Prevalence of the DPYD variant (Y186C) in Brazilian individuals of African ancestry.

PURPOSE: The presence of deleterious variants of dihydropyrimidine-dehydrogenase gene (DPYD) is associated with 5-Fluorouracil toxicity. Most of the data are based on findings in Caucasian populations. The variant Y186C (rs115232898) is found almost exclusively in African populations and is related to low DPD function. Its prevalence may vary among African subpopulations and in African Americans. There is no information in other populations. Brazil has the biggest African population outside Africa. We studied for the first time the frequency of this mutation in African Brazilians. METHODS: We amplified exon 6 of DPYD extracted from genomic DNA of 79 healthy volunteers of genetically defined African ancestry from Southeast Brazil and 36 self-reported African descendants from Northeast Brazil in order to determine the prevalence of the variant Y186C in Brazilians of African ancestry. RESULTS: The variant Y186C was found in heterozygosity in two samples from Southeast (2.53%) and one from Northeast (2.77%) Brazil. Overall, the prevalence of this mutation in the 115 African Brazilians was 2.6%. CONCLUSIONS: The variant Y186C is prevalent among Brazilians of African ancestry and should be taken in account in targeted genotyping for fluoropyrimidine risk variants.

Pericytes Make Spinal Cord Breathless after Injury.

Traumatic spinal cord injury is a devastating condition that leads to significant neurological deficits and reduced quality of life. Therapeutic interventions after spinal cord lesions are designed to address multiple aspects of the secondary damage. However, the lack of detailed knowledge about the cellular and molecular changes that occur after spinal cord injury restricts the design of effective treatments. Li and colleagues using a rat model of spinal cord injury and in vivo microscopy reveal that pericytes play a key role in the regulation of capillary tone and blood flow in the spinal cord below the site of the lesion. Strikingly, inhibition of specific proteins expressed by pericytes after spinal cord injury diminished hypoxia and improved motor function and locomotion of the injured rats. This work highlights a novel central cellular population that might be pharmacologically targeted in patients with spinal cord trauma. The emerging knowledge from this research may provide new approaches for the treatment of spinal cord injury.

Hypothalamic Neurons Take Center Stage in the Neural Stem Cell Niche.

Neural stem cells (NSCs) are a heterogeneous population of cells that generate new neurons in adult animals. Recently in Science, Paul et al. (2017) show that hypothalamic neurons control activation of a subset of NSCs in response to feeding, providing insights into how physiological cues may influence stem cell activation.

Repetitive transcranial magnetic stimulation induces long-lasting changes in protein expression and histone acetylation.

The use of non-invasive brain stimulation like repetitive transcranial magnetic stimulation (rTMS) is an increasingly popular set of methods with promising results for the treatment of neurological and psychiatric disorders. Despite great enthusiasm, the impact of non-invasive brain stimulation on its neuronal substrates remains largely unknown. Here we show that rTMS applied over the frontal cortex of awaken mice induces dopamine D2 receptor dependent persistent changes of CDK5 and PSD-95 protein levels specifically within the stimulated brain area. Importantly, these modifications were associated with changes of histone acetylation at the promoter of these genes and prevented by administration of the histone deacetylase inhibitor MS-275. These findings show that, like several other psychoactive treatments, repeated rTMS sessions can exert long-lasting effects on neuronal substrates. This underscores the need of understanding these effects in the development of future clinical applications as well as in the establishment of improved guidelines to use rTMS in non-medical settings.

Evaluation of NCS-1, DARPP-32, and neurotrophins in hippocampus and prefrontal cortex in rats submitted to sepsis.

Sepsis is defined as the host's reaction to infection and it is characterized by a systemic inflammatory response with important clinical implications. Central nervous system dysfunction secondary to sepsis is associated with local generation of pro- and anti-inflammatory cytokines, impaired cerebral microcirculation, disturbance of neurotransmitters, apoptosis, and cognitive impairment. It is known that during the process of learning and memory formation several pathways are involved such as dopaminergic and cholinergic systems. Thus, the objective of this study is to evaluate the neuronal calcium sensor (NCS-1) and dopamine-cAMP regulated phosphoprotein of 32,000 kDa (DARPP-32) expression as well as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in prefrontal cortex and hippocampus of rats 12, 24, and 48 h after sepsis induction. To this aim, we used sham-operated Wistar rats or submitted to the cecal ligation and perforation procedure. After 12 and 24 h, there was an increase of NGF levels in hippocampus; and up to 48 h, a decrease of NCS-1 expression in prefrontal cortex, a decrease of BDNF levels in hippocampus and an increase of NGF levels in hippocampus. In conclusion, we believe that the low expression of NCS-1 in prefrontal cortex and low levels of BDNF in hippocampus may be associated with the pathophysiology of cognitive impairment during sepsis and a putative role of the dopaminergic system.

Dissociations between cognitive and motor effects of psychostimulants and atomoxetine in hyperactive DAT-KO mice.

RATIONALE: Psychostimulants such as amphetamine and methylphenidate, which target the dopamine transporter (DAT), are the most frequently used drugs for the treatment of hyperactivity and cognitive deficits in humans with attention deficit hyperactivity disorder (ADHD). While psychostimulants can increase activity in healthy subjects, they exert a "paradoxical" calming effect in humans with ADHD as well as in hyperactive mice lacking the dopamine transporter (DAT-KO mice). However, the mechanism of action of these drugs and their impact on cognition in the absence of DAT remain poorly understood. OBJECTIVES: This study was conducted to investigate the effects of psychostimulants and noradrenergic and serotonergic drugs on cognition in DAT-KO mice and normal (WT) littermates. METHODS: We used a recently developed behavioral apparatus, the automated H-maze. The H-maze involves the consecutive learning of three different rules: delayed alternation, nonalternation, and reversal tasks. RESULTS: Treatment of WT animals with the psychostimulants replicated the behavior observed in untreated DAT-KO mice while "paradoxically" restoring cognitive performances in DAT-KO mice. Further investigation of the potential involvement of other monoamine systems in the regulation of cognitive functions showed that the norepinephrine transporter blocker atomoxetine restored cognitive performances in DAT-KO mice without affecting hyperactivity. In contrast, the nonselective serotonin receptor agonist 5CT, which antagonizes hyperactivity in DAT-KO mice, had no effect on cognitive functions. CONCLUSIONS: Taken together, these data allow dissociation of the locomotor and cognitive effects of ADHD drugs and suggest that the combination of DAT-KO mice with the automated H-maze can constitute a powerful experimental paradigm for the preclinical development of therapeutic approaches for ADHD.

Factors influencing possible delay in the diagnosis of Alzheimer's disease: Findings from a tertiary Public University Hospital / Fatores que influenciam o possível atraso no diagnóstico da doença de Alzheimer: achados de um Hospital Universitário Público

Alzheimer's disease (AD) is characterized by impairment in memory and autonomy, causing excessive pressure on family and an overburdened health care system. Early diagnosis, with the appropriate treatment, is important to reduce the pattern of disease progression. Objective: The study sought to identify the most probable causes of delay in diagnosis. Methods: A cross-sectional study involving AD patients followed at an Outpatient Geriatric Clinic from a tertiary public university hospital was conducted between June 2009 and February 2011. Results: Ninety-four patients were evaluated (66% women), aged 77.76±6.8 years and with median educational level of 3 years (95% CI 2.7-3.80). Regarding severity of dementia, 51.8% of patients were classified as having mild dementia (CDR 1), 40% moderate dementia (CDR 2) and 8.2% severe dementia (CDR 3). Mean educational level of caregivers was 8.3±3.9 years. Among those who believed there was a delay, 36% stated that the "family thought that the changes were normal for the age of the patient" reporting average delay of 1.8 years (95% CI: 1.3-2.5) while 45.3% stated that the "doctor did not reach a diagnosis" reporting a median delay of 1.5 years (95% CI: 1.4-2.3). Conclusion: Based on these results, it can be concluded the time between onset of symptoms and diagnosis was excessive. This study may be useful to help increase awareness of issues not sufficiently discussed in the literature, such as diagnostic delay and influence of caregivers' educational level on treatment.

A doença de Alzheimer é caracterizada por comprometimento na memória e na autonomia, causando pressão excessiva em familiares e sobrecarregando o sistema público de saúde. O diagnóstico precoce, com o tratamento adequado, é importante para reduzir o padrão de evolução da doença. Objetivo: O estudo pretende identificar as causas mais prováveis de atraso no diagnóstico. Métodos: Trata-se de um estudo transversal envolvendo pacientes com DA acompanhados em Ambulatório de Geriatria de um hospital terciário público entre junho de 2009 e fevereiro de 2011. Resultados: Noventa e quatro pacientes foram avaliados (66% mulheres), com média de idade de 77,8±6,8 anos e com mediana de escolaridade de 3 anos (IC 95%: 2,7-3,8). Quanto à gravidade da doença, 51,8% foram classificados como demência leve (CDR 1), 40% como demência moderada (CDR 2) e 8,2% como demência grave (CDR 3). A escolaridade do cuidador foi de 8,3±3,9 anos. Entre aqueles que acreditavam que havia um atraso no diagnóstico, 36% responderam que "a família achava as alterações como normais para a idade do paciente", com média de 1,8 anos (IC 95%: 1,3-2,5) e 45,3% responderam que "o médico não fez o diagnóstico", com mediana de 1,5 anos (IC 95%: 1,4-2,3). Foi observado que o tempo entre o início dos sintomas e o diagnóstico foi maior do que deveria ser. Conclusão: Este estudo pode contribuir para aumentar o conhecimento sobre questões ainda pouco discutidas na literatura científica, como atraso no diagnóstico e influência da escolaridade do cuidador no tratamento.

Genetic variations in FOXO3A are associated with Bipolar Disorder without confering vulnerability for suicidal behavior.

BACKGROUND: Genetic variation plays an important role in Bipolar Disorder (BD) and suicide susceptibility. However, little is known about the genetic influence on the risk of suicide, particularly in BD patients. Since FOXO3A plays a role in distinct mood-relevant behavioral processes, this gene could be a novel gene candidate for BD. Thus, we investigated whether FOXO3A polymorphisms are associated with BD and suicidal behavior in BD patients. METHODS: TaqMan genotyping was used to detect FOXO3A SNPs in 273 BD patients and 264 control subjects. RESULTS: Three SNPs (rs1536057, rs2802292 and rs1935952) were associated with BD, but none was positively linked with suicidal behavior. LIMITATION: A systematic evaluation within the whole FOXO3A gene and drug treatment in patients was not performed. CONCLUSIONS: These data suggest that FOXO3A is a novel susceptibility locus for BD, but not for suicidal behavior in BD patients. These results may contribute to a better understanding of the BD genetics.

Factors influencing possible delay in the diagnosis of Alzheimer's disease: Findings from a tertiary Public University Hospital.

Alzheimer's disease (AD) is characterized by impairment in memory and autonomy, causing excessive pressure on family and an overburdened health care system. Early diagnosis, with the appropriate treatment, is important to reduce the pattern of disease progression. OBJECTIVE: The study sought to identify the most probable causes of delay in diagnosis. METHODS: A cross-sectional study involving AD patients followed at an Outpatient Geriatric Clinic from a tertiary public university hospital was conducted between June 2009 and February 2011. RESULTS: Ninety-four patients were evaluated (66% women), aged 77.76±6.8 years and with median educational level of 3 years (95% CI 2.7-3.80). Regarding severity of dementia, 51.8% of patients were classified as having mild dementia (CDR 1), 40% moderate dementia (CDR 2) and 8.2% severe dementia (CDR 3). Mean educational level of caregivers was 8.3±3.9 years. Among those who believed there was a delay, 36% stated that the "family thought that the changes were normal for the age of the patient" reporting average delay of 1.8 years (95% CI: 1.3-2.5) while 45.3% stated that the "doctor did not reach a diagnosis" reporting a median delay of 1.5 years (95% CI: 1.4-2.3). CONCLUSION: Based on these results, it can be concluded the time between onset of symptoms and diagnosis was excessive. This study may be useful to help increase awareness of issues not sufficiently discussed in the literature, such as diagnostic delay and influence of caregivers' educational level on treatment.

A doença de Alzheimer é caracterizada por comprometimento na memória e na autonomia, causando pressão excessiva em familiares e sobrecarregando o sistema público de saúde. O diagnóstico precoce, com o tratamento adequado, é importante para reduzir o padrão de evolução da doença. OBJETIVO: O estudo pretende identificar as causas mais prováveis de atraso no diagnóstico. MÉTODOS: Trata-se de um estudo transversal envolvendo pacientes com DA acompanhados em Ambulatório de Geriatria de um hospital terciário público entre junho de 2009 e fevereiro de 2011. RESULTADOS: Noventa e quatro pacientes foram avaliados (66% mulheres), com média de idade de 77,8±6,8 anos e com mediana de escolaridade de 3 anos (IC 95%: 2,7-3,8). Quanto à gravidade da doença, 51,8% foram classificados como demência leve (CDR 1), 40% como demência moderada (CDR 2) e 8,2% como demência grave (CDR 3). A escolaridade do cuidador foi de 8,3±3,9 anos. Entre aqueles que acreditavam que havia um atraso no diagnóstico, 36% responderam que "a família achava as alterações como normais para a idade do paciente", com média de 1,8 anos (IC 95%: 1,3-2,5) e 45,3% responderam que "o médico não fez o diagnóstico", com mediana de 1,5 anos (IC 95%: 1,4-2,3). Foi observado que o tempo entre o início dos sintomas e o diagnóstico foi maior do que deveria ser. CONCLUSÃO: Este estudo pode contribuir para aumentar o conhecimento sobre questões ainda pouco discutidas na literatura científica, como atraso no diagnóstico e influência da escolaridade do cuidador no tratamento.

Interethnic diversity of NAT2 polymorphisms in Brazilian admixed populations.

BACKGROUND: N-acetyltransferase type 2 (Nat2) is a phase II drug- metabolizing enzyme that plays a key role in the bioactivation of aromatic and heterocyclic amines. Its relevance in drug metabolism and disease susceptibility remains a central theme for pharmacogenetic research, mainly because of its genetic variability among human populations. In fact, the evolutionary and ethnic-specific SNPs on the NAT2 gene remain a focus for the potential discoveries in personalized drug therapy and genetic markers of diseases. Despite the wide characterization of NAT2 SNPs frequency in established ethnic groups, little data are available for highly admixed populations. In this context, five common NAT2 SNPs (G191A, C481T, G590A, A803G and G857A) were investigated in a highly admixed population comprised of Afro-Brazilians, Whites, and Amerindians in northeastern Brazil. Thus, we sought to determine whether the distribution of NAT2 polymorphism is different among these three ethnic groups. RESULTS: Overall, there were no statistically significant differences in the distribution of NAT2 polymorphism when Afro-Brazilian and White groups were compared. Even the allele frequency of 191A, relatively common in African descendents, was not different between the Afro-Brazilian and White groups. However, allele and genotype frequencies of G590A were significantly higher in the Amerindian group than either in the Afro-Brazilian or White groups. Interestingly, a haplotype block between G590A and A803G was verified exclusively among Amerindians. CONCLUSIONS: Our results indicate that ethnic admixture might contribute to a particular pattern of genetic diversity in the NAT2 gene and also offer new insights for the investigation of possible new NAT2 gene-environment effects in admixed populations.

Glutathione S-transferases: an overview in cancer research.

IMPORTANCE OF THE FIELD: The Glutathione S-transferases (GSTs) have advanced beyond the classic view of their role in metabolism and are encouraging scientists to assess new approaches to cancer risk characterization and chemotherapy resistance and are opening up exciting possibilities in drug discovery. AREAS COVERED IN THIS REVIEW: In this review, the most recent knowledge about the impact of GST genetic polymorphisms in human's cancer susceptibility, ethnic differences in the effects of risk factors and the rise of the GSTs as important targets for drug development are presented. In this context, the ethnic distribution of GST alleles in different populations, which is an important concept that is being incorporated in epidemiologic studies of cancer risk and environmental exposure, was also evaluated. We present up-to-date information about the new generation of GST-activated cytotoxic prodrugs based on GST overexpression in tumor-acquired drug resistance and the newest results of clinical trials. WHAT THE READER WILL GAIN: A critical approach of the major advances in research of GST, underlining the new advances of GST genes polymorphisms in cancer susceptibility and target for therapeutic intervention. TAKE HOME MESSAGE: Although polygenic factors are involved in increased risk of cancer, the interindividual GST variability plays a central role in reduce cells exposure to carcinogens.

Glutathione s-transferase variants in a brazilian population.

Recent pharmacogenomic studies have revealed significant interethnic differences in glutathione S-transferase (GST) allelic frequencies among various ethnic groups. Therefore, we have investigated GSTM1 (gene deletion), GSTT1 (gene deletion) and GSTP1 (rs1695) polymorphism frequencies in 3 Brazilian ethnic groups (n = 203). GSTM1 and GSTT1 polymorphism analyses were performed by multiplex polymerase chain reaction, and GSTP1 (rs1695) analysis was done by polymerase chain reaction restriction fragment length polymorphism. GSTM1- polymorphism frequency was 33.2%, while GSTT1 null (GSTT1-) was 30.2%. The valine GSTP1*B (rs1695) allele was present in 35.1% subjects, while the heterozygous form (isoleucine/valine) was the most prevalent genotype (46.6%). We found a statistically significant difference in genotype frequency among Amerindians versus Caucasians (p = 0.016) and among Amerindians versus African-Americans (p = 0.033). Considerable frequency variation was found in our study, even when compared with other studies showing phylogeographical heterogeneity to the genes studied in Brazilian populations.