IL18 rs360717 and rs187238 genetic variants are associated with migraine diagnosis.

BACKGROUND: Migraine is a genetically determined disorder that predisposes to recurrent episodes of headache. Interleukin (IL)-18 is a pro-inflammatory cytokine that seems to play a role in migraine pathophysiology, and its genetic variants could potentially impact susceptibility to migraine. OBJECTIVE: To investigate the association between IL18 rs360717 and rs187238 genetic variants with migraine diagnosis and its clinical characteristics. METHODS: A case-control study was conducted with 152 people with migraine and 155 healthy controls, matched by sex, age, ethnicity, and body mass index. Clinical characteristics of migraine, as well as validated questionnaires regarding disability and impact of migraine, presence of allodynia, anxiety, depression, and hyperacusis were collected. Genotyping for IL18 rs360717 and rs187238 variants was performed using real-time polymerase chain reaction (qPCR) and TaqMan™ method. RESULTS: The IL18 rs360717A and rs187238G alleles were associated with increased chance of being diagnosed with migraine (OR = 1.53, 95%CI 1.05-2.24, p = 0.028 and OR = 1.46, 95%CI 1.00-2.14, p = 0.049, respectively). In the dominant model, the rs360717GA + AA genotypes were also associated with a higher chance of migraine than the GG genotype (OR = 1.69, 95%CI 1.05-2.73, p = 0.030). In women, in addition to the previous associations, there was also an effect of the variants on the chance of migraine in the codominant models and dominant models. Furthermore, among women, there was an influence on the prevalence of postdrome perception with rs360717GA + AA (OR = 3.04, 95%CI 1.10-8.42, p = 0.032) and rs187238CG + GG (OR = 2.97, 95%CI 1.08-8.21, p = 0.035). CONCLUSION: IL18 rs360717 and rs187238 variants were associated with migraine diagnosis and postdrome symptoms, especially in women. SIGNIFICANCE: This study has demonstrated that IL18 rs360717 and rs187238 variants play a role in migraine, influencing the chance of being diagnosed with migraine, particularly among women. There are prospects that IL18 variants could be considered potential genetic biomarkers for migraine.

CTLA4 genetic variants associated with urothelial bladder cancer susceptibility.

PURPOSE: The study evaluated the relationship between the CTLA4 rs231775 (+49A>G) and rs231779 (+1822C>T) variants and susceptibility, stage, prognosis and response to treatment of the urothelial bladder cancer (UBC). METHODS: A total of 140 patients with UBC and 145 controls were enrolled. The patients were stratified as non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MICB), metastasis, recurrence, low/moderate/high/very high risk. Demographic, anthropometric, epidemiological, and clinical data were obtained from all individuals using a structured questionnaire. The CTLA4 variants were determined using real-time polymerase chain reaction (qPCR) and the genotypes were tested in the allelic, codominant, dominant, recessive, and overdominant genetic models. RESULTS: The UBC patients were older and mostly smokers (P < 0.001), with greater waist circumference, systolic, and diastolic arterial pressure (P = 0.005, P = 0.006, and P < 0.001, respectively) than controls. A protective effect for the UBC was observed among the patients carrying the heterozygote genotypes of the CTLA4 rs231775 [odds ratio (OR = 0.40; 95% confidence interval (CI): 0.160.98, P = 0.045) and rs231779 (OR = 0.35; 95% CI: 0.14-0.87, P = 0.024). R2 Nagelkerke analysis demonstrated that a model with age and smoking added to the CTLA4 rs231775 SNVs explained 77.0% of the susceptibility to UBC and a model with age and smoking added to the CLTA4 rs231779 explained 77.2% of the susceptibility to UBC. CONCLUSION: The CTLA4 rs231775 AG and rs231779 CT heterozygous genotypes in the overdominant model together with age and smoking may be useful as potential biomarkers for the UBC susceptibility.

MTHFR 677C>T (rsRS1801133) variant is associated with hyperhomocysteinemia but not with clinical severity in patients with peripheral arterial disease.

Background: The MTHFR 677C>T variant's involvement with hyperhomocysteinemia and peripheral arterial disease (PAD) is still unclear. Objectives: To evaluate associations between the MTHFR 677C>T (rs1801133) variant and susceptibility to and severity of PAD and homocysteine (Hcy) levels. Methods: The study enrolled 157 PAD patients and 113 unrelated controls. PAD severity and anatomoradiological categories were assessed using the Fontaine classification and the Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC), respectively. The variant was genotyped using real-time polymerase chain reaction and Hcy levels were determined using chemiluminescence microparticle assay. Results: The sample of PAD patients comprised 60 (38.2%) females and 97 (61.8%) males. Patients were older and had higher Hcy than controls (median age of 69 vs. 45 years, p<0.001; and 13.66 µmol/L vs. 9.91 µmol/L, p=0.020, respectively). Hcy levels and the MTHFR 677C>T variant did not differ according to Fontaine or TASC categories. However, Hcy was higher in patients with the CT+TT genotypes than in those with the CC genotype (14.60 µmol/L vs. 12.94 µmol/L, p=0.008). Moreover, patients with the TT genotype had higher Hcy than those with the CC+CT genotypes (16.40 µmol/L vs. 13.22 µmol/L, p=0.019), independently of the major confounding variables. Conclusions: The T allele of MTHFR 677C>T variant was associated with higher Hcy levels in PAD patients, but not in controls, suggesting a possible interaction between the MTHFR 677C>T variant and other genetic, epigenetic, or environmental factors associated with PAD, affecting modulation of Hcy metabolism.

Contexto: O envolvimento da variante MTHFR 677C>T na hiperhomocisteinemia e na doença arterial periférica (DAP) ainda não está claro. Objetivos: Avaliar a associação da variante MTHFR 677C>T (rs1801133) com suscetibilidade e gravidade da DAP e valores séricos de homocisteína (Hcy). Métodos: Este estudo caso-controle envolveu 157 pacientes com DAP e 113 controles não relacionados. A gravidade e as categorias anatomorradiológicas da DAP foram avaliadas pela classificação de Fontaine e pelo Inter-Society Consensus for the Management of Peripheral Arterial Disease, respectivamente. A genotipagem foi realizada por meio de reação em cadeia da polimerase em tempo real, e os valores de Hcy foram determinados por ensaio de micropartículas de quimioluminescência. Resultados: Entre os pacientes com DAP, 97 (61,8%) eram homens e 60 (38,2%) eram mulheres, com mediana de idade de 69 anos. Os pacientes com DAP eram mais velhos e apresentaram valores mais elevados de Hcy do que os controles (mediana de 69 vs. 45 anos de idade, p < 0,001; 13,66 µmol/L vs. 9,91 µmol/L, p = 0,020, respectivamente). Os valores de Hcy foram mais elevados em pacientes com os genótipos CT+TT do que aqueles com o genótipo CC (14,60 µmol/L vs. 12,94 µmol/L, p = 0,008). Além disso, os pacientes com o genótipo TT apresentaram valores mais elevados de Hcy do que aqueles com os genótipos CC+CT (16,40 µmol/L vs. 13,22 µmol/L, p = 0,019, respectivamente), independentemente das principais variáveis confundidoras. Conclusões: O alelo T da variante MTHFR 677C>T foi associado a valores mais elevados de Hcy nos pacientes com DAP, mas não em controles, sugerindo uma possível interação entre a variante genética MTHFR 677C>T e outros fatores genéticos, epigenéticos ou ambientais associados com a DAP na modulação do metabolismo da Hcy.

IL36G genetic variant is independently associated with susceptibility, severity and joint involvement in psoriasis.

Psoriasis (PsO) is a chronic, immune-mediated, inflammatory and polygenic dermatosis associated with both physical and psychological burden that can be triggered by injury, trauma, infections and medications. The etiology of PsO is not fully elucidated but genetic, epigenetic and environmental factors are all likely to play a role. A case-control study was carried out to evaluate the frequency of the IL36G C>T (rs13392494) and the IL36G A>G (rs7584409) variants and their association with susceptibility, joint involvement and severity of PsO. The study included 154 patients with PsO and 154 controls from Brazilian population. The severity of PsO was assessed by the Psoriasis Area and Severity Index (PASI). The IL36G (rs13392494 and rs7584409) variants were genotyped by allelic discrimination assay using the real-time polymerase chain reaction. The association between the IL36G genetic variants and the study variables was analyzed in allelic, dominant, codominant, overdominant, recessive, and haplotype models. The main results were that PsO patients were older (p < 0.001) and had higher body mass index (p < 0.001) than controls; 95.8% of the patients had plaque PsO, 16.1% had psoriatic arthritis (PsA), and 27.9% had PASI > 10. The IL36G rs1339294 variant showed no association with PsO in all genetic models while the IL36G rs7584409 variant showed a protective effect in PsO. However, the G allele of the IL36G rs7584409 in the dominant model was positively associated with PASI > 10 (p = 0.031). Moreover, patients with the GG genotype of the IL36G rs7584409 variant had about 5.0 times more chance of PsA than those with the AA genotype (p = 0.014). Regarding the haplotypes, the C/A in a recessive model (CACA versus C/G and T/A carriers) was associated with PsO (p = 0.035) while the C/G haplotype in a dominant model (C/A carriers versus C/G and T/A carriers) showed a protective effect for PsO (p = 0.041). In conclusion, the G allele of the IL36G rs7584409 variant was associated with protection to PsO; however, in patients with PsO, this same allele was associated with moderate to severe disease and PsA. These results suggest that the IL36G rs7584409 variant may be used as a possible genetic biomarker to predict severity and joint involvement of PsO.

Baseline severity and soluble vascular cell adhesion molecule 1 (sVCAM-1) as biomarker predictors of short-term mortality in acute ischemic stroke.

The aim was to investigate the association between plasma levels of cellular adhesion molecules (CAMs) and risk factors, subtypes, severity and short-term mortality of acute ischemic stroke (IS), and to identify a panel of biomarkers to predict short-term mortality after IS. The prospective study evaluated 132 IS patients within 24 h of their hospital admission. The baseline IS severity was assessed using the National Institutes Health Stroke Scale (NIHSS) and categorized as mild (NIHSS < 5), moderate (NIHSS 5-14) and severe (NIHSS ≥ 15). After three-month follow-up, the disability was assessed using the modified Rankin Scale (mRS); moreover, the patients were classified as survivors and non-survivors. Baseline inflammatory and anti-inflammatory cytokines and soluble CAMs were evaluated. Twenty-nine (21.9%) IS patients were non-survivors and showed higher NIHSS and soluble vascular cellular adhesion molecule 1 (sVCAM-1) than the survivors. The sVCAM-1 levels positively correlated with age, homocysteine, severity, and disability. The model #3 combining sVCAM-1 and NIHSS showed better results to predict short-term mortality with an area under the curve receiving operating characteristics (AUC/ROC) of 0.8841 [95% confidence interval (CI): 0.795-0.941] than the models with sVCAM-1 and NIHSS alone, with positive predictive value of 68.0%, negative predictive value of 91.3%, and accuracy of 86.5%. In conclusion, the combined model with baseline severity of IS and sVCAM-1 levels can early predict the prognosis of IS patients who may benefit with therapeutic measures of personalized therapy that taken into account these biomarkers. Moreover, this result suggests that VCAM-1 might be a potential target for the therapeutic strategies in IS.

MTHFR 677C>T (rsRS1801133) variant is associated with hyperhomocysteinemia but not with clinical severity in patients with peripheral arterial disease / A variante MTHFR 677C>T (RS1801133) está associada a hiperhomocisteinemia, mas não a gravidade clínica em pacientes com doença arterial periférica

Abstract Background The MTHFR 677C>T variant's involvement with hyperhomocysteinemia and peripheral arterial disease (PAD) is still unclear. Objectives To evaluate associations between the MTHFR 677C>T (rs1801133) variant and susceptibility to and severity of PAD and homocysteine (Hcy) levels. Methods The study enrolled 157 PAD patients and 113 unrelated controls. PAD severity and anatomoradiological categories were assessed using the Fontaine classification and the Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC), respectively. The variant was genotyped using real-time polymerase chain reaction and Hcy levels were determined using chemiluminescence microparticle assay. Results The sample of PAD patients comprised 60 (38.2%) females and 97 (61.8%) males. Patients were older and had higher Hcy than controls (median age of 69 vs. 45 years, p<0.001; and 13.66 µmol/L vs. 9.91 µmol/L, p=0.020, respectively). Hcy levels and the MTHFR 677C>T variant did not differ according to Fontaine or TASC categories. However, Hcy was higher in patients with the CT+TT genotypes than in those with the CC genotype (14.60 µmol/L vs. 12.94 µmol/L, p=0.008). Moreover, patients with the TT genotype had higher Hcy than those with the CC+CT genotypes (16.40 µmol/L vs. 13.22 µmol/L, p=0.019), independently of the major confounding variables. Conclusions The T allele of MTHFR 677C>T variant was associated with higher Hcy levels in PAD patients, but not in controls, suggesting a possible interaction between the MTHFR 677C>T variant and other genetic, epigenetic, or environmental factors associated with PAD, affecting modulation of Hcy metabolism.

Resumo Contexto O envolvimento da variante MTHFR 677C>T na hiperhomocisteinemia e na doença arterial periférica (DAP) ainda não está claro. Objetivos Avaliar a associação da variante MTHFR 677C>T (rs1801133) com suscetibilidade e gravidade da DAP e valores séricos de homocisteína (Hcy). Métodos Este estudo caso-controle envolveu 157 pacientes com DAP e 113 controles não relacionados. A gravidade e as categorias anatomorradiológicas da DAP foram avaliadas pela classificação de Fontaine e pelo Inter-Society Consensus for the Management of Peripheral Arterial Disease, respectivamente. A genotipagem foi realizada por meio de reação em cadeia da polimerase em tempo real, e os valores de Hcy foram determinados por ensaio de micropartículas de quimioluminescência. Resultados Entre os pacientes com DAP, 97 (61,8%) eram homens e 60 (38,2%) eram mulheres, com mediana de idade de 69 anos. Os pacientes com DAP eram mais velhos e apresentaram valores mais elevados de Hcy do que os controles (mediana de 69 vs. 45 anos de idade, p < 0,001; 13,66 µmol/L vs. 9,91 µmol/L, p = 0,020, respectivamente). Os valores de Hcy foram mais elevados em pacientes com os genótipos CT+TT do que aqueles com o genótipo CC (14,60 µmol/L vs. 12,94 µmol/L, p = 0,008). Além disso, os pacientes com o genótipo TT apresentaram valores mais elevados de Hcy do que aqueles com os genótipos CC+CT (16,40 µmol/L vs. 13,22 µmol/L, p = 0,019, respectivamente), independentemente das principais variáveis confundidoras. Conclusões O alelo T da variante MTHFR 677C>T foi associado a valores mais elevados de Hcy nos pacientes com DAP, mas não em controles, sugerindo uma possível interação entre a variante genética MTHFR 677C>T e outros fatores genéticos, epigenéticos ou ambientais associados com a DAP na modulação do metabolismo da Hcy.

FOXP3 variants are independently associated with transforming growth factor Β1 plasma levels in female patients with inflammatory bowel disease.

OBJECTIVE: The aim of this study was to evaluate the association of -924 G>A (rs2232365) and -3279 C>A (rs3761548) FOXP3 variants with IBD susceptibility, clinical and endoscopic activity, and IL-10 and TGF-ß1 plasma levels. METHOD: The study included 110 IBD female patients, 60 with Ulcerative Colitis (UC) and 50 with Crohn's Disease (CD), and 154 female controls. FOXP3 variants were determined with Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). Plasma levels of IL-10 and TGF-ß1 were determined using immunofluorimetric assay. RESULTS: AA genotype of rs2232365 and rs3761548 was associated with CD (OR = 3.147, 95% CI 1.015-9.758, p = 0.047) and UC (OR = 3.221, 95% CI 1.050-9.876, p = 0.041) susceptibility, respectively. However, were not associated with TGF-ß1 and IL-10 levels, and endoscopic/clinical activity disease. GAGA haplotype was associated with IBD (OR = 4.003, 95% CI 1.100-14.56, p = 0.035) and UC susceptibility (OR = 6.107, 95% CI 1.609-23.18, p = 0.008). In addition, IBD patients with the GAGA haplotype had lower TGF-ß1 levels (p = 0.041). Moreover, G/C haplotype (dominant model) had a protective effect of 60% in CD susceptibility and lower Endoscopic Severity Index. CONCLUSIONS: These results suggest that FOXP3 variants could exert a role in the Treg, which could be one of the factors involved in the susceptibility and pathogenesis of IBD.

In COVID-19, NLRP3 inflammasome genetic variants are associated with critical disease and these effects are partly mediated by the sickness symptom complex: a nomothetic network approach.

In coronavirus disease (COVID-19), the nucleotide-binding domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome is activated in response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Acute infections are accompanied by a sickness symptom complex (SSC) which is highly conserved and protects against infections and hyperinflammation. The aim of this study is to delineate the associations of COVID-19, SSC and NLPR3 rs10157379 T > C and NLPR3 rs10754558 C > G variants; and the protective role of SSC in SARS-CoV-2 infection. We recruited COVID-19 patients, 308 with critical, 63 with moderate and 157 with mild disease. Increased SSC protects against SARS, critical disease, and death due to COVID-19. Increasing age, male sex and rs10754558 CG significantly reduce SSC protection. The rs10157379 CT and rs10754558 GG genotypes are positively associated with SARS. Partial Least Squares analysis shows that a) 41.8% of the variance in critical COVID-19 symptoms is explained by SSC and oxygen saturation (inversely associated), inflammation, chest computed tomography abnormalities, increased body mass index, SARS and age (positively associated); and b) the effects of the NLRP3 rs10157379 and rs10754558 variants on critical COVID-19 are mediated via SSC (protective) and SARS (detrimental). SSC includes anosmia and dysgeusia, and maybe gastrointestinal symptoms. In conclusion, intersections among the rs10754558 variant, age, and sex increase risk towards critical COVID-19 by attenuating SSC. NLRP3 variants play an important role in SARS, and severe and critical COVID-19 especially in elderly male individuals with reduced SSC and with increased BMI, hypertension, and diabetes type 2.

TGFB1 (rs1800470 and rs1800469) variants are independently associated with disease activity and autoantibodies in rheumatoid arthritis patients.

To evaluate the association between TGFB1 + 869 T > C (rs1800470) and TGFB1-509 C > T (rs1800469) variants with susceptibility for rheumatoid arthritis (RA), disease activity, presence of rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) and TGF-ß1 plasma levels. A total of 262 patients with RA and 168 control individuals were tested for the TGFB1 variants using a TaqMan genotyping assay. Disease activity score in 28 joints (DAS28) classified RA patients into two groups of disease activity: remission/mild (DAS28 < 3.2) and moderate/severe (DAS28 ≥ 3.2). TGFB1 + 869 T > C and -509 C > T variants, independently or in haplotype combination, were not associated with RA's susceptibility. Patients with the TGFB1-509 TT genotype had a higher frequency of DAS28 ≥ 3.2 (OR 2.58, 95% CI 1.04-6.42, p = 0.041). The TGFB1 + 869 CC genotype in seropositive patients for RF or anti-CCP was associated with decreased TGF-ß1 levels (p = 0.032 and p = 0.039, respectively). Patients with the TGFB1 + 869 C allele and elevated RF titles demonstrated a higher frequency of DAS28 ≥ 3.2 (p = 0.037). The TGFB1 + 869 T > C variant was associated with diminished TGF-ß1 plasma levels and moderate/severe activity disease only in seropositive RF patients. This is the first study showing that TGF-ß1 plasma levels can be modulated by the interaction between the TGFB1 + 869 T > C variant and autoantibodies. However, the TGFB1-509 C > T variant was associated with moderate/severe activity disease, independently of autoantibodies positivity. Thus, our findings suggest that TGFB1 + 869 T > C and -509 C > T variants can predict activity disease in different RA patient subgroups.

Immune-inflammatory, coagulation, adhesion, and imaging biomarkers combined in machine learning models improve the prediction of death 1 year after ischemic stroke.

Some clinical, imaging, and laboratory biomarkers have been identified as predictors of prognosis of acute ischemic stroke (IS). The aim of this study was to evaluate the prognostic validity of a combination of clinical, imaging, and laboratory biomarkers in predicting 1-year mortality of IS. We evaluated 103 patients with IS within 24 h of their hospital admission and assessed demographic data, IS severity using the National Institutes of Health Stroke Scale (NIHSS), carotid intima-media thickness (cIMT), and degree of stenosis, as well as laboratory variables including immune-inflammatory, coagulation, and endothelial dysfunction biomarkers. The IS patients were categorized as survivors and non-survivors 1 year after admission. Non-survivors showed higher NIHSS and cIMT values, lower antithrombin, Protein C, platelet counts, and albumin, and higher Factor VIII, von Willebrand Factor (vWF), white blood cells, tumor necrosis factor (TNF)-α, interleukin (IL)-10, high-sensitivity C-reactive protein (hsCRP), and vascular cellular adhesion molecule 1 (VCAM-1) than survivors. Neural network models separated non-survivors from survivors using NIHSS, cIMT, age, IL-6, TNF-α, hsCRP, Protein C, Protein S, vWF, and platelet endothelial cell adhesion molecule 1 (PECAM-1) with an area under the receiving operating characteristics curve (AUC/ROC) of 0.975, cross-validated accuracy of 93.3%, sensitivity of 100% and specificity of 85.7%. In conclusion, imaging, immune-inflammatory, and coagulation biomarkers add predictive information to the NIHSS clinical score and these biomarkers in combination may act as predictors of 1-year mortality after IS. An early prediction of IS outcome is important for personalized therapeutic strategies that may improve the outcome of IS.

FOXP3 variants are independently associated with transforming growth factor B1 plasma levels in female patients with inflammatory bowel disease

Abstract Objective: The aim of this study was to evaluate the association of -924 G>A (rs2232365) and -3279 C>A (rs3761548) FOXP3 variants with IBD susceptibility, clinical and endoscopic activity, and IL-10 and TGF-β1 plasma levels. Method: The study included 110 IBD female patients, 60 with Ulcerative Colitis (UC) and 50 with Crohn's Disease (CD), and 154 female controls. FOXP3 variants were determined with Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). Plasma levels of IL-10 and TGF-β1 were determined using immuno-fluorimetric assay. Results: AA genotype of rs2232365 and rs3761548 was associated with CD (OR = 3.147, 95% CI 1.015-9.758, p = 0.047) and UC (OR = 3.221, 95% CI 1.050-9.876, p = 0.041) susceptibility, respectively. However, were not associated with TGF-β1 and IL-10 levels, and endoscopic/clinical activity disease. GAGA haplotype was associated with IBD (OR = 4.003, 95% CI 1.100-14.56, p = 0.035) and UC susceptibility (OR = 6.107, 95% CI 1.609-23.18, p = 0.008). In addition, IBD patients with the GAGA haplotype had lower TGF-β1 levels (p = 0.041). Moreover, G/C haplotype (dominant model) had a protective effect of 60% in CD susceptibility and lower Endoscopic Severity Index. Conclusions: These results suggest that FOXP3 variants could exert a role in the Treg, which could be one of the factors involved in the susceptibility and pathogenesis of IBD.

TGFB1 +869 T > C (rs1800470) variant is independently associated with susceptibility, laboratory activity, and TGF-ß1 in patients with systemic lupus erythematosus.

The aim of this study was to evaluate the association of the +869 T > C (rs1800470) and -509 C > T (rs1800469) TGFB1 variants, individually or in haplotypes structure, with susceptibility, autoantibodies, disease activity, and TGF-ß1 plasma levels in patients with systemic lupus erythematosus (SLE). The study included 203 patients with SLE and 165 healthy controls. TGFB1 variants were determined by real-time polymerase chain reaction (qPCR). Plasma levels of TGF-ß1 were determined using immunofluorimetric assay. The TGFB1 + 869 CC genotype was associated with SLE susceptibility (OR: 1.710, 95%CI: 1.020-2.866, p = 0.042) and with reduction of C4 (p = 0.040) and TGF-ß1 levels (p = 0.044). In addition, patients with TGFB1 + 869 TC and CC genotypes and positive anti-dsDNA had lower TGF-ß1 levels than those with TT (p = 0.004). TGFB1 -509 TT genotype was associated with reduced levels of C4 (p = 0.032). There was no association between haplotypes and clinical and laboratory parameters. Our data demonstrated that the TGFB1 + 869 T > C variant could be used as a genetic marker for SLE susceptibility and both variants as predictors of laboratory activity. This is the first study to demonstrate that TGF-ß1 levels could be modulated by the interaction between TGFB1 + 869 C allele, in homozygosity, or heterozygosity, and the presence of anti-dsDNA.

Carotid intima media thickness measurements coupled with stroke severity strongly predict short-term outcome in patients with acute ischemic stroke: a machine learning study.

Acute ischemic stroke (IS) is one of the leading causes of morbidity, functional disability and mortality worldwide. The objective was to evaluate IS risk factors and imaging variables as predictors of short-term disability and mortality in IS. Consecutive 106 IS patients were enrolled. We examined the accuracy of IS severity using the National Institutes of Health Stroke Scale (NIHSS), carotid intima-media thickness (cIMT) and carotid stenosis (both assessed using ultrasonography with doppler) predicting IS outcome assessed with the modified Rankin scale (mRS) three months after hospital admission. Poor prognosis (mRS ≥ 3) at three months was predicted by carotid stenosis (≥ 50%), type 2 diabetes mellitus and NIHSS with an accuracy of 85.2% (sensitivity: 90.2%; specificity: 81.8%). The mRS score at three months was strongly predicted by NIHSS (ß = 0.709, p < 0.001). Short-term mortality was strongly predicted using a neural network model with cIMT (≥ 1.0 mm versus < 1.0 mm), NIHSS and age, yielding an area under the receiving operator characteristic curve of 0.977 and an accuracy of 94.7% (sensitivity: 100.0%; specificity: 90.9%). High NIHSS (≥ 15) and cIMT (≥ 1.0 mm) increased the probability of dying with hazard ratios of 7.62 and 3.23, respectively. Baseline NIHSS was significantly predicted by the combined effects of age, large artery atherosclerosis stroke, sex, cIMT, body mass index, and smoking. In conclusion, high values of cIMT and NIHSS at admission strongly predict short-term functional impairment as well as mortality three months after IS, underscoring the importance of those measurements to predict clinical IS outcome.

Mixture of probiotics reduces inflammatory biomarkers and improves the oxidative/nitrosative profile in people with rheumatoid arthritis.

OBJECTIVES: Studies have demonstrated that the gut microbiota of people with rheumatoid arthritis (RA) is different from that of healthy individuals and could influence inflammation and oxidative stress. In this study, we sought to evaluate the effects of supplementation with a mixture of probiotics on cytokine plasma levels, inflammatory biomarkers, oxidative/nitrosative stress profile, and Disease Activity Score-28 in people with RA. METHODS: A randomized and double-blind placebo-controlled study was carried out with 42 participants with RA divided into two groups-the probiotic group (n = 21), who over 60 d took a daily ingestion of probiotics in a sachet containing 109 CFU/g each of five freeze-dried strains: Lactobacillus acidophilus La-14, Lactobacillus casei Lc-11, Lactococcus lactis Ll-23, Bifidobacterium lactis Bl-04 and B. bifidum Bb-06; and the placebo group (n = 21) who over 60 d took a daily ingestion of maltodextrin. RESULTS: The probiotic group showed a significant reduction in white blood cell count (P = 0.012) and tumor necrosis factor-α (P = 0.004) and interleukin 6 plasma levels (P = 0.039). However, no differences were observed in interleukin-10, adiponectin, C-reactive protein, erythrocyte sedimentation rate, ferritin, or Disease Activity Score-28 between the two groups. Regarding oxidative/nitrosative stress biomarkers, the probiotic group showed lower nitric oxide metabolites (P = 0.004) and higher sulfhydryl group (P = 0.028) and total radical-trapping antioxidant parameters (P = 0.019) than the placebo group. However, lipid hydroperoxide and protein carbonyl did not differ between groups (P > 0.05). CONCLUSIONS: The mixture of probiotics reduced inflammatory biomarkers and improved the oxidative/nitrosative profile in people with RA.

Haplotypes of FOXP3 genetic variants are associated with susceptibility, autoantibodies, and TGF-ß1 in patients with systemic lupus erythematosus.

The aim of this study was to evaluate the association of rs2232365 (-924 G > A) and rs3761548 (-3279 C > A) FOXP3 variants with systemic lupus erythematosus (SLE) susceptibility, TGF-ß1 plasma levels, autoantibodies, and LN nephritis, and SLE disease activity index (SLEDAI). The study included 196 SLE female patients and 157 female controls. FOXP3 variants were determined with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Plasma levels of TGF-ß1 were determined using immunofluorimetric assay. The AA genotype [OR: 2.650, CI 95%(1.070-6.564), p = 0.035] and A allele [OR: 2.644, CI 95%(1.104-6.333), p = 0.029] were associated with SLE diagnosis in the -3279 C > A. The A/A haplotype was associated with SLE [OR: 3.729, CI 95%(1.006-13.820), p = 0.049]. GCGC haplotype patients had higher TGF-ß1 levels (p = 0.012) than other haplotypes. Patients with -924 AA genotype showed higher frequency of anti-dsDNA (p = 0.012) and anti-U1RNP (p = 0.036). The A/C haplotype had higher SLEDAI score [OR: 1.119, CI 95%(1.015-1.234), p = 0.024] and ACAC haplotype higher frequency of anti-dsDNA [OR: 3.026, CI 95%(1.062-8.624), p = 0.038], anti-U1RNP [OR: 5.649, CI 95%(1.199-26.610), p = 0.029] and nephritis [OR: 2.501, CI 95%(1.004-6.229), p = 0.049]. Our data demonstrate that the G/C haplotype provides protection for SLE. While the presence of allele A of both variants could favor autoimmunity, disease activity, and LN.

Cytokines in psoriasis.

Psoriasis is chronic, immune-mediated, inflammatory disease with a multifactorial etiology that affects the skin tissue and causes the appearance of dry and scaly lesions of anywhere on the body. The study of the pathophysiology of psoriasis reveals a network of immune cells that, together with their cytokines, initiates a chronic inflammatory response. Previously attributed to T helper (Th)1 cytokines, currently the Th17 cytokine family is the major effector in the pathogenesis of psoriatic disease and strongly influences the inflammatory pattern established during the disease activity. In addition, the vast network of cells that orchestrates the pathophysiology makes psoriasis complex to study. Along with this, variations in genes that code the cytokines make psoriasis more clinically heterogeneous and present a challenge for the development of drugs that can be used in the treatment of the patients with this disease. Therefore, it is important to clarify the mechanisms by which the cytokines are involved in the pathophysiology of psoriasis and how this knowledge is translated to the medical practice.

IL6 genetic variants haplotype is associated with susceptibility and disease activity but not with therapy response in patients with inflammatory bowel disease.

PURPOSE: The aim of the present study was to evaluate the IL6 -174 G>C (rs1800795) and -572 G>C (rs1800796) genetic variants and their association with inflammatory bowel diseases (IBDs), disease activity, and response to TNF-α inhibitors. METHODS: The study included 178 patients with IBD and 224 healthy controls. Among the IBD patients, 66 of them were in use of TNF-α inhibitors therapy and were followed during 48 weeks and categorized as responders and non-responders. RESULTS: In total, 89 (50.0%) had ulcerative colitis (UC) and 89 (50.0%) had Crohn's disease (CD). The IL6 -572 CC genotype presented a protective effect in CD patients in codominant and recessive models, while the IL6 -174 CC genotype was associated with susceptibility to UC and CD. The presence of G/C haplotype in the recessive model (GCGC) was associated with UC. The Crohn's disease endoscopic index of severity was low in those patients carrying the GCGC haplotype. It was observed that there was no association between the IL6 genetic variants and TNF-α inhibitor therapy response. CONCLUSION: The G/C haplotype (recessive model) was associated with susceptibility to UC but not to CD. However, the G/C haplotype (dominant model) was associated with the endoscopic activity of CD. Moreover, these IL6 variants did not predict the TNF-α inhibitor therapy response.

Lower thiol, glutathione, and glutathione peroxidase levels in prostate cancer: a meta-analysis study.

PURPOSE: Lowered thiol (-SH) groups and glutathione (GSH) metabolism may be associated with prostate cancer (PCa) and benign prostatic hyperplasia (BPH). The objectives of this study were to systematically review and meta-analyze the associations among -SH groups, GSH, GSH peroxidase (GPx), GSH reductase (GR), and GSH transferase (GST) and PCa/BPH. METHODS: Four electronic databases were searched for studies that reported -SH and GSH variables in PCa/BPH and healthy controls (HC) and the data were meta-analyzed by calculating Hedges's g with 95% confidence intervals. RESULTS: Twenty studies were included in this meta-analysis. Total -SH (g = -1.750, -2.341/-1.159), GPx (g = -0.789, -1.234/-0.344), GSH (g = -2.219, -4.132/-0.305), and the combination of -SH, GPx, and GSH (g = -1.271, -1.271/-0.800) were significantly lower in PCa patients than in HC. -SH (g = -1.752, -3.123/-0.381) and the combination of -SH, GPx, and GSH (g = -0.813, -1.298/-0.327) were significantly lower in BPH patients than in HC. GPx was significantly lower in PCa than in BPH patients (g = -0.455, -0.896/-0.014). Heterogeneity levels were very high, but Egger's test showed that none of the biomarkers showed significant publication bias. CONCLUSION: Thiol/GPx antioxidant defenses are significantly attenuated in patients with PCa while patients with BPH occupy an intermediate risk group position between PCa patients and HC.

Association of Lower Adiponectin Plasma Levels, Increased Age and Smoking with Subclinical Atherosclerosis in Patients with HIV-1 Infection.

BACKGROUND: The association between subclinical atherosclerosis and traditional cardiovascular disease (CVD) risk factors, inflammatory and metabolic biomarkers has been demonstrated around the world and specifically Brazilian human immunodeficiency virus type 1 (HIV-1)- infected individuals. However, the association between subclinical atherosclerosis and these aforementioned factors combined with anti-inflammatory biomarkers has not been examined in these populations. OBJECTIVES: To evaluate the association of the carotid intima-media thickness (cIMT) with CVD risk factors, inflammatory, metabolic and HIV-1 infection markers combined with adiponectin and interleukin (IL)-10 as anti-inflammatory variables. METHODS: In this case-control study, 49 HIV-1-infected patients on combined antiretroviral therapy (cART) and 85 controls were compared for traditional CVD risk factors, inflammatory, metabolic, and anti-inflammatory variables. Further, we compared HIV-1-infected patients according to their cIMT (as continuous and categorized <0.9 or ≥0.9 mm variable) visualized by carotid ultrasonography doppler (USGD). RESULTS: Twenty-four (48.9%) HIV-1-infected patients showed cIMT ≥0.9 mm. The patients had higher levels of C reactive protein on high sensitivity assay (hsCRP), tumor necrosis factor α, IL-6, IL-10, triglycerides, and insulin, and lower levels of adiponectin, total cholesterol and low-density lipoprotein cholesterol than controls (all p<0.05). Low levels of adiponectin were negatively associated with cIMT ≥0.9 mm (p=0.019), and explained 18.7% of the cIMT variance. Age (p=0.033) and current smoking (p=0.028) were positively associated with cIMT values, while adiponectin levels (p=0.008) were negatively associated with cIMT values; together, these three variables explained 27.3% of cIMT variance. CONCLUSION: Low adiponectin was associated with higher cIMT in HIV-1-infected patients on cART. Low adiponectin levels in combination with age and smoking could explain, in part, the increased subclinical atherosclerosis observed in these patients. Adiponectin may be a good candidate for predicting subclinical atherosclerosis in the management of HIV-1-infected patients in public health care, especially where USGD is not available.

Thiol Groups as a Biomarker for the Diagnosis and Prognosis of Prostate Cancer.

Oxidative stress (OS) is associated with the onset of prostate cancer (PCa). The aims of this study are to examine whether OS biomarkers may be employed as external validating criteria for the diagnosis PCa. This case-control study recruited 204 subjects, 73 patients with PCa, 67 patients with benign prostate hyperplasia (BPH), and 64 healthy controls (HC) and assayed plasma prostate-specific antigen (PSA), protein thiol (-SH) groups, lipid hydroperoxides, carbonyl proteins (PCB), advanced oxidation protein products (AOPP), and total radical-trapping antioxidant parameter (TRAP). -SH groups were significantly and inversely associated with PSA levels. PCa was characterized by lowered -SH groups and red blood cell TRAP levels, and higher PSA, AOPP and PCB levels as compared with BPH and HC. Support vector machine with 10-fold cross-validation showed that PSA values together with -SH groups, PCB and AOPP yielded a cross-validation accuracy of 96.34% for the differentiation of PCa from BPH and HC. The area under the ROC curve using PSA and -SH differentiating PCa from BPH and controls was 0.945. Moreover, lowered -SH, but not PSA, are associated with PCa metastasis and progression. Inflammatory biomarkers were not associated with PCa or BPH. PCa, its progression and metastatic PCa are characterized by lowered antioxidant defenses, especially lowered thiol groups, and increased oxidative stress toxicity, suggesting that these processes play a key role in the pathophysiology of PCa. An algorithm based on -SH and PSA values may be used to differentiate patients with PCa from those with BPH and controls.