Papers by Sintia Iole Nogueira Belangero
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 2014
There is robust evidence that schizophrenia is characterized by immune-inflammatory abnormalities... more There is robust evidence that schizophrenia is characterized by immune-inflammatory abnormalities, including variations on cytokine levels. The results of previous studies, however, are heterogeneous due to several confounding factors, such as the effects of antipsychotic drugs. Therefore, research on drug-naïve first-episode psychosis (FEP) patients is essential to elucidate the role of immune processes in that disorder. The aim of this study is to compare cytokine levels (IL-2, IL-10, IL-4, IL-6, IFN-γ, TNF-α, and IL-17) in drug-naïve FEP patients both before and after treatment with risperidone for 10 weeks, and to investigate possible associations between cytokine levels and clinical responses to treatment and presence of depressive symptoms. It this study, we included 55 drug-naïve FEP patients who had repeated measurements of cytokine levels and 57 healthy controls. We found that FEP patients had significantly higher IL-6, IL-10 and TNF-α levels than healthy controls. After ri...
Pediatric cardiology, 2010
Congenital heart disease (CHD) is the most common birth defect and the leading cause of mortality... more Congenital heart disease (CHD) is the most common birth defect and the leading cause of mortality in the first year of life. In fetuses with a heart defect, chromosomal abnormalities are very frequent. Besides aneuploidy, 22q11.2 deletion is one of the most recognizable chromosomal abnormalities causing CHD. The frequency of this abnormality varies in nonselected populations. This study aimed to investigate the incidence of the 22q11.2 deletion and other chromosomal alterations in a Brazilian sample of fetuses with structural cardiac anomalies detected by fetal echocardiography. In a prospective study, 68 fetuses with a heart defect were evaluated. Prenatal detection of cardiac abnormalities led to identification of aneuploidy or structural chromosomal anomaly in 35.3% of these cases. None of the fetuses with apparently normal karyotypes had a 22q11.2 deletion. The heart defects most frequently associated with chromosomal abnormalities were atrioventricular septal defect (AVSD), ven...
Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays an important role in the de... more Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays an important role in the development, differentiation, maintenance, and survival of neurons 1 .
Age at Onset of Schizophrenia and Volume Reduction in Orbitofrontal Gyrus are Associated with UFD1L Polymorphism
INTERACTION BETWEEN UFD1L AND ZDHHC8 GENE POLYMORPHISMS IS ASSOCIATED WITH AGE AT ONSET OF SCHIZOPHRENIA
PRODH GENE POLYMORPHISMS AND RISK FOR SCHIZOPHRENIA
FUNCTIONAL POLYMORPHISMS OF DGCR2 GENE MAY BE ASSOCIATED TO SCHIZOPHRENIA PATHOGENESIS AND PLAY A ROLE IN NEURODEVELOPMENT
Schizophrenia Research, 2015
Schizophrenia is accompanied by alterations in immuno-inflammatory pathways, including abnormalit... more Schizophrenia is accompanied by alterations in immuno-inflammatory pathways, including abnormalities in cytokine profile. The immune assessment of patients in a first episode of psychosis (FEP) and particularly in drug naïve patients is very important to further elucidate this association. The objectives of this study are to delineate the cytokine profile (IL-2, IL-10, IL-4, IL-6, IFNγ, TNFα and IL-17) in FEP patients (n = 55) versus healthy controls (n = 57) and to examine whether the presence of depressive symptoms in FEP is accompanied by a specific cytokine profile. We found increased levels of IL-6, IL-10 and TNFα in FEP patients when compared to healthy controls. FEP patients with depression showed higher IL-4 and TNFα levels versus those without depression. Cytokine levels were not correlated to the total PANSS and the positive or negative subscale scores. Our results suggest that FEP is accompanied by a cytokine profile indicative of monocytic and T regulatory cell (Treg) activation. Depression in FEP is accompanied by monocytic and Th-2 activation, whereas FEP without depression is characterized by Treg activation only. In conclusion, depression emerged as a key component explaining the cytokines imbalance in FEP that is responsible for a large part of the immune-inflammatory abnormalities described.
ACE I/D genotype-related increase in ACE plasma activity is a better predictor for schizophrenia diagnosis than the genotype alone
Schizophrenia Research, 2015
Angiotensin-I converting enzyme (ACE) is a key component of the renin-angiotensin system (RAS). A... more Angiotensin-I converting enzyme (ACE) is a key component of the renin-angiotensin system (RAS). Although the several contradictory data, ACE has been associated with schizophrenia (SCZ) pathophysiology. Here the ACE activity of SCZ patients and healthy controls (HCs), and its possible correlations with the ACE polymorphism genotype and symptomatic dimensions, was investigated. ACE activity of 86 SCZ patients and 100 HCs paired by age, gender and educational level was measured, using the FRET peptide substrate and the specific inhibitor lisinopril. The ACE insertion/deletion (I/D) genotypes were assessed by the restriction fragment length polymorphism (RFLP) technique. Significantly higher ACE activity was observed in SCZ patients compared to HCs (t=-5.09; p<0.001). The area under the receiver operating characteristic (ROC) curve was 0.701. Mean ACE activity levels were higher for the D-allele carriers (F=5.570; p=0.005), but no significant difference was found among SCZ patients and HCs for genotypes frequencies (Chi-squared=2.08; df=2; p=0.35). Interestingly, we found that the difference between the measured ACE activity for each SCZ patient and the expected average mean value for each respective genotype group (for control subjects) was a better predictor of SCZ than the ACE dichotomized values (high/low) or ACE I/D. Our results suggest that higher levels of ACE activity are associated with SCZ with stronger impact when the genetic background of each individual is considered. This may explain the heterogeneity of the results on ACE previously reported.
Bipolar Disorder (BD) has been conceptualized as both a cyclic and a progressive disorder. Mechan... more Bipolar Disorder (BD) has been conceptualized as both a cyclic and a progressive disorder. Mechanisms involved in neuroprogression in BD remain largely unknown although several non-mutually exclusive models have been proposed as explanatory frameworks. In the present paper, we propose that the pathophysiological Q2 changes observed in BD (e.g. brain structural alterations, cognitive deficits, oxidative stress imbalance, amyloid metabolism, immunological deregulation, immunosenescence, neurotrophic deficiencies and telomere shortening) converge on a model of accelerated aging (AA). Aging can be understood as a multidimensional process involving physical, neuropsychological, and social changes, which can be highly variable between individuals. Determinants of successful aging (e.g environmental and genetic factors), may also confer differential vulnerability to components of BD pathophysiology and contribute to the clinical presentation of BD. Herein we discuss how the understanding of aging and senescence can contribute to the search for new and promising molecular targets to explain and ameliorate neuroprogression in BD. We also present the strengths and limitations of this concept.
Gene expression analysis in patients with traumatic anterior shoulder instability suggests deregulation of collagen genes
Journal of Orthopaedic Research, 2014
Shoulder dislocation occurs in 1-2% of the population. Capsular deformation is a key factor in sh... more Shoulder dislocation occurs in 1-2% of the population. Capsular deformation is a key factor in shoulder dislocation; however, little is known about capsule biology. We evaluated, for the first time in literature, the expression of COL1A1, COL1A2, COL3A1 and COL5A1 in the antero-inferior, antero-superior and posterior regions of the glenohumeral capsule of 31 patients with anterior shoulder instability and eight controls. The expression of collagen genes was evaluated by quantitative reverse transcription-PCR. The expression of COL1A1, COL3A1 and the ratio of COL1A1/COL1A2 were increased in all three portions of the capsule in patients compared to controls (p < 0.05). COL1A2 expression was upregulated in the antero-superior and posterior sites of the capsule of patients (p < 0.05). The ratio of COL1A2/COL3A1 expression was reduced in capsule antero-inferior and posterior sites of patients compared to controls (p < 0.05). In the capsule antero-inferior site of patients, the ratios of COL1A1/COL5A1, CO1A2/COL5A1 and COL3A1/COL5A1 expression were increased (p < 0.05). In patients, COL1A1/COL5A1 was also increased in the posterior site (p < 0.05). We found deregulated expression of collagen genes across the capsule of shoulder instability patients. These molecular alterations may lead to modifications of collagen fibril structure and impairment of the healing process, possibly with a role in capsular deformation.
PLoS ONE, 2014
Schizophrenia is a neurodevelopmental disorder with high heritability. Several lines of evidence ... more Schizophrenia is a neurodevelopmental disorder with high heritability. Several lines of evidence indicate that the PRODH gene may be related to the disorder. Therefore, our study investigates the effects of 12 polymorphisms of PRODH on schizophrenia and its phenotypes. To further evaluate the roles of the associated variants in the disorder, we have conducted magnetic resonance imaging (MRI) scans to assess cortical volumes and thicknesses. A total of 192 patients were evaluated using the Structured Clinical Interview for DSM-IV (SCID), Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale, Global Assessment of Functioning (GAF) and Clinical Global Impression (CGI) instruments. The study included 179 controls paired by age and gender. The samples were genotyped using the real-time polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP)-PCR and Sanger sequencing methods. A sample of 138 patients and 34 healthy controls underwent MRI scans. One polymorphism was associated with schizophrenia (rs2904552),
Schizophrenia research, 2014
Schizophrenia is a severe mental health disorder with high heritability. The investigation of ind... more Schizophrenia is a severe mental health disorder with high heritability. The investigation of individuals during their first-episode psychosis (FEP), before the progression of psychotic disorders and especially before treatment with antipsychotic medications, is particularly helpful for understanding this complex disease and for the identification of potential biomarkers. In this study, we compared the expression of genes that are involved in neurotransmission and neurodevelopment of antipsychotic-naive FEP in the peripheral blood of patients (n=51) and healthy controls (n=51). In addition, we investigated the differentially expressed genes with respect to a) DNA methylation, b) the correlation between gene expression and clinical variables (PANSS), and c) gene expression changes after risperidone treatment. Expression levels of 11 genes were quantified with SYBR Green. For methylation analysis, bisulfite sequencing was performed. A significant decrease in GCH1 mRNA levels was obser...
Schizophrenia Research, 2014
drugs (APDs) are the standard treatment for schizophrenia. The therapeutic effect of these drugs ... more drugs (APDs) are the standard treatment for schizophrenia. The therapeutic effect of these drugs is dependent upon the dopaminergic D2 blockade, but they also modulate other neurotransmitter pathways. The exact mechanisms underlying the clinical response to APDs are not fully understood. In this study, we compared three groups of animals for the expression of 84 neurotransmitter genes in the prefrontal cortex (PFC) and nucleus accumbens (NAcc). Each group was treated with a different APD (risperidone, clozapine or haloperidol), and with a non-treated group of spontaneously hypertensive rats (SHRs), which is an animal model for schizophrenia. This study also explored whether or not differential expression was regulated by DNA methylation in the promoter region (PR). In the clozapine group, we found that Chrng was downregulated in the NAcc and six genes were downregulated in the PFC. In the haloperidol group, Brs3 and Glra1 were downregulated, as was Drd2 in the clozapine group and Drd3, Galr3 and Gabrr1 in the clozapine and haloperidol groups. We also encountered four hypermethylated CG sites in the Glra1 PR, as well as three in the risperidone group and another in the haloperidol group, when compared to non-treated rats. Following the APD treatment, the gene expression results revealed the involvement of genes that had not previously been described, in addition to the activity of established genes. The investigation of the involvement of these novel genes can lead to better understanding about the specific mechanisms of action of the individual APDs studied.
Poster #12 EXPRESSION OF NEUROTRANSMITTER RECEPTOR AND REGULATOR GENES IN TWO BRAIN REGIONS AND PERIPHERAL BLOOD IN A NEW ANIMAL MODEL OF SCHIZOPHRENIA: THE SPONTANEOUSLY HYPERTENSIVE RATS (SHR)
Schizophrenia Research, 2012
Psychiatry Research, 2014
The spontaneously hypertensive rat (SHR) strain was shown to be a useful animal model to study se... more The spontaneously hypertensive rat (SHR) strain was shown to be a useful animal model to study several behavioral, pathophysiological and pharmacological aspects of schizophrenia and attention-deficit/ hyperactivity disorder. To further understand the genetic underpinnings of this model, our primary goal in this study was to compare the gene expression profile of neurotransmitter receptors and regulators in the prefrontal cortex (PFC) and nucleus accumbens (NAcc) of SHR and Wistar rats (control group). In addition, we investigated DNA methylation pattern of promoter region of the genes differentially expressed. We performed gene expression analysis using a PCRarray technology, which simultaneously measures the expression of 84 genes related to neurotransmission. Four genes were significantly downregulated in the PFC of SHR compared to Wistar rats (Gad2, Chrnb4, Slc5a7, and Qrfpr) and none in nucleus accumbens. Gad2 and Qrfpr have CpG islands in their promoter region. For both, the promoter region was hypomethylated in SHR group, and probably this mechanism is not related with the downregulation of these genes. In summary, we identified genes that are downregulated in the PFC of SHR, and might be related to the behavioral abnormalities exhibited by this strain.
Journal of Psychiatric Research, 2014
A study of the gene expression levels in the blood of individuals with schizophrenia in the begin... more A study of the gene expression levels in the blood of individuals with schizophrenia in the beginning of the disease, such as first-episode psychosis (FEP), is useful to detect gene expression changes in this disorder in response to treatment. Although a large number of genetic studies on schizophrenia have been conducted, little is known about the effects of antipsychotic treatment on gene expression. The aim of the present study was to examine differences in the gene expression in the blood of antipsychoticnaïve FEP patients before and after risperidone treatment (N ¼ 44) and also to verify the correlation with treatment response. In addition, we determined the correlations between differentially expressed genes and clinical variables. The expression of 40 neurotransmitter and neurodevelopment-associated genes was assessed using the RT 2 Profiler™ PCR Array. The results indicated that the GABRR2 gene was downregulated after risperidone treatment, but no genes were associated with response to treatment and clinical variables after Bonferroni correction. GABRR2 downregulation after treatment can both suggest an effect of risperidone treatment or processes related to disease progression, either not necessarily associated with the improvement of symptoms. Despite this change was observed in blood, this decrease in GABRR2 mRNA levels might be an effect of changes in GABA concentrations or other systems interplay consequently to D2 blockage induced by risperidone, for example. Thus, it is important
Factor structure of the Positive and Negative Syndrome Scale (PANSS) in Brazil: convergent validation of the Brazilian version
Revista Brasileira de Psiquiatria, 2014
The Positive and Negative Syndrome Scale (PANSS) was developed to assess the symptoms of schizoph... more The Positive and Negative Syndrome Scale (PANSS) was developed to assess the symptoms of schizophrenia dimensionally. Although it is widely used in clinical trials in Brazil, it is not fully validated. The aim of this study is to assess the factor structure of the Brazilian PANSS and generate validation data for its current version. A total of 292 patients diagnosed with schizophrenia were enrolled. Principal component analysis suggested a forced five-factor final model that accounted for 58.44% of the total variance, composed of negative, disorganization/cognition, excitement, positive, and depression/anxiety. The Brazilian PANSS has a similar factor structure and internal consistency compared to versions in several other languages.
The Lancet Psychiatry, 2014
Child maltreatment is associated with an increased risk of psychiatric disorders, and a range of ... more Child maltreatment is associated with an increased risk of psychiatric disorders, and a range of health problems later in life. Research suggests that adverse events early in life can lead to changes in gene expression through epigenetic mechanisms that alter stress reactivity, brain function, and behaviour. Although epigenetic changes are often long lasting, they can be reversed with pharmacological and environmental manipulations. The complexity of the epigenome is not fully understood. The aim of this Review is to assess emerging data for the role of epigenetic mechanisms in stress-related psychiatric disorders with a focus on future research. We describe the epigenetic processes, key fi ndings in this specialty, clinical implications of research, and methodological issues. Studies are needed to investigate new epigenetic processes other than methylation and assess the effi cacy of interventions to reverse epigenetic processes associated with the eff ects of early life adversity. Lancet Psychiatry 2014; 2: 461-66 McGill Group for Suicide Studies,
International braz j urol, 2011
Purpose: To determine the frequency of genetic alterations in a population of Brazilian infertile... more Purpose: To determine the frequency of genetic alterations in a population of Brazilian infertile men with severe oligozoospermia or non-obstructive azoospermia. Materials and Methods: Retrospective study of a group of 143 infertile men with severe oligozoospermia or non-obstructive azoospermia from the Andrology Outpatient Clinic of the Human Reproduction Service at the ABC School of Medicine. Of these patients, 100 had severe oligozoospermia, and 43 non-obstructive azoospermia. All patients underwent a genetic study which included karyotype analysis and Y-microdeletion investigation. Results: Genetic abnormalities were found in 18.8% of the studied patients. Chromosomal abnormalities were found in 6.2% of the patients, being more prevalent in the azoospermia group (11.6%) than in the oligozoospermia group (4%). Chromosomal variants were found in 8.3%, and Y-chromosome microdeletions in 4.2% of patients. Conclusion: The high frequency of genetic alterations (18.8%) in our series justified performing a genetic investigation in a population with idiopathic infertility, as results may help determine the prognosis, as well as the choice of an assisted reproduction technique. Moreover, a genetic investigation could minimize the risk of transmitting genetic abnormalities to future generations such as genetic male infertility, mental retardation, genital ambiguity and/or birth defects.
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Papers by Sintia Iole Nogueira Belangero