UGT1A1 gene variations in individuals with and without clinical diagnosis of Gilbert Syndrome

UGT1A1 gene variations in individuals with and without clinical diagnosis of Gilbert Syndrome Bilirubin is a non-polar metabolite, results from catabolism of haemoglobin and is bound to glucuronic acid in the liver by the uridine diphosphate glucuronosyltransferase (UGT1A1) activity. Molecular studies showed that the presence of two extra bases (TA duplication) in the promoter region of the UGT1A1 gene is responsible for the reduced UGT1A1 glucuronization activity and is the main cause of unconjugated hyperbilirubinemia observed in patients with Gilbert Syndrome (GS). However, individuals with normal bilirubin levels and no clinical symptoms of SG may also present this polymorphism in homozygosity 1,2,3. Consequently, the aim of this work is to determine the presence of other mutations in the UGT1A1gene, downstream of the TA duplication, and how they may contribute towards the inter-individual variation of serum bilirubin levels. This study was carried out in two groups: one comprising 36 individuals without clinical diagnosis of GS (14 with 6/6TA, 11 with 6/7TA, and 11 with 7/7TA repeats); the other group consisting of 36 patients clinically diagnosed with GS. In both, bilirubin levels were determined and direct sequencing of the UGT1A1 was performed. Among the individuals without clinical diagnosis of GS, two new sequence variants were found in heterozygosity (c.643A>G, and c.1156G>A), in the 6/6TA group. No additional mutations were detected in the 6/7 and 7/7 TA groups. In patients clinically diagnosed with GS, 28 were homozygous and 7 heterozygous for the TA duplication, and one with a normal number of repeats. Molecular analysis showed that one (3,6%) of the 7/7TA patients had another mutation in the UGT1A1 gene (c.674T>G). In the 6/7TA group, one additional mutation was also found in three patients (43%), two of which had been previously described (c.674T>G and c.923G>A) and a new one (c.1423C>T). No further mutations were detected in the 6/6TA group. Additionally, 4 polymorphisms were found (c.864+89C>T; c.997-37T>C; c.997-82A>C; c.997-87A>C). In conclusion, we can infer that homozygosity for the TA duplication is associated with GS. In the group without GS, no further mutations were detected in the 6/7 and 7/7 clusters, but in the 6/6 group, two new mutations were found in heterozygosity. These mutations are not associated with increased bilirubin levels. However, they could be associated with GS in the presence of other UGT1A1 mutations. Furthermore, in the GS group with heterozygosity for the TA duplication, we found mutations in 43% of the patients, emphasizing the importance of complete UGT1A1 analysis

Knowledge of Dentists about Hypomineralization Enamel Defects: A Cross-Sectional Study

Objective: To evaluate a group of Brazilian dentists on their knowledge of Molar Incisor Hypomineralization (MIH) and Hypomineralized Second Primary Molars (HSPM) related to clinical aspects, consequences, and diagnostic criteria. Material and Methods: In this cross-sectional, the participants were invited by e-mail and Whatsapp® to answer a questionnaire about their knowledge of hypomineralization enamel defects (MIH/HSPM) on the Google Forms® platform. The questionnaire comprised eight questions about personal data and multiple-choice questions about their knowledge concerning clinical aspects, diagnostic criteria of MIH/HSPM and differential diagnosis through clinical images. Chi-square test was applied with the significance level set at 5%. Results: Most participants (n = 492; 91.1%) reported having knowledge about MIH/HSPM. The general dentists gave more incorrect answers (n = 40; 65.6 %;) about dental tissues affected by MIH/HSPM. Overall, 83.3% of the dentists gave the correct answer to which dentitions are associated with this condition. In addition, most dentists presented knowledge about the consequences related to possible fractures (n= 487; 90.2%) and about an increased risk of caries (n= 479; 88.9%) in the affected teeth.  Regarding the differential diagnosis performed through clinical images, most participants gave incorrect answers (p≤0.001). Conclusion: The participants presented knowledge about the dentition associated with this condition and possible consequences related to the teeth affected by MIH/HSPM; however, they showed difficulties concerning clinical diagnostic criteria

Impact of UGT1A1 gene variants on total bilirubin levels in Gilbert syndrome patients and in healthy subjects

A significant different allelic distribution, in Gilbert patients and in controls, was found for two promoter polymorphisms. Among patients, 82.2% were homozygous and 17.8% heterozygous for the c.− 41_ − 40dupTA allele; in control group, 9.9% were homozygous and 43.5% heterozygous for this promoter variant, while 46.6% (n = 75) presented the [A(TA)6TAA]. For the T>G transition at c.− 3279 promoter region, in patients, 86.7% were homozygous and 13.3% heterozygous; in control group, 33.5% were homozygous for the wild type allele, 44.1% were heterozygous and 22.4% homozygous for the mutated allele. The two polymorphisms were in Hardy–Weinberg equilibrium in both groups. Sequencing of UGT1A1 coding region identified nine novel variants, five in patients and four in controls. In silico analysis of these amino acids replacements predicted four of them as benign and three as damaging. In conclusion, we demonstrated that total bilirubin levels are mainly determined by the TA duplication in the TATA-box promoter and by the c.− 3279T>G variant. Alterations in the UGT1A1 coding region seem to be associated with increased bilirubin levels, and, therefore, with Gilbert syndrome.A PhD grant (SFRH/BD/42791/2007) attributed to Carina Rodrigues, from Fundação para a Ciência e Tecnologia (FCT) and Fundo Social Europeu (FSE), supported this work

Bilirubin dependent on UGT1A1 polymorphisms, hemoglobin, fasting time and body mass index

In PressIn humans, bilirubin levels are influenced by different factors. This study aims to evaluate the influence of several nongenetic factors (hematologic data, smoking status, alcohol intake, fasting time, physical activity, oral contraceptive therapy and caloric intake) and the genetic contribution of UGT1A1 polymorphisms for the bilirubin levels, in a cohort of young women. Hematologic data, bilirubin and screening of TA duplication in the TATA box region of the UGT1A1 gene were performed in 146 young white women. Body mass index (BMI) and body fat were determined, and a questionnaire about fasting time, smoking habits, oral contraceptive therapy, caloric intake and physical activity was performed. Participants were divided into 3 groups according to the tertiles of bilirubin levels. Subjects from the second and third tertile had significant increases in hemoglobin (Hb) concentration, hematocrit, mean cell Hb and mean cell Hb concentration compared with those in the first tertile. Red blood cell count was significantly increased in subjects in the third tertile. A significant increased frequency was found for the c.-41_-40dupTA allele in homozygosity for both second and third tertiles. Multiple linear regression analysis showed that the c.-41_-40dupTA allele, Hb, BMI and fasting hours were independent variables associated with bilirubin serum levels. Hb concentration, fasting time and BMI were identified as nongenetic causes, together with the genetic UGT1A1 polymorphisms, as the main factors associated with variations in bilirubin levels in a healthy female population.Bolsa de doutoramento SFRH/BD/42791/2007 da Fundação para a Ciência e Tecnologia (FCT) e Fundo Social Europeu

Knowledge of Dentists about Hypomineralization Enamel Defects: A Cross-Sectional Study

Objective: To evaluate a group of Brazilian dentists on their knowledge of Molar Incisor Hypomineralization (MIH) and Hypomineralized Second Primary Molars (HSPM) related to clinical aspects, consequences, and diagnostic criteria. Material and Methods: In this cross-sectional, the participants were invited by e-mail and Whatsapp® to answer a questionnaire about their knowledge of hypomineralization enamel defects (MIH/HSPM) on the Google Forms® platform. The questionnaire comprised eight questions about personal data and multiple-choice questions about their knowledge concerning clinical aspects, diagnostic criteria of MIH/HSPM and differential diagnosis through clinical images. Chi-square test was applied with the significance level set at 5%. Results: Most participants (n = 492; 91.1%) reported having knowledge about MIH/HSPM. The general dentists gave more incorrect answers (n = 40; 65.6 %;) about dental tissues affected by MIH/HSPM. Overall, 83.3% of the dentists gave the correct answer to which dentitions are associated with this condition. In addition, most dentists presented knowledge about the consequences related to possible fractures (n= 487; 90.2%) and about an increased risk of caries (n= 479; 88.9%) in the affected teeth.  Regarding the differential diagnosis performed through clinical images, most participants gave incorrect answers (p≤0.001). Conclusion: The participants presented knowledge about the dentition associated with this condition and possible consequences related to the teeth affected by MIH/HSPM; however, they showed difficulties concerning clinical diagnostic criteria

Ugt1a1 gene variants and total bilirubin levels in healthy subjects and in gilbert syndrome patients

Gilbert syndrome (GS, OMIM 606785) is an autosomal recessive condition characterized by unconjugated hiperbilirubinemia in the absence of hemolysis or underlying liver disease due to the reduced activity of the uridine diphosphate-glucuronosyltransferase (UGT1A1). This enzyme is mainly expressed in the liver and has an important role in the glucuronidation of bilirubin, 17β-estradiol, some therapeutic drugs and mutagenic xenobiotics. Absence or severe reductions of UGT1A1 activity are associated with Crigler-Najjar syndrome type I and type II, respectively. Heterozygous carriers of Crigler-Najjar syndrome also present a high incidence of mild hyperbilirubinemia, a feature of GS. Aim: This work investigated the effect of UGT1A1 variants on total bilirubin levels in Gilbert patients (n=45) and healthy controls (n=161). Total bilirubin levels were determined using a colorimetric method. Molecular analysis of exons 1-5 and two UGT1A1 promoter regions were performed by direct sequencing and automatic analysis of fragments. Five in silico methods predicted the effect of new identified variants. A significant different allelic distribution, in Gilbert patients and in controls, was found for two promoter polymorphisms. Among patients, 82.2% were homozygous and 17.8% heterozygous for the c.-41_-40dupTA allele; in control group, 9.9% were homozygous and 43.5% heterozygous for this promoter variant, while 46.6% (n=75) presented the [A(TA)6TAA]. For the T>G transition at c.-3279 promoter region, in patients, 86.7% were homozygous and 13.3% heterozygous; in control group, 33.5% were homozygous for the wild type allele, 44.1% were heterozygous and 22.4% homozygous for the mutated allele. The two polymorphisms were in Hardy-Weinberg equilibrium in both groups. Sequencing of UGT1A1 coding region identified nine novel variants, five in patients and four in controls. In silico analysis of these amino acids replacements predicted four of them as benign and three as damaging. We demonstrated that total bilirubin levels are manly determined by the TA duplication in the TATA-box promoter and by the c.-3279T>G variant. Alterations in the UGT1A1 coding region seem to be associated with increased bilirubin levels, and therefore with Gilbert Syndrome

Esquizofrenia: perspectivas atuais acerca do diagnóstico, tratamento e evolução clínica da doença

A esquizofrenia é uma patologia de início precoce, não possui sua etiologia completamente explicada e se caracteriza por sintomas como delírios e alucinações que cursam com distorção da realidade, do pensamento, percepção, cognição e do comportamento. Apesar de muitos estudos, a esquizofrenia ainda é uma incógnita para muitos estudiosos e médicos, principalmente, acerca do tratamento que ainda é inespecífico e varia de acordo com a aceitação de cada paciente. Este artigo buscou revisar por meio da atual literatura as perspectivas acerca da esquizofrenia e os desdobramentos do tratamento e evolução clínica dessa enfermidade de alta complexibilidade que se enquadra como uma das síndromes psicóticas mais graves. Ademais, a necessidade de aprimorar os conhecimentos sobre uma doença psiquiátrica de difícil diagnóstico e tratamento é de alta relevância para a comunidade médica, principalmente, como forma de romper barreiras sociais e históricas que rondam os pacientes com esquizofrenia que são estigmatizados e necessitam de um atendimento mais humanizado, respeitoso e que proporcione melhor qualidade de vida

Are There Differences in the Anthropometric, Hemodynamic, Hematologic, and Biochemical Profiles between Late- and Early-Onset Preeclampsia?

Preeclampsia (PE) is classified as early-onset PE (EOPE) and late-onset PE (LOPE) when present before or after 34 weeks of gestation, respectively. This transversal study aimed to investigate the differences and possible associations existing in the anthropometric, hemodynamic, hematologic, and biochemical profiles of late- and early-onset preeclampsia. The study included 65 volunteers admitted to a tertiary hospital in Brazil: 29 normotensive and 36 with preeclampsia (13 with EOPE and 23 with LOPE). Pregnant women with LOPE presented greater weight gain and borderline increase in body mass index at the end of gestation in relation to the other groups, which is compatible with the metabolic origin, associated with obesity, attributed to this form of the disease. Pregnant women with EOPE presented a borderline reduction in the number of erythrocytes and a significant decrease in the number of platelets, in addition to a significant increase in reticulocytes, serum iron, and ferritin when compared to normotensive pregnant women and pregnant women with LOPE. A significant increase in osmotic stability of erythrocytes was observed in the EOPE group in relation to other groups. Hemodynamic analysis by Doppler ultrasonography of the ophthalmic artery showed that both groups of pregnant women with PE presented alterations compatible with the occurrence of hyperflow in the orbital territory. These hemodynamic changes were associated with changes in hematimetric indices

Consumo alimentar, segundo o grau de processamento, de crianças e adolescentes com transtorno do espectro autista / Food consumption by the processing level of children and adolescents with autistic spectrum disorders

Objetivo: Avaliar o consumo alimentar, conforme o grau de processamento dos alimentos, em autistas. Métodos: Trata-se de um estudo transversal realizado com crianças portadoras de transtorno do espectro autista cadastrados em quatro instituições localizadas em Maceió-AL, em 2019. Foram coletadas informações socioeconômicos, antecedentes pessoais, perinatais e dados clínicos, e para avaliação do consumo alimentar, foi utilizado um questionário alimentar semiquantitativo. Os alimentos foram categorizados conforme grau de processamento segundo a classificação do Guia alimentar para a população brasileira. Os dados foram analisados com o apoio do software SPSS versão 22.0. Resultados: A amostra foi composta por 180 indivíduos e, verificou-se que mais de 1/4 dos avaliados consomem alimentos ultraprocessados diariamente. Com relação aos alimentos in natura, aproximadamente 34% das crianças não consomem fruta diariamente, e apenas 45,56% ingere algum vegetal de forma habitual. Conclusão: O público avaliado possui um padrão alimentar inadequado, marcado pelo baixo consumo de alimentos minimamente processados e uma ingestão elevada de ultraprocessados, o que pode interferir sobre o estado nutricional e de saúde dessa população

Sedação inalatória com óxido nitroso em pessoas com necessidades especiais: revisão integrativa / Inhaled sedation with nitrous oxide in people with special needs: integrative review

A sedação odontológica é uma medida complementar utilizada no controle da dor e da ansiedade, sentimentos amplamente relatados dentro da rotina clínica de atendimentos. Quando busca setorializar essas condições para os pacientes portadores de necessidades especiais (PPNE), o atendimento torna-se ainda mais desafiador. O objetivo deste trabalho foi realizar uma revisão de literatura e analisar os estudos sobre os preceitos do tratamento com sedação inalatória nos pacientes portadores de necessidades especiais. Os artigos refinados neste estudo foram selecionados por meio das bases de dados: PubMed, Lilacs e Scielo. O levantamento limitou-se aos artigos publicados nos idiomas inglês e português, entre os anos de 2010 a 2020. Embora existam diversas publicações  que envolvam esta área de conhecimento, foi verificado poucos registros a cerca do protocolo ideal para os tratamentos. Contudo, a sedação consciente com óxido nitroso demonstrou-se ser uma técnica segura e eficaz no controle da ansiedade dos pacientes portadores de necessidades especiais ou não, sem contraindicação absoluta, permitindo que o profissional minimize as possíveis consequências negativas advindas do atendimento odontológico e obtenha uma abordagem comportamental satisfatória em seus pacientes