Modulating Expression of Endogenous Interleukin 1 Beta in the Acute Phase of the Pilocarpine Model of Epilepsy May Change Animal Survival.

The pilocarpine-induced (PILO) model has helped elucidate the electrophysiological and molecular aspects related to mesial temporal lobe epilepsy. It has been suggested that the extensive cell death and edema observed in the brains of these animals could be induced by increased inflammatory responses, such as the rapid release of the inflammatory cytokine interleukin 1 beta (Il1b). In this study, we investigate the role of endogenous Il1b in the acute phase of the PILO model. Our aim is twofold. First, we want to determine whether it is feasible to silence Il1b in the central nervous system using a non-invasive procedure. Second, we aim to investigate the effect of silencing endogenous Il1b and its antagonist, Il1rn.We used RNA interference applied non-invasively to knockdown Il1b and its endogenous antagonist Il1rn. We found that knocking down Il1b prior to pilocarpine injection increased the mortality rate of treated animals. Furthermore, we observed that, when exposing the animals to more Il1b by silencing its endogenous antagonist Il1rn, there was a better response to status epilepticus with decreased animal mortality in the acute phase of the PILO model. Thus, we show the feasibility of using a novel, less invasive approach to study genes involved in the inflammatory response in the central nervous system. Furthermore, our results provide suggestive evidence that modulating endogenous Il1b improves animal survival in the acute phase of the PILO model and may have effects that extend into the chronic phase.

TSHR intronic polymorphisms (rs179247 and rs12885526) and their role in the susceptibility of the Brazilian population to Graves' disease and Graves' ophthalmopathy.

PURPOSE: Intronic thyroid-stimulating hormone receptor polymorphisms have been associated with the risk for both Graves' disease and Graves' ophthalmopathy, but results have been inconsistent among different populations. We aimed to investigate the influence of thyroid-stimulating hormone receptor intronic polymorphisms in a large well-characterized population of GD patients. METHODS: We studied 279 Graves' disease patients (231 females and 48 males, 39.80 ± 11.69 years old), including 144 with Graves' ophthalmopathy, matched to 296 healthy control individuals. Thyroid-stimulating hormone receptor genotypes of rs179247 and rs12885526 were determined by Real Time PCR TaqMan(®) SNP Genotyping. RESULTS: A multivariate analysis showed that the inheritance of the thyroid-stimulating hormone receptor AA genotype for rs179247 increased the risk for Graves' disease (OR = 2.821; 95 % CI 1.595-4.990; p = 0.0004), whereas the thyroid-stimulating hormone receptor GG genotype for rs12885526 increased the risk for Graves' ophthalmopathy (OR = 2.940; 95 % CI 1.320-6.548; p = 0.0083). Individuals with Graves' ophthalmopathy also presented lower mean thyrotropin receptor antibodies levels (96.3 ± 143.9 U/L) than individuals without Graves' ophthalmopathy (98.3 ± 201.9 U/L). We did not find any association between the investigated polymorphisms and patients clinical features or outcome. CONCLUSION: We demonstrate that thyroid-stimulating hormone receptor intronic polymorphisms are associated with the susceptibility to Graves' disease and Graves' ophthalmopathy in the Brazilian population, but do not appear to influence the disease course.

Polymorphisms of cell cycle control genes influence the development of sporadic medullary thyroid carcinoma.

BACKGROUND: The role of key cell cycle regulation genes such as, CDKN1B, CDKN2A, CDKN2B, and CDKN2C in sporadic medullary thyroid carcinoma (s-MTC) is still largely unknown. METHODS: In order to evaluate the influence of inherited polymorphisms of these genes on the pathogenesis of s-MTC, we used TaqMan SNP genotyping to examine 45 s-MTC patients carefully matched with 98 controls. RESULTS: A multivariate logistic regression analysis demonstrated that CDKN1B and CDKN2A genes were related to s-MTC susceptibility. The rs2066827*GT+GG CDKN1B genotype was more frequent in s-MTC patients (62.22%) than in controls (40.21%), increasing the susceptibility to s-MTC (OR=2.47; 95% CI=1.048-5.833; P=0.038). By contrast, the rs11515*CG+GG of CDKN2A gene was more frequent in the controls (32.65%) than in patients (15.56%), reducing the risk for s-MTC (OR=0.174; 95% CI=0.048-0.627; P=0.0075). A stepwise regression analysis indicated that two genotypes together could explain 11% of the total s-MTC risk. In addition, a relationship was found between disease progression and the presence of alterations in the CDKN1A (rs1801270), CDKN2C (rs12885), and CDKN2B (rs1063192) genes. WT rs1801270 CDKN1A patients presented extrathyroidal tumor extension more frequently (92%) than polymorphic CDKN1A rs1801270 patients (50%; P=0.0376). Patients with the WT CDKN2C gene (rs12885) presented larger tumors (2.9±1.8 cm) than polymorphic patients (1.5±0.7 cm; P=0.0324). On the other hand, patients with the polymorphic CDKN2B gene (rs1063192) presented distant metastases (36.3%; P=0.0261). CONCLUSION: In summary, we demonstrated that CDKN1B and CDKN2A genes are associated with susceptibility, whereas the inherited genetic profile of CDKN1A, CDKN2B, and CDKN2C is associated with aggressive features of tumors. This study suggests that profiling cell cycle genes may help define the risk and characterize s-MTC aggressiveness.

Clinical outcomes of periodontal therapy are not influenced by the ATC/TTC haplotype in the IL8 gene.

BACKGROUND AND OBJECTIVE: Although chronic periodontitis (CP) is a multifactorial condition, few studies have investigated the potential association of gene variants with the outcome of periodontal therapy. In a previous study, we reported that variants in the interleukin-8 (IL8) gene were associated with CP in a Brazilian population. The aim of this nonrandomized study was to investigate whether genetic susceptibility to CP, conferred by the presence of the IL8 ATC/TTC haplotype, influences the clinical outcomes of nonsurgical periodontal therapy and the IL-8 protein levels in the gingival crevicular fluid. MATERIAL AND METHODS: Forty-one individuals were grouped according to the presence (susceptible to CP; n = 21) or absence (not susceptible to CP; n = 20) of the IL8 ATC/TTC haplotype. These individuals received nonsurgical periodontal therapy from one periodontist, who was blinded to the genetic status of each patient, and follow up continued for 45 d. The clinical parameters and gingival crevicular fluid samples were collected at baseline and on day 45. The IL-8 levels were determined by an ELISA. The data were subjected to the Mann-Whitney U-test, Wilcoxon and Spearman tests and to multiple logistic-regression analysis. RESULTS: No significant differences between patients with or without the IL8 ATC/TTC haplotype were found for the outcome of nonsurgical periodontal therapy and IL-8 levels. The multiple logistic-regression analysis did not show a statistically significant association between the IL8 haplotype and the variables studied. CONCLUSION: In this longitudinal clinical study, we observed that neither the outcome of nonsurgical periodontal therapy nor the IL-8 levels were influenced by the IL8 ATC/TTC CP-susceptibility haplotype. Additional studies of CP patients from other ethnic populations are necessary to confirm these results.

Study of candidate genes for dyslexia in Brazilian individuals.

Dyslexia or reading disability (RD) is the most common childhood learning disorder and a significantly heritable trait. Many recent studies have investigated the genetic basis of dyslexia, and several candidate genes have been proposed. Among these, DCDC2 and KIAA0319 have emerged as the strongest candidate genes for dyslexia; however studies have not provided uniformly supportive results. The aim of this study was to assess the contribution of proposed candidate genes to the molecular etiology of dyslexia in a Brazilian sample. Large deletions and duplications in the candidate genes DCDC2, KIAA0319, and ROBO1 were investigated in 51 dyslexic subjects. Furthermore, a family-based association study was performed to investigate whether associations observed in other populations with variants in the DCDC2 and KIAA0319 genes were reproducible in Brazilian dyslexic individuals. Our analysis did not detect any deletions or duplications in the genes studied, and we found no evidence that the allelic variants in the two candidate genes were significantly associated with RD in our sample. Our data do not support a role of the DCDC2/KIAA0319 locus in influencing dyslexia as a categorical trait. Given the genetic complexity of dyslexia, it is plausible that both genes contribute to an increased risk, but the relative influence of these 2 genes on RD varies in different study samples, and/or depends on analytical approaches.

Association between IL8 haplotypes and pathogen levels in chronic periodontitis.

Chronic periodontitis (CP) is considered to be a multifactorial disease influenced by microbial and genetic factors. The aim of the present study was to investigate whether the genetic susceptibility to CP in individuals with the IL8 ATC/TTC haplotype is associated with subgingival levels of periodontopathogens. Sixty-five individuals, grouped according to the presence (n = 28) or absence (n = 37) of the IL8 haplotype, were evaluated. After clinical periodontal evaluation, each group was subdivided according to the presence (CP) or absence (H) of periodontitis. Four subgingival samples were obtained from CP and two samples per subject from H patients. The levels and proportions of Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola were analyzed using quantitative real-time polymerase chain reaction (q-PCR). No differences were found in the proportion of periodontopathogenic bacteria between groups with the presence or absence of the IL8 haplotype. However, in the CP groups, the levels of periodontopathogens were significantly higher in the individuals without the IL8 haplotype than in the individuals with the IL8 haplotype. These results suggest that periodontal destruction may occur in patients who are considered to be genetically susceptible to CP with a lower microbial challenge because of the presence of the IL8 ATC/TTC haplotype than in patients without this haplotype.

The periodized resistance training promotes similar changes in lipid profile in middle-aged men and women.

AIM: The aim of the present study was to evaluate the effects of 16 weeks of periodized resistance training in lipid profile in sedentary middle-aged men and women. METHODS: Healthy subjects (N.=50), middle-aged men and postmenopausal women (>12 months amenorrhea), were randomized into resistance training men (RTM), resistance training women (RTW), control group men (CGM) and control group women (CGW). They performed three weekly sessions for 16 weeks (9 exercises with 3 x 8-10 RM and with a 60-90 seconds rest period). RESULTS: Trained groups showed significant decrease in total cholesterol (TC) (RTM -23.61%; RTW -21.08%; P=0.0001) and LDL-C (RTM -35.68%; RTW -38.53%; P=0.0001). No significant changes were observed in HDL-C and triglycerides (TG). No significant changes were found in plasma levels of LDL-C, HDL-C and TG for control groups, though there were significant differences between CGM and CGW for TC. CONCLUSION: The present results indicate that 16 weeks of periodized RT contribute to decrease of cardiovascular risk factors, such as LDL-C and TC in middle-aged men and women, even without changes in body mass and body mass index.

Evidence that polymorphisms in detoxification genes modulate the susceptibility for sporadic medullary thyroid carcinoma.

AIM: Polymorphic low-penetrance genes have been consistently associated with the susceptibility to a series of human tumors, including differentiated thyroid cancer. METHODS: To determine their role in medullary thyroid cancer (MTC), we used TaqMan SNP method to genotype 47 sporadic MTC (s-MTC) and a control group of 578 healthy individuals for CYP1A2*F, CYP1A1m1, GSTP1, NAT2 and 72TP53. A logistic regression analysis showed that NAT2C/C (OR=3.87; 95% CI=2.11-7.10; P=2.2×10(-5)) and TP53C/C genotypes (OR=3.87; 95% CI=1.78-6.10; P=2.8×10(-4)) inheritance increased the risk of s-MTC. A stepwise regression analysis indicated that TP53C/C genotype contributes with 8.07% of the s-MTC risk. RESULTS: We were unable to identify any relationship between NAT2 and TP53 polymorphisms suggesting they are independent factors of risk to s-MTC. In addition, there was no association between the investigated genes and clinical or pathological features of aggressiveness of the tumors or the outcome of MTC patients. CONCLUSION: In conclusion, we demonstrated that detoxification genes and apoptotic and cell cycle control genes are involved in the susceptibility of s-MTC and may modulate the susceptibility to the disease.