Impaired decision-making and time perception in individuals with stroke: Behavioral and neural correlates.

Several studies have demonstrated that stroke subjects present impairment of functions related to decision-making and timing, involving the information processing in the neural circuits of the cerebellum in association with the prefrontal cortex. This review is aimed to identify the gaps, and demonstrate a better understanding of decision-making and timing functions in the patients with stroke. Electronic literature database was searched and the findings of relevant studies were used to explore the mechanisms of decision-making and timing in patients with stroke, as well as the circuit connections in timing mediated by prefrontal cortex and cerebellum. A literature review was conducted with 65 studies that synthesized findings on decision-making and time perception in individuals with stroke. Types of neurobiological modalities in this study included: Relationships among decision-making, time perception, related cognitive aspects (such as discrimination tasks, verbal estimation, bisection tasks, time production and motor reproduction), and motor control. We demonstrate that the timing processes are important for the performance in cognitive tasks and that the cerebellum and prefrontal cortex are involved in decision-making and time perception. In the context, the decision-making is impaired in stroke patients has a great impact on executive functions, and this seems to be important in determining neurobiological aspects relevant to the time interval interpretation.

Prevalence of CCR5-Δ32 and CCR2-V64I polymorphisms in a mixed population from northeastern Brazil.

Chemokines are low-molecular weight proteins that play a key role in inflammatory processes. Genomic variations in chemokine receptors are associated with the susceptibility to various diseases. Polymorphisms in chemokine receptor type 5 (CCR5)-Δ32 and CCR2-V64I are related to human immunodeficiency virus infection resistance, which has led to genetic association studies for several other diseases. Given the heterogeneous distribution of these polymorphisms in different global populations and within Brazilian populations, we analyzed the prevalence of CCR5-Δ32 and CCR2-V64I polymorphisms in a mixed population from northeastern Brazil. The study included 223 individuals from the general population of the city of Parnaíba, Piauí, who had a mean age of 73 years. Of these individuals, 37.2% were men and 62.8% were women. Polymorphisms were analyzed using DNA extracted from peripheral blood leukocytes by using polymerase chain reaction alone (CCR5-Δ32) or accompanied by restriction endonuclease digestion (CCR2-V64I). In both cases, the genotypes were determined using 8% polyacrylamide gel electrophoresis and silver nitrate staining. The population conformed to Hardy-Weinberg equilibrium for both the loci studied. No individuals were homozygous for allele-Δ32, which was present in 1.8% of the population, whereas allele-64I was present in 13.9% of the participants studied; 74.9% were homozygous for the wild-type allele, while 22.4 and 2.7% were heterozygous and homozygous for the mutant allele, respectively. Additional studies are needed to investigate the relationship between these polymorphisms and disease etiopathogenesis in reference populations.

Frequency of SNP -336A/G in the promoter region of CD209 in a population from northeastern Brazil.

Dendritic cells (DCs) mediate the initiation of the immune response against a variety of pathogens. The DC-SIGN receptor is encoded by the gene CD209 and is expressed on the surface of DCs. It binds to mannose-rich carbohydrates and enables the recognition of bacteria, fungi, parasites, and viruses. SNP -336A/G in the promoter region of CD209 influences the expression of the DC-SIGN receptor. Several studies have associated this SNP with an increased susceptibility to infectious diseases and the development of more severe forms of disease. Therefore, the aim of this study was to determine the prevalence of SNP -336A/G in a population from northeastern Brazil. We analyzed 181 individuals from the general population of Parnaíba, Piauí, Brazil, of which 37% were men and 63% were women. SNP -336A/G was detected by polymerase chain reaction and treatment with the restriction enzyme MscI and visualized by electrophoresis on an 8% polyacrylamide gel stained with silver nitrate. Of the individuals analyzed, 116 (64.1%) were homozygous AA, 57 (31.5%) were heterozygous (AG), and 8 (4.4%) were homozygous GG. The allele frequency of -336G was 20.2%. Genotype frequencies were in Hardy-Weinberg equilibrium. To the best of our knowledge, this is the first report to describe the frequency of the CD209 SNP -336A/G in a population in the State of Piauí. Further studies are needed to determine the relationship between this SNP and the vulnerability of this population to major infectious diseases.

Study of polymorphic variants of the serotonin 2A receptor gene (5-HT2A) and its possible effects on smoking habits of a population from northeastern Brazil.

Previous studies have revealed a genetic component, including genetic polymorphisms in the serotonergic pathway, particularly in the serotonin receptor gene (5-HT2A). The aim of this study was to investigate associations of the T102C (rs6313) and A-1438G (rs6311) polymorphisms with tobacco use in a population from northeastern Brazil. We evaluated these polymorphisms in 135 nonsmokers and 135 smokers using polymerase chain reaction-restricted fragment length polymorphism. The distribution of allele and genotype frequencies and associations of polymorphisms with smoking were assessed with the chi-squared (χ(2)) test, the Fisher exact test, and odds ratio (OR) with a 95% confidence interval (CI). There were no differences in the distribution of genotype and allele frequencies between nonsmokers and smokers for A-1438G (P = 0.80) and T102C (P = 0.35). However, these polymorphisms were significantly associated with habit frequency (A/G: P = 0.02, OR = 6.87, 95%CI = 1.23-38.31, P = 0.04; A/G+G/G: P = 0.04, OR = 3.67, 95%CI = 1.06-12.75, P = 0.07), age of onset (C/C: P = 0.02, OR = 3.26, 95%CI = 1.17-9.07, P = 0.03, and nicotine dependence level (A/G: P = 0.02, OR = 3.28, 95%CI = 1.17-9.18, P = 0.04; A/G+G/G: P = 0.04, OR = 2.81, 95%CI = 1.13-6.99, P = 0.04; T/C: P = 0.03, OR = 3.12, 95%CI = 1.13-8.57, P = 0.04; T/C+C/C: P = 0.02, OR = 3.06, 95%CI = 1.22-7.70, P = 0.02). Therefore, these polymorphisms may not contribute significantly to smoking initiation, they do appear to be associated with habit maintenance.

Association of the rs7903146 and rs12255372 polymorphisms in the TCF7L2 gene with type 2 diabetes in a population from northeastern Brazil.

Approximately 200 million people suffer from type 2 diabetes (T2D) worldwide, and the rapid increase in the prevalence of this disease is likely a result of multiple environmental factors, such as increased food intake and decreased physical activity in genetically predisposed individuals. Different population studies have demonstrated a strong association of two polymorphic variations in the TCF7L2 gene, the noncoding single nucleotide polymorphisms (SNPs) rs7903146 (C/T) and rs12255372 (G/T), with T2D. Herein, we analyzed the association of these SNPs with T2D in a population from northeastern Brazil. Our results showed that the genotype and allele frequencies in TCF7L2 rs7903146 and rs12255372 were similar in the patient and control groups (P > 0.05). In addition, the allele frequencies were not significantly associated with T2D risk [rs7903146: odds ratio (OR) = 0.95, 95% confidence interval (CI) = 0.52-1.76, P = 1.00, and rs12255372: OR = 1.38, 95%CI = 0.72-2.62, P = 0.41]. These data suggest that the TCF7L2 SNPs rs7903146 and rs12255372 may not significantly contribute to T2D susceptibility in this population. However, our results may reflect the small number of subjects. Alternatively, these results may be attributable to specific ethnic effects, as most of the previously reported associations were demonstrated with predominantly European populations. To reach a definitive conclusion on the role of such gene variants for T2D in mixed populations, additional efforts are necessary to replicate this study with larger populations from areas with more ethnic heterogeneity.

Prevalence of variants that confer risk for venous thromboembolism in an elderly population of northeastern Brazil.

Venous thromboembolism (VTE) is an important cause of morbidity and mortality stemming from cardiovascular disease. It is a multifactorial disease caused by a combination of acquired risk factors, of which advanced age is the most significant, and genetic factors, including the variants FV G1691A, FII G20210A, and MTHFR C677T. We estimated the prevalence of these genomic variants in an elderly population of northeastern Brazil. The study included 188 elderly persons (65-93 years), of which 68 (36.2%) were men and 120 (63.8%) were women. Variants were detected by polymerase chain reaction-restriction fragment length polymorphism analysis, and subsequent electrophoresis on an 8% polyacrylamide gel stained with silver nitrate. The study population was in Hardy-Weinberg equilibrium for the 3 loci. Of the individuals analyzed, none carried variants of FV or FII (0%), and 24.7% had the MTHFR C677T polymorphism: 59 subjects (31.4%) were heterozygous (CT) and 17 subjects (9%) were homozygous (TT). Based on the analysis of these particular genes, we conclude that the study population does not present an increased risk for the development of VTE. Faced with a growing aging population worldwide, similar studies in other countries will help in the prevention of VTE in older individuals.

Variation in DNA repair gene XRCC3 affects susceptibility to astrocytomas and glioblastomas.

The gene XRCC3 (X-ray cross complementing group 3) has the task of repairing damage that occurs when there is recombination between homologous chromosomes. Repair of recombination between homologous chromosomes plays an important role in maintaining genome integrity, although it is known that double-strand breaks are the main inducers of chromosomal aberrations. Changes in the XRCC3 protein lead to an increase in errors in chromosome segregation due to defects in centrosomes, resulting in aneuploidy and other chromosomal aberrations, such as small increases in telomeres. We examined XRCC3 Thr241Met polymorphism using PCR-RFLP in 80 astrocytoma and glioblastoma samples. The individuals of the control group (N = 100) were selected from the general population of the São Paulo State. Odds ratio and 95%CI were calculated using a logistic regression model. Patients who had the allele Met of the XRCC3 Thr241Met polymorphism had a significantly increased risk of tumor development (odds ratio = 3.13; 95% confidence interval = 1.50-6.50). There were no significant differences in overall survival of patients. We suggest that XRCC3 Thr241Met polymorphism is involved in susceptibility for developing astrocytomas and glioblastomas.

Analysis of the polymorphisms XRCC1Arg194Trp and XRCC1Arg399Gln in gliomas.

XRCC genes (X-ray cross-complementing group) were discovered mainly for their roles in protecting mammalian cells against damage caused by ionizing radiation. Studies determined that these genes are important in the genetic stability of DNA. Although the loss of some of these genes does not necessarily confer high levels of sensitivity to radiation, they have been found to represent important components of various pathways of DNA repair. To ensure the integrity of the genome, a complex system of DNA repair was developed. Base excision repair is the first defense mechanism of cells against DNA damage and a major event in preventing mutagenesis. Repair genes may play an important role in maintaining genomic stability through different pathways that are mediated by base excision. In the present study, we examined XRCC1Arg194Trp and XRCC1Arg399Gln polymorphism using PCR-RFLP in 80 astrocytoma and glioblastoma samples. Patients who had the allele Trp of the XRCC1Arg194Trp polymorphism had an increased risk of tumor development (OR = 8.80; confidence interval at 95% (95%CI) = 4.37-17.70; P < 0.001), as did the allele Gln of XRCC1Arg399Gln (OR = 1.01; 95%CI = 0.53-1.93; P = 0.971). Comparison of overall survival of patients did not show significant differences. We suggest that XRCC1Arg194Trp and XRCC1Arg399Gln polymorphisms are involved in susceptibility for developing astrocytomas and glioblastomas.

GSTP1 Ile105Val polymorphism in astrocytomas and glioblastomas.

Glutathione S-transferases (GSTs) constitute a superfamily of ubiquitous multifunctional enzymes that are involved in the cellular detoxification of a large number of endogenous and exogenous chemical agents that have electrophilic functional groups. People who have deficiencies in this family of genes are at increased risk of developing some types of tumors. We examined GSTP1 Ile105Val polymorphism using PCR-RFLP in 80 astrocytoma and glioblastoma samples. Patients who had the Val allele of the GSTP1 Ile105Val polymorphism had an increased risk of tumor development (odds ratio = 8.60; 95% confidence interval = 4.74-17.87; P < 0.001). Overall survival of patients did not differ significantly. We suggest that GSTP1 Ile105Val polymorphisms are involved in susceptibility to developing astrocytomas and glioblastomas.

Pisosterol induces interphase arrest in HL60 cells with c-MYC amplification.

The leukaemia cell line HL60 is widely used in studies of the cell cycle, apoptosis and adhesion mechanisms in cancer cells. One marked characteristic of HL60 cells is the c-MYC proto-oncogene amplification, resulting in the formation of homogeneously staining regions (HSRs) at 8p24. We conducted a fluorescence in situ hybridization study in an HL60 cell line, using a locus-specific probe for c-MYC, before and after treatment with pisosterol (at 0.5, 1.0 and 1.8 microg/mL), a triterpene isolated from the fungus Pisolithus tinctorius. Before treatment, 87.5% of the cells showed HSRs. After treatment, no effects were detected at lower concentrations of pisosterol (0.5 and 1.0 microg/mL). However, at 1.8 microg/mL only 15% of the cells presented HSRs, and 39.5% presented few fluorescent signals (3 or 4 alleles), suggesting that pisosterol probably blocks the cells with HSRs at interphase. This result is particularly interesting because cells that do not show a high degree of c-MYC gene amplification have a less aggressive and invasive behaviour and are easy targets for chemotherapy. Therefore, further studies are needed to examine the use of pisosterol in combination with conventional anti-cancer therapy.

Polymorphisms and DNA methylation of gene TP53 associated with extra-axial brain tumors.

The p53 tumor suppressor gene is the most frequently mutated gene in human cancer; this gene is mutated in up to 50% of human tumors. It has a critical role in the cell cycle, apoptosis and cell senescence, and it participates in many crucial physiological and pathological processes. Polymorphisms of p53 have been suggested to be associated with genetically determined susceptibility in various types of cancer. Another process involved with the development and progression of tumors is DNA hypermethylation. Aberrant methylation of the promoter is an alternative epigenetic change in genetic mechanisms, leading to tumor suppressor gene inactivation. In the present study, we examined the TP53 Arg72Pro and Pro47Ser polymorphisms using PCR-RFLP and the pattern of methylation of the p53 gene by methylation-specific PCR in 90 extra-axial brain tumor samples. Patients who had the allele Pro of the TP53 Arg72Pro polymorphism had an increased risk of tumor development (odds ratio, OR = 3.23; confidence interval at 95%, 95%CI = 1.71-6.08; P = 0.003), as did the allele Ser of TP53 Pro47Ser polymorphism (OR = 1.28; 95%CI = 0.03-2.10; P = 0.01). Comparison of overall survival of patients did not show significant differences. In the analysis of DNA methylation, we observed that 37.5% of meningiomas, 30% of schwannomas and 52.6% of metastases were hypermethylated, suggesting that methylation is important for tumor progression. We suggest that TP53 Pro47Ser and Arg72Pro polymorphisms and DNA hypermethylation are involved in susceptibility for developing extra-axial brain tumors.

Prognostic value of TP53 Pro47Ser and Arg72Pro single nucleotide polymorphisms and the susceptibility to gliomas in individuals from Southeast Brazil.

The TP53 tumor suppressor gene codifies a protein responsible for preventing cells with genetic damage from growing and dividing by blocking cell growth or apoptosis pathways. A common single nucleotide polymorphism (SNP) in TP53 codon 72 (Arg72Pro) induces a 15-fold decrease of apoptosis-inducing ability and has been associated with susceptibility to human cancers. Recently, another TP53 SNP at codon 47 (Pro47Ser) was reported to have a low apoptosis-inducing ability; however, there are no association studies between this SNP and cancer. Aiming to study the role of TP53 Pro47Ser and Arg72Pro on glioma susceptibility and oncologic prognosis of patients, we investigated the genotype distribution of these SNPs in 94 gliomas (81 astrocytomas, 8 ependymomas and 5 oligodendrogliomas) and in 100 healthy subjects by the polymerase chain reaction-restriction fragment length polymorphism approach. Chi-square and Fisher exact test comparisons for genotype distributions and allele frequencies did not reveal any significant difference between patients and control groups. Overall and disease-free survivals were calculated by the Kaplan-Meier method, and the log-rank test was used for comparisons, but no significant statistical difference was observed between the two groups. Our data suggest that TP53 Pro47Ser and Arg72Pro SNPs are not involved either in susceptibility to developing gliomas or in patient survival, at least in the Brazilian population.

Prognostic value of TP53 Pro47Ser and Arg72Pro single nucleotide polymorphisms and the susceptibility to gliomas in individuals from Southeast Brazil

The TP53 tumor suppressor gene codifies a protein responsible for preventing cells with genetic damage from growing and dividing by blocking cell growth or apoptosis pathways. A common single nucleotide polymorphism (SNP) in TP53 codon 72 (Arg72Pro) induces a 15-fold decrease of apoptosis-inducing ability and has been associated with susceptibility to human cancers. Recently, another TP53 SNP at codon 47 (Pro47Ser) was reported to have a low apoptosis-inducing ability; however, there are no association studies between this SNP and cancer. Aiming to study the role of TP53 Pro47Ser and Arg72Pro on glioma susceptibility and oncologic prognosis of patients, we investigated the genotype distribution of these SNPs in 94 gliomas (81 astrocytomas, 8 ependymomas and 5 oligodendrogliomas) and in 100 healthy subjects by the polymerase chain reaction-restriction fragment length polymorphism approach. Chi-square and Fisher exact test comparisons for genotype distributions and allele frequencies did not reveal any significant difference between patients and control groups. Overall and disease-free survivals were calculated by the Kaplan-Meier method, and the log-rank test was used for comparisons, but no significant statistical difference was observed between the two groups. Our data suggest that TP53 Pro47Ser and Arg72Pro SNPs are not involved either in susceptibility to developing gliomas or in patient survival, at least in the Brazilian population.

Mutation analysis of gene PAX6 in human gliomas.

Gliomas are the most common tumors of the central nervous system. In spite of the marked advances in the characterization of the molecular pathogenesis of gliomas, these tumors remain incurable and, in most of the cases, resistant to treatments, due to their molecular heterogeneity. Gene PAX6, which encodes a transcription factor that plays an important role in the development of the central nervous system, was recently recognized as a tumor suppressor in gliomas. The objective of the present study was to analyze the mutational status of the coding and regulating regions of PAX6 in 94 gliomas: 81 astrocytomas (11 grade I, 23 grade II, 8 grade III, and 39 grade IV glioblastomas), 5 oligodendrogliomas (3 grade II, and 2 grade III), and 8 ependymomas (5 grade II, and 3 grade III). Two regulating regions (SX250 and EIE) and the 11 coding regions (exons 4-13, plus exon 5a resulting from alternative splicing) of gene PAX6 were analyzed and no mutation was found. Therefore, we conclude that the tumor suppressor role of PAX6, reported in previous studies on gliomas, is not due to mutation in its coding and regulating regions, suggesting the involvement of epigenetic mechanisms in the silencing of PAX6 in these tumors.

Mutation analysis of gene PAX6 in human gliomas

Gliomas are the most common tumors of the central nervous system. In spite of the marked advances in the characterization of the molecular pathogenesis of gliomas, these tumors remain incurable and, in most of the cases, resistant to treatments, due to their molecular heterogeneity. Gene PAX6, which encodes a transcription factor that plays an important role in the development of the central nervous system, was recently recognized as a tumor suppressor in gliomas. The objective of the present study was to analyze the mutational status of the coding and regulating regions of PAX6 in 94 gliomas: 81 astrocytomas (11 grade I, 23 grade II, 8 grade III, and 39 grade IV glioblastomas), 5 oligodendrogliomas (3 grade II, and 2 grade III), and 8 ependymomas (5 grade II, and 3 grade III). Two regulating regions (SX250 and EIE) and the 11 coding regions (exons 4-13, plus exon 5a resulting from alternative splicing) of gene PAX6 were analyzed and no mutation was found. Therefore, we conclude that the tumor suppressor role of PAX6, reported in previous studies on gliomas, is not due to mutation in its coding and regulating regions, suggesting the involvement of epigenetic mechanisms in the silencing of PAX6 in these tumors.

Cytogenetic characteristics of patients with signs and symptoms of myelodysplastic syndromes in the State of Pará, Brazil

The myelodysplastic syndromes (MDS) are clonal hematopoietic diseases characterized by medullary dysplasia, cytopenias, and frequent evolution to acute myeloid leukemia. In 1982, the French-American-British (FAB) group proposed a classification for the MDS, based on morphological characteristics of peripheral blood and of the bone marrow. Later, cytogenetics proved to be a useful tool for the refinement of prognosis, through the use of the International Prognosis Score System (IPSS), as well as through evidence of clonality. Recently, the World Health Organization (WHO) proposed a new classification for the MDS, based on significant modifications of the FAB proposal, with the inclusion of chromosome analysis. A cytogenetic analysis was made of 17 patients with symptoms of MDS in the State of Para, based on WHO recommendations, and application of the IPSS. Good metaphases were obtained for 13 patients; 12 had a normal karyotype and only one had a clonal abnormality, del(3)(p25). The genes related to neoplastic processes that have been mapped to 3p are: XPC in 3p25.1 and FANCD2 and VHL in 3p25-26. Four patients had classic symptoms of MDS; in the rest the possibility of MDS was excluded or several months of observation before diagnosis were recommended. Among those with MDS, it was not possible to apply IPSS and WHO recommendations, because fundamental data were lacking, specifically the medullary blast and ring sideroblast counts. We advocate the implementation of routine cytogenetic analyses for the study of MDS, especially in patients with moderate hematopoietic dysplasia

[The influence of smoking on fertility, pregnancy and lactation] / Influência do tabagismo na fertilidade, gestação e lactação.

OBJECTIVE: To decribe the influence of smoking on different phases of the reproductive process, fecundation, pregnancy and lactation, drawing special attention to the mechanisms of action of the main toxic components found in cigarettes. To suggest prophylactic measures for environmental control and how to reduce childrens exposure to tobacco smoke. METHODS: Nonsystematic literature review using MEDLINE database. RESULTS: Smoking has a negative effect on different phases of the reproduction process, by direct action of main toxic components, nicotine and carbon monoxide. Smoking reduces fertility, compromises the length of gestation and infant birthweight. Smoking mothers also have reduced breast milk production and shorter lactation, which affects infant weight gain through unclear mechanisms in which prolactin may probably be involved. CONCLUSIONS: Smoking compromises reproductive function quality in different phases, acting mainly on intrauterine and extrauterine development of infants. Since during pregnancy and lactation women are in closer contact with health professionals, antismoking campaigns should be especially addressed to this period.