Waterpipe Tobacco Smoking and Multiple Sclerosis: A Systematic Review and Meta-Analysis.

BACKGROUND: Multiple sclerosis (MS), as an autoimmune disease of the central nervous system, has a significant burden among people worldwide. Tobacco smoking is one of the most prevalent habits of patients with different diseases including those with MS, and among the methods of use, waterpipe tobacco smoking is gaining popularity. Herein, we aimed to systematically evaluate the association between waterpipe smoking and MS. METHODS: Relevant studies were identified to be included in this systematic review and meta-analysis through a systematic search in PubMed, Scopus, Web of Science, and Embase. Studies were screened by the title/abstract and then by their full text. Extraction of data was performed for relevant studies. Odds ratios (ORs) and their 95% confidence intervals (CIs) of the association between waterpipe smoking and MS were used to pool the results observed in each study. RESULTS: After the screening, a total of five studies were included in our systematic review, comprised of 3,087 individuals, among which there were 1,135 cases with MS. Random-effect meta-analysis revealed that ever-smoking waterpipe had a significant association with MS (OR: 1.73, 95% CI: 1.38-2.17, p value <0.0001). Similarly, past waterpipe smoking was significantly higher in those with MS, compared with controls (OR: 2.17, 95% CI: 1.61-2.92, p value <0.0001). Based on the reported results, smoking both tobacco and waterpipe had an additive association with MS. Finally, no association was found between the Expanded Disability Status Scale (EDSS) and waterpipe smoking. CONCLUSION: Waterpipe as one of the common ways of tobacco smoking becoming popular has an association with MS, and even the use of waterpipe for a certain period in the lifetime has a significant correlation with MS. Further large-scale studies are needed to confirm these findings. These results could help clinicians in risk-stratifying the patients and to provide better care for the MS population.

Switching from injectable to other Disease Modifying Therapies may improve sexual dysfunction in people with Multiple Sclerosis.

BACKGROUND: Multiple Sclerosis (MS) a central nervous system autoimmune disorder, mainly affecting young adults and more prevalent among women, can lead to sexual dysfunction (SD) among both males and females with MS. Female sexual dysfunction can be defined as dyspareunia, a lack of sexual desire, disorders in the arousal and orgasm phases, and sexual pain disorders. The purpose of this study is to investigate the changes in sexual function among females with MS whose treatment was switched from first-line injectable medications to other agents after a six-month duration. And assess the changes in all three domains of SD. METHODS: In this longitudinal study females diagnosed with MS, aged between 18 and 50 years old, and were candidates for switching their treatment from interferon beta-1a (intra-muscular and subcutaneous), and Glatiramer Acetate (GA), to Fingolimod, Dimethyl Fumarate (DMF), or Natalizumab (NTZ) due to patients' convenience and tolerability and adverse events were included. "Multiple Sclerosis Intimacy and Sexuality Questionnaire-19" was used to evaluate the SD changes before and six months after the new treatment initiation. Statistical analysis was conducted using SPSS V.24 software. Histograms and the Shapiro-Wilk test were used to assess the normality of the variables; due to the non-normal distribution of quantitative variables (except for age), the Wilcoxon signed-rank test was used to compare the scores, before and six months after the medication change. The level of significance was considered less than 0.05. RESULTS: Out of 107 female participants (average age: 35.09 ± 5.61), The mean of overall MSISQ-19 scores, before and six months after the medication change were not significant (p-value = 0.091). However, considering the subdomains, the medication changes only affected the tertiary subdomain of MSISQ-19 (p-value = 0.017). Still, the scores of other subdomains did not change significantly (p-value = 0.761 for primary SD and 0.479 for secondary SD). Also, there wasn't any significant difference between EDSS before and after the medication change (p-value = 0.461). CONCLUSIONS: To our knowledge, this was the first study, assessing the effect of MS medication change on the improvement of SD among patients. According to the results of the presented cross-sectional study, we found that during a six-month period, the tertiary subdomain of MSISQ-19 symptoms improved significantly, while the changes in other SD domains were not significant.

T1 hypointense brain lesions in NMOSD and its relevance with disability: a single institution cross-sectional study.

BACKGROUND: T1 hypointense lesions are considered a surrogate marker of tissue destruction. Although there is a shortage of evidence about T1 hypointense brain lesions, black holes, in patients with Neuromyelitis Optica Spectrum Disorder (NMOSD), the clinical significance of these lesions is not well determined. OBJECTIVES: The impact of T1 hypointense brain lesions on the clinical status and the disability level of patients with NMOSD was sought in this study. METHODS: A total of 83 patients with the final diagnosis of NMOSD were recruited. Aquaporin-4 measures were collected. The expanded disability status scale (EDSS) and MRI studies were also extracted. T1 hypointense and T2/FLAIR hyperintense lesions were investigated. The correlation of MRI findings, AQP-4, and EDSS was assessed. RESULTS: T1 hypointense brain lesions were detected in 22 patients. Mean ± SD EDSS was 3.7 ± 1.5 and significantly higher in patients with brain T1 hypointense lesions than those without them (p-value = 0.01). Noticeably, patients with more than four T1 hypointense lesions had EDSS scores ≥ 4. The presence of T2/FLAIR hyperintense brain lesions correlated with EDSS (3.6 ± 1.6 vs 2.3 ± 1.7; p-value = 0.01). EDSS was similar between those with and without positive AQP-4 (2.7 ± 1.6 vs. 3.2 ± 1.7; p-value = 0.17). Also, positive AQP-4 was not more prevalent in patients with T1 hypointense brain lesions than those without them (50.9 vs 45.4%; p-value = 0.8). CONCLUSION: We demonstrated that the presence of the brain T1-hypointense lesions corresponds to a higher disability level in NMOSD.

Lifetime exposure to smoking and substance abuse may be associated with late-onset multiple sclerosis: a population-based case-control study.

BACKGROUND: Late-onset multiple sclerosis (LOMS), defined as the development of MS after the age of 50, has shown a substantial surge in incidence rates and is associated with more rapid progression of disability. Besides, studies have linked tobacco smoking to a higher chance of MS progression. However, the role of smoking on the risk of developing LOMS remains unclear. This study aims to evaluate the possible association between lifetime exposure to cigarette and waterpipe smoking, drug abuse, and alcohol consumption and the risk of LOMS. METHODS: This population-based case-control study involved LOMS cases and healthy sex and age-matched controls from the general population in Tehran, Iran. The primary data for confirmed LOMS cases were obtained from the nationwide MS registry of Iran (NMSRI), while supplementary data were collected through telephone and on-site interviews. Predesigned questionnaire for multinational case-control studies of MS environmental risk factors was used to evaluate the LOMS risk factors. The study employed Likelihood ratio chi-square test to compare qualitative variables between the two groups and utilized two independent sample t-test to compare quantitative data. Adjusted odds ratio (AOR) for age along with 95% confidence intervals (CI) were calculated using matched logistic regression analysis in SPSS 23. RESULTS: Totally, 83 LOMS cases and 207 controls were included in the analysis. The female to male ratio in the cases was 1.5: 1. The mean ± SD age of 83 cases and 207 controls was 61.14 ± 5.38) and 61.51 ± 7.67 years, respectively. The mean ± SD expanded disability status scale (EDSS) score was 3.68 ± 2.1. Although the results of waterpipe exposure had no significant effect on LOMS development (P-value: 0.066), ever cigarette-smoked participants had a significantly higher risk of developing LOMS than those who never smoked (AOR: 2.57, 95% CI: 1.44-4.60). Furthermore, people with a history of smoking for more than 20 years had 3.45 times the odds of developing MS than non-smokers. Drug and alcohol abuse were both associated with LOMS in our study; of which opioids (AOR: 5.67, 95% CI: 2.05-15.7), wine (AOR: 3.30, 95% CI: 1.41-7.71), and beer (AOR: 3.12, 95% CI: 1.45-6.69) were found to pose the greatest risk of LOMS, respectively. CONCLUSION: For the first time, we identified smoking, drug, and alcohol use as potential risk factors for LOMS development. According to the global increase in cigarette smoking and alcohol use, these findings highlight the importance of conducting interventional approaches for prevention.

Good manufacturing practices production of human placental derived mesenchymal stem cells for therapeutic applications: focus on multiple sclerosis.

BACKGROUND: Among neurological diseases, multiple sclerosis (MS) affects mostly young adults and can cause long-term disability. While most medications with approval from regulatory agencies are very effective in treating MS disease, they are unable to repair the tissue damage found in the central nervous system (CNS). Consequently, Cell-based therapy particularly using mesenchymal stem/stromal cells (MSCs), holds promise for neuroprotection and tissue repair in MS treatment. Furthermore, placenta-derived MSCs (PLMSCs) have shown the potential to treat MS due to their abundance, noninvasive isolation from discarded tissues, no ethical problems, anti-inflammatory, and reparative properties. Accordingly, good manufacturing practices (GMPs) plays a crucial part in clinical SCs manufacturing. The purpose of our article is to discuss GMP-grade PLMSC protocols for treating MS as well as other clinical applications. METHODS AND RESULTS: Placental tissue obtained of a healthy donor during the caesarean delivery and PLMSCs isolated by GMP standards. Flow cytometry was used to assess the expression of the CD markers CD34, CD105, CD90, and CD73 in the MSCs and the mesodermal differentiation ability was evaluated. Furthermore, Genetic evaluation of PLMSCs was done by G-banded karyotyping and revealed no chromosomal instability. In spite of the anatomical origin of the starting material, PLMSCs using this method of culture were maternal in origin. CONCLUSIONS: We hope that our protocol for clinical manufacturing of PLMSCs according to GMP standards will assist researchers in isolating MSCs from placental tissue for clinical and pre-clinical applications.

The effect of crocin-selenium nanoparticles on the cognition and oxidative stress markers of multiple sclerosis patients: a randomized triple-blinded placebo-controlled clinical trial.

The prevalence of cognitive impairment in multiple sclerosis (MS) patients is estimated to be approximately 40-60%. There is an increasing body of evidence regarding the impact of both selenium and crocin as antioxidant agents on cognitive function. In the present study, for the first time, we investigated the effect of crocin-selenium nanoparticles (Cor@SeNs) on cognitive function and oxidative stress markers in MS patients. A triple-blind randomized clinical trial was conducted among 60 MS patients. The participants were randomly divided in a 1:1 ratio to either the Cor@SeNs or placebo group, employing block randomization. During the course of 12 weeks, the participants received Cor@SeNs capsules, containing 5.74 mg crocin and 55 mcg Selenium, or placebo capsules. Cognition assessed using the Persian version of the Brief International Cognitive Assessment for MS (BICAMS) battery. Serum levels of total antioxidant capacity (TAC), glutathione reductase (GR) activity and malondialdehyde (MDA) determined by colorimetric kits. Data analysis was performed in SPSS, version 26. P < 0.05 was considered as the significant range. The mean ± SD of TAC change was 0.03 ± 0.07 mM vs. - 0.03 ± 0.09 mM in intervention and placebo groups, respectively (Time × group effect P: 0.01; effect size: 0.10). The time effect of intervention on the California Verbal Learning Test second edition (CVLT-II) (P < 0.01; effect size: 0.29), CVLT-II-delay (P < 0.01; effect size: 0.29), and the Symbol Digit Modalities Test (SDMT) (P < 0.01; effect size: 0.18) was increasing and significant. In addition, the time effect of intervention on GR activity was significant and decreasing in both groups (P < 0.01; effect size: 0.20). Our results suggested a significant effect of the Cor@SeNs intervention in improving TAC. We also observed a significant improvement in cognitive function in both groups during our study. However, although not statistically significant, a higher amount of change in cognitive function and serum antioxidant markers was noted in the Cor@SeNs group compared to the placebo group. This is the first study on this nano product with low dose of selenium and crocin. More investigations with longer duration and varied doses are suggested.

The incidence and prevalence of crude and familial multiple sclerosis in Tehran, Iran in 2021.

Our registry-based cross-sectional study covered 27,508 PwMS in Tehran with a point incidence rate and prevalence of 7.87 and 194.62 per 100,000 in 2021, respectively. We found that the incidence and prevalence of MS in Tehran are still on an upward trend which requires general attention and measures to overcome. The proportion of men with a family history of MS was significantly higher. Whilst IMSS deals with economic difficulties, it continues to collect new PwMS to reach regional-level coverage in Tehran for better MS care services.

Effect of an educational intervention based on the theory of planned behavior on improving medication adherence in patients with multiple sclerosis treated with injectable disease-modifying drugs: randomized controlled trial.

BACKGROUND: Adherence to prescribed treatment in chronic diseases, as occurs in multiple sclerosis (MS), is a critical factor for a successful therapeutic response. This study aimed to investigate the effect of educational program based on Theory of Planned Behavior (TPB) on treatment adherence in patients with multiple sclerosis (MS) receiving injectable immunomodulatory drugs. METHODS: The present study is an educational randomized controlled trial research that was conducted on 100 patients with MS who had gone to MS clinic in Tehran city (Iran). The samples were randomly assigned to the intervention (N = 50) and control groups (N = 50). Data collection instrument was a researcher-made questionnaire based on TPB. Then, educational program was performed for the intervention group through four educational sessions. After three months, data collection was repeated for the two groups and data were analyzed. RESULTS: The knowledge and performance of the intervention group on treatment adherence drugs increased from 56.25 ± 20.3 to 78.31 ± 15.57 and 56.22 ± 5.76 to 71.62 ± 12.01 after the education respectively (p < 0.001). The mean of construct of TPB in the intervention group also increased after the intervention (p < 0.05). CONCLUSION: Applying the TPB model proved is very effective in developing an educational program for patients with MS, to enhance treatment adherence drugs. Besides such programs, follow-up education for controlling and monitoring are highly recommended. TRIAL REGISTRATION: This trial has been registered at Iranian Registry of Clinical Trials, IRCT20210808052109N1. Prospectively registered at 12-Aug-2021, (12/8/2021) available at: URL: https://en.irct.ir/trial/57994.

Vascular Endothelial Growth Factor as a Predictive and Prognostic Biomarker for Multiple Sclerosis.

BACKGROUND: Growing bodies of evidence suggest that angiogenesis plays a crucial role in the development and progression of multiple sclerosis (MS). Vascular endothelial growth factor (VEGF) is one of the key factors involved in angiogenesis. Because of this importance, we investigated the serum levels of VEGF in MS patients according to their clinical phase and subtype of MS in this study. MATERIAL AND METHODS: This case-control study was done on 47 definite MS patients with the first clinical attack and 47 randomly selected individuals without any underlying inflammatory and autoimmune disease as the control group. The total serum VEGF level was measured from the subject's peripheral blood sample by ELISA during the first and second attacks of MS and 6 months after the first attack in the remission phase as well as the control group. In addition, the correlation between these variables and the influence of gender, age, and duration of the remission phase on such associations was evaluated by using the independent t test and Pearson's correlation coefficient. RESULTS: There was an increase in the serum level of VEGF in all phases of MS compared with non-MS individuals (p value <0.0001) and a significant correlation between the serum level of VEGF and the interval between first and second attacks (r = -720, p < 0.0001). A higher serum level of VEGF in the first attack leads to higher VEGF levels in the second and sixth mount of remission phases. CONCLUSION: Rise in the serum VEGF level may be involved in MS's relapsing phases and a shorter remission phase. Therefore, it could be used as a prognostic and predictive biomarker for MS disease.

Epidemiology of familial multiple sclerosis in Iran: a national registry-based study.

BACKGROUND: Admittedly, little is known about the epidemiological signatures of familial multiple sclerosis (FMS) in different geographical regions of Iran. OBJECTIVE: To determine the epidemiology and the risk of FMS incidence in several provinces of Iran with a different ethnic population including, Fars, Tehran, Isfahan (Persians), and Mazandaran (Mazanis), Kermanshah (Kurds), and Chaharmahal and Bakhtiari (Lors). METHODS: This cross-sectional registry-based study was performed on nationwide MS registry of Iran (NMSRI) data collected from 2018 to 2021. This system, registers baseline characteristics, clinical presentations and symptoms, diagnostic and treatments at regional and national levels. RESULTS: A total of 9200 patients including, 7003 (76.1%) female and 2197 (23.9%) male, were participated. About 19% of patients reported a family history of MS; the order from highest to lowest FMS prevalence was as follows: Fars (26.5%), Chaharmahal and Bakhtiari (21.1%), Tehran (20.5%), Isfahan (20.3%), Mazandaran (18.0%), and Kermanshah (12.5%). Of all FMS cases, 74.7% (1308 cases) were female and 25.3% (442 cases) were male. FMS occurrence was much more common in females than males (P-value = 0.001). Further, the mean age at onset was 30 years among FMS cases. A substantially higher probability of relapsing-remitting MS and secondary-progressive MS was found among FMS cases than sporadic MS (SMS) (P_value = 0.001). There was no significant difference in Expanded Disability Status Scale (EDSS) scores between FMS and SMS. The majority of FMS cases were observed among first-degree relatives, with the highest rate in siblings. There was a significant association between MS risk and positive familial history in both maternal and paternal aunt/uncle (P_value = 0.043 and P_value = 0.019, respectively). Multiple sclerosis occurrence among offspring of females was higher than males (P_value = 0.027). CONCLUSIONS: In summary, our findings imply a noteworthy upward trend of FMS in Iran, even more than the global prevalence, which suggests a unique Atlas of FMS prevalence in this multi-ethnic population. Despite the highest rate of FMS within Persian and Lor ethnicities, no statistically significant difference was observed among the provinces.

Depression, anxiety, and fear of COVID-19 in patients with multiple sclerosis in pandemic era: a cross-sectional study.

BACKGROUND: Depression and anxiety are the two important factors determining quality of life of patients with multiple sclerosis (PWMS). In COVID-19 pandemic era, several factors can provoke mental issues of people and patients. In this cross-sectional study, we aim to estimate the new prevalence of anxious and depressive symptoms and their relating factors in PWMS. METHODS: In this cross-sectional study, we include PWMS who are recruited in the MS clinic of Sina Hospital, Tehran, and are joined in our channel of Telegram media. A self-designed online questionnaire consisted of 4 parts handed out between patients: demographic and clinical data, Beck depression inventory, Beck anxiety inventory, and Fear of COVID-19 Scale. Univariate and multiple logistic regression analyses were performed to find the relating factors of expression of depressive and anxious symptoms in PWMS. RESULTS: Of a total of 282 participants with the mean age of 35.66 (30.75-40) years, had been suffering from multiple sclerosis for 7.36 (3-10) years, 81.7% were women and 69.1% classified as relapsing-remitting MS. Mean score of BDI was 17.13 ± 11.51 which is classified as minimal-moderate depressive symptoms. 48.6% of patients did not express depressive symptoms (BDI-II ≤ 14) and the others reported some degrees of depression. In the univariate analysis employment (p = 0.015), marital status (p = 0.022), level of education (p = 0.004), number of hospitalization due to MS attacks (p = 0.048), and fear of COVID-19 (p ≤ 0.0001) associated significantly with presence of depressive symptoms. After entering these factors in a binary logistic regression model, level of education (p = 0.019), marital status (p = 0.044), number of hospital admissions due to MS relapses (ß = 1.10, p = 0.02), and fear of COVID-19 (ß = 1.07, p ≤ 0001) remained significant as relating factors. Mean score of the anxiety calculated 14.54 ± 9.75 and just 3.2% of patients had severe anxiety. Employment (p = 0.045), EDSS score (p = 0.004), and fear of COVID-19 (p ≤ 0.0001) reported relating to anxious symptoms significantly in the univariate analysis. After entering in the logistic regression analysis, EDSS (ß = 1.30, p = 0.001) and fear of COVID-19 (ß = 1.13, p ≤ 0.0001) remained as significant relating factors of anxious symptoms. CONCLUSION: The overall prevalence of depressive symptoms in PWMS in our MS clinic is 51.4% which is obviously higher than other world's centers which could be due to fear of COVID-19. In addition to fear of COVID-19, presence of depressive symptoms in PWMS is related significantly with level of education, number of hospital admissions due to MS relapses, and marital status. Other side, the patients classified as suffering from anxious symptoms had more severe problems on fear of COVID-19. But it is recommended for future studies to compare patients score in the COVID-19 era with their score before this pandemic.

Investigating the association of polymorphisms of ANKRD55 and MMEL1 with susceptibility to multiple sclerosis in Iranian population.

OBJECTIVE: Multiple sclerosis (MS) is an autoimmune neurological disability in which immune cells attack the myelin sheaths that protect nerve fibers. The pathogenesis of the disease involves both complex genetic effects as well as multifaceted gene-environment interactions. In the present study, we examined the association of two Single nucleotide polymorphisms (SNPs) in ANKRD55 (rs6859219) and MMEL (rs3748816) with MS in the Iranian population. ANKRD55 is specifically expressed in human peripheral blood mononuclear cells and CD4 + T cells, while MMEL1is involved in the degradation of both neuropeptides and ß-amyloid. METHODS: In this case-control study, 110 patients with MS and 110 matched healthy controls were enrolled. The Participants were genotyped for ANKRD55 and MMEL1 SNPs using PCR-RFLP and Real-Time TaqMan SNP Genotyping respectively. The results were finally analyzed using SPSS software version 22. RESULTS: Our results did not show significant differences in allelic frequencies of two SNPs among cases and controls (P-Value >0.05). However, for ANKRD55 (rs6859219), CA genotype was shown to have a protective effect (p = 0.035 and OR = 0.55), while CC genotype was a susceptive genotype to MS (p = 0.036 and OR = 1.8). There was no significant difference in genotypic frequencies of SNP rs3748816 in MMEL1. CONCLUSION: We could successfully replicate the association of ANKRD55 (rs6859219) with susceptibility to MS in the Iranian population. Our result can provide an insight into better understanding the pathogenesis of MS and also improve the genetic counseling for patients affected with multiple sclerosis in Iran.

Exome sequencing reveals novel rare variants in Iranian familial multiple sclerosis: The importance of POLD2 in the disease pathogenesis.

The prevalence of familial multiple sclerosis (FMS) is increasing worldwide which endorses the heritability of the disease. Given that many genome variations are ethnicity-specific and consanguineous marriage could affect genetic diseases, hereditary disease gene analysis among FMS patients from Iran, a country with high rates of parental consanguinity, could be highly effective in finding mutations underlying disease pathogenesis. To examine rare genetic mutations, we selected three Iranian FMS cases with ≥3 MS patients in more than one generation and performed whole exome sequencing. We identified a homozygous rare missense variant in POLD2 (p. Arg141Cys; rs372336011). Molecular dynamics analysis showed reduced polar dehydration energy and conformational changes in POLD2 mutant. Further, we found a heterozygote rare missense variant in NBFP1 (p. Gly487Asp; rs778806175). Our study revealed the possible role of novel rare variants in FMS. Molecular dynamic simulation provided the initial evidence of the structural changes behind POLD2 mutant.

Low carbohydrate diet score and odds of neuromyelitis optica spectrum disorder: A case-control study.

Introduction: Neuromyelitis optica spectrum disorder (NMOSD) is a demyelinating inflammatory disease of The Central nervous system. We aimed to investigate the association between low carbohydrate diet (LCD) and NMOSD odds. Method: Seventy NMOSD patients with definite diagnosis and 164 hospital-based controls were enrolled in this case-control study. Dietary data was obtained using a validated 168-item food frequency questionnaire. To determine the LCD score, participants were stratified into 11 groups according to carbohydrate, protein, fat, animal fat, animal protein, vegetable fat and vegetable protein intakes. Higher intake of protein and fat, and lower intake of carbohydrate received a higher score between 0-10. Macronutrients scores were summed together and LCD scores calculated. The association between LCD scores and likelihood of being assigned to NMOSD group was investigated using multiple regression models. Results: Total LCD scores increased from the median of 21.00 in the first decile to 53.00 in the tenth decile of LCD score. After adjustment for confounding factors including age, gender, BMI, energy intake, cigarette smoking and alcohol consumption, an inverse association was detected between LCD scores and odds of NMOSD. The odds of suffering from NMOSD declined significantly about 78% (OR: 0.22; 95% CI: 0.05-0.87) and 76% (OR: 0.24; 95% CI: 0.06-0.93) in the fifth and sixth deciles of LCD score compared to the first decile. Conclusion: From the obtained results it can be speculated that higher carbohydrate and lower protein and fat intakes may be associate with the increased odds of NMOSD. However, further studies are needed to confirm these results.

Illuminating the in vitro effects of Epstein-Barr virus and vitamin D on immune response in multiple sclerosis patients.

Given the complexity of immune complex diseases including multiple sclerosis (MS) and the plausible interactions between different risk factors, delineating the interplay between them would be imperative. The current study aimed to evaluate the in vitro effects of Epstein-Barr virus (EBV) and vitamin D on immune response in MS patients and healthy controls. The status of vitamin D and EBV load was evaluated using multiple techniques. In vitro EBV-infected peripheral blood mononuclear cells (PBMCs), in the presence or absence of vitamin D, were checked for IL-10, IFN-γ, and vitamin D receptor. MS patients showed significantly higher plasma levels of 1,25-(OH)2D but not 25-OHD, increased EBV load, and lower levels of vitamin D receptor (VDR) expression compared with healthy controls. Interestingly, an inverse correlation was observed between VDR expression and EBV load in PBMCs. Indeed, the levels of IFN-γ and IL-10 production were significantly higher in supernatant collected from in vitro EBV-infected PBMCs in MS patients compared with controls. While all vitamin D-treated PBMCs showed reduced levels of IFN-γ production, in vitro treatment of vitamin D showed no influence in IL-10 production. EBV and vitamin D were found to exert opposite in vitro effects on immune dysregulation in these patients. Our results highlight the complex interactions of different risk factors with immune system.

Umbilical cord mesenchymal stem cells as well as their released exosomes suppress proliferation of activated PBMCs in multiple sclerosis.

Multiple sclerosis (MS) is a central nervous system (CNS) degenerative disorder which is caused by a targeted autoimmune-mediated attack on myelin proteins. Previously, mesenchymal stem cells were considered as a novel and successful treatment of MS. One of the underlying mechanisms behind their immunomodulatory function is the release of extracellular vesicles, particularly exosomes. In this study, we aimed to evaluate the suppressive efficacy of MSCs and their exosomes on the proliferation of peripheral mononuclear blood cells (PBMC) in relapsing-remitting MS (RRMS) patients and healthy subjects. To do, mesenchymal stem cells were derived from human umbilical cord tissues and used for exosome isolation through ultracentrifugation. Suppressive function of MSCs and MSC-derived exosomes was examined in a coculture with CFSE-labelled PBMCs in vitro. PBMC proliferation of the patients and healthy individuals was measured using flow cytometry. We first demonstrated that proliferation of PBMCs decreased in the presence of MSCs and suppression was more efficient by MSC-derived exosomes, with a minimum alloreaction rate. However, suppression capacity of MSCs and their exosomes significantly decreased during extensive sub-culturing. The present study showed that MSC-derived exosomes as an effective cell-free therapy could prevent proliferation of PBMCs. However, further evaluations are need to move towards a functional approach that can be translated to the clinic.

Ischemic Stroke in Patients with COVID-19 Disease: A Report of 10 Cases from Iran.

Ischemic stroke seems to be one of the most serious neurologic complications in patients with COVID-19 infection. Herein, we report a series of 10 ischemic stroke patients with concomitant COVID-19 disease. Out of 10, 8 had large infarcts (3 massive middle cerebral artery, 2 basilar artery, 2 posterior cerebral artery, and 1 internal carotid artery infarct territory). Two had cardiogenic embolic stroke due to atrial fibrillation. Almost half of our patients did not have a vascular risk factor. Nine did not have fever and were diagnosed with COVID-19 upon admission for stroke. Stroke occurred in the first week of respiratory symptoms with moderate pulmonary involvement. Most Patients did not have hypoxia and did not establish respiratory failure or acute respiratory distress syndrome. The blood pressures were low and hemorrhagic transformation did not occur even after antiplatelet or anticoagulant therapy. Patients had markedly increased levels of lactate dehydrogenase, C-reactive protein, and D-dimer. Three patients died. It seems that ischemic strokes in COVID-19 patients tend to occur as large infarct and can be seen in patients with mild to moderate pulmonary involvement.

Reduction in circulating vitamin D binding protein in patients with multiple sclerosis.

BACKGROUND: In this study, we aimed to determine the risk association between vitamin D binding protein (VDBP) polymorphism in patients with multiple sclerosis (MS) in a MS biobank and the difference in VDBP serum levels in MS patients who were recently diagnosed. METHOD: The current case-control study was performed on 296 MS patients and 313 controls. Thereafter, two common missense VDBP polymorphisms, named rs7041and rs4588, were evaluated in all the participants. Serum levels of vitamin D and vitamin D binding protein were assessed in 77 MS patients who were diagnosed since one year ago and in 67 healthy people who were matched in terms of age and sex. RESULT: The frequency distributions of VDBP genotypes and alleles of SNP rs7041 and rs4588 were observed to be similar in both the MS and control groups (p > 0.05). The VDBP haplotypes, as Gc2/Gc2, Gc1/Gc1, and Gc1/Gc2, were found to be similar in the MS and control groups (p > 0.05). In subgroup analysis, circulating VDBP was lower in MS patients (Ln-VDBP (µgr/ml): 3.64 ± 0.91 vs. 5.31 ± 0.77, p = 0.0001) even after adjusting for vitamin D levels, body mass index, and taking vitamin D supplement. There was no significant association between VDBP haplotypes and vitamin D levels in the two groups. CONCLUSION: The present study suggested an association between lower levels of circulating VDBP and multiple sclerosis in newly diagnosed patients. However, the VDBP causative role in the development of MS is still unclear, so it needs more studies.

Multiple sclerosis projection in Tehran, Iran using Bayesian structural time series.

BACKGROUND: The prevalence of Multiple Sclerosis (MS) has been increasing worldwide and the highest prevalence ratio among Asian countries was reported in Iran. This study aims to estimate the increase in MS occurrence during more than three decades in Tehran and forecast the future condition of the disease using time series approaches for the next ten years. METHODS: The cross-sectional study was conducted from 1999 to 2019 based on records of MS cases from Iranian MS Society (IMSS) registry system. The prevalence was estimated using population data presented by the Statistical Centre of Iran. Through Bayesian Structural Time Series (BSTS) model, we want to predict the prevalence of familial and sporadic MS in the next ten years. . RESULTS: Among 22,421 cases with MS, 16,831 (75.1 %) were female and 5589 (24.9 %) were male. Female to male ratio was 3.0:1 and the number of familial MS cases were 2982 (13.3 %) of subjects. Female gender was less responsible for higher rate of MS in familial definition (beta = 0.020) in comparison to sporadic cases (beta = 0.034). Forecasting by BSTS revealed an increase in MS prevalence for the next ten years so that the prevalence rate for total, familial and sporadic MS respectively begins with 189.50 (183.94-195.14), 25.69 (24.97-26.45) and 163.74(159.06-168.57) in 2020 and ends with 220.84 (171.48-266.92), 30.79 (24.16-37.15), and 189.33(146.97-230.19) in 2029. CONCLUSIONS: According to the findings, MS prevalence increased during three decades and it will increase over the next ten years. Tehran province is one of the regions with highest MS prevalence in Asia. The results of present study indicated that females are at higher risk for MS than males in both sporadic and familial MS.

The possible role of Interleukin-6 as a regulator of insulin sensitivity in patients with neuromyelitis optica spectrum disorder.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is associated with inflammatory mediators that may also trigger downstream signaling pathways leading to reduce insulin sensitivity. METHODS: We aimed to determine the risk association of hyperinsulinemia in NMOSD patients with seropositive AQP4-IgG and the serum levels of interleukin (IL)-6 and IL-17A compared with the control group. Serum levels of metabolic (Insulin, Fasting Blood Sugar (FBS), lipid profile) and inflammatory (IL-6 and IL-17) markers were assessed in 56 NMOSD patients and 100 controls. RESULTS: Hyperinsulinemia was more prevalent in NMOSD patients independent of age, sex and body mass index (BMI) (48.2% vs. 26%, p = 0.005) compared to control group. After adjusting age, sex and BMI, there was significant association between lower insulin sensitivity (IS) and NMOSD risk (95% CI: Beta = 0.73, 0.62 to 0.86, p = 0.0001). Circulating levels of IL-6 and IL-17 were higher in NMOSD patients, and only IL-6 had an effect modifier for the association between lower insulin sensitivity and NMOSD risk. CONCLUSIONS: Our data suggests that inflammatory pathogenesis of NMOSD leads to hyperinsulinemia and increases the risk of insulin resistance.