Brain Gene Expression Profiling of Individuals With Dual Diagnosis Who Died by Suicide.

Objective: Dual diagnosis (DD) is the co-occurrence of at least one substance use disorder and one or more mental disorders in a given individual. Despite this comorbidity being highly prevalent and associated with adverse clinical outcomes, its neurobiology remains unclear. Furthermore, patients with DD are at higher risk for suicidal behavior in comparison with single disorder patients. Our objective was to evaluate brain gene expression patterns in individuals with DD who died by suicide. Methods: We compared the gene expression profile in the dorsolateral prefrontal cortex of suicides with DD (n = 10) to the transcriptome of suicides with substance use disorder alone (n = 10), suicides with mood disorders (MD) alone (n = 13), and suicides without mental comorbidities (n = 5). Gene expression profiles were assessed by microarrays. In addition, we performed a brain cell type enrichment to evaluate whether the gene expression profiles could reflect differences in cell type compositions among the groups. Results: When comparing the transcriptome of suicides with DD to suicides with substance use disorder alone and suicides with MD alone, we identified 255 and 172 differentially expressed genes (DEG), respectively. The overlap of DEG between both comparisons (112 genes) highlighted the presence of common disrupted pathways in substance use disorder and MD. When comparing suicides with DD to suicides without mental comorbidities, we identified 330 DEG, mainly enriched in neurogenesis. Cell type enrichment indicated higher levels of glial markers in suicides with DD compared to the other groups. Conclusions: Suicides with DD exhibited a gene expression profile distinct from that of suicides with a single disorder, being substance use disorder or MD, and suicides without mental disorders. Our results suggest alteration in the expression of genes involved in glial specific markers, glutamatergic and GABAergic neurotransmission in suicides with DD compared to suicides with a single disorder and suicides without mental comorbidities. Alterations in the expression of synaptic genes at different levels were found in substance use disorder and MD.

Concurrent mood and anxiety disorders are associated with pharmacoresistant seizures in patients with MTLE.

OBJECTIVE: To investigate whether mood disorders (MD) and anxiety disorders (AD) are associated with seizure control in patients with mesial temporal lobe epilepsy (MTLE). We compared patients without any current psychiatric disorder, patients with current MD and/or AD, patients with subsyndromic depression episodes (SSDE) and anxiety episodes (SSAE), and patients with family psychiatric history. METHODS: In a cross-sectional study, we included 144 consecutive patients with MTLE (82 pharmacoresistant and 62 treatment-responsive patients). Every patient underwent a psychiatric evaluation including the Structured Clinical Interview for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) Axis I (SCID-I), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Neurological Disorders Depression Inventory for Epilepsy (NDDI-E), and Interictal Dysphoric Disorder Inventory (IDDI). Patients were divided into four groups: PsychNeg (G1, n = 61), current SSDE and SSAE (G2, n = 26), Current MD or AD (G3, n = 25), and current mixed MD/AD (G4, n = 32). RESULTS: Among patients with pharmacoresistant MTLE, 68.3% (56/82) experienced symptoms of depression and/or anxiety (G2, G3, and G4) (odds ratio [OR] 2.8, 95% confidence interval [CI] 1.41-5.53, p < 0.01). Patients with mixed MD/AD (G4, n = 24/32) were more likely to have pharmacoresistant MTLE (OR 4.04, 95% CI 1.57-10.42, p < 0.01) than psychiatric asymptomatic patients (G1, n = 26/61), and their seizure frequency was significantly higher (p < 0.01). Positive family psychiatric history was more frequent in pharmacoresistant patients (n = 27/82, OR 2.28, 95% CI 1.02-5.05, p = 0.04). Finally, 31.6% of patients with MD and or AD were not receiving psychiatric treatment. SIGNIFICANCE: Identification of comorbid MD/AD and of family psychiatric history is of the essence in patients with MTLE, as they appear to be associated with worse seizure control.

Regulation of the glucocorticoid response to stress-related disorders by the Hsp90-binding immunophilin FKBP51.

Immunophilin is the collective name given to a family of proteins that bind immunosuppressive drugs: Some immunophilins are Hsp90-binding cochaperones that affect steroid receptor function. Mood and anxiety disorders are stress-related diseases characterized by an impaired function of the mineralocorticoid and glucocorticoid receptors, two of the major regulatory elements of the hypothalamus-pituitary-adrenocortical axis. Genetic variations of the FK506-binding protein of 51-kDa, FKBP51, one of the immunophilins bound to those steroid receptor complexes, were associated with the effectiveness of treatments against depression and with a major risk-factor for the development of post-traumatic stress disorders. Interestingly, immunophilins show polymorphisms and some polymorphic isoforms of FKBP51 correlate with a greater impairment of steroid receptor functions. In this review, we discuss different aspects of the role of FKBP51 in such steroid receptor function and the impact of genetic variants of the immunophilin on the dysregulation of the stress response.

Exploring the implications of INDELs in neuropsychiatric genetics: challenges and perspectives.

The decade passed after publishing the Human Genome first draft faced an enormous growth at the understanding of the genomic variation among different subjects, populations, and groups of patients. Single nucleotide polymorphisms (SNPs) and insertion or deletions (INDELs) have been increasingly recognized as a major type of genetic variations, with potential impact in protein activities and gene expression changes observed in complex genetic traits, like neuropsychiatric diseases. INDELs represent the second most common class of variations after SNPs, but there is still an important gap between the number of INDELs reported and the actual knowledge about the functional implications of such variations. There are approximately 10 million SNPs already reported, and the human populations are expected to collectively harbor at least 1.6-2.5 million INDELs. One of the major challenges is to find better platforms to screen for INDELs in a high throughput manner. The discordance in between the data from different studies might be explained by the diverse approaches employed to sequence the genomes with variable platforms. Short INDEL variations increased the scope of genetic markers in human genetic diseases, and various studies showed that common microdeletions and smaller INDELs might be highly associated with neuropsychiatric diseases such as schizophrenia, autism, mental retardation, and Alzheimer disease. The rapidly increasing amount of resequencing, genotyping, and personal genome data generated by large-scale genetic human projects require the development of integrated bioinformatics tools able to efficiently manage and analyze these genetic data. Our group is currently dealing with different approaches that might optimize sequencing and bioinformatics analyses of short INDELs to broaden our research capabilities of identifying those intriguing genetic variations. Hopefully, INDELs might become a new trend in association studies in neuropsychiatric genetics since so far the level of significant and positive associations with the standard SNPs reported presents limited predictive application.

Left-sided EEG focus and positive psychiatric family history are independent risk factors for affective disorders in temporal lobe epilepsy.

OBJECTIVE: To identify independent risk factors for affective disorders in temporal lobe epilepsy. METHODS: We studied 97 patients with temporal lobe epilepsy (TLE) exploring variables like age, gender, family history of epilepsy and psychiatric disorders, duration of epilepsy, control of seizures, presence of aura and initial precipitant insult, abuse of substances, neuroimaging and EEG features. RESULTS: Forty-one patients (42.3% of the total population) had affective disorders. A positive family history of psychiatric disorders (O.R.=3.8; p=0.003) and interictal EEG epileptiform discharges involving the left temporal lobe (O.R.=2.9; p=0.041) were significantly associated with an increased risk for an affective disorder. These associations remained significant after logistic regression, confirming the independent effects of the risk factors observed. Moreover, a binary logistic regression model obtained was able to correctly predict presence or absence of a life-time affective disorder in 71.1% of patients. CONCLUSION: This study points out that a positive family history of psychiatric disorders and interictal EEG epileptiform discharges involving the left temporal lobe are isolated risk factors for affective disorders in TLE. Our results suggest that biological factors are crucial for affective disorders development in TLE. Further studies are necessary to better specify the genetic and anatomical substracts involved and how they come together to generate affective disorders in those patients.

[Timekeeping molecules: implications for circadian phenotypes]. / Moléculas que marcam o tempo: implicações para os fenótipos circadianos.

OBJECTIVE: The aim of this study was to review the molecular chronobiology studies in the last 36 years in order Eto point out the advances in this area to health professionals. METHOD: We searched in the PubMed and Scopus data banks for articles related with human molecular chronobiology. The keywords used were 'clock genes, circadian rhythms, diurnal preference, delayed sleep phase syndrome, advanced sleep phase syndrome, photoperiod and mood disorder'. DISCUSSION: The knowledge about molecular mechanism of circadian rhythms increased a lot in the last years and now we are able to better understand the details of molecular processes involved in circadian and sleep regulation. Studies show that polymorphisms in clock genes are associated with sleep and mood disorders. These studies will be helpful to further elucidate the regulation of molecular mechanisms of circadian rhythms. CONCLUSIONS: The development of these studies in molecular chronobiology can be helpful to treat circadian and mood disorders and to prevent health risks caused by intercontinental flights (Jet Lag), nocturnal or shift work schedule.

Moléculas que marcam o tempo: implicações para os fenótipos circadianos / Timekeeping molecules: implications for circadian phenotypes

OBJETIVO: Revisar resumidamente a literatura dos últimos 36 anos de pesquisa em cronobiologia molecular a fim de informar aos profissionais de saúde os avanços obtidos nesta área e os potenciais para aplicação na clínica médica. MÉTODO: Buscas na literatura foram realizadas utilizando as bases de dados PubMed e Scopus usando como palavras-chave "clock genes, circadian rhythms, diurnal preference, delayed sleep phase syndrome, advanced sleep phase syndrome, photoperiod and mood disorder". DISCUSSÃO: Atualmente, o mecanismo molecular da regulação da ritmicidade circadiana é compreendido em grande detalhe. Muitos estudos publicados mostram associações de polimorfismos nos genes relógio com transtornos do ritmo circadiano e com transtornos do humor. CONCLUSÕES: De maneira geral, o progresso obtido na área de cronobiologia molecular traz um melhor entendimento da regulação do sistema de temporização biológico. O desenvolvimento de estudos nesta área tem o potencial de ser aplicável ao tratamento dos transtornos dos ritmos circadianos e certos transtornos do humor, além de prevenir riscos à saúde causados por viagens intercontinentais (Jet Lag) e por trabalhos noturnos e por turnos.

OBJECTIVE: The aim of this study was to review the molecular chronobiology studies in the last 36 years in order Eto point out the advances in this area to health professionals. METHOD: We searched in the PubMed and Scopus data banks for articles related with human molecular chronobiology. The keywords used were "clock genes, circadian rhythms, diurnal preference, delayed sleep phase syndrome, advanced sleep phase syndrome, photoperiod and mood disorder". DISCUSSION: The knowledge about molecular mechanism of circadian rhythms increased a lot in the last years and now we are able to better understand the details of molecular processes involved in circadian and sleep regulation. Studies show that polymorphisms in clock genes are associated with sleep and mood disorders. These studies will be helpful to further elucidate the regulation of molecular mechanisms of circadian rhythms. CONCLUSIONS: The development of these studies in molecular chronobiology can be helpful to treat circadian and mood disorders and to prevent health risks caused by intercontinental flights (Jet Lag), nocturnal or shift work schedule.

Tradução para o português e validação de conteúdo da Social Rhythm Metric-17 (SRM-17) / Translation into Portuguese and content validation of the Social Rhythm Metric-17 (SRM-17)

Objetivos: Traduzir para o português a Social Rhythm Metric-17 (SRM-17), escala que afere ritmo social, e realizar validação de conteúdo da versão produzida. Método: Foi utilizada uma adaptação do método para validação de instrumentos que compreendeu as seguintes etapas: preparação, tradução, conciliação, retrotradução, revisão da retrotradução, avaliação de clareza, revisão de resultados da avaliação de clareza e finalização, prova de leitura e relatório final. Resultados: A versão final brasileira manteve uma equivalência de itens com relação à primeira versão em inglês do instrumento original, incorporando melhorias. A transposição do instrumento alternativo criado pelo grupo de Cronobiologia Humana do Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre (RS), para a SRM-17 não mostrou discrepâncias significativas e revelou que, embora essa escala seja um instrumento genérico, é sensível às diferenças individuais quanto à aferição de ritmo social. A versão avaliada demonstrou um grau satisfatório de clareza e equivalência semântica. Conclusão: Este trabalho apresenta uma versão adaptada à realidade brasileira de um instrumento específico para aferir ritmo social. O processo de adaptação transcultural deve efetivar-se com estudos de validação do instrumento final em uma amostra maior da população, nos quais também poderão ser avaliadas as equivalências operacional, de medida e funcional.

Objectives: To translate the Social Rhythm Metric-17 (SRM-17), a scale that assesses social rhythm, into Portuguese and to validate the content of the Portuguese version. Methods: An adaptation of the method for validation of instruments was used and it included the following stages: preparation, translation, reconciliation, back translation, revision of back translation, comprehension assessment, review of the results of comprehension assessment and completion, proofreading, and final report. Results: The final Brazilian version has the same number of items as the first English version of the original instrument, and included some enhancements. The adaptation of the alternative instrument developed by the Human Chronobiology Group of Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil, to the SRM-17 did not show any significant discrepancies and revealed that, in spite of being a generic instrument, it is sensitive to the individual differences regarding the assessment of social rhythm. The Portuguese version showed a satisfactory level of understanding and semantic equivalence. Conclusion: A version of an instrument to assess social rhythm adapted to the Brazilian reality is presented in this study. The cross-cultural adaptation process must be completed by validation studies of the fi nal instrument in a larger population sample, which will also be able to evaluate the equivalences related to operation, measures, and functionality.

Depressão: como eu trato? / Depression: how I treat?

A condução médica de casos de depressão é tão ampla e diversificada conforme a complexidade diagnóstica desta patologia. Tratar um paciente com transtorno depressivo do humor vem se tornando um desafio na prática clínica, frente aos diversos tipos de manifestações e classificações dos quadros encontrados. Cada vez maior é o arsenal terapêutico e a cada hora surgem novas técnicas de abordagem para os mais diferentes casos. Esta evolução certamente traz benefícios ao paciente, mas pode gerar dúvidas e angústias em quem os trata. Este artigo tem por objetivo auxiliar no raciocínio médico e, humildemente, servir de caminho na escolha das terapias a serem instituídas, respeitando a individualidade de cada caso.

The medical conduction of depression cases is so wide and diversified as is the complex diagnosis of this pathology. The treatment of a patient with humor depressive disturb is becoming a challenge in clinical practice in face of the different manifestations and classifications of this disease. More and more reports are found on the therapeutic arsenal and techniques to approach the differents cases. This evolution surely brings benefits to patients, but it can generate doubts and anxiety to whom deals with them. This present article aims to help in the medical thinking of this subject and humbly to point a way in the choice of therapies to be chosen, respecting the infividuality of each case.

Bipolar disorders and affective temperaments: a national family study testing the "endophenotype" and "subaffective" theses using the TEMPS-A Buenos Aires.

BACKGROUND: The purpose of this study is to examine the prevalence of affective temperaments between clinically unaffected relatives of bipolar patients and secondarily to investigate the impact of these "subaffective" forms on their quality of life (QoL). METHODS: The study was performed in seven sites across Argentina. We administered the scales TEMPS-A and Quality of Life Index to a sample of 114 non-ill first degree relatives of bipolar disorder patients ("cases") and 115 comparison subjects without family history of affective illness ("controls"). We used The Mood Disorder Questionnaire to rule out clinical bipolarity. RESULTS: Mean scores on all TEMPS-A subscales were significantly higher in cases, except for hyperthymia. The prevalence of affective temperaments, according to Argentinean cut-off points, was also higher, with statistical significance for cyclothymic and anxious temperaments. Regarding QoL, we found no significant differences between both groups, except for interpersonal functioning, which was better in controls. A detailed subanalysis showed significant effects of QoL domains for all temperaments, except for the hyperthymic. LIMITATIONS: We used self-report measures. A larger sample size would have provided us greater statistical power for certain analyses. CONCLUSIONS: Our findings support the concept of a spectrum of subthreshold affective traits or temperaments - especially for the cyclothymic and anxious - in bipolar pedigrees. We further demonstrated that, except for the hyperthymic, quality of life was affected by these temperaments in "clinically well" relatives. Overall, our data are compatible with the "endophenotype" and "subaffective" theses for affective temperaments.

Toward an integrative model of the spectrum of mood, behavioral and personality disorders based on fear and anger traits: II. Implications for neurobiology, genetics and psychopharmacological treatment.

Current psychiatry relies on a purely categorical paradigm for diagnosis of mental disorders that profoundly impacts research and clinical practice. However, high comorbidity rates and relative non-specificity of family history for psychiatric disorders suggests that this categorical approach fails to identify the underlying diathesis. As an attempt to overcome such limitations, we developed a bidimensional model based on fear and anger traits or temperaments which does not preclude the use of a categorical approach. As a result, it is hypothesized that mood, behavioral and personality disorders share a neurobiological substrate according to combinations of fear and anger traits. Both fear and anger, when excessive or deficient, lead to increased risk for mental disorders and should be considered in genetic, neurobiological and neuroimaging studies. Fear traits are much influenced by the amygdala and the serotonergic, noradrenergic and GABAergic systems, whereas anger seems to be mostly regulated by the nucleus accumbens and the dopaminergic and glutamatergic systems. Pharmacological treatments with antidepressants and anxiolytics can be considered as essentially restraint on fear, whereas lithium and alpha2 noradrenergic agonists would attenuate fear deficiency. Dopaminergic antidepressants and psychostimulants are anger enhancers and antipsychotics and mood stabilizers, such as divalproate and carbamazepine, may share antianger effects. Drugs effective for manic and depressive phases probably have both antianger and antifear effects. This framework may lead to a better understanding of the neurobiological basis of mental health and disease, providing an integrative approach for future research.

Detection of Borna disease virus p24 RNA in peripheral blood cells from Brazilian mood and psychotic disorder patients.

BACKGROUND: Borna disease virus (BDV) is a virus that naturally infects a broad range of warm-blooded animals. BDV is an enveloped virus, non-segmented, negative-stranded RNA genome and has an organization characteristic of a member of Bornaviridae in the order of Mononegavirale. In the present work we investigated the presence of BDV p24 RNA in peripheral blood cells from 30 psychiatric patients (19 with mood disorder and 11 with psychotic disorder) and 30 healthy volunteers as the control group. METHODS: All subjects were interviewed by structured diagnostic criteria categorized according to the DSM-IV, Axis I (SCID-V). The presence of BDV p24 RNA was investigated by nested reverse transcriptase PCR (RT-PCR) using specific primers to p24 from BDV. The specificity of the detection was analyzed by the sequencing of PCR products. RESULTS: The mean duration of illness in mood and psychotic patients with p24 RNA of BDV was 25 (+/-12.3) years and the median age was 43.77 (+/-15.2) years. There were no significant differences in gender and age among patients and control group, neither duration of illness among patients with mood and psychotic disorders in the presence or absence of p24 RNA of BDV. We found a frequency of 33.33% (10/30) of BDV-RNA on patient's group and 13.33% (4/30) on control group. The given sequences revealed identity with GenBank database sequence for BDV. CONCLUSION: The detection of a higher level of BDV-RNA in the peripheral blood cells of patients than on control group should help our understanding of the pathogenesis in the disease.

Fine-scale mapping of a locus for severe bipolar mood disorder on chromosome 18p11.3 in the Costa Rican population.

We have searched for genes predisposing to bipolar disorder (BP) by studying individuals with the most extreme form of the affected phenotype, BP-I, ascertained from the genetically isolated population of the Central Valley of Costa Rica (CVCR). The results of a previous linkage analysis on two extended CVCR BP-I pedigrees, CR001 and CR004, and of linkage disequilibrium (LD) analyses of a CVCR population sample of BP-I patients implicated a candidate region on 18p11.3. We further investigated this region by creating a physical map and developing 4 new microsatellite and 26 single-nucleotide polymorphism markers for typing in the pedigree and population samples. We report the results of fine-scale association analyses in the population sample, as well as evaluation of haplotypes in pedigree CR001. Our results suggest a candidate region containing six genes but also highlight the complexities of LD mapping of common disorders.

Darier's disease: a new paradigm for genetic studies in psychiatric disorders.

CONTEXT: One strategy for identifying susceptibility genes for common disorders is to investigate Mendelian diseases, cosegregating with these common disease phenotypes. CASE REPORT: A family with seven members is described, in which three members present Darier's disease and depression. This apparent cosegregation, if true, would support the hypothesis that in some pedigrees, a gene for mood disorder may be located on chromosome 12.

Darier's disease: a new paradigm for genetic studies in psychiatric disorders

CONTEXT: One strategy for identifying susceptibility genes for common disorders is to investigate Mendelian diseases, cosegregating with these common disease phenotypes. CASE REPORT: A family with seven members is described, in which three members present Darier's disease and depression. This apparent cosegregation, if true, would support the hypothesis that in some pedigrees, a gene for mood disorder may be located on chromosome 12

Trastorno afectivo bipolar: análisis de segregación compleja y de heterogeneidad fenotípica en un grupo familiar extenso proveniente de El Tambo, Cauca, Colombia / Bipolar disorder: complex segregation and phenotypic heterogeneity analyses on a familial cluster from El Tambo, Cauca, Colombia

Se presenta un análisis de segregación compleja encaminado a discriminar los componentes genético y ambiental responsables de la agregación familiar en el desarrollo del trastorno afectivo bipolar (TAB), en un grupo de familias seleccionadas a partir de probandos provenientes de El Tambo, Cauca, Colombia. Se realizaron dos tipos de análisis: el primero considera como afectados sólo a aquellos individuos con trastorno afectivo bipolar I y, el segundo, asume que los fenotipos correspondientes al trastorno afectivo bipolar II y a la esquizofrenia representan status de afección y hacen parte de un sólo desorden con expresividad variable. En conjunto, el modelo que explica mejor la varianza fenotípica es el modelo mixto, es decir, el que combina la existencia de un gen mayor más efectos multifactoriales. Cuando se consideró únicamente el trastorno afectivo bipolar I, los resultados fueron compatibles con la existencia de un modelo mixto con una alta dependencia del fenotipo al ambiente. En la segunda aproximación, se magnificó la importancia del componente de gen mayor, pero no se presentaron variaciones en las estimaciones paramétricas. Esto último hace pensar que existe un solo gen con una amplia expresión fenotípica que puede ser responsable del status de afección en esta familia. Esto implica que aquellos individuos afectados de trastorno afectivo bipolar II y de esquizofrenia representan status de afección con formas variantes del trastorno afectivo bipolar I. En el modelo general, el parámetro t2 tuvo como asíntota a 0 y su iteración dentro del modelo general cambió significativamente la maximización del modelo. Esto hace suponer que existan efectos epistáticos sobre el gen mayor

Genética dos transtornos afetivos: uma revisäo crítica / Genetics of affective disorders: a critical review

A distribuiçäo predominantemente familiar de alguns distúrbios psiquiátricos é bastante conhecida e neste fato estäo envolvidos, possivelmente, fatores genéticos e ambientais. Entretanto, pouco se sabe sobre os genes envolvidos onde estäo, que substâncias codificam e de que forma se expressam. O presente trabalho se propöe a revisar os principais estudos dos Transtornos Afetivos, desde as primeiras pesquisas realizadas com família até os recentes estudos de ligaçäo, avaliar as contribuiçöes destes achados para a prática clínica e vice-versa e as perspectivas futuras nesta área

La biología molecular en psiquiatría / Molecular biology in psychiatry

En el presente trbajo realizamos una revisión de las principales aportaciones, tanto nacionales como extranjeras, de la biología molecular a la psiquiatría. Se describen algunos conceptos fundamentales con el objeto de permitir al lector un entendimiento claro de las aportaciones actuales, y sentar las bases teóricas para el seguimiento de la literatura en el campo. Hasta ahora los hallazgos principales se han dado en las siguientes patologías: trastornos afectivos, esquizofrenia, alcoholismo, ansiedad y psicofarmacología. Finalmente, se describen algunas de las principales innovaciones metodológicas que se están llevando a cabo, y que seguramente se traducirán en la generación de un mayor nivel de conocimiento en cuanto a los mecanismos moleculares etiológicos en la patología mental

Avaliaçäo familial de distúrbios mentais em depressöes infanto-juvenis / A family study of psychiatric disorders in children and adolescent with depression

O presente estudo analisa 74 familiares em primeiro grau e 597 familiares em segundo grau de 21 probandos com depressäo na infância e adolescência e os compara a 93 familiares em primeiro grau e 898 familiares em segundo grau de um grupo controle de hospital geral, para evidenciar a importância de fatores familiares na vulnerabilidade à depressäo. A proporçäo de distúrbios mentais em parentes em primeiro e como no parente em segundo grau é estatisticamente significativa nos parentes dos probandos depressivos do que nos parentes controles