Antioxidant and Anti-inflammatory Diagnostic Biomarkers in Multiple Sclerosis: A Machine Learning Study.

An imbalance of inflammatory/anti-inflammatory and oxidant/antioxidant molecules has been implicated in the demyelination and axonal damage in multiple sclerosis (MS). The current study aimed to evaluate the plasma levels of tumor necrosis factor (TNF)-α, soluble TNF receptor (sTNFR)1, sTNFR2, adiponectin, hydroperoxides, advanced oxidation protein products (AOPP), nitric oxide metabolites, total plasma antioxidant capacity using the total radical-trapping antioxidant parameter (TRAP), sulfhydryl (SH) groups, as well as serum levels of zinc in 174 MS patients and 182 controls. The results show that MS is characterized by lowered levels of zinc, adiponectin, TRAP, and SH groups and increased levels of AOPP. MS was best predicted by a combination of lowered levels of zinc, adiponectin, TRAP, and SH groups yielding an area under the receiver operating characteristic (AUC/ROC) curve of 0.986 (±0.005). The combination of these four antioxidants with sTNFR2 showed an AUC/ROC of 0.997 and TRAP, adiponectin, and zinc are the most important biomarkers for MS diagnosis followed at a distance by sTNFR2. Support vector machine with tenfold validation performed on the four antioxidants showed a training accuracy of 92.9% and a validation accuracy of 90.6%. The results indicate that lowered levels of those four antioxidants are associated with MS and that these antioxidants are more important biomarkers of MS than TNF-α signaling and nitro-oxidative biomarkers. Adiponectin, TRAP, SH groups, zinc, and sTNFR2 play a role in the pathophysiology of MS, and a combination of these biomarkers is useful for predicting MS with high sensitivity, specificity, and accuracy. Drugs that increase the antioxidant capacity may offer novel therapeutic opportunities for MS.

Prolactin is Not Associated with Disability and Clinical Forms in Patients with Multiple Sclerosis.

An association between prolactinemia with disability, clinical forms, and sex of patients with multiple sclerosis (MS) remains unclear. The aim of this study was to evaluate the association of prolactin with clinical forms and accumulating disability over time in patients with MS. A longitudinal study was carried out with 101 patients with relapsing-remitting MS (RRMS) and 19 with progressive forms of MS (ProgMS). The disability over time, as well as prolactin and ferritin serum levels were evaluated at baseline (T0), 8-month follow-up (T8), and 16-month follow-up. The disability at T0, T8, and T16 was higher among patients with ProgMS than those with RRMS. Prolactin and ferritin levels did not differ over time between both groups. Initially, prolactin was associated with MS disability. After introducing age and sex, the effects of prolactin on disability were no longer significant. Prolactin was associated with age and sex, whereby age was positively associated with disability. In the same way, after introducing age and sex, the effects of diagnosis on prolactin levels, as well as the association between prolactin and ferritin, were no longer significant (P = 0.563 and P = 0.599, respectively). Moreover, 21.6% of the variance in the disability was predicted by age (P < 0.001), and sex (P = 0.049), while prolactin was not significant. In conclusion, the effects of prolactin on the disability and clinical forms of MS patients may be spurious results because those correlations reflect the positive associations of age with the disability and the negative association of age with prolactin.

Immune-inflammatory, metabolic and hormonal biomarkers are associated with the clinical forms and disability progression in patients with multiple sclerosis: A follow-up study.

The objective of this study was to evaluate the role of immune-inflammatory, metabolic, hormonal, and oxidative stress biomarkers in disability progression (DP) and clinical forms of multiple sclerosis (MS). The study evaluated 140 MS patients at admission (T0), and eight (T8) and 16 months (T16) later. The Expanded Disability Status Score (EDSS) and biomarkers were determined at T0, T8, and T16. A DP index (DPI) defined as an increase of ≥1 rank on the EDSS score indicated that 39.3% of the patients had significant DP. Quantification of the ordinal EDSS rank score was performed using optimal scaling methods. Categorical regression showed that the quantitative T16 EDSS score was predicted by T0 homocysteine (Hcy), T0 parathormone (PTH), T0 advanced oxidized protein products (AOPP) (all positively), low T0 vitamin D (<18.3 ng/mL) and T8 folic acid (<5 ng/mL) concentrations while higher T8 calcium concentrations (≥8.90 mg/dL) had protective effects. Linear Mixed Models showed that the change in EDSS from T0 to T16 was significantly associated with changes in IL-17 (positively) and IL-4 (inversely) independently from the significant effects of clinical MS forms, treatment modalities, smoking, age and systemic arterial hypertension. Hcy, PTH, IL-6, and IL-4 were positively associated with progressive versus relapsing-remitting MS while 25(OH)D was inversely associated. In conclusion, the ordinal EDSS scale is an adequate instrument to assess DP after category value estestimation. Aberrations in immune-inflammatory, metabolic and hormonal biomarkers are associated with DP and with the progressive form of MS.

The rs3761548 FOXP3 variant is associated with multiple sclerosis and transforming growth factor ß1 levels in female patients.

OBJECTIVE: The aim of this study was to evaluate the association between rs3761548 FOXP3 (-3279 C > A) variant and multiple sclerosis (MS), disability, disability progression, as well as transforming growth factor (TGF)-ß1 and interleukin (IL)-10 plasma levels in MS patients. METHODS AND SUBJECTS: The study included 170 MS patients and 182 controls. Disability was evaluated using Expanded Disability Status Scale (EDSS) and categorized as mild (EDSS ≤ 3) and moderate/high (EDSS > 3). Disability progression was evaluated using Multiple Sclerosis Severity Score (MSSS). The rs3761548 variant was determined with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Plasma levels of TGF-ß1 and IL-10 were determined using immunofluorimetric assay. RESULTS: CA and AA genotypes were associated with MS [odds ratio (OR) 2.03, 95% confidence interval (CI) 1.66-3.53, p = 0.012; OR 8.19, 95% CI 3.04-22.07, p < 0.001, respectively). With the dominant model, the CA + AA genotypes were associated with MS (OR 2.57, 95% CI 1.50-4.37, p < 0.001). In the recessive model, the AA genotype was also associated with MS (OR 5.38, 95% CI 2.12-13.64, p < 0.001). After adjustment by age, ethnicity, BMI and smoking, all these results remained significant, as well as female patients carrying the CA + AA genotypes showed higher TGF-ß1 than those carrying the CC genotype (OR 1.35, 95% CI 1.001-1.054, p = 0.043). No association was observed between the genotypes and disability, disability progression and IL-10 levels. CONCLUSION: These results suggest that the A allele of FOXP3 -3279 C > A variant may exert a role in the T regulatory cell function, which could be one of the factors involved in the susceptibility for MS in females.

Disability in multiple sclerosis is associated with age and inflammatory, metabolic and oxidative/nitrosative stress biomarkers: results of multivariate and machine learning procedures.

The aim of this study was to evaluate the immune-inflammatory, metabolic, and nitro-oxidative stress (IM&NO) biomarkers as predictors of disability in multiple sclerosis (MS) patients. A total of 122 patients with MS were included; their disability was evaluated using the Expanded Disability Status Scale (EDSS) and IM&NO biomarkers were evaluated in peripheral blood samples. Patients with EDSS ≥3 were older and showed higher homocysteine, uric acid, advanced oxidized protein products (AOPP) and low-density lipoprotein (LDL)-cholesterol and higher rate of metabolic syndrome (MetS), while high-density lipoprotein (HDL)-cholesterol was lower than in patients with EDSS <3; 84.6% of all patients were correctly classified in these EDSS subgroups. We found that 36.3% of the variance in EDSS score was explained by age, Th17/T regulatory (Treg) and LDL/HDL ratios and homocysteine (all positively related) and body mass index (BMI) (inversely related). After adjusting for MS treatment modalities, the effects of the LDL/HDL and zTh17/Treg ratios, homocysteine and age on disability remained, whilst BMI was no longer significant. Moreover, carbonyl proteins were associated with increased disability. In conclusion, the results showed that an inflammatory Th17 profile coupled with age and increased carbonyl proteins were the most important variables associated with high disability followed at a distance by homocysteine, MetS and LDL/HDL ratio. These data underscore that IM&NO pathways play a key role in increased disability in MS patient and may be possible new targets for the treatment of these patients. Moreover, a panel of these laboratory biomarkers may be used to predict the disability in MS.

Elevated plasma homocysteine levels are associated with disability progression in patients with multiple sclerosis.

The aims of this study were to verify whether hyperhomocysteinemia is associated with disability progression in Multiple Sclerosis (MS) patients and whether TNF pathways and cellular adhesion molecules (CAM) are involved in this process. This study included 180 MS patients, who were divided according to their levels of homocysteine (Hyperhomocysteinemia ≥11.35 µmol/L) and 204 healthy individuals (control group). MS patients showed higher levels of homocysteine (p < 0.001), tumor necrosis factor alpha (TNF-α, p < 0.001), TNF receptor 1 (TNFR1, p = 0.038), TNF receptor 2 (TNFR2, p < 0.001), and lower levels of PECAM (p = 0.001), ICAM (p < 0.001) and VCAM (p = 0.005) than controls. The multivariate binary logistic regression analysis showed that plasma levels of homocysteine, TNFR1, TNFR2 and PECAM were associated with the presence of disease. MS patients with hyperhomocysteinemia showed higher disease progression evaluated by the Multiple Sclerosis Severity Score (MSSS, p < 0.001), disability evaluated by Expanded Disability Status Score EDSS (p < 0.001), TNFR1 (p = 0.039) and ICAM (p = 0.034) than MS patients with lower levels of homocysteine. Hyperhomocysteinemia was independently associated with MSSS in MS patients, but were not associated with TNF-α, TNFR, and CAM. Homocysteine levels was higher in progressive forms than relapsing-remitting MS (p < 0.001), independently of sex and age. In conclusion, this is the first study in which homocysteinemia was associated with progression of the disease (MSSS), although this finding was not directly related to TNF-α and TNFR pathways or to CAM.

Vitamin D deficiency is associated with disability and disease progression in multiple sclerosis patients independently of oxidative and nitrosative stress.

The aim of this study was to assess vitamin D status in patients with multiple sclerosis (MS) and to evaluate whether it was associated with oxidative and nitrosative stress (O&NS) markers and disability. This study included 137 patients with MS and 218 healthy controls. The markers evaluated were serum levels of 25-hydroxyvitamin D, lipid hydroperoxides, advanced oxidation protein products (AOPP), nitric oxide metabolites (NOx), and total radical-trapping antioxidant parameter TRAP/UA. Patients with 25(OH)D<20ng/mL showed higher EDSS (p=0.016), MSSS (p=0.005) and lower AOPP (p=0.046) than those with 25(OH)D≥20ng/mL. After the binary logistic regression analyses, EDSS and MSSS remained significantly associated with vitamin D deficiency. We showed that lower levels of 25(OH)D were associated with higher EDSS and MSSS independently of variables such as O&NS, age, sex, body mass index, ethnicity, MS therapy, use of interferon beta, and clinical forms of MS (odds ratio: 1.380, 95% confidence interval 1.030-1.843, p=0.031). Moreover, the study showed an association between serum levels of 25(OH)D and EDSS (r2=0.115, p=0.002), demonstrating that 25(OH)D may contribute with 11.5% of increase in EDSS. Our results suggest that vitamin D deficiency may be considered one of the predictors of the disability in MS patients, independently of their redox status and influence the progression of disability in MS.

Insulin resistance, atherogenicity, and iron metabolism in multiple sclerosis with and without depression: Associations with inflammatory and oxidative stress biomarkers and uric acid.

Depression is accompanied by metabolic disorders in iron metabolism, lipoproteins, and insulin resistance. We measured plasma levels of ferritin, iron, lipids, insulin, and glucose and computed the homeostasis model assessment (HOMA2IR) and atherogenic index of plasma (AIP) in MS patients with and without depression and healthy controls. Explanatory variables were serum uric acid, interleukin (IL)-6, lipid hydroperoxides (CL-LOOH), albumin, and C-reactive protein (CRP). Depression was assessed using the Hospital Anxiety and Depression Scale (HADS), neurological disability using the Expanded Disability Status Scale (EDSS), and disease progression using ∆EDSS over five years earlier. HOMA2IR and insulin were predicted by diagnosis (increased in MS), age and body mass index (BMI); AIP by diagnosis, sex, BMI, CRP, and uric acid; triglycerides by diagnosis (higher in MS without depression), age, BMI and uric acid; ferritin by diagnosis (higher in MS), sex, CRP, and albumin; and iron by albumin. The HADS score was significantly predicted by ∆EDSS, gastro-intestinal symptoms, iron (inverse), and age. MS is characterized by significantly increased insulin resistance, which is determined by increased insulin levels; and increased ferritin, a biomarker of inflammation. Depression in MS is not associated with increased insulin resistance and atherogenicity but with lowered iron.

Disease progression and oxidative stress are associated with higher serum ferritin levels in patients with multiple sclerosis.

Hyperferritinemia and oxidative stress have been implicated in the pathogenesis of multiple sclerosis (MS). The aim of the present study was to evaluate the serum levels of ferritin and to verify their association with oxidative stress markers and MS progression. This study included 164 MS patients, which were divided in two groups according to their levels of ferritin (cut off 125.6µg/L). Oxidative stress was evaluated by tert-butyl hydroperoxide-initiated chemiluminescence (CL-LOOH), advanced oxidation protein products (AOPP), carbonyl protein, nitric oxide metabolites (NOx), sulfhydryl groups of protein and total radical-trapping antioxidant parameter (TRAP). MS patients with elevated levels of ferritin showed higher disease progression (p=0.030), AOPP (p=0.001), and lower plasma NOx levels (p=0.031) and TRAP (p=0.006) than MS patients with lower ferritin levels. The multivariate binary logistic regression analysis showed that increased AOPP and progression of disease were significantly and positively associated with increase of ferritin. The combination of serum ferritin levels and oxidative stress markers were responsible for 13,9% in the disease progression. In conclusion, our results suggest that ferritin could aggravate oxidative stress in patients with MS and contribute to progression of disease.

Genetic, Immune-Inflammatory, and Oxidative Stress Biomarkers as Predictors for Disability and Disease Progression in Multiple Sclerosis.

The aim of this study was to evaluate the TNFß NcoI polymorphism (rs909253) and immune-inflammatory, oxidative, and nitrosative stress (IO&NS) biomarkers as predictors of disease progression in multiple sclerosis (MS). We included 212 MS patients (150 female, 62 male, mean (±standard deviation (SD)) age = 42.7 ± 13.8 years) and 249 healthy controls (177 female, 72 male, 36.8 ± 11 years). The disability was measured the Expanded Disability Status Scale (EDSS) in 2006 and 2011. We determined the TNFß NcoI polymorphism and serum levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-4, IL-10, and IL-17, albumin, ferritin, and plasma levels of lipid hydroperoxides (CL-LOOH), carbonyl protein, advanced oxidation protein products (AOPPs), nitric oxide metabolites (NOx), and total radical-trapping antioxidant parameter (TRAP). The mean EDSS (±SD) in 2006 was 1.62 ± 2.01 and in 2011 3.16 ± 2.29, and disease duration was 7.34 ± 7.0 years. IL-10, TNF-α, IFN-γ, AOPP, and NOx levels were significantly higher and IL-4 lower in MS patients with a higher 2011 EDSS scores (≥3) as compared with those with EDSS < 3. The actual increases in EDSS from 2006 to 2011 were positively associated with TNF-α and IFN-γ. Increased IFN-γ values were associated with higher pyramidal symptoms and increased IL-6 with sensitive symptoms. Increased carbonyl protein and IL-10 but lowered albumin levels predicted cerebellar symptoms. The TNFB1/B2 genotype decreased risk towards progression of pyramidal symptoms. Treatments with IFN-ß and glatiramer acetate significantly reduced TNF-α but did not affect the other IO&NS biomarkers or disease progression. Taken together, IO&NS biomarkers and NcoI TNFß genotypes predict high disability in MS and are associated with different aspects of disease progression. New drugs to treat MS should also target oxidative stress pathways.

Cytokine Profile in Patients with Progressive Multiple Sclerosis and Its Association with Disease Progression and Disability.

Inflammation is the driving force for brain injury in patients with multiple sclerosis (MS). The objective of the present study is to delineate the serum cytokine profile in patients with progressive MS in a Southern Brazilian population compared with healthy controls and patients with relapsing-remitting MS (RRMS) and its associations with disease progression and disability. We included 32 patients with progressive MS, 126 with RRMS, and 40 healthy controls. The patients were evaluated using the Expanded Disability Status Scale (EDSS) and magnetic resonance imaging (MRI) with gadolinium. Serum interleukin (IL)-1ß, IL-6, IL-12, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-10, IL-4, and IL-17 levels were assessed using an enzyme-linked immunosorbent assay. IL-1ß, IL-6, TNF-α, IFN-γ, IL-17, IL-4, and IL-10 levels were higher in progressive MS than in controls. Increased IL-1ß and IFN-γ and decreased IL-12 and IL-4 levels were found in progressive MS compared with RRMS. Patients with progressive MS with disease progression presented higher TNF-α, IFN-γ, and IL-10 levels than those without disease progression. Patients with progressive MS with disease progression showed a higher frequency of positive gadolinium-enhanced lesions in MRI; higher TNF-α, IFN-γ, and IL-17 levels; and decreased IL-12 levels compared with RRMS patients with progression. There was a significant inverse correlation between IL-10 levels and EDSS score in patients with progressive MS. The results underscore the complex cytokine network imbalance exhibited by progressive MS patients and show the important involvement of TNF-α, IFN-γ, and IL-17 in the pathophysiology and progression of the disease. Moreover, serum IL-10 levels were inversely associated with disability in patients with progressive MS.

Albumin and Protein Oxidation are Predictors that Differentiate Relapsing-Remitting from Progressive Clinical Forms of Multiple Sclerosis.

The aim of the present study was to evaluate inflammatory, oxidative, and nitrosative stress (IO&NS) blood markers as possible predictors of multiple sclerosis (MS) and its clinical forms. This study included 258 MS patients (175 with relapsing-remitting MS (RRMS) and 83 with progressive MS clinical forms) and 249 healthy individuals. Peripheral blood samples were obtained to determine serum levels of albumin, ferritin, C-reactive protein (CRP), total protein, lipid hydroperoxide by tert-butyl hydroperoxide-initiated chemiluminescence (CL-LOOH), carbonyl protein content, advanced oxidation protein products (AOPP), nitric oxide metabolites (NOx), and total radical-trapping antioxidant parameter (TRAP). MS patients showed higher ferritin (p < 0.001) and CL-LOOH (p < 0.001) and lower albumin (p = 0.001), TRAP (p < 0.001), AOPP (p = 0.013), and NOx values (p < 0.001) than controls. Difference was not observed in CRP, total protein, and carbonyl proteins between patients and controls. In the logistic regression age-adjusted, ferritin and CL-LOOH showed positive association with MS and were predictors of MS development (OR: 1.006, 95 % CI: 1.003-1.009, p < 0.001 and OR: 1.029, 95 % CI: 1.007-1.052, p = 0.009, respectively). Albumin, TRAP, AOPP, and NOx were negatively associated with MS (p = 0.019, p = 0.003, p = 0.001, and p = 0.003, respectively). Moreover, other logistic regression age-adjusted showed that MS patients with progressive clinical forms had lower albumin and higher AOPP than those with RRMS (p = 0.037). In conclusion, ferritin, albumin, and biomarkers of IO&NS, such as CL-LOOH, AOPP, TRAP, and NOx were predictors of MS diagnosis, whereas albumin and AOPP were predictors that differentiated RRMS from the progressive clinical forms of MS.

Frequency of autoimmune disorders and autoantibodies in patients with neuromyelitis optica.

OBJECTIVE: The aim of this study was to report the frequency of autoimmune disorders and autoantibodies in 22 patients with neuromyelitis optica (NMO), as well as whether the seropositivity for autoantibodies differs between anti-aquaporin 4 (AQP4) positive and AQP4 negative NMO patients. METHODS: Demographic, medical records, and a profile of autoantibodies were evaluated in 22 NMO patients, including AQP4, anti-thyroid-stimulating hormone receptor, antinuclear antibodies (ANA), anti-thyroperoxidase (anti-TPO), anti-thyroglobulin (anti-Tg), anti-double-stranded DNA, anti-neutrophil cytoplasmic, anti-cyclic citrullinate peptide, rheumatoid factor, anti-SSA/Ro, anti-SSB/La, anti-Smith antibodies (anti-Sm), anti-ribonucleoprotein, anti-nucleosome, and anti-Scl70. Thyroid-stimulating hormone and free thyroxin were measured. RESULTS: The frequency of women was higher than men (95.5% vs. 4.5%) and 68.2% were Afro-Brazilians. Six (27.3%) patients presented other autoimmune disorders, such as Hashimoto thyroiditis (n=2), Graves' disease (n=1), juvenile idiopathic arthritis (n=1), systemic lupus erythematosus and systemic sclerosis (n=1), and Raynaud's phenomenon (n=1). The most frequent autoantibodies were anti-AQP4 (54.5%), anti-nucleosome (31.8%), ANA (27.3%), anti-TPO (22.7%), and anti-Tg (22.7%). Difference was not observed in the frequency of autoimmune disorders when the patients were compared according to their anti-AQP4 status. CONCLUSION: The results of the present study underscored that the NMO patients present high frequency of autoantibodies against cellular antigens and the presence of autoimmune disorders. Further studies with large number of NMO patients may contribute to advances in the understanding of NMO disease mechanisms.

Influence of Insulin Resistance and TNF-α on the Inflammatory Process, Oxidative Stress, and Disease Activity in Patients with Rheumatoid Arthritis.

The aim of this study was to evaluate the involvement of TNF-α and insulin resistance (IR) in the inflammatory process, oxidative stress, and disease activity in patients with rheumatoid arthritis (RA). This cross-sectional study included 270 subjects (control group, n = 97) and RA patients (n = 173). RA patients were divided into four groups: the first group without IR and not using antitumor necrosis factor-α (TNF-) (G1, IR- TNF-); the second group without IR and using anti-TNF-α (G2, IR- TNF+); the third group with IR and not using anti-TNF-α (G3, IR+ TNF-); and the fourth group with IR and using anti-TNF-α (G4, IR+ TNF+). G3 and G4 had higher (p < 0.05) advanced oxidation protein products (AOPPs) and oxidative stress index (OSI) compared to G1. G4 group presented higher (p < 0.05) AOPPs and OSI than G2. TRAP was significantly lower in G3 compared to G1. Plasma TNF-α levels were significantly higher in G4 and G2 compared to G1 (p < 0.0001) and G3 (p < 0.0001 and p < 0.01, resp.). The presence of insulin resistance was robustly associated with both oxidative stress and TNF-α levels. More studies are warranted to verify if IR can be involved in therapeutic failure with TNF-α inhibitors. This trial is registered with Brazilian Clinical Trials Registry Register number RBR-2jvj92.

Profile of oxidative stress markers is dependent on vitamin D levels in patients with chronic hepatitis C.

OBJECTIVES: Although vitamin D deficiency can change liver injury progression in patients with hepatitis C virus (HCV), the main molecular mechanisms involved are largely unknown. The first aim of this study was to evaluate the association between oxidative stress and hypovitaminosis D in patients with HCV. The second aim was to verify whether oxidative stress is involved in the molecular mechanisms related to liver injury. METHODS: The study included 147 participants: 89 controls and 58 patients with HCV (vitamin D < 30, n = 32; vitamin D > 30, n = 26). RESULTS: Patients with HCV and hypovitaminosis D presented significantly higher aminotransferase-to-platelet ratio index (APRI; P = 0.0464) and viral load (P = 0.0426) levels than patients with HCV without hypovitaminosis D. Regarding oxidative stress, HCV patients with hypovitaminosis D had higher advanced oxidation protein products (P = 0.0409), nitric oxide metabolites (P = 0.0206) levels, and oxidative stress index (P = 0.0196), whereas total radical-trapping antioxidant parameter (P = 0.0446) levels were significantly lower than HCV patients without hypovitaminosis D. Vitamin D in patients with HCV showed inverse correlations with levels of iron (r = -0.407, P = 0.0285), ferritin (r = -0.383, P = 0.0444), APRI (r = -0.453, P = 0.0154) and plasma lipid hydroperoxides levels (r = -0.426, P = 0.0189). CONCLUSION: Vitamin D insufficiency contributes to the inflammatory process and oxidative stress imbalance in patients with HCV. The profile of oxidative stress markers in these patients depends on vitamin D levels, which probably change intracellular signalling pathways and increase inflammation and liver injury.

CCR5Δ32 (rs333) polymorphism is associated with the susceptibility to systemic lupus erythematosus in female Brazilian patients.

The role of CCR5Δ32 (rs333) polymorphism in the pathogenesis of systemic lupus erythematosus (SLE) has been evaluated worldwide. The aim of this study was to determine the association between CCR5Δ32 polymorphism with the susceptibility to SLE and the activity of disease in female Southern Brazilian patients. The study enrolled 169 female SLE patients and 132 unrelated female healthy individuals. Baseline clinical, laboratorial characteristics, and the SLE activity (determined using the SLEDAI) were evaluated according to the CCR5Δ32 genotypes. The CCR5Δ32 polymorphism was determined from genomic DNA using a polymerase chain reaction. The frequencies of the genotypes CCR5/CCR5, CCR5/CCR5Δ32, and CCR5Δ32/CCR5Δ32 were 87.6, 11.8, and 0.6 %, respectively, among the patients and 96.2, 3.8, and 0.0 %, respectively, among the controls [CCR5/CCR5 vs. CCR5/CCR5Δ32 + CCR5Δ32/CCR5Δ32: p = 0.0081, odds ratio 3.604 (95 % confidence interval 1.321-9.4836)]. The frequencies of the CCR5 and the CCR5Δ32 alleles were 93.2 and 6.8 % among the patients, and 98.1 and 1.9 % among the controls, respectively (p = 0.0047, OR 3.758, 95 % CI 1.409-10.80). Patients carrying the genotypes with the CCR5Δ32 allele presented earlier age of onset of disease (p = 0.0293) and higher levels of anti-dsDNA (p = 0.0255) than those carrying the wild-type genotype. When the analysis was adjusted for ethnicity, only the age at onset of disease remained significant (p > 0.05). The results suggest that the CCR5Δ32 polymorphism might be associated with SLE genetic predisposition among female Brazilian patients and the age at onset of the disease; however, this genetic variant was not associated with the activity of SLE in this population.

Immune-Inflammatory and Oxidative and Nitrosative Stress Biomarkers of Depression Symptoms in Subjects with Multiple Sclerosis: Increased Peripheral Inflammation but Less Acute Neuroinflammation.

There is evidence that activated immune-inflammatory and oxidative and nitrosative stress (IO&NS) pathways play a role in the pathophysiology of multiple sclerosis (MS) and depression. This study examines serum levels of interleukin (IL)-1ß, IL-4, IL-6, and IL-10; peroxides (LOOH); nitric oxide metabolites (NOx); albumin; ferritin; C-reactive protein (CRP); and tumor necrosis factor (TNF)-ß NcoI polymorphism (rs909253) and gadolinium-enhanced magnetic resonance imaging (MRI) scan in MS patients with (n = 42) and without (n = 108) depression and normal controls (n = 249). Depression is scored using the depressive subscale of the Hospital Anxiety and Depression Scale (HADS). The extent of neurological disability is measured using the Expanded Disability Status Scale (EDSS) at the same time of the abovementioned measurements and 5 years earlier. Disease progression is assessed as actual EDSS-EDSS 5 years earlier. Three variables discriminate MS patients with depression from those without depression, i.e., increased IL-6 and lower IL-4 and albumin. Binary logistic regression showed that MS with depression (versus no depression) was characterized by more gastrointestinal symptoms and disease progression, higher serum IL-6, and lower albumin levels. In subjects with MS, the HADS score was significantly predicted by three EDSS symptoms, i.e., pyramidal, gastrointestinal, and visual symptoms. Fifty-eight percent of the variance in the HADS score was predicted by gastrointestinal symptoms, visual symptoms, the TNFB1/B2 genotype, and contrast enhancement (both inversely associated). There were no significant associations between depression in MS and type of MS, duration of illness, age, sex, nicotine dependence, and body mass index. MS with depression is associated with signs of peripheral inflammation, more disability, disease progression, gastrointestinal and visual symptoms, but less contrast enhancement as compared to MS without depression. It is concluded that depression is part of the neurological symptoms of MS and that its expression is primed by peripheral inflammation while acute neuroinflammation and the TNFB1/B2 genotype may be protective.

Inflammatory and metabolic markers and short-time outcome in patients with acute ischemic stroke in relation to TOAST subtypes.

The aim of this study was to evaluate the association between inflammatory and metabolic markers and short-time outcome with acute ischemic stroke subtypes. A total of 121 patients was classified according to TOAST criteria, such as large artery atherosclerosis (LAAS), lacunar infarct (LAC), cardioembolic infarct (CEI), other determined etiology (ODE), and undetermined etiology (UDE). The functional impairment was evaluated within the first eight hours of stroke and the outcome after three-month follow-up using the modified Rankin Scale. Blood samples were obtained up to 24 h of stroke. Compared with 96 controls, patients with LAAS, CEI, and LAC subtypes showed higher levels of white blood cells, high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), metalloproteinase 9 (MMP-9), glucose, and iron (p < 0.05); and lower high-density lipoprotein cholesterol (HDL-C) (p < 0.0001); platelets, insulin, insulin resistance, and homocysteine were higher in LAC (p < 0.0001); ferritin was higher in LAAS (p < 0.0001); and total cholesterol (TC) was lower in LAAS and CEI (p < 0.01). When stroke subtypes were compared, insulin was higher in LAAS vs. LAC and in LAC vs. CEI (p < 0.05); and TC was lower in LAAS vs. LAC (p < 0.05). Outcome and rate of mortality after three-month were higher in LAAS vs. LAC (p < 0.001 and p = 0.0391 respectively). The results underscored the important role of the inflammatory response and metabolic changes in the pathogenesis of ischemic stroke subtypes that might be considered on the initial evaluation of stroke patients to identify those that could benefit with individualized therapeutic strategies that taken into account these markers after acute ischemic event.

Avaliação do polimorfismo genético pvuII do receptor de lipoproteína de baixa densidade (RLDL) em pacientes com lúpus eritematoso sistêmico / Evaluation of genetic polymorphism pvuII of low density lipoprotein receptor (LDLR) in patients with systemic lupus erythematosus

Lúpus Eritematoso Sistêmico (LES) é uma doença inflamatória crônica do tecido conjuntivo, relacionada a alterações do perfil lipídico e ao metabolismo de lipoproteínas. Estudos mostram que o polimorfismo genético PvuII do receptor de lipoproteína de baixa densidade (RLDL) está associado às diferentes concentrações de lipoproteína de baixa (LDL) na população em geral. O presente estudo avaliou o polimorfismo genético PvuII do RLDL e o perfil lipídico em pacientes com LES da população sul brasileira. Foram incluídos 72 pacientes com LES e 154 doadores de sangue. Pacientes com LES apresentaram elevados níveis séricos de triglicerídeos (TG) quando comparados com o grupo controle (p<0,0001). Semelhantemente, pacientes com LES ativo apresentaram maiores níveis de TG quando comparados a pacientes com LES sem atividade da doença (p=0,0113). Em relação à frequência do polimorfismo genético PvuII do RLDL, 35 (48,6%) dos pacientes com LES apresentavam o genótipo P1P1, 32 (44,4%) o genótipo P1P2 e 5 (6,9%) o genótipo P2P2. Não foram encontradas diferenças nas frequências do genótipo P1P1 vs P1P2 e P1P1 vs P2P2 quando comparado entre pacientes com LES e controles (p>0,05). Pacientes com LES e genótipo P1P1 apresentaram uma tendência a ter valores mais elevados de TG quando comparados a pacientes com LES e genótipo P1P2+P2P2 (p=0,0687). Conclui-se que polimorfismos genéticos podem contribuir para o aumento de risco cardiovascular; no entanto,deve-se levar em consideração a complexidade dos componentes genéticos e da doença avaliada.Maiores investigações são necessárias para outros genes que possam estar envolvidos na alteração do perfil lipídico nesta população.

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease of connective tissue related to changes in lipid profile and lipoprotein metabolism. Studies show that the genetic polymorphism of PvuII low density lipoprotein receptor (LDLR) is associated with different concentrations of low-density lipoprotein (LDL) in general population. The present study evaluated the genetic polymorphism of PvuII of LDLR and lipid profile in patients with SLE in southern Brazilian population. We included 72 patients with SLE and 154 blood donors. In assessing the lipid profile, SLE patients had elevated serum triglycerides (TG) levels compared with the control group (p <0.0001). Similarly, patients with active SLE have elevated TG levels when compared to patients without SLE disease activity (p = 0.0113). Regarding the frequency of genetic polymorphism of PvuII of LDLR, 35 (48.6%) patients with SLE had P1P1 genotype, 32 (44.4%) P1P2 genotype and 5 (6.9%) the P2P2 genotype. There were no differences in the genotype frequencies P1P1 vs P1P2 and P1P1vs P2P2 compared between SLE patients and controls (p>0.05). Patients with SLE and P1P1 genotype tended to have higher levels of TG compared with patients with SLE and P1P2 + P2P2 genotype (p = 0.0687). We conclude that genetic polymorphism may contribute to increased cardiovascular risk; however, the complexity of genetic components and disease evaluated should be taken into consideration. Further investigations are needed for other genes that may be involved in altering the lipid profile in this population.

Epidemiological, clinical, and immunological characteristics of neuromyelitis optica: A review.

The aim of this study was to review the epidemiological and clinical characteristics of neuromyelitis optica (NMO) and the immunopathological mechanisms involved in the neuronal damage. NMO is an inflammatory demyelinating autoimmune disease of the central nervous system that most commonly affects the optic nerves and spinal cord. NMO is thought to be more prevalent among non-Caucasians and where multiple sclerosis (MS) prevalence is low. NMO follows a relapsing course in more than 80-90% of cases, which is more commonly in women. It is a complex disease with an interaction between host genetic and environmental factors and the main immunological feature is the presence of anti-aquaporin 4 (AQP4) antibodies in a subset of patients. NMO is frequently associated with multiple other autoantibodies and there is a strong association between NMO with other systemic autoimmune diseases. AQP4-IgG can cause antibody-dependent cellular cytotoxicity (ADCC) when effector cells are present and complement-dependent cytotoxicity (CDC) when complement is present. Acute therapies, including corticosteroids and plasma exchange, are designed to minimize injury and accelerate recovery. Several aspects of NMO pathogenesis remain unclear. More advances in the understanding of NMO disease mechanisms are needed in order to identify more specific biomarkers to NMO diagnosis.