in 2020. The prevalence of MS was 90 and 104 per 100,000 inhabitants, respectively. The median MSSS was 1.77 (IQR 0.76–4.28) in 2017 and 2.03 (IQR 0.82–4.36) in 2020. The median ARMSSS was 2.90 (IQR 1.47–5.72) in 2017 and 2.93 (IQR 1.51–5.56) in 2020. No significant differences were found. Conclusions: According to the MSSS and ARMSSS, the severity of MS in our area is mild, and these instruments are consistent. These measures could be reliable health outcome measures. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is a common chronic autoimmune disease of the central nervous system. In MS, disability progresses unpredictably. Dopamine (DA) is a modulator of immune functions, and compelling evidence supports its involvement in both pathogenesis and treatment of MS. Although single nucleotide polymorphisms (SNPs) in dopaminergic receptor (DR) genes have been extensively studied, their role in MS progression remains unexplored. Therefore, the aim of this explorative study is to investigate the potential association between functional SNPs in DR genes and MS progression. Methods: Caucasian patients with relapsing–remitting (RR) MS were enrolled, and disease progression assessed by the Multiple Sclerosis Severity Score (MSSS). Results: Out of the 59 RRMS patients enrolled, those with the G/G genotype for rs6280 and rs1800828 SNPs in DRD3 showed significantly higher MSSSs compared to those with ancestral and heterozygous genotypes. Conclusions: If confirmed in a larger prospective study, the reported findings could contribute to a better understanding of MS pathophysiological mechanisms, opening the way for the identification of marker(s) for assessing MS progression as well as novel therapeutic strategies. A personalized approach to MS management has the potential to improve the overall well-being of MS patients and alleviate the burden on their caregivers. [ABSTRACT FROM AUTHOR]

Introduction: The visual system is a prominent site of damage in MS since the earliest phases of the disease. Altered low-contrast visual acuity (LCVA) test has been associated with visual impairment and retinal degeneration, predicting medium- and long-term disability. However, it is unclear whether LCVA may also represent a reliable measure of neuroinflammation and a predictor of disease evolution in the very early stages of MS. Methods: We explored in a group of 76 consecutive newly diagnosed relapsing-- remitting MS (RR-MS) patients without visual impairment or altered visual evoked potentials, the association between LCVA scores at 2.5% and 1.25% and clinical characteristics, including prospective disability evaluated after 1- and 2 years of follow-up. Associations between LCVA and the CSF levels of IL-10 at diagnosis were also analyzed. Results: A negative correlation was found between LCVA at 2.5% and Expanded Disability Status Scale (EDSS) evaluated at first (Spearman's Rho= -0.349, p =0.005, n =62) and second year (Spearman's Rho= -0.418, p <0.001, n =62) of follow-up, and negative correlations were found with Multiple Sclerosis Severity Score (MSSS) at first (Spearman's Rho= -0.359, p =0.004, n =62) and second year (Spearman's Rho= -0.472, p <0.001, n=62). All the data were confirmed by a mixed effect model, considering other clinical variables. A positive correlation was found between the CSF concentrations of IL-10 and LCVA at 2.5% (Spearman's Rho=0.272, p =0.020, n =76), and 1.25% (Spearman's Rho, = 0.276, p =0.018, n=76), also evidenced in a linear regression. Discussion: In MS patients at diagnosis, altered LCVA may be associated with CSF inflammation and represent a useful parameter to identify patients with worse disease course. [ABSTRACT FROM AUTHOR]

The Mediterranean Diet (MD) is described in the literature as a beneficial dietary pattern for neurodegenerative diseases such as Multiple Sclerosis (MS). The objective of this study was to evaluate the dietary habits in people with MS (pwMS) and to test whether adherence to the MD could have an impact on the severity of the disease measured as the MS severity score (MSSS). Adherence to the MD was assessed in 31 PwMS using the Mediterranean Diet Adherence Screener (MEDAS), the Pyramid-based Mediterranean Diet Score (PyrMDS) index, and the Italian Mediterranean Index (IMI), and their eating habits were recorded in a food diary for a one-year follow-up. When data obtained from dietary analysis were compared to the MSSS, results showed that pwMS with lower MSSS adhere more to the MD than the other pwMS groups according to the MEDAS index. Furthermore, a high consumption of fiber in the MS mild severity class was observed. Further studies are needed to clarify which of the nutritional components of the MD may impact the course of MS and if the sensitization of pwMS to MD adherence can be a strategy for mitigating the disease. [ABSTRACT FROM AUTHOR]

IntroductionThe visual system is a prominent site of damage in MS since the earliest phases of the disease. Altered low-contrast visual acuity (LCVA) test has been associated with visual impairment and retinal degeneration, predicting medium- and long-term disability. However, it is unclear whether LCVA may also represent a reliable measure of neuroinflammation and a predictor of disease evolution in the very early stages of MS.MethodsWe explored in a group of 76 consecutive newly diagnosed relapsing–remitting MS (RR-MS) patients without visual impairment or altered visual evoked potentials, the association between LCVA scores at 2.5% and 1.25% and clinical characteristics, including prospective disability evaluated after 1- and 2 years of follow-up. Associations between LCVA and the CSF levels of IL-10 at diagnosis were also analyzed.ResultsA negative correlation was found between LCVA at 2.5% and Expanded Disability Status Scale (EDSS) evaluated at first (Spearman’s Rho = −0.349, p = 0.005, n = 62) and second year (Spearman’s Rho = −0.418, p

Abstract Background The role of adipokines such as leptin and adiponectin in regulating the immunity has been documented, however data concerning their consequence on multiple sclerosis (MS) Egyptian patients are deficient. The aim of this study is to demonstrate the serum levels of leptin and adiponectin in MS patients and to assess their association with disease disability and severity. A case–control study including 60 subjects (30 MS patients and 30 age, sex and body mass index-matched healthy controls) was performed. Results Serum leptin level was significantly higher among MS patients than controls (P

Background: This study aimed to explore the possible association of single nucleotide polymorphisms (SNPs) in the upstream (rs9402373) and downstream regions (rs9399005 and rs12526196) of the gene encoding connective tissue growth factor (CTGF/CCN2) with relapsing–remitting multiple sclerosis (RRMS) risk and clinical parameters including disability scores and rate of disability progression. Materials and methods: In total, 200 patients with RRMS and 305 controls were genotyped using real-time PCR (rs1252696 C/T and rs9402373 G/C) or PCR–RFLP (rs9399005 C/T) methods. Furthermore, the association between these genotypes and clinical parameters including Expanded Disability Status Scale (EDSS) score, Multiple Sclerosis Severity Score (MSSS), age at onset, duration of disease, duration of treatment, and presence of contrast-enhancing lesions was analyzed. Results: rs9399005 genotypes TT and CT in the dominant model were significant predictors of RRMS vs. control status by logistic regression analysis (OR = 1.45, 95% CI = 1.01–2.08, P =.04). Moreover, these genotypes for rs9399005 were associated with a MSSS ≥ 2.4 (OR = 3.54, 95% CI = 1.56–8.05, P =.003). In addition, MSSS was lower in patients who had at least one rs12526196C allele than in the corresponding patients with the TT genotype (P =.02). Conclusion: To our knowledge, this is the first evidence of the involvement of variants around the CTGF gene in MS risk and disability progression. [ABSTRACT FROM AUTHOR]

Background: The role of adipokines such as leptin and adiponectin in regulating the immunity has been documented, however data concerning their consequence on multiple sclerosis (MS) Egyptian patients are deficient. The aim of this study is to demonstrate the serum levels of leptin and adiponectin in MS patients and to assess their association with disease disability and severity. A case–control study including 60 subjects (30 MS patients and 30 age, sex and body mass index-matched healthy controls) was performed. Results: Serum leptin level was significantly higher among MS patients than controls (P < 0.001) while adiponectin was not significantly elevated in MS patients (P = 0.24). There was a significant positive correlation between leptin levels with MS disability (Expanded Disability Status Scale) (r = 0.678; P < 0.001), severity (Multiple Sclerosis Severity Score) (r = 0.631; P < 0.001) and progression (progression index) (r = 0.461; P = 0.01). There was no statistically significant correlation between adiponectin with disease disability, severity or progression. Conclusions: MS patients had significantly higher serum leptin levels and insignificant adiponectin levels compared to controls. Leptin has a potential role in multiple sclerosis disability and severity. However, adiponectin is not useful as a biomarker of MS disease, disability and severity. [ABSTRACT FROM AUTHOR]

• Expanded disability status scale (EDSS) is limited when utilized in highly disabled people with multiple sclerosis (pwMS). • This study explores the utility of multiple disability MS scales for assessment of severely affected pwMS. • The scripps neurological rating scale (SNRS) and combinatorial weight-adjusted disability score (CombiWISE) provide dynamic and greater spread of scores for disability assessment. • SNRS and CombiWISE significantly reduce the clinic-radiological gap in severely-affected pwMS. Expanded Disability Status Scale (EDSS) is limited when utilized in highly disabled people with multiple sclerosis (pwMS). To explore the relationship between disability measures and MRI outcomes in severely-affected pwMS. PwMS recruited from The Boston Home (TBH), a specialized residential facility for severly-affected pwMS and University at Buffalo (UB) MS Center were assessed using EDSS, MS Severity Scale, age-related MSS, Scripps Neurological Rating Scale (SNRS) and Combinatorial Weight-Adjusted Disability Score (CombiWISE). In all scores except SNRS, higher score indicates greater disability. MRI measures of T1, T2-lesion volume (LV), whole brain, gray matter, medulla oblongata and thalamic volumes (WBV, GMV, MOV, TV) and thalamic dysconnectivity were obtained. Greatest disability differences between the TBH and UB pwMS were in SNRS (24.4 vs 71.9, p < 0.001, Cohen's d = 4.05) and CombiWISE (82.3 vs. 38.9, p < 0.001, Cohen's d = 4.02). In combined analysis of all pwMS, worse SNRS scores were correlated with worse MRI pathology in 8 out of 9 outcomes. EDSS only with 3 measures (GMV, MOV and TV). In severely-affected pwMS, SNRS was associated with T1-LV, T2-LV and WBV (not surviving false discovery rate (FDR) correction for multiple comparisons) whereas EDSS did not. Granular and dynamic disability measures may bridge the clinico-radiologcal gap present in severely affected pwMS. [ABSTRACT FROM AUTHOR]

The aim of the current study is to determine and analyze the prevalence among forestry workers of self-reported musculoskeletal disorder symptoms (MSSs) in specific areas of the body. The Standardized Nordic Questionnaire (SNQ) was used, which was specifically modified and adapted for the assessment of lower back, neck, and shoulder symptoms. The questionnaire was completed by 100 professional forestry workers, who were divided into four groups according to their distinct work duties. Almost 50% of the participants reported that they had experienced some kind of problem in their lower back, neck or shoulder at least once during their entire professional life. The results also show that forestry workers who perform motor-manual felling with chainsaws and skidding with the use of mules present the highest frequency of complaints in the lower back and shoulder. An additional finding is that the increase in the length of work experience is positively associated with a reduction in the occurrence of symptoms in the three examined body parts; in other words, the longer the work experience, the more proper and efficient the execution of timber harvesting tasks and duties, since these job skills are acquired only through experience in Greece. More generally, the factor years of experience has been found to constitute the most important parameter in explaining the variations in the musculoskeletal symptoms among forestry workers. [ABSTRACT FROM AUTHOR]

Background: It is unclear whether EDSS is responsive to disability worsening in advanced MS. Objective: To explore the dynamics of disability worsening in persons with advanced-stage MS (EDSS ≥5.5) using three disability worsening definitions (EDSS, Rivermead Mobility Index (RMI), 9-Hole Peg Test (9-HPT)). Methods: EDSS-, RMI- and 9-HPT-based disability worsening were assessed over a minimum of two years in a cohort of 286 persons with advanced MS attending inpatient rehabilitation using Kaplan-Meier Curves and multivariable Cox regression. Furthermore, the correspondence between EDSS-, RMI- and 9-HPT-based disability worsening was analyzed. Results: Disability progression was observed in 49% (9-HPT), 52% (EDSS) and 53% (RMI), with 9-HPT-based worsening slightly lagging behind. The Multiple Sclerosis Severity Score (MSSS) was the only consistent factor predicting disability worsening based on all three definitions (EDSS: hazard ratio 1.48 [1.30;1.68]; RMI: 1.12 [0.99;1.27]; 9-HPT: 1.36 [1.18;1.57]). Correspondence between EDSS and the other definitions (9-HPT and RMI) was 44.3% and 55.7% at time of EDSS progression and 65.1% and 72.5% overall, respectively. Conclusion: In persons with advanced-stage MS, half still developed disability worsening in different functional systems over a median of 6 years. MSSS seems a valid predictor for disability worsening in all three outcome measures in advanced MS. [ABSTRACT FROM AUTHOR]

Objectives: Neuroinflammation represents one of the two major pathological components of multiple sclerosis (MS). The aim of our study was to find the role of the late pro-inflammatory cytokine HMGB1 (high mobility group box) in MS pathogenesis.Subjects and Methods: A total of 165 patients from three MS centers in Slovakia were enrolled in the study. Patients underwent a complex clinical investigation and their plasma levels of HMGB1 were analyzed by a sandwich ELISA test.Results: MS patients had 4.5 times higher plasma level of HMGB1 (median, 13.529 ng/mL; IQR = 2.330-113.45) than healthy controls (median, 2.999 ng/mL; IQR = 1.686-9.844; P < 0.0001). The concentrations of HMGB1 were significantly associated with increased number of affected areas diagnosed by MRI (P < 0.0001) (the median for one affected area, 4.205 ng/mL; median for five affected areas, 17.843 ng/mL; P < 0.05). Patients with at least one active lesion in any of the affected areas in the brain had significantly higher plasma levels of HMGB1 (median, 20.118 ng/mL; IQR, 3.693-100.12) than those without any active lesion (median, 16.695 ng/mL; IQR, 3.255-113.45; P < 0.0235). We found also a very highly significant association of HMGB1 plasma levels with clinical condition expressed as EDSS (expanded disability status scale) (P < 0.0001); patients with higher EDSS had higher levels of HMGB1 (EDSS ≤ 2.5, 11.648 ng/mL vs. EDSS ≥ 3, 17.549 ng/mL; P = 0.0115).Conclusion: Our results suggest chronic low-grade inflammation in MS patients that correlates with clinical conditions of MS patients, and for HMGB1 as a possible target molecule in future therapy. [ABSTRACT FROM AUTHOR]

Background: The association between tumor necrosis factor (TNF)-α, soluble TNF receptor (sTNFR)1 and sTNFR2 with clinical characteristics of multiple sclerosis (MS) remains unclear. Objective: To examine whether TNF-α, sTNFR1 and sTNFR2 are associated with MS diagnosis, disability, disability progression and clinical forms of MS. Materials and subjects: The study included 147 patients with relapsing–remitting MS (RRMS), 21 with progressive clinical forms (ProgMS) and 70 controls. Expanded Disability Status Scale (EDSS) evaluated disability as mild (EDSS < 3.0) or moderate/high (EDSS ≥ 3.0). Multiple Sclerosis Severity Score (MSSS) evaluated disability progression as no progression (MSSS < 5) and progression (MSSS ≥ 5). Baseline data of subjects and plasma levels of TNF-α, sTNFR1, sTNFR2 were obtained. Results: The MS diagnosis explained 44.6% and 12.3% of TNF-α and sTNFR2 levels, respectively. Moderate/high disability and disability progression were best predicted by sTNFR1 and age (positively) and ProgMS were best predicted by sTNFR1 (positively) and sTNFR2 (negatively), coupled with age and sex. A composite score reflecting the sTNFR1/sTNFR2 ratio showed a positive association with ProgMS after adjusting for age and sex. Conclusion: Increased sTNFR1 and age were positively associated with disability and disability progression, whereas increased sTNFR1 (positively) and sTNFR2 (negatively) were associated with ProgMS, suggesting a distinct role of them in the immunopathological mechanisms of MS. [ABSTRACT FROM AUTHOR]

The paper deals with controller design for stochastic Markovian switching systems with time-varying delay and actuator saturation by implying a new criterion for the domain of attraction firstly. By constructing more appropriate Lyapunov-Krasovskii functional, some new conditions for verifying stochastic stability of the plant are established. Then, the state feedback controller is designed to expand the domain of attraction of the corresponding closed-loop system. The procedure of deriving controller gain matrices is converted into an optimisation problem with constraints of a set of linear matrix inequalities. The mathematical model of RLC series circuit illustrates the validity of the obtained results. [ABSTRACT FROM AUTHOR]

Objective: The aim of our present study was to analyse the association of HLA-DRB1 and -DQB1 alleles and genotypes with Multiple Sclerosis (MS) disability progression in a cohort of Central European Slovak population. Methods: The allele and genotype variants were analyzed in 282 non-related MS patients. Rate of disease disability progression was evaluated using EDSS score in the 5th, 7th, 10th, and 15th year of disease duration, time to reach EDSS score 3 and 5, and MSSS score. Genotyping was performed by polymerase chain reaction with sequence-specific primers. Results: We found that carriers of homozygous genotype for alleles DRB1*15 and DQB1*03 reached EDSS score 3 significantly earlier than non-carriers of these alleles (p = 0.0172; p = 0.00183, respectively). Genotype DQB1*03/03 carriage was also associated with significantly reduced time to reach EDSS score 5 (p = 0.00316). Lower EDSS score in the 5th year of disease duration was found in carriers of DRB1*07 allele (p cor = 0.028). When MSSS score was used, genotype DRB1*15/15 was found to be less frequent in slow progressing MS patients, when compared to MS patients with mid-rate and rapid disease disability progression (p cor = 0.0305). Discussion: We showed for the first time that HLA-DRB1 and -DQB1 genotypes are genetic markers associated with disability progression in Slovak MS patients. Genotypes DRB1*15/15 and DQB1*03/*03 were identified as short-term clinical negative prognostic factors, while allele DRB1*07 carriage appeared to be a positive prognostic marker of better MS outcome. [ABSTRACT FROM AUTHOR]

Vitamin D receptor polymorphisms have been the target of many studies focusing on multiple sclerosis. However, previously reported results have been inconclusive. The objective of this study was to investigate the association between five vitamin D receptor polymorphisms (EcoRV, FokI, ApaI, TaqI, and BsmI) and multiple sclerosis susceptibility and its course. The study was carried out as a case-control and genotype-phenotype study, consisted of 296 Czech multiple sclerosis patients and 135 healthy controls. Genotyping was carried out using polymerase chain reaction and restriction analysis. In multiple sclerosis men, allele and/or genotype distributions differed in EcoRV, TaqI, BsmI, and ApaI polymorphisms as compared to controls (EcoRV, pa = 0.02; Taq, pg = 0.02, pa = 0.02; BsmI, pg = 0.02, pa = 0.04; ApaI, pg = 0.008, pa = 0.005). In multiple sclerosis women, differences in the frequency of alleles and genotypes were found to be significant in ApaI (controls vs multiple sclerosis women: pg = 0.01, pa = 0.05). Conclusive results were observed between multiple sclerosis women in the case of EcoRV [differences in Expanded Disability Status Scale (p = 0.05); CT genotype was found to increase the risk of primary progressive multiple sclerosis 5.5 times (CT vs CC+TT pcorr = 0.01, sensitivity 0.833, specificity 0.525, power test 0.823)] and FokI [borderline difference in Multiple Sclerosis Severity Score (p = 0.05)]. Our results indicate that the distribution of investigated vitamin D receptor polymorphisms is a risk factor for multiple sclerosis susceptibility and progression in the Czech population. The association between disease risk and polymorphisms was found to be stronger in men. The association of disease progression with polymorphisms was observed only in women. [ABSTRACT FROM AUTHOR]

Background Alcohol and in particular red wine have both immunomodulatory and neuroprotective properties, and may exert an effect on the disease course of multiple sclerosis (MS). Objective To assess the association between alcohol and red wine consumption and MS course. Methods MS patients enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB) who completed a self-administered questionnaire about their past year drinking habits at a single time point were included in the study. Alcohol and red wine consumption were measured as servings/week. The primary outcome was the Expanded Disability Status Scale (EDSS) at the time of the questionnaire. Secondary clinical outcomes were the Multiple Sclerosis Severity Score (MSSS) and number of relapses in the year before the questionnaire. Secondary MRI outcomes included brain parenchymal fraction and T2 hyperintense lesion volume (T2LV). Appropriate regression models were used to test the association of alcohol and red wine intake on clinical and MRI outcomes. All analyses were controlled for sex, age, body mass index, disease phenotype (relapsing vs. progressive), the proportion of time on disease modifying therapy during the previous year, smoking exposure, and disease duration. In the models for the MRI outcomes, analyses were also adjusted for acquisition protocol. Results 923 patients (74% females, mean age 47 ± 11 years, mean disease duration 14 ± 9 years) were included in the analysis. Compared to abstainers, patients drinking more than 4 drinks per week had a higher likelihood of a lower EDSS score (OR, 0.41; p = 0.0001) and lower MSSS (mean difference, − 1.753; p = 0.002) at the time of the questionnaire. Similarly, patients drinking more than 3 glasses of red wine per week had greater odds of a lower EDSS (OR, 0.49; p = 0.0005) and lower MSSS (mean difference, − 0.705; p = 0.0007) compared to nondrinkers. However, a faster increase in T2LV was observed in patients consuming 1–3 glasses of red wine per week compared to nondrinkers. Conclusions Higher total alcohol and red wine intake were associated with a lower cross-sectional level of neurologic disability in MS patients but increased T2LV accumulation. Further studies should explore a potential cause-effect neuroprotective relationship, as well as the underlying biological mechanisms. [ABSTRACT FROM AUTHOR]

Immune-mediated and neurodegenerative mechanisms are involved in multiple sclerosis (MS). Growing evidences highlight the role of HSP70 genes in the susceptibility of some neurological diseases. In this explorative study we analyzed a polymorphism (i.e. HSP70-hom rs2227956) of the gene HSPA1L, which encodes for the protein hsp70-hom. We sequenced the polymorphism by polymerase chain reaction (PCR), in 191 MS patients and 365 healthy controls. The hsp70-hom protein expression was quantified by western blotting. We reported a strong association between rs2227956 polymorphism and MS risk, which is independent from the association with HSP70-2 rs1061581, and a significant link between hsp70-hom protein expression and MS severity. [ABSTRACT FROM AUTHOR]

Objective: Vitamin D acts through vitamin D receptor (VDR) and has promising beneficial effects in the development and progression of multiple sclerosis (MS). The purpose of our study was to investigate the possible association of the VDR gene polymorphisms ApaI, BsmI and TaqI with the MS susceptibility and with the rate of disease disability progression in the Central European Slovak population. Methods: The allele and genotype variants of ApaI, TaqI and BsmI VDR gene polymorphisms were analysed in 270 clinically diagnosed MS patients and 303 healthy controls. Genotyping was performed by polymerase chain reaction and restriction analysis. Patients were stratified by the rate of disease disability progression using MSSS scores. Results: By logistic regression analysis, we revealed that genotype BB (AA) of BsmI VDR gene polymorphism is decreasing the risk of MS (BB (AA) vs Bb (AG) + bb (GG); OR = 0.59, 95% CI = 0.39–0.90, plog = 0.014). We did not identify any association of ApaI and TaqI polymorphisms neither with MS development nor with the disease progression. Discussion: We showed for the first time that BsmI genotype BB (AA) is associated with the decreased susceptibility to MS in Slovak population. We propose the BsmI gene polymorphism to be one of the important genetic markers in evaluation of the risk of MS. However, our data suggest that VDR gene polymorphisms ApaI, BsmI and TaqI are not useful in the prediction of disease disability progression rate in MS in Slovaks. [ABSTRACT FROM AUTHOR]

Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. It is a clinically heterogeneous disorder especially in terms of disease severity. Current investigations suggest that genes and gene-gene interactions not only influence on susceptibility to MS but also affect the disease severity. In this study, we investigated the contribution of the HLADRB1*1501 allele and single nucleotide polymorphism (SNP) in CD24 gene and also combined genotypes of the HLADRB1*1501 and CD24 SNP to disease severity in Iranian MS patients. We have reported previously that the HLA- DRB1*1501 allele and the CD24v/v genotype associated with disease susceptibility and some other studies proposed that HLA-DRB1*1501 allele be associated with MS severity. In this study, the results showed a significant difference in the Multiple Sclerosis Severity Score (MSSS) of the nine different genotypes (F=2.838, P=0.007). Subsequent analysis revealed a statistically significant difference in the MSSS between the MS patients who were carriers of HLA-DRB1*1501/1501 and those who were not carriers of HLA-DRB1*1501/1501 genotypes (P=0.04). Moreover, the MS patients carrying combined genotypes of the HLA- DRB1*1501/x-CD24 v/v had statistically severe disease than the patients who did not carry the HLA- DRB1*1501- CD24 v/v (P=0.047). In conclusion, our findings suggest that, HLA-DRB1*1501/1501 and bigenic genotypes of the HLA- DRB1*1501/x- CD24 v/v may influence on disease severity in Iranian MS patients.

This study aimed to assess the possible association between cognitive impairment and two important biochemical biomarkers of oxidative stress, thiol-disulfide homeostasis (TDH), and ischemia-modified albumin (IMA) in patients with multiple sclerosis (MS). This study included 85 patients with MS (38 treatment-naïve relapsing-remitting MS (RRMS), 31 RRMS on fingolimod therapy, and 16 secondary progressive MS (SPMS)) and 33 healthy controls. Cognitive evaluation was carried out by applying the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) test battery and the scores were adjusted for age and years of education. Plasma TDH was assessed using an automated method and plasma IMA levels were determined using the cobalt-albumin binding assay. Plasma native thiol and total thiol levels were significantly decreased in patients with SPMS when compared with the naïve patients and healthy controls. Cognitive impairment was detected in 47.4% of naïve patients, 64.5% of patients on fingolimod therapy, and 80% of patients with SPMS. Naïve patients or patients on fingolimod therapy who were cognitively impaired had significantly decreased levels of native thiol and total thiol compared to the cognitively normal patients. Logistic regression analysis revealed total thiol and native thiol to be significantly associated with cognitive impairment in naïve patients and patients on fingolimod therapy. Significant correlations were determined between BICAMS scores, TDH, IMA, clinical indices of disease severity (EDSS and MSSS), and magnetic resonance imaging parameters. This study has shown for the first time that plasma TDH parameters are associated with cognitive impairment in MS., (© 2023 Wiley Periodicals LLC.)

Background: Despite pleiotropic immunomodulatory effects of apolipoprotein E (apoE) in vitro, its effects on the clinical course of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) are still controversial. As sex hormones modify immunomodulatory apoE functions, they may explain contentious findings. This study aimed to investigate sex-specific effects of apoE on disease course of EAE and MS.Methods: MOG(35-55) induced EAE in female and male apoE-deficient mice was assessed clinically and histopathologically. apoE expression was investigated by qPCR. The association of the MS severity score (MSSS) and APOE rs429358 and rs7412 was assessed across 3237 MS patients using linear regression analyses.Results: EAE disease course was slightly attenuated in male apoE-deficient (apoE (-/-) ) mice compared to wildtype mice (cumulative median score: apoE (-/-)  = 2 [IQR 0.0-4.5]; wildtype = 4 [IQR 1.0-5.0]; n = 10 each group, p = 0.0002). In contrast, EAE was more severe in female apoE (-/-) mice compared to wildtype mice (cumulative median score: apoE (-/-)  = 3 [IQR 2.0-4.5]; wildtype = 3 [IQR 0.0-4.0]; n = 10, p = 0.003). In wildtype animals, apoE expression during the chronic EAE phase was increased in both females and males (in comparison to naïve animals; p < 0.001). However, in MS, we did not observe a significant association between MSSS and rs429358 or rs7412, neither in the overall analyses nor upon stratification for sex.Conclusions: apoE exerts moderate sex-specific effects on EAE severity. However, the results in the apoE knock-out model are not comparable to effects of polymorphic variants in the human APOE gene, thus pinpointing the challenge of translating findings from the EAE model to the human disease. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an autoimmune neuro-inflammatory disease arising from complex interactions of genetic, epigenetic, and environmental factors. Variations in genes of some microRNAs-key post-transcriptional regulators of many genes-can influence microRNAs expression/function and contribute to MS via expression changes of protein-coding target mRNA genes. We performed an association study of polymorphous variants of MIR146A rs2910164, MIR196A2 rs11614913, MIR499A rs3746444 MIR223 rs1044165 and their combinations with MS risk and severity. 561 unrelated patients with bout-onset MS and 441 healthy volunteers were enrolled in the study. We observed associations of MS risk with allele MIR223*T and combination (MIR223*T + MIR146A*G/G) carriage in the entire groups and in women at Bonferroni-corrected significance level (pcorr < 0.05). Besides, MIR146A*G/G association with MS was observed in women with nominal significance (pf = 0.025). No MS associations were found in men. A more severe MS course (MSSS value > 3.5) was associated with the carriage of MIR499A*C/T and, less reliably, of MIR499A*C (pcorr = 0.006 and pcorr = 0.024, respectively) and with the carriage of combinations (MIR499A*C/T + MIR196A2*C) and (MIR499A*C + MIR196A2*C) (pcorr = 0.00078 and pcorr = 0.0059, respectively). These associations also showed gender specificity, as they were not significant in men and substantially reinforced in women. The strongest association with MS severity was observed in women for combination (MIR499A*C/T + MIR196A2*C): pcorr = 4.43 × 10-6 and OR = 3.23 (CI: 1.99-5.26). [ABSTRACT FROM AUTHOR]

A method for optimizing the number of segment sources needed to discretize UV lamps for fluence rate modeling and dose calculations when using the multiple segment source summation (MSSS) fluence rate model (FRM) is presented. An ideal location for determining the optimal number of point or segment sources was found using the multiple point source summation (MPSS) method with no reflection and refraction. This location was then used to conduct a fast discretization study for the MSSS FRM. A lower than previously used number of segment sources was required. This method reduced the time needed to perform a discretization study and thus for fluence rate and dose distribution calculations in UV reactors. [ABSTRACT FROM AUTHOR]

In this study, we determined the association between rs6897932 in interleukin 7 receptor α ( IL7Ra ) gene and the risk and disability progression of multiple sclerosis (MS) in 270 MS patients and 303 controls. We found allele C to be associated with the risk of MS and minor allele T to be protective against MS development. Moreover, we revealed for the first time that rs6897932 in IL7Ra gene is associated with the progression of MS, evaluated by MSSS scores. The minor allele T and genotype TT are protective against a rapid disability progression in MS in the Central European Slovak population. [ABSTRACT FROM AUTHOR]

Objective: It is still unclear as to why multiple sclerosis (MS) is so devastating and rapidly progressive in one patient and less so in another. Recent data implicate vitamin D in modulation of the risk as well as the clinical course of disease. Since vitamin D acts through the vitamin D receptor (VDR), association of single nucleotide polymorphisms (SNPs) in the VDR gene might account for variations in the MS risk within populations. The aim of our study was to determine the association between FokI gene polymorphism (rs10735810) and the risk of MS in a cohort of Slovak population and to investigate possible correlations of this SNP with the rate of disease disability progression. Methods: FokI SNP was detected in 270 clinically diagnosed MS patients and 303 healthy control subjects. Genotyping was performed by polymerase chain reaction (PCR) and restriction analysis. We used multiple sclerosis severity score (MSSS) for patient's stratification by the rate of disease disability progression. Results: We observed a significantly higher frequency of Ff genotype of FokI SNP (53.4 vs 43.7%, P = 0.042) in women with MS compared to women of the control group. There was no significant association between FokI SNP and the rate of disease disability progression. Discussion: Although our findings suggest a weak association between VDR SNP FokI and the MS risk in women, further studies are needed to explore the role of VDR polymorphic alterations in MS disease etiology and pathogenesis. [ABSTRACT FROM AUTHOR]

The recent studies in Multiple sclerosis field keep bringing up the current knowledge about MS prodrome period and its importance. Poorly studied and often underdiagnosed prodrome period can manifest in a variety of different symptoms affecting many organ systems. Based on literature findings regarding this topic, we suggest a hypothesis that some prodrome symptoms are seen more often in some courses of the MS. A careful and close investigation of the first symptoms which appear before the actual MS diagnosis could possibly help to predict the course and the severity of the disease and also be a forecast factor for future disability level. Acknowledging the significance of a MS prodrome period and new findings which could benefit both the physicians and the patients, we conducted a study in a local MS center in order to explore this hypothesis. [ABSTRACT FROM AUTHOR]

Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. It is a clinically heterogeneous disorder especially in terms of disease severity. Current investigations suggest that genes and gene-gene interactions not only influence on susceptibility to MS but also affect the disease severity. In this study, we investigated the contribution of the HLADRB1*1501 allele and single nucleotide polymorphism (SNP) in CD24 gene and also combined genotypes of the HLADRB1*1501 and CD24 SNP to disease severity in Iranian MS patients. We have reported previously that the HLA- DRB1*1501 allele and the CD24v/v genotype associated with disease susceptibility and some other studies proposed that HLADRB1* 1501 allele be associated with MS severity. In this study, the results showed a significant difference in the Multiple Sclerosis Severity Score (MSSS) of the nine different genotypes (F=2.838, P=0.007). Subsequent analysis revealed a statistically significant difference in the MSSS between the MS patients who were carriers of HLA-DRB1*1501/1501 and those who were not carriers of HLA-DRB1*1501/1501 genotypes (P=0.04). Moreover, the MS patients carrying combined genotypes of the HLA- DRB1*1501/x- CD24 v/v had statistically severe disease than the patients who did not carry the HLA- DRB1*1501- CD24 v/v (P=0.047). In conclusion, our findings suggest that, HLA-DRB1*1501/1501 and bigenic genotypes of the HLA- DRB1*1501/x- CD24 v/v may influence on disease severity in Iranian MS patients. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis outcome may be influenced by ultraviolet radiation and vitamin D synthesis, suggesting skin type and genes determining this phenotype are candidates for disability. However, though associations between melanocortin 1 receptor (MC1R) single nucleotide polymorphisms and disability are reported, some data are incompatible with their expected influence on skin type. Objective: Determine which MC1R single nucleotide polymorphisms affect disability and establish if ultraviolet radiation modifies such associations. Methods: We studied using linear regression in 525 cases, associations of the Multiple Sclerosis Severity Score (MSSS) with skin type, gender, ultraviolet radiation exposure and six MC1R single nucleotide polymorphisms (rs1805005, rs1805006, rs2228479, rs1805007, rs1805008, rs1805009). Results: CG294 with GG294 genotypes (rs1805009) (coefficient = -1.44, 95% CI -2.30, -0.59, mean MSSS±SD = 4.33±2.87) and AC84 (rs1805006) (coefficient = 1.62, 95% CI 0.17, 3.06, mean MSSS = 7.62±2.43) were associated with MSSS. Associations with Asp294His were found in those with skin types ½ and ¾, and cases stratified by ultraviolet radiation exposure. However, they were seen only in cases with a history of childhood sunburn and not in those without sunburn. We found no significant associations between exposure parameters and MSSS. Conclusions: Multiple Sclerosis outcome is influenced by interactions between host response to ultraviolet radiation and MC1R single nucleotide polymorphisms. The influence of the single nucleotide polymorphisms appears distinct from their association with skin type. [ABSTRACT FROM AUTHOR]

Abstract: Multiple Sclerosis (MS) is a genetically complex immune mediated, demyelinating disease of the central nervous system. To date no genetic variants have been unambiguously linked to disease severity. We have conducted a genome wide screen, using Affymetrix Genechip® 500K technology, for severity in 1040 MS patients. Two markers within MGAT5, a gene coding for a glycosylation enzyme, were found to be significantly associated with outcome in the screening as well as in an independent population (combined p-values: 2.8×10−6 and 1.5×10−7). [Copyright &y& Elsevier]

Abstract: Background: The multiple sclerosis severity scale (MSSS) adds the element of disease duration to the expanded disease status score (EDSS) and is designed to provide a measure of disease severity. We have used this tool to address two questions: Can it be used to predict the accrual of disability over time in individual patients? Do the currently available therapies have an impact upon disease severity over time? Methods: All patients who were followed and treated by a single neurologist in an MS center in the USA over a two year period were evaluated. The MSSS was retrospectively tabulated in 195 MS patients and the course and severity of the disease was analyzed in a sample of 10 randomly selected patients. 177/195 (94%) of patients received disease-modifying therapies for at least a year during the period that was evaluated. Results: The mean duration of symptoms in our patients was 9.7 years (range 0.3–26) with an EDSS mean score of 3.5 (range 0–9.5). The average MSSS rating for the entire cohort of 195 patients was 48.7, similar to that observed in the European cohort. In 9/10 patients, randomly selected and representative of the entire group, the MSSS assessments were consistent over time and irrespective of therapy with a range over 5–12 years of disease duration averaging only 11.3 points (range 3.7–18.8). Conclusions: The MSSS may allow the prediction of disease severity over time, and is consistent with the lack of a major impact of disease-modifying drugs upon disease severity as measured by the MSSS. These results need to be verified in a larger cohort of patients. [Copyright &y& Elsevier]

Ultraviolet radiation (UVR) may contribute to multiple sclerosis (MS) outcome by a mechanism involving vitamin D and the vitamin D receptor (VDR). In 512 patients with MS duration of 10 or more years, we studied the association of VDR single nucleotide polymorphisms (A/G1229, C/C3444, G/A3944, CC20965, CC30056, F/f30875, C/T48200, T/t65013) with outcome or disability, ff30875 frequency was lower in cases with EDSS ≥ 6.0 than with scores < 6.0 (odds ratio = 0.38, 95% Cl = 0.20-0.70). The association of ff30875 with outcome was not mediated by cumulative exposure to UVR as assessed by questionnaire; low exposure (odds ratio = 0.42, 95% Cl = 0.14-1.34) and high exposure (odds ratio = 0.34, 95% Cl = 0.16-0.73). [ABSTRACT FROM AUTHOR]

Abstract: Matrix metalloproteinases (MMPs) are proteolytic enzymes involved in remodeling of the extracellular matrix. MMPs are suggested to play a role in the influx of inflammatory cells into the CNS, disruption of the blood brain barrier, and to degrade myelin in vitro. In this study, we have investigated the possible association of MMP-3 5A/6A gene polymorphism with MS susceptibility and/or severity in patients from Serbia. A total of 184 MS patients (150 RR, 34 SP) and 236 controls have been studied. Results show that the distribution of MMP-3 5A/6A genotype frequencies between MS patients and controls were not significantly different. In bout onset patients, carriers of MMP-3 6A/6A genotype had significantly higher mean MSSS values compared to the carriers of 5A allele (6.29±1.89 vs. 5.29±2.62, respectively, ANCOVA, p =0.01 Scheffe post-hoc test). In conclusion, our results indicate association of MMP-3 6A/6A genotype with significantly higher mean MSSS values. Thus, the obtained results suggest that it should be carefully considered during follow up of patients with MS. Further genetic and functional studies are needed to resolve the complex role of MMPs and their tissue inhibitors in MS pathology and/or regeneration. [Copyright &y& Elsevier]

This study investigated whether the new Global Multiple Sclerosis Severity Scale (MSSS) correlated with cerebrospinal fluid biomarkers for axonal and glial pathology. The MSSS correlated with the phosphorylated neurofilament heavy chain (NfH-SMI35, R = 0.44, P = 0.016). The degree of neurofilament phosphorylation (ratio NfH-SMI34 to NfH-SMI35) was 8-fold higher in severely (median MSSS 6.5) versus mildly (MSSS 3.2) disabled patients (7.3 versus 0.9, P = 0.03). The MSSS may provide a statistically powerful tool for comparing overall disease severity and be useful for validating the biomarker concept in MS. [ABSTRACT FROM AUTHOR]

Abstract: Recently, several non-HLA loci have been shown to be convincingly associated with Multiple Sclerosis (MS) susceptibility, assumingly indicating important pathways in the pathogenesis. A genotype influence on disease outcome measures by these genes would support a role of these pathways in ongoing tissue damage. Here, however, we report a consistent dissociation between causation and progression for five non-HLA genotypes (IL7R, IL2RA, CLEC16A, CD226 and SH2B3) in 1776 Scandinavian MS patients. [Copyright &y& Elsevier]

Background: Multiple Sclerosis (MS) is a demyelinating CNS disease. Most MS cases are sporadic, however about 20 percent of them are hereditary (Ramagopalan and Sadovnick, 2011). The incidence of familial MS is greater in regions with the highest prevalence of this disease (in North America, Europe) (Ramagopalan and Sadovnick, 2011). It is still unclear whether heredity affects the progression and severity of the disease. The aim of this study is to assess the effect of heredity on the development of multiple sclerosis and on the course of disease by analyzing the results of disability and severity scales, as well as clinical studies, and comparing them with sporadic cases.Methods: Our study included 104 patients with MS. The study group was comprised of 38 patients with history of first degree relative also affected by MS; the control group consisted of 66 patients with no family history (sporadic case). The anonymous survey included questions about demographic and clinical characteristics. Diagnostic results of magnetic resonance imaging (MRI), oligoclonal bands (OCBs) and visual evoked potentials (VEP) were evaluated retrospectively from medical records. Disability assessment was made according to expanded disability status scale (EDSS). Multiple Sclerosis Severity Score (MSSS) score was calculated using conversion table based on EDSS score and duration of disease in years.Results: MS patients with first degree relative affected by MS tend to have slower onset of the disease, while control group is more likely to have an acute onset (p < 0.001). The majority of MS with family history considered that their disease is caused by certain factors, while patients in the control group considered that the disease started without any identifiable cause (p < 0.05). Study group more often complained of pyramidal disorders (74% vs. 50%), symptoms related to brainstem (68% vs. 20%) and cortical lesions (47% vs. 20%), headache (37% vs. 9%), back pain (32% vs. 9%) than those in control group, p < 0.05. The degree of disability according to EDSS and MSSS scores were higher in the group of patients with first degree relative with MS (p < 0.05). The number of exacerbations per year was also higher in study group than in the control group (1.4 vs. 0.8; p < 0.05). Patients with a family history have a higher incidence of MRI changes in brainstem (74% vs. 30%) and cerebellum (58% vs. 30%) than the control group (p < 0.01).Conclusions: MS patients with a family history of MS tend to have slower onset of the disease, while control group is more likely to have an acute onset. Patients with a family history of MS more often complained of brainstem and cortical dysfunction, and pain in head or back. Both the degree of disability according to EDSS and MSSS scores were higher in familial cases. They also have a higher number of exacerbations per year. Patients with a history of first degree relative with MS have a higher incidence of MRI changes in brainstem and cerebellum. [ABSTRACT FROM AUTHOR]

Background: The Multiple Sclerosis Severity Score (MSSS), combining the Expanded Disability Status Scale (EDSS) and disease duration, attempts to stratify multiple sclerosis (MS) patients based on their rate of progression. Its prognostic ability in the individual patient remains unproven., Objectives: To assess the stability of MSSS within individual persons with MS in a longitudinal cohort, to evaluate whether certain factors influence MSSS variability, and to explore the ability of MSSS to predict future ambulatory function., Methods: A single-center retrospective review was performed of patients following a single provider for at least 8 years. Mixed model regression modeled MSSS over time. A Kaplan-Meier survival plot was fitted, using change of baseline MSSS by at least one decile as the event. Cox modeling assessed the influence of baseline clinical and demographic factors on the hazard of changing MSSS by at least one decile. Linear models evaluated the impact of baseline EDSS, baseline MSSS, and other factors on the Timed 25-Foot Walk (T25FW)., Results: Out of 122 patients, 68 (55.7%) deviated from baseline MSSS by at least one decile. Final T25FW had slightly weaker correlation to baseline MSSS than to baseline EDSS, which was moderately strongly correlated with future log T25FW., Conclusion: Individual MSSS scores often vary over time. Clinicians should exercise caution when using MSSS to prognosticate.