Isoniazid (INH) is related to the development of hepatotoxicity in some patients.
To investigate the role of N-acetyl transferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1) in the hepatotoxicity of ...patients treated with INH in an Amazonian Brazilian population.
Patients undergoing anti-tuberculosis treatment were investigated. Hepatotoxicity was defined as an increase of more than three times the upper limit of normal in serum alanine aminotransferase levels after treatment. NAT2 genotypes were identified by sequencing, whereas CYP2E1 alleles were detected using polymerase chain reaction based methods.
Of the 270 individuals included in the study, 18 (6.7%) developed drug-related hepatotoxicity. A high association was found between slow acetylators and hepatotoxicity, particularly with regard to allele *5. The adjusted risk of developing hepatotoxicity was significant in individuals carrying two slow acetylation alleles (P = 0.036, OR 3.05, 95%CI 1.07-8.64). In all of the CYP2E1 markers examined, wild homozygous genotypes were more prevalent in subjects with hepatotoxicity than in controls; however, the difference was not statistically significant. Joint evaluation of the genes revealed a high risk of developing hepatotoxicity in slow acetylators with CYP2E1 wild alleles (adjusted OR 4.26; 95%CI 1.47-12.37, P = 0.008).
Large-scale screening for NAT2 and CYP2E1 genotypes can prove useful in predicting the risk of adverse effects.
Since approximately 70% of adult patients with attention-deficit/hyperactivity disorder (ADHD) have at least one comorbid disorder, rating of impairment specifically attributable to ADHD is a hard ...task. Despite the evidence linking environmental adversities with negative outcomes in ADHD, life events measures have not been used to rate the disorder impairment. The present study tested for the first time the hypothesis that increased ADHD severity is associated with an increase in negative recent life events, independently of comorbidity status. The psychiatric diagnoses of 211 adult ADHD outpatients were based on DSM-IV criteria assessed through structured interviews (K-SADS-E for ADHD and ODD, MINI for ASPD and SCID-IV-R for other comorbidities). ADHD severity was evaluated with the Swanson, Nolan and Pelham rating scale (SNAP-IV) and recent life events with the Life Experience Survey. Higher SNAP-IV inattention and hyperactivity scores, female gender, lower socioeconomic status and the presence of comorbid mood disorders were associated with negative life events. Poisson regression models with adjustment for possible confounders confirmed the effect of inattention and hyperactivity severity on negative life events. Our results suggest that the negative life events experienced by these patients are associated to the severity of ADHD independently from comorbid psychiatric disorders.
Levodopa is the most used drug to treat motor symptoms in Parkinson's disease (PD). However, dopaminergic side effects such as nausea and vomiting may occur. Several evidences indicate a major role ...for dopamine receptors D2 (DRD2) and D3 (DRD3) in emetic activity. The aim of this study was to investigate the relationship of DRD2 rs1799732 and DRD3 rs6280 gene polymorphisms with gastrointestinal (GI) symptoms induced by levodopa in PD patients. Two hundred and seventeen PD patients on levodopa therapy were investigated. DRD2 rs1799732 and DRD3 rs6280 polymorphisms were genotyped by PCR-based methods. Multiple Poisson regression method with robust variance estimators was performed to assess the association between polymorphisms and gastrointestinal symptoms. The analyses showed that DRD2 Ins/Ins (prevalence ratio (PR)=2.374, 95% confidence interval (CI): 1.105-5.100; P=0.027) and DRD3 Ser/Ser genotypes (PR=1.677, 95% CI 1.077-2.611; P=0.022) were independent and predictors of gastrointestinal symptoms associated with levodopa therapy. Despite all the efforts to alleviate GI symptoms, this adverse effect still occurs in PD patients. Pharmacogenetic studies of GI symptoms induced by levodopa therapy have the potential to display new ways to better understand the molecular mechanisms involved in these side effects.
Levodopa is the most effective symptomatic therapy for Parkinson's disease, but its chronic use could lead to chronic adverse outcomes, such as motor fluctuations, dyskinesia and visual ...hallucinations. HOMER1 is a protein with pivotal function in glutamate transmission, which has been related to the pathogenesis of these complications. This study investigates whether polymorphisms in the HOMER1 gene promoter region are associated with the occurrence of the chronic complications of levodopa therapy. A total of 205 patients with idiopathic Parkinson's disease were investigated. Patients were genotyped for rs4704559, rs10942891 and rs4704560 by allelic discrimination with Taqman assays. The rs4704559 G allele was associated with a lower prevalence of dyskinesia (prevalence ratio (PR)=0.615, 95% confidence interval (CI) 0.426-0.887, P=0.009) and visual hallucinations (PR=0.515, 95% CI 0.295-0.899, P=0.020). Our data suggest that HOMER1 rs4704559 G allele has a protective role for the development of levodopa adverse effects.
Background
Non‐erosive reflux disease (NERD) patients generally present with heartburn as the main symptom. Antidepressants might help to relieve heartburn by acting on the esophagus‐brain axis. We ...aimed to assess the effect of nortriptyline on behavioral and brain responses to painful esophageal acid infusion in NERD patients evaluated with functional magnetic resonance imaging (fMRI).
Methods
In a randomized double‐blind crossover design, 20 NERD patients off proton pump inhibitors (36.1 ± 9.3 years, 75% women) were assigned to 21 days of nortriptyline and placebo, in counterbalanced order, with a 21 days washout period in between both treatment periods. Changes in acid‐induced brain response on fMRI and heartburn perception were assessed and at the end of each treatment.
Key Results
Nortriptyline significantly reduced the acid‐induced brain response in prefrontal cortex (median IQR: −1.9 −4.5 to −0.1 vs −0.3 −2.5 to 2.3; p = 0.050), caudate (−3.0 −5.1 to −0.01 vs 0.48 −1.9 to 3.1; p = 0.029), insula (−2.4 −4.8 to −0.6 vs −0.2 −1.5 to 1.5; p = 0.029), cingulate (−4.2 −8.8 to −0.1 vs −0.6 −1.8 to 3.0; p = 0.017), and hippocampus (−2.7 −6.0 to 0.5 vs −0.04 −2.3 to 1.9; p = 0.006) in comparison with placebo. However, there was no significant difference between nortriptyline and placebo in clinical outcomes and side effects.
Conclusions & Inferences
Nortriptyline decreased the brain response to esophageal acid infusion more markedly than placebo, but without clinical significance.
This is a randomized clinical trial designed to compare the effect of nortriptyline with that of placebo on brain response to painful esophageal acid infusion in NERD patients evaluated with functional magnetic resonance imaging. Secondary objectives were to evaluate clinical parameters. Nortriptyline had a stronger attenuation in brain response to esophageal acid infusion, but without clinical advantage over placebo.
The rodent Deltamys kempi Thomas, 1917 is found on the Coastal Plain - a recently formed geographic region located on Brazil's south-east coast. Considering that Deltamys is the only South American ...sigmodontine with a sex chromosome system of type X₁X₁X₂X₂/X₁X₂Y, this investigation was focused on the phylogeographic history of this taxon by using gene sequence analysis, trying to clarify when Deltamys differentiated, what was its centre of diversification, and what were the probable routes it used to reach its present distribution. We analysed sequences of the mitochondrial cytochrome b gene and nuclear recombination activating gene 2, performed cranial measurements and searched for centric fusions in individuals collected in distinct localities. The results, clearly demonstrate that D. kempi, on the Coastal Plain, divided into two groups, one occupying a small portion to the north of this region and the other spreading widely to the south. In this process, the phenomena of marine transgression and regressions which moulded its habitat, together with the occurrence of successive chromosomal rearrangements, were certainly the fundamental factors in shaping D. kempi diversification.
Summary
Ten ancestry informative markers were investigated in 101 coronary artery disease patients and 102 healthy controls from a Southern Brazilian population, in order to determine if ...stratification occurs in this population. The degree of African admixture detected in this population was estimated to be as high as 6%, but no differences between cases and controls were observed. Using an African Ancestry Index (AAI) that estimates admixture at the individual level it was possible to remove from the samples those individuals with evidence of African admixture. Therefore we have shown that it is possible to control for population stratification by choosing individuals, without the loss of statistical power that occurs with the use of other methods of genomic control.
The sigmodontine South American rodent genus Oligoryzomys was first described as a subgenus of the genus Oryzomys to group together species distinguished by morphological measurements. To describe ...the dispersion patterns of this genus in South America, in this study, a total of 100 sequences were analyzed and compared with sequences of 9 Oligoryzomys species from GenBank. The sequences comprised 90 mitochondrial cytochrome b genes and 10 nuclear interphotoreceptor retinoid-binding protein genes, from 75 individuals of 7 species from 27 localities. Topologies of different phylogenetic trees revealed Oligoryzomys as a monophyletic genus containing 2 main species groups, one designated as the "Amazon-Cerrado" assemblage and the second as the "Pampa-Andean" clade. The north-to-south geographic pattern observed supports the hypothesis that the genus started from the northern Andes, occupied the Amazon and the Cerrado, and later inhabited the more southern regions of South America.
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