Evaluation of CD137 and CD137L Transcript Levels and the Serum sCD137 in Immune-mediated Polyneuropathy.

Background: Abnormal humoral and cellular immune responses have been reported in immune-mediated polyneuropathies. CD137, as a costimulatory molecule and a TNF receptor superfamily member, has been demonstrated to have a key role in the pathogenesis of many autoimmune as well as inflammatory disorders. Objective: To evaluate the transcripts levels of CD137, its ligand (CD137L), and the serum levels of soluble CD137 (sCD137) in patients with immune-mediated polyneuropathy. Methods: A total of 45 patients and 46 sex and age-matched healthy individuals were enrolled in the study. CD137 and CD137L transcript levels were assessed by the Real-Time PCR, and the serum level of sCD137 was measured using the ELISA technique. The Bayesian regression model was used for statistical analysis at the 0.05 significance level in R 4.1.0 statistical environment. Results: Transcript levels of the CD137 and CD137L were higher in polyneuropathy patients in comparison with the healthy subjects (P=0.006 for both). Conversely, the mean level of sCD137 was significantly lower in the sera of patients compared to the controls (P<0.001). Conclusion: Our findings point to the possible role of CD137 and CD137L in immune-mediated polyneuropathy pathogenesis. More investigations are required to clarify the exact contributions of the mentioned molecules to the pathogenesis of immune-mediated polyneuropathies.

An inclusive study on cytokine gene expression in Parkinson's disease: Advanced analysis using Bayesian regression model.

BACKGROUND: Parkinson's disease (PD) is the second most prevalent neurodegenerative disease throughout the globe whose specific pathophysiology is unknown. Researchers believe that inflammation and oxidative stress contribute to PD development. Also, alterations in cytokines production appear to have a key role in the pathogenesis of PD. The aim of the current study was to evaluate gene expression levels of nine cytokines in the peripheral blood of PD patients compared to a healthy control group. METHODS: Real-time PCR was used to analyze cytokines gene expression followed by advanced statistical analysis performed using Bayesian regression model in R (version 4.1.0) statistical software. RESULTS: TNF-α, IL-1ß, IL-2, IL-4, IFN-γ, IL-17 and IL-6 transcript levels were upregulated in patients compared to healthy controls. However, CXCL8 expression was downregulated in patients compared to controls and IFN-ß expression was not statistically different between the two groups. While we found no significant difference between the groups based on gender and age regarding TNF-α, IL-1ß, CXCL8, IL-2, IL-4, IFN-γ and IFN-ß gene expression, IL-6 and IL-17 transcript levels showed significant upregulations in older subjects and in females, respectively. In addition, we found that the interaction effects between gender and group on gene expression levels were not significant. In this way, the subgroup analysis within gender revealed that in each gender, expression levels of TNF-α, IL-2, IL-4, IL-6, IFN-γ and IL-17 were significantly higher in patients than controls. However, IFN-ß expression level did not show any significant difference between groups and subgroups. CONCLUSION: The present study provides evidence on significant alterations in cytokine expression with different patterns and points to immune system dysregulation in PD.

Clinical Evidence of Acetyl-L-Carnitine Efficacy in the Treatment of Acute Ischemic Stroke: A Pilot Clinical Trial.

Background: This study was undertaken to evaluate the influence of oral Acetyl-L-carnitine (ALC) in patients with acute ischemic stroke. Methods: Sixty-nine cases with acute ischemic stroke with the onset of symptoms less than 24 hours not candidates for reperfusion therapy were randomly assigned to either the ALC group (1000 mg three times per day for three consecutive days) or the matching placebo group. The study outcomes based on intention-to-treat criteria included the change in the modified Rankin Scale (mRS) and National Institutes of Health Stroke Scale (NIHSS) score from baseline to day 90, as well as the change in serum levels of the inflammatory and oxidative stress biomarkers over the 3-day treatment protocol. Results: The NIHSS score and mRS score on day 90 were improved by 5.82 and 0.94 scores, respectively, in the ALC-treated group compared to 2.83 and 0.11 scores, respectively, in the placebo-treated group, which demonstrated the superiority of ALC relative to placebo. By using the multivariable analysis after adjusting for other variables in the model, compared to the group treated with placebo, patients in the ALC group had lower NIHSS score (ß: -2.40, 95% CI: -0.69, -4.10 (p = 0.007)) and mRS score (ß: -1.18, 95% CI: -0.52, -1.84 (p = 0.001)) 90 days after the intervention. The percentage of patients with a favourable functional outcome at day 90, defined as mRS scores of 0 or 1, was significantly higher in the ALC group in comparison to the placebo group (52.9% versus 28.6%). Further, over the 3-day treatment protocol, in the patients receiving ALC, the serum levels of proinflammatory biomarkers, including soluble intercellular adhesion molecule-1 (sICAM-1), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), and neuron-specific enolase (NSE), showed a significant decrease, while the serum levels of antioxidant biomarkers, including glutathione peroxidase (GPx), superoxide dismutase (SOD), and total antioxidant capacity (TAC), as well as the total L-carnitine's level showed a significant increase compared to those in patients receiving placebo indicating significant alteration. Conclusions: Although preliminary, these results suggested that ALC administration during the acute phase of ischemic stroke might be helpful in improving functional and neurological outcomes that are probably linked to its anti-inflammatory and antioxidant properties. Trial Registration. This trial is registered with IRCT20150629022965N17 at Iranian Registry of Clinical Trials (registration date: 25/07/2018).

Parkinson's Disease Is Associated With Dysregulation of Circulatory Levels of lncRNAs.

Long non-coding RNAs (lncRNAs) have been recently reported to be involved in the pathoetiology of Parkinson's disease (PD). Circulatory levels of lncRNAs might be used as markers for PD. In the present work, we measured expression levels of HULC, PVT1, MEG3, SPRY4-IT1, LINC-ROR and DSCAM-AS1 lncRNAs in the circulation of patients with PD versus healthy controls. Expression of HULC was lower in total patients compared with total controls (Expression ratio (ER)=0.19, adjusted P value<0.0001) as well as in female patients compared with female controls (ER=0.071, adjusted P value=0.0004). Expression of PVT1 was lower in total patients compared with total controls (ER=0.55, adjusted P value=0.0124). Expression of DSCAM-AS1 was higher in total patients compared with total controls (ER=5.67, P value=0.0029) and in male patients compared with male controls (ER=9.526, adjusted P value=0.0024). Expression of SPRY4-IT was higher in total patients compared with total controls (ER=2.64, adjusted P value<0.02) and in male patients compared with male controls (ER=3.43, P value<0.03). Expression of LINC-ROR was higher in total patients compared with total controls (ER=10.36, adjusted P value<0.0001) and in both male and female patients compared with sex-matched controls (ER=4.57, adjusted P value=0.03 and ER=23.47, adjusted P value=0.0019, respectively). Finally, expression of MEG3 was higher in total patients compared with total controls (ER=13.94, adjusted P value<0.0001) and in both male and female patients compared with sex-matched controls (ER=8.60, adjusted P value<0.004 and ER=22.58, adjusted P value<0.0085, respectively). ROC curve analysis revealed that MEG3 and LINC-ROR have diagnostic power of 0.77 and 0.73, respectively. Other lncRNAs had AUC values less than 0.7. Expression of none of lncRNAs was correlated with age of patients, disease duration, disease stage, MMSE or UPDRS. The current study provides further evidence for dysregulation of lncRNAs in the circulation of PD patients.

Over-expression of IL-6 coding gene in the peripheral blood of migraine with aura patients.

Migraine is a common disorder which is placed among the top ten reasons of years lived with disability. Cytokines are among the molecules that contribute in the pathophysiology of migraine. In the current study, we evaluated expression levels of IL-6 coding gene in the peripheral blood of 120 migraine patients (54 migraine without aura and 66 migraine with aura patients) and 40 healthy subjects. No significant difference was detected in expression of IL-6 between total migraine patients and healthy controls (Posterior beta = 0.253, P value = 0.199). The interaction effect between gender and group was significant (Posterior beta =-1.274, P value = 0.011), therefore, we conducted subgroup analysis within gender group. Such analysis revealed that while expression of this gene is not different between male patients and male controls (Posterior beta =-0.371, P value > 0.999), it was significantly over-expressed in female patients compared with female controls (Posterior beta = 0.86, P= 0.002). Expression of IL-6 was significantly higher in patients with aura compared with controls (Posterior beta = 0.63, adjusted P value = 0.019). However, expression of this cytokine coding gene was not different between patients without aura and healthy subjects (Posterior beta = 0.193, adjusted P value = 0.281). Therefore, IL-6 might be involved in the pathophysiology of migraine among females and migraine with aura among both sexes.

Upregulation of VEGF-A and correlation between VEGF-A and FLT-1 expressions in Iranian multiple sclerosis patients.

Multiple sclerosis (MS) is among the most common diseases affecting brain and spinal cord. MS progression is characterized by breakdown of blood brain barrier which leads to increased vascular permeability and angiogenesis. Consequently, vascular endothelial growth factor A (VEGF) and its receptors are considered to be important components of MS progression. VEGFA and fms-related tyrosine kinase 1 (FLT1) play important roles in various aspects of MS. In this study, we investigated the relationship between these genes and MS. For this purpose, the expression levels of VEGFA and FLT1 were measured in the blood of 50 relapsing-remitting MS (RR-MS) patients and 50 healthy individuals using TaqMan quantitative real-time PCR. A significant upregulation of VEGFA expression was observed among MS patients compared with controls (p = 0.04). However, the difference in FLT1 gene expression between study groups was insignificant (p = 0.947). In addition, there was a significant positive correlation between VEGFA and FLT1 genes expressions (r = 0.769, p < 0.0001). In spite of the highly complex molecular mechanisms behind this, the findings imply participation of VEGFA in the pathogenesis of MS.

MALAT1 Genomic Variants and Risk of Multiple Sclerosis.

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long noncoding RNA (lncRNA) with a possible role in the regulation of immune responses. A previous study has demonstrated down-regulation of this lncRNA in multiple sclerosis (MS) patients. In the current study, we genotyped two MALAT1 single nucleotide polymorphisms (SNPs) in 428 Iranian MS patients and 505 healthy subjects. The G allele of the rs619586 was significantly under-represented in MS patients compared with controls (OR (95% CI) = 0.65 (0.46-0.92), adjusted P value = 0.03). This SNP was associated with lower MS risk in dominant model (OR (95% CI) = 0.63 (0.43-0.91), adjusted P value = 0.03). The rs3200401 was not associated with MS risk in any inheritance model. Moreover, the A T haplotype (rs619586 and rs3200401, respectively) within MALAT1 was associated with MS risk. The current study provides additional evidences for contribution of MALAT1 in the pathogenesis of MS.

GAS5 genomic variants and risk of multiple sclerosis.

The lncRNA Growth arrest-specific 5 (GAS5) has crucial roles in the apoptosis, suppression of cell growth and regulation of response to glucocorticoids. Previous studies have demonstrated its role in the pathogenesis of some immune-related disorders such as systemic lupus erythematosus and multiple sclerosis (MS). In the current study, we genotyped two possibly functional GAS5 polymorphisms (rs2067079 and rs6790) in 810 individuals including 410 MS patients and 400 age and sex-matched healthy subjects. There was a significant over-representation of the rs2067079 T allele in MS patients compared with healthy individuals (OR (95% CI) = 1.38 (1.12-1.71), adjusted P value = 0.008). This SNP was associated with MS risk in co-dominant and recessive models (OR (95% CI) = 2.70 (1.54-4.76), adjusted P value = 0.003; OR (95% CI) = 2.58 (1.5-4.42), adjusted P value = 7.9E-4 respectively). The rs6790 was not associated with MS risk in any inheritance models. The T G haplotype (rs2067079 and rs6790 respectively) was significantly more prevalent among cases compared with controls (OR (95% CI) = 1.48 (1.16-1.89), adjusted P value = 0.005). Our results further highlight the role of GAS5 in the pathogenesis of MS.

Expression analysis of long non-coding RNAs and their target genes in multiple sclerosis patients.

Multiple sclerosis (MS) is a progressive chronic autoimmune-mediated disease. Recently, long non-coding RNAs (lncRNAs) are characterized to participate in the adjustment of immune responses. Here, we evaluated the expression levels of GSTT1-AS1 and IFNG-AS1 lncRNAs and their targets (TNF and IFNG, respectively) in Iranian MS patients.In this case-control study, 50 relapsing-remitting MS patients and 50 healthy subjects were recruited. Expressions of GSTT1-AS1 and IFNG-AS1 lncRNAs, as well as TNF and IFNG genes, were assessed in their peripheral blood samples by SYBR Green-based Real-time quantitative PCR.Expression levels of GSTT1-AS1 and IFNG-AS1 lncRNAs were both significantly downregulated (p values 0.032 and 0.013, respectively). On the other hand, the expression of TNF and IFNG showed increased levels, however, did not reach statistical significance after our analysis (p > 0.05). Spearman correlation analysis showed that GSTT1-AS1 had a significant positive moderate correlation with IFNG-AS1 (r = 0.541, p < 0.0001), IFNG (r = 0.329, p = 0.001), and TNF (r = 0.204, p = 0.041). Also, IFNG-AS1 revealed the same correlation with IFNG (r = 0.475, p < 0.0001) as well as TNF (r = 0.399, p < 0.0001). Furthermore, GSTT1-AS1 (r = 0.313, p = 0.027) and (IFNG r = 0.478, p < 0.0001) demonstrated a significant positive correlation with age at onset.Briefly, the current study provided for the first time dysregulation of GSTT1-AS1 and IFNG-AS lncRNAs network in MS, which highlights the significant role of epigenetic pathways in this autoimmune disorder. Larger sample size and further investigation assays could shed light on the underlying mechanisms in this area of science.

The Growth Arrest-Specific Transcript 5 (GAS5) and Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1): Novel Markers Involved in Multiple Sclerosis.

Recent studies have revealed that long noncoding RNAs (lncRNAs) are connected with pathogenesis of neurodegenerative diseases. Additionally, glucocorticoids have fundamental regulatory roles on the immune system, and act as potent therapeutic compounds for autoimmune and inflammatory diseases. The long noncoding RNA growth arrest-specific 5 (GAS5) which accumulates inside the cells in response to cellular starvation/growth arrest, acts as a potent repressor of the glucocorticoid receptor (GR) through its glucocorticoid response element (GRE). The aim of the present study was to investigate the role of lncRNA GAS5 and its downstream target Nuclear Receptor Subfamily 3 Group C Member 1(NR3C1) in the pathogenesis of multiple sclerosis (MS), and to define the role of GAS5 in the regulation of NR3C1 expression. Quantitative polymerase chain reaction was performed for investigating the expression of GAS5 and NR3C1 in MS patients and healthy subjects. We found that GAS5 levels were up-regulated in the MS patients, blood compared with healthy subjects in correlation with NR3C1 expression. Our findings suggest that GAS5 may play on important role in the molecular etiology and treatment of MS.

Dysregulation of long non-coding RNA profile in peripheral blood of multiple sclerosis patients.

Multiple sclerosis (MS) is a chronic autoimmune disorder in which dysregulation or aberrant expressions of several immune-related genes have been noted. More recently, the participation of long non-coding RNAs (lncRNAs) in regulation of immune responses has been highlighted. In the present study, we evaluated expression levels of three lncRNAs named Nuclear Paraspeckle Assembly Transcript 1 (NEAT1), P21 associated ncRNA DNA damage activated (PANDA) and Taurine-up-regulated gene 1 (TUG1) in peripheral blood of 50 relapsing-remitting MS patients and 50 matched healthy subjects. All three lncRNAs have been significantly over-expressed in MS patients compared with healthy subjects. In addition, significant correlations were found between expression levels of these three lncRNAs in the patients group. NEAT1 expression was inversely correlated with age at onset and disease duration in female patients. Moreover, TUG1 expression was inversely correlated with disease duration in female patients. The present study provides further evidences for the role of lncRNAs in pathogenesis of MS.

Cytokine profile in autistic patients.

The etiology of Autism Spectrum Disorders (ASDs) as severe neurodevelopmental ailments is not known. However, several evidences point to dysregulation of immune system as an underlying cause of ASD. In the present study we evaluated the mRNA expression levels of TNF-α, TGF-ß, IFN-γ, CXCL8, IL-1ß, IL-2, 1L-4, IL-6, IL-17 in whole blood samples of 30 ASD patients and 41 age and sex-matched healthy subjects with means of real-time PCR. TNF-α, IL-6 and IL-17 have been shown to be significantly up-regulated in ASD patients compared with healthy subjects (P < 0.0001, P = 0.001 and P < 0.0001 respectively). IL-2 has been shown to be significantly down-regulated in total ASD patients (P < 0.0001). No significant difference has been found in expression levels of other cytokines between patients and healthy subjects. The present study provides further evidences for dysregulation of immune response in ASD patients.

STAT5a and STAT6 gene expression levels in multiple sclerosis patients.

Multiple sclerosis (MS) is a complex inflammatory, autoimmune disease of the central nervous system (CNS). The disease pathogenesis is not well defined yet. Cytokines have an important role in inflammation as characteristic feature of the disease. Janus kinase/signal transducers and activators of transcriptions (JAK/STAT) family promote cytokine-mediated cell activation. Failure in the JAK/STAT signaling pathway is associated with the pathological outcome in MS. In this study, we compared the expression levels of STAT5a and STAT6 genes in the blood of 50 relapsing-remitting MS (RR-MS) patients and 50 healthy controls by Taqman Quantitative Real-Time PCR in patients and healthy control group. We found that STAT5a expression was significantly down-regulated (p = .049), whereas STAT6 gene expression was significantly up-regulated (p = .046) in MS patients compared with controls. Moreover, there was significant correlation between the STAT6 gene expression and Kurtzke Expanded Disability Status Scale (EDSS) criterion. However, no significant correlation was demonstrated between the expression of STAT5a gene and clinical findings. Furthermore, there was not significant correlation between expression levels of STAT5a and STAT6 genes. Our findings suggest that STAT5a and STAT6 dysregulation may have a critical role in modification of immune responses leading to imbalance between Th2- and Th1-related cytokines. However, the mechanisms underlying it still remain to be elucidated. Future studies are needed to explore the role of STAT5a and STAT6 as prognostic biomarkers in research, design of experimental therapies or clinical settings of the MS.

Down-regulation of TYK2, CBLB and LMP7 genes expression in relapsing-remitting multiple sclerosis patients treated with interferon-beta.

This study aimed to examine the expression of TYK2, CBLB and LMP7 genes at both mRNA and protein levels in relapsing-remitting MS (RRMS) patients in compare with healthy controls. Seventy-eight RRMS patients treated with IFNß-1a and 79 age- and ethnic-matched healthy subjects were studied. The mRNA expression levels of TYK2, CBLB and LMP7 in PBMCs were quantified by real-time PCR and plasma concentrations of three molecules were measured by ELISA. Results were compared between patients and controls, IFNß-responders and non-responders. Forty-nine of 78 patients were classified as IFNß-responders and 29 cases were non-responders. Significantly down-regulated expression of TYK2, CBLB and LMP7 genes was found in the patients group versus controls (P<0.001). Decreased plasma levels of three molecules were observed in patients compared to controls (P<0.001). IFNß-responders had significantly higher expressions for CBLB (P=0.001) and LMP7 (P=0.02) than non-responders. Also, we observed increased expressions of LMP7 (P=0.39) and CBLB (P=0.02) genes in patients under 30y and increased expression of TYK2 in patients >40years (P=0.002). Our results suggest that expression analysis of TYK2, CBLB and LMP7 genes could be useful for evaluation of T cells immunity and clinical response to IFNß-therapy in RRMS patients.

Ecotropic Viral Integration Site 5 (EVI5) variants are associated with multiple sclerosis in Iranian population.

BACKGROUND: Multiple sclerosis (MS) is a multifactorial disorder with immunological basis. Numerous genetic and environmental factors contribute in its pathogenesis. Several genetic loci have been shown to be associated with MS risk. Among genes whose participation in MS has been evaluated is Ecotropic Viral Integration Site 5 (EVI5). EVI5 is a common site of retroviral integration with a possible role in T-cell lymphomagenesis. METHODS: In the current study, we aimed to confirm association of the single nucleotide polymorphisms (SNPs) within EVI5 gene with MS in 410 relapsing-remitting MS patients and 410 controls from Iranian population. The rs6680578, rs10537781 and rs11810217 genotypes were defined by amplification-refractory mutation system (ARMS)-PCR method. RESULTS: The allele and genotype frequencies of rs6680578 and rs11810217 were not significantly different between cases and controls. However, in the rs10735781 the GG genotype was significantly associated with MS risk in recessive (P = 0.03, OR (95%CI) = 1.84 (1.05-3.19)) and co-dominant models (P = 0.02, OR 95%CI) = 1.90 (1.08-3.35)). In addition, T G T haplotype (rs6680578, rs10735781 and rs11810217 respectively) was associated with MS risk while T C C, A G T and A C T had a protective effect against MS. CONCLUSION: The results of the current study provide further evidences for participation of EVI5 in MS pathogenesis.

Expression Analysis of Long Non-coding RNAs in the Blood of Multiple Sclerosis Patients.

Multiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system (CNS) with multiple genetic and environmental risk factors. Long non-coding RNAs (lncRNAs) have been recently reported to participate in the regulation of immune responses. Consequently, aberrant expression of lncRNAs has been suggested as an underlying cause of MS. In the present study, we evaluated the expression of three lncRNAs with putative roles in the regulation of immune response, namely TNF-α and heterogeneous nuclear ribonucleoprotein L (THRIL), Fas cell surface death receptor- antisense 1 (FAS-AS1), and plasmacytoma variant translocation 1 (PVT1) in circulating blood cells of 50 Iranian relapsing-remitting multiple sclerosis (RRMS) patients compared with healthy subjects by means of quantitative real-time polymerase chain reaction (PCR). We detected a significant downregulation of PVT1 and FAS-AS1 expressions in RRMS patients while a significant upregulation of THRIL in patients compared with controls (P < 0.001). Correlation analyses between lncRNA expression levels and clinical data of MS patients revealed no significant correlation between lncRNAs expression levels and Expanded Disability Status Scale (EDSS), a moderate correlation between PVT1 expression levels and duration of the disorder and no significant correlation between lncRNAs expression levels and age at onset. In addition, we demonstrated correlations between the expression levels of PVT1 and THRIL as well as expression levels of THRIL and FAS-AS1 in RRMS patients. In brief, we have demonstrated dysregulation of three lncRNAs in MS patients. Further studies are needed to explore the exact mechanisms by which these lncRNAs participate in regulation of immune responses.

Determination of cytokine levels in multiple sclerosis patients and their relevance with patients' response to Cinnovex.

Multiple sclerosis (MS) is a heterogeneous chronic immune-mediated disorder of the central nervous system (CNS) with several environmental and genetic factors participating in its development and disease course. Interferon (IFN)-ß therapy is considered as the first line treatment in this disorder. The present study enrolled 231 relapsing-remitting MS patients who were diagnosed as IFN-ß responders (n=146) and non-responders (n=85). Serum cytokine levels were analyzed by commercially available ELISA kits in distinct groups based on HLA-A, -B and -DRB1 alleles. IFN-γ levels were significantly higher in responders compared with non-responders, whereas IL-17A and IL-6 had the opposite trend. The levels of IL-10 and IL-4 were not significantly different between two groups. IFN-γ and IL-17A levels were associated with response to IFN-ß. Comparison of cytokine levels revealed higher IFN-γ levels in HLA-DRB1∗04 positive patients (n=72) compared with HLA-DRB1∗04 negative patients (n=159). In responder group, patients who were positive for HLA-DRB1∗15 had significantly higher levels of IL-6 compared to HLA-DRB1∗15 negative patients. IL-17A levels tend to be higher in responder patients who were positive for HLA-DRB1∗04 compared with those were negative for the same allele. This study suggests that the serum levels of pro- and anti-inflammatory cytokines are different among IFN-ß responders and non-responders. Future studies are needed to confirm their efficiency in determination of response to IFN-ß in MS patients.

The Importance of VEGF-KDR Signaling Pathway Genes should Not Be Ignored When the Risk of Developing Multiple Sclerosis is Taken into Consideration.

Vascular endothelial growth factor (VEGF) and its receptor kinase insert domain-containing receptor (KDR) pathway trigger the process of angiogenesis as well as inflammation, which contributes to the development and progression of demyelinating lesions in multiple sclerosis. This work is a case-control study comprising of a total of 400 subjects with multiple sclerosis and 400 healthy controls. Participants were subjected to neurological examination and peripheral blood sampling for genotyping. Polymorphisms in the VEGF and KDR genes were assessed using the restriction fragment length polymorphism (RFLP-PCR) method. A significantly higher frequency of the T allele and TT genotype of the VEGF 936C > T (rs3025039) polymorphism was found in the multiple sclerosis group than in the healthy control group (P = 0.01 [OR = 1.41] and P = 0.01 [OR = 3.12], respectively). In addition, VEGF 936C  >  T showed an association with patients in a recessive model. However, the KDR -604T > C (rs2071559) polymorphism showed no significant difference in either allelic or genotype frequency between the two groups. Taken together, the results of the present study suggests that the T allele of the rs3025039 in VEGF gene could be considered a risk factor for developing multiple sclerosis in the Iranian population.

Phospholipase D1 expression analysis in relapsing-remitting multiple sclerosis patients.

Multiple sclerosis (MS) is a chronic disorder resulting from destruction of the myelin or insulating covers of neurons in the central nervous system (CNS). Several lines of evidence suggest a role for immune response in the occurrence and progression of this disorder. Several disease-modifying agents (DMA) including ß-interferons (IFNß) are being used in MS patients in order to stop the disease at the early inflammatory stage, postpone disease progression and diminish future disability. Phospholipase D1 (PLD1) is a critical enzyme responsible for the making lipid second messenger phosphatidic acid. It has an established function in regulation of immune response. In the present study we have evaluated PLD1 transcript levels and plasma concentrations in 78 relapsing-remitting MS (RRMS) patients as well as 78 normal age- and sex-matched healthy subjects using real-time quantitative RT-PCR and enzyme-linked immunosorbent assay (ELISA), respectively. Significant PLD1 down-regulation has been observed in total MS patients compared with controls (P < 0.001) as well as IFN-ß responders (P = 0.034) and non-responders (P < 0.001) compared with controls, respectively. However, a significant up-regulation has been detected in IFN-ß responders compared with non-responders (P = 0.047). In both males and females groups, significant down-regulations have been detected in patients compared with controls (P = 0.014 and P = 0.002, respectively). The same results have been detected in PLD1 plasma concentrations. In conclusion, PLD1 transcripts in blood and its plasma concentrations can be used as putative biomarkers for evaluation of therapeutic responses to IFN-ß in RRMS patients. However, this result should be validated in future studies.

Frequency of viral infections and environmental factors in multiple sclerosis.

OBJECTIVES: Multiple sclerosis (MS) is a complicated disease which occurs due to relationship between genes and environmental factors that causes tissue damage by autoimmune mechanisms.We investigated and illustrated the hypotheses correlated to the evidence of several putative environmental risk factors for MS onset and progression in this part of Iran. MATERIALS AND METHODS: Univariate logistic regression was used to detect the effects of environmental factors on the risk of MS. Data were analyzed using SPSS version 16. RESULTS: The childhood history of patients with rubella, measles and chickenpox increased the risk of MS significantly. Moreover, low consumption of dairy products, avoidance of seafood consumption, cigarette smoking and exposure to tobacco smoke, stress, anxiety disorders, depress and disturbing thoughts, negative and disturbing thoughts, developing a sudden shock upon hearing bad news, having obsessive-compulsive and being depressed increased the risk of MS significantly. CONCLUSIONS: The results of the current research partially solved the puzzling question of complex interplay between environmental factors and MS disease in this part of Iran. Incorporating these factors enables more powerful and accurate detection of novel risk factors with diagnostic and prognostic methods.