Recent evidence points to a pathogenic role for CD8+ cytotoxic T (Tc) cells in Multiple sclerosis (MS). Based on cytokine profile, Tc cells can be divided into different subsets: IFN-γ (Tc1), IL-4 ...(Tc2), IL-10 (Tc10), IL-17 (Tc17), IL-21 (Tc21), IL-22 (Tc22) and TNF-α producing cells. In this study we evaluated the frequency of Tc cell subsets and the serum level of Tc17 differentiation cytokines in MS patients with different clinical patterns. We analyzed Tc cell subsets percentage in peripheral blood of relapsing-remitting (RRMS) (n = 28), secondary-progressive (SPMS) (n = 10) and primary-progressive (PPMS) (n = 4) MS patients in comparison to healthy controls (n = 15) using flow cytometry. Serum level of TGF-β, IL-6 and IL-23 were measured by ELISA. We showed elevated levels of Tc1 and Tc17 cells in SPMS and RRMS patients in relapse phase, respectively (P = 0.04). Interestingly, the percentage of TNF-α producing CD8+ T cells in relapse and remission phase of RRMS and SPMS patients were higher than controls (P = 0.01, P = 0.004, P = 0.01, respectively) and Tc21 increased in remission phase of RRMS compared to SPMS (P = 0.03). We also found higher frequency of CD8+ IFN-γ+ TNF-α+ IL-17+ T cells in relapse phase of RRMS compared to remission phase, SPMS patients and controls (P = 0.01, P = 0.004 and P = 0.02, respectively). TGF- β increased in sera of RRMS patients in remission phase (P = 0.03) and SPMS (P = 0.05) compared to healthy subjects. Increased level of Tc17 and CD8+ IFN-γ+ TNF-α+ IL-17+ T cells in relapse phase highlights the critical role of IL-17 in RRMS pathogenesis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
Sarcoidosis is a systemic inflammatory disease histologically defined by the non-caseation granulomas formation in different organs, most commonly lungs, liver, skin, ...gastrointestinal system, eyes, neurologic and cardiac system
Case presentation
We report the case of a 42-year-old Gilaks woman who presented with myelopathy with characteristic MRI finding called trident sign. By finding this view in axial spinal Magnetic Resonance Imaging (MRI) imaging, a systemic evaluation was performed on the patient, which led to the diagnosis of cardiac involvement in Sarcoidosis with the specific appearance of this disease in cardiac MRI despite the negative Fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan.
Conclusions
Sometimes characteristic findings such as the trident sign prompt the physician to high suspicion and wide evaluation of the patient to reveal important organ involvement that changes the treatment decision and saves the patient.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Diffusion tensor imaging (DTI) is a noninvasive, quantitative MRI technique that measures white matter (WM) integrity. Many brain dimensions are heritable, including white matter integrity measured ...with DTI. Family studies are valuable to provide insights into the interactive effects of non-environmental factors on multiple sclerosis (MS). To examine the contribution of familial factors to the diffusion signals across WM microstructure, we performed DTI and calculated neurite orientation dispersion plus density imaging (NODDI) diffusion parameters in two patient groups comprising familial and sporadic forms of multiple sclerosis and their unaffected relatives. We divided 111 subjects (49 men and 62 women: age range 19–60) into three groups conforming to their MS history. The familial MS group included 30 participants (patients;
n
= 16, healthy relatives;
n
= 14). The sporadic group included 41 participants (patients;
n
= 10, healthy relatives;
n
= 31). Forty age-matched subjects with no history of MS in their families were defined as the control group. To study white matter integrity, two methods were employed: one for calculating the mean of DTI, FA, and MD parameters on 18 tracts using Tracts Constrained by Underlying Anatomy (TRACULA) and the other for whole brain voxel-based analysis using tract-based spatial statistics (TBSS) on NDI and ODI parameters derived from NODDI and DTI parameters. Voxel-based analysis showed considerable changes in FA, MD, NDI, and ODI in the familial group when compared with the control group, reflecting widespread impairment of white matter in this group. The analysis of 18 tracts with TRACULA revealed increased MD and FA reduction in more tracts (left and right ILF, UNC, and SLFT, forceps major and minor) in familial MS patients vs. the control group. There were no significant differences between the patient groups. We found no consequential changes in healthy relatives of both patient groups in voxel-based and tract analyses. Considering the multifactorial etiology of MS, familial studies are of great importance to clarify the effects of certain predisposing factors on demyelinating brain pathology.
Background:
Complement system activation products are present in areas of neuroinflammation, demyelination, and neurodegeneration in brains of patients with multiple sclerosis (MS). C3 is a central ...element in the activation of complement cascades. A common coding variant in the C3 gene (rs2230199, C3R102G) affects C3 activity.
Objectives:
To assess the effects of rs2230199 on MS severity using clinical, cognitive, and imaging measures.
Methods:
In total, 161 relapse-onset MS patients (Expanded Disability Status Scale (EDSS) ≤ 6) underwent physical assessments, cognitive tests (Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT), and California Verbal Learning Test (CVLT)), and magnetic resonance imaging (MRI). Lesion volumes were quantified semi-automatically. Voxel-wise analyses were performed to assess the effects of rs2230199 genotype on gray matter (GM) atrophy (n = 155), white matter (WM) fractional anisotropy (FA; n = 105), and WM magnetization transfer ratio (MTR; n = 90).
Results:
While rs2230199 minor-allele dosage (C3-102G) showed no significant effect on EDSS and Multiple Sclerosis Functional Composite (MSFC), it was associated with worse cognitive performance (p = 0.02), lower brain parenchymal fraction (p = 0.003), and higher lesion burden (p = 0.02). Moreover, voxel-wise analyses showed lower GM volume in subcortical structures and insula, and lower FA and MTR in several WM areas with higher copies of rs2230199 minor allele.
Conclusion:
C3-rs2230199 affects white and GM damage as well as cognitive impairment in MS patients. Our findings support a causal role for complement system activity in the pathophysiology of MS.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Patients with multiple sclerosis (MS) suffer from a wide range of psychological problems. Application of a valid and reliable tool for psychosocial assessment is required for Iranian patients. The ...aim of this study is to determine the psychometric properties of the Persian version of the PARADISE-24 questionnaire in Iranian patients with multiple sclerosis.
One hundred and thirteen multiple sclerosis cases were enrolled in this study. Participants were asked to answer the valid and reliable Persian version of the fatigue severity scale, social support scale, Pittsburg sleep quality index, and hospital anxiety and depression scale and translated version of the PARADISE-24 questionnaire. Twenty cases filed the questionnaire 2 weeks later to assess reliability. The intraclass correlation coefficient, Cronbach's alpha, correlation coefficients, and multiple regression analysis were used.
Mean age and mean duration of the disease were 35.8 ± 9.9 and 8.7 ± 5.6 years, respectively. The intraclass correlation coefficients ranged from 0.8 to 0.94 and Cronbach's alpha values (Cronbach's alpha was calculated as 0.91 for the whole questionnaire) were also significant. There were significant correlations between PARADISE-24 score and expanded disability status scale (
= 0.42,
< 0.001), fatigue severity scale (
= 0.62,
< 0.001), anxiety (
= 0.43, P < 0.001) and Pittsburg sleep quality index scores (
= 0.46,
< 0.001). Regression analysis by considering PARADISE-24 as dependent and other variables as independent showed that expanded disability status scale, fatigue severity scale, anxiety score, and Pittsburg sleep quality index were positive predictors of PARADISE-24 score.
Persian version of PARADISE-24 questionnaire is a valid and reliable instrument for evaluating psychosocial aspects in patients with multiple sclerosis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Neuromyelitis optica (NMO) exhibits substantial similarities to multiple sclerosis (MS) in clinical manifestations and imaging results and has long been considered a variant of MS. With the advent of ...a specific biomarker in NMO, known as anti-aquaporin 4, this assumption has changed; however, the differential diagnosis remains challenging and it is still not clear whether a combination of neuroimaging and clinical data could be used to aid clinical decision-making. Computer-aided diagnosis is a rapidly evolving process that holds great promise to facilitate objective differential diagnoses of disorders that show similar presentations. In this study, we aimed to use a powerful method for multi-modal data fusion, known as a multi-kernel learning and performed automatic diagnosis of subjects. We included 30 patients with NMO, 25 patients with MS and 35 healthy volunteers and performed multi-modal imaging with T1-weighted high resolution scans, diffusion tensor imaging (DTI) and resting-state functional MRI (fMRI). In addition, subjects underwent clinical examinations and cognitive assessments. We included 18 a priori predictors from neuroimaging, clinical and cognitive measures in the initial model. We used 10-fold cross-validation to learn the importance of each modality, train and finally test the model performance. The mean accuracy in differentiating between MS and NMO was 88%, where visible white matter lesion load, normal appearing white matter (DTI) and functional connectivity had the most important contributions to the final classification. In a multi-class classification problem we distinguished between all of 3 groups (MS, NMO and healthy controls) with an average accuracy of 84%. In this classification, visible white matter lesion load, functional connectivity, and cognitive scores were the 3 most important modalities. Our work provides preliminary evidence that computational tools can be used to help make an objective differential diagnosis of NMO and MS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Fingolimod was the first oral therapy approved for treating relapsing-remitting multiple sclerosis (RRMS) in 2010. This open-label study evaluated the safety and efficacy of fingolide
, 0.5 mg in ...Iranian MS patients during one-year follow-up.
A multicenter, open-label, longitudinal was designed to evaluate the safety and efficacy of fingolide
, 0.5 mg over a one-year follow-up period across 11 centers. The patients were visited by their neurologists every two months to evaluate possible adverse events and clinical disease activity considered by recording Kurtzke's Expanded Disability Status Scale (EDSS).
A total of 252 patients with the mean treatment duration of 343±45.70 days were. 20 patients experienced adverse events (AEs) and serious adverse events (SAEs) such as resistant urinary tract infection (UTI), premature atrial contraction (PAC), skin allergic reaction, macular edema, chicken pox, zona, panic attacks, and exacerbations associated with steroids treatment, all of which led to Fingolide
discontinuation. The mean EDSS decreased from (2.15±1.29, 95%CI: 1.99to2.32) at baseline to (1.85±1.22, 95%CI: 1.68to2.02) at 12th month (final visit) while a p-value revealed significant differences comparing baseline and final EDSS (p<0.001). Mean annualized relapse rate (ARR) of the patients in one year prior to the study was (0.006±0.016, 95%CI: 0.004to0.008) which changed to (0.005±0.016, 95%CI: 0.003to0.007) at the end of the study period. Patients with a 12-month period of fingolide
treatment experienced sustained ARR and disease progression (p<0.001).
The obtained findings suggest that the administration of Fingolide
, 0.5 mg (Fingolimod, Osvahpharma, Tehran, Iran) is safe and efficient for Iranian MS patients.
Multiple sclerosis is a chronic inflammatory disease of the central nervous system characterized by a complex immune response. Because of the complex nature of MS pathogenesis, a panel of biomarkers ...derived from different platforms will be required to reflect disease-related alterations. Monitoring and evaluation of molecules associated with the pathogenesis of the disease would provide useful information on disease progression and therapeutic assessment. In view of this, we evaluated the mRNA expression levels of B-cell activating factor (BAFF), high mobility group box 1 (HMGB-1), Toll like receptor (TLR) 4 and TLR7 in MS. These molecules are implicated in the pathogenesis of MS; however, they havereceived little attention. PBMCs were isolated from whole blood of 84 Relapsing Remitting Multiple Sclerosis patients and 70 healthy controls. Relative quantitative RT-PCR was applied to quantify the transcriptional levels of the immune markers. The mRNA expression levels of TLR7 were significantly elevated in RRMS patients than healthy controls. Whereas, TLR4 expression was found to be significantly lower in the patients than control group. We found no difference analyzing the mRNA levels of BAFF and HMGB1. Our data highlights the immune marker correlates in RRMS patients. However, further in-depth studies are warranted to check for their reliability of biomarkers in autoimmune diseases such as MS.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
•Neuromyelitis Optica Spectrum Disorders is an autoimmune inflammatory demyelinating disease of the central nervous system.•There have been many reports on its association with other disorders ...including systemic and organ specific autoimmune diseases.•Here, we reviewed other immune mediated diseases associated with NMOSD and try to categorize them.
Neuromyelitis Optica (NMO) is an autoimmune inflammatory demyelinating disease of the central nervous system (CNS) which predominantly involves optic nerves and spinal cord. Since the introduction of Neuromyelitis Optica Spectrum Disorders (NMOSD) as a separate entity, there have been many reports on its association with other disorders including systemic and organ-specific autoimmune diseases. Here, we reviewed other immune-mediated diseases associated with NMOSD and tried to categorize them.
The present review was conducted using the PUBMED database based on papers from 1976 (i.e., since the first NMO comorbidity with SLE was reported) to 2017. We included all articles published in English. The keywords utilized included Neuromyelitis optica, Neuromyelitis Optica Spectrum Disorders, Devic's disease, in combination with comorbidity or comorbidities.
Diseases with immune-based pathogenesis are the most frequently reported co-morbidities associated with NMOSD, most of which are antibody-mediated diseases. According to literature, Sjogren's Syndrome (SS) and Systemic Lupus Erythematosus (SLE) are the most frequently reported diseases associated with NMOSD among systemic autoimmune diseases. Further, myasthenia gravis in neurological and autoimmune thyroid diseases in non-neurological organ-specific autoimmune diseases are the most reported comorbidities associated with NMOSD in the literature.
NMOSD may be associated with a variety of different types of autoimmune diseases. Therefore, systemic or laboratory signs which are not typical for NMOSD should be properly investigated to exclude other associated comorbidities. These comorbidities may affect the treatment strategy and may improve the patients' care and management.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) is a rare autosomal recessive disorder that has been known in recent years. Clinically, patients usually ...present slowly progressive symptoms of pyramidal, cerebellar and dorsal column dysfunction. In 2012 magnetic resonance imaging (MRI) criteria were proposed for diagnosing these patients based on characteristic MRI abnormalities in selective areas of the brain and spinal cord. These imaging features help clinicians to distinguish it from other white matter diseases. Here we report a case diagnosed based on characteristic MRI abnormalities in selective areas and high lactate in the magnetic resonance spectroscopy (MRS).
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