Oferta da fonoaudiologia pelo Sistema Único de Saúde em Sergipe: 2012 a 2021 / Speech therapy offered by the single health system in Sergipe: 2012 to 2021

Introdução: A inclusão do fonoaudiólogo nos serviços públicos promoveu mudanças no processo de trabalho, com foco numa abordagem integral e intervenção em diversos setores. Porém, observa-se desigualdade na disposição e déficit no quantitativo desse profissional. Objetivo: Descrever a oferta da fonoaudiologia no Sistema Único de Saúde no Estado de Sergipe no período de 2012 a 2021. Método: Estudo ecológico, descritivo e observacional, utilizando dados secundários do Cadastro Nacional de Estabelecimentos de Saúde, Sistema de Informações Ambulatoriais do SUS do Departamento de Informática do SUS e do Instituto Brasileiro de Geografia e Estatística de 2012 a 2021 no estado de Sergipe. As variáveis foram: número de fonoaudiólogos, número de procedimentos realizados, grupos de procedimentos e nível de complexidade. Análise estatística descritiva a partir da variação proporcional percentual do período investigado. Resultado: Houve evolução na oferta da fonoaudiologia no estado de Sergipe, evoluindo de 74 para 251 fonoaudiólogos, porém somente as regiões de saúde Aracaju e Lagarto tiveram as maiores ofertas (1,71/10.000 e 1,44/10.000, respectivamente) apresentando mais de 1 fonoaudiólogo/10.000 habitantes em 2021. Observou-se aumento acentuado na oferta dos procedimentos a partir de 2015. Destacaram-se atendimentos na média complexidade com 97% em 2021, predominando procedimentos clínicos (68%) e de finalidade diagnóstica (29%). Conclusão: Evidenciou-se evolução da oferta da fonoaudiologia e número de procedimentos em Sergipe (2012 a 2021), porém observou-se oferta insuficiente e disparidades entre os municípios, dificultando o acesso e ampliação da oferta fonoaudiológica

Avaliação neuropsicológica de crianças diagnosticadas com apneia obstrutiva do sono / Neuropsychological evaluation of children diagnosed with obstructive sleep apnea

A apneia obstrutiva do sono (AOS) pediátrica é um distúrbio respiratório, caracterizado por episódios recorrentes de obstrução das vias aéreas superiores. Muitas pesquisas evidenciam déficits relacionados aos distúrbios do sono, como dificuldade em atenção, memória, habilidades visuomotoras e funções executivas. A patogênese das comorbidades associadas à AOS está ligada à hipoxemia e às fragmentações no sono. A AOS infantil afeta negativamente resultados de testes neuropsicológicos, que incluem habilidades de linguagem expressiva e receptiva. A principal conduta terapêutica citada na literatura é cirúrgica, porém existem outras alternativas. A polissonografia (PSG) é o exame padrão para diagnóstico, e define a gravidade da doença, além de registrar outros parâmetros fisiológicos relacionados à arquitetura do sono. Por meio desse exame, foram selecionadas crianças com AOS para realizar um teste neuropsicológico e associar os resultados de ambos. A presente dissertação apresentará dois estudos, um de revisão de literatura e um estudo observacional transversal. OBJETIVOS: o objetivo do primeiro estudo é realizar uma revisão da literatura sobre a presença de déficits neuropsicológicos em crianças com apneia do sono; e o objetivo do segundo estudo é pesquisar crianças do ensino fundamental, diagnosticadas com AOS, por meio da associação dos seus resultados de um teste neuropsicológico, com seus respectivos dados polissonográficos. MÉTODOS: para o primeiro estudo foi realizada uma revisão integrativa da literatura, buscando publicações dos últimos dez anos que descreveram aspectos neuropsicológicos de crianças, de 6 a 12 anos, com AOS. Para o segundo estudo, observacional analítico transversal, a amostra incluiu 17 crianças, faixa etária entre 6 e 12 anos, com diagnóstico de AOS e sem comorbidades associadas, tais como síndromes genéticas e alterações craniofaciais. O diagnóstico de AOS foi feito com PSG, realizada em laboratório de sono. Nessa instituição, foram selecionados os laudos e contactadas as famílias para aplicação do teste NEUPSILIN-Inf, em um único encontro. Em seguida, realizou-se análise estatística descritiva, por meio do teste Mann-Whitney associando as variáveis explicativas (tarefas neuropsicológicas) e os desfechos (dados da PSG). RESULTADOS: os resultados são apresentados por meio da produção de dois artigos científicos. O Estudo 1, que é apresentado pelo artigo de revisão de literatura, consistiu em 21 artigos, selecionados entre 219 artigos encontrados em bases de dados. Foram incluídos ensaios clínicos randomizados, revisões da literatura, estudos transversais e de coorte. Dificuldade em atenção, memória e habilidades visuomotoras, verbais e funções executivas foram alterações neuropsicológicas, associadas a distúrbios do sono, destacadas nas pesquisas selecionadas. O segundo estudo incluiu avaliação neuropsicológica de crianças na faixa etária citada, associação entre os resultados do teste e dados polissonográficos. Valores significativos entre o índice de dessaturação inadequado e déficits de linguagem oral e escrita foram encontrados, evidenciando que prejuízos na qualidade de sono podem afetar negativamente habilidades neuropsicológicas. CONCLUSÃO: a AOS pode causar déficits neuropsicológicos relacionados à atenção, à memória declarativa, às funções executivas e às habilidades de linguagem. Na análise estatística foram encontrados valores significativos entre o índice de dessaturação inadequado e déficits de linguagem oral e escrita. Tais quadros podem ser amenizados com tratamento adequado, porém a relação entre dados diagnósticos e prognósticos carece de mais evidências. É de suma importância a abordagem preventiva e interdisciplinar de crianças com queixas respiratórias de sono para definir melhor intervenção, otimizar desempenho escolar e qualidade de vida das crianças com esse diagnóstico.

To elaborate a bibliographical review on neuropsychological deficits in children with sleep apnea. METHODS: An integrative review on theoretical literature was used to achieve the purpose, analyzing, thereby, specific literature from the last ten years describing neuropsychological aspects of children with sleep apnea. Database consulted were: "Portal Regional da Biblioteca Virtual de Saúde", "PubMed", "Portal CAPES", "PEDro" and "OTseeker". RESULTS: The sample has 21 selected articles, selected from a population of 219 articles found on the databases. Randomized clinical trials, bibliographical reviews, cross- sectional and cohort studies were included. Both Redundant publications or articles that did not specify for age or focused on comorbidities were not considered. Most of the surveys evidenced the existence of neuropsychological changes related to sleep disturbance, which could cause difficulties at paying attention. Memorization and visual motor, speech and executive functions were compromised. Pathogenesis of comorbidities related to obstructive sleep apnea are caused by hypoxemia and sleep interruptions. Surgery is the main medical intervention mentioned in the literature, since there was no other research so far exploring other possibilities to solve these neuropsychological deficits. CONCLUSION: Articles indicate that sleep apnea can cause neuropsychological deficits on attention, memory, and executive functions. In addition, these articles suggests that this situation could be softened with proper treatment, although prognosis and diagnosis data need further evidence.

Morphometrical, Morphological, and Immunocytochemical Characterization of a Tool for Cytotoxicity Research: 3D Cultures of Breast Cell Lines Grown in Ultra-Low Attachment Plates.

Three-dimensional cell cultures may better mimic avascular tumors. Yet, they still lack characterization and standardization. Therefore, this study aimed to (a) generate multicellular aggregates (MCAs) of four breast cell lines: MCF7, MDA-MB-231, and SKBR3 (tumoral) and MCF12A (non-tumoral) using ultra-low attachment (ULA) plates, (b) detail the methodology used for their formation and analysis, providing technical tips, and (c) characterize the MCAs using morphometry, qualitative cytology (at light and electron microscopy), and quantitative immunocytochemistry (ICC) analysis. Each cell line generated uniform MCAs with structural differences among cell lines: MCF7 and MDA-MB-231 MCAs showed an ellipsoid/discoid shape and compact structure, while MCF12A and SKBR3 MCAs were loose, more flattened, and presented bigger areas. MCF7 MCAs revealed glandular breast differentiation features. ICC showed a random distribution of the proliferating and apoptotic cells throughout the MCAs, not fitting in the traditional spheroid model. ICC for cytokeratin, vimentin, and E-cadherin showed different results according to the cell lines. Estrogen (ER) and progesterone (PR) receptors were positive only in MCF7 and human epidermal growth factor receptor 2 (HER-2) in SKBR3. The presented characterization of the MCAs in non-exposed conditions provided a good baseline to evaluate the cytotoxic effects of potential anticancer compounds.

Oxidative damage and DNA repair in desiccated recalcitrant embryonic axes of Acer pseudoplatanus L.

BACKGROUND: Most plants encounter water stress at one or more different stages of their life cycle. The maintenance of genetic stability is the integral component of desiccation tolerance that defines the storage ability and long-term survival of seeds. Embryonic axes of desiccation-sensitive recalcitrant seeds of Acer pseudoplatnus L. were used to investigate the genotoxic effect of desiccation. Alkaline single-cell gel electrophoresis (comet assay) methodology was optimized and used to provide unique insights into the onset and repair of DNA strand breaks and 8-oxo-7,8-dihydroguanine (8-oxoG) formation during progressive steps of desiccation and rehydration. RESULTS: The loss of DNA integrity and impairment of damage repair were significant predictors of the viability of embryonic axes. In contrast to the comet assay, automated electrophoresis failed to detect changes in DNA integrity resulting from desiccation. Notably, no significant correlation was observed between hydroxyl radical (Ù OH) production and 8-oxoG formation, although the former is regarded to play a major role in guanine oxidation. CONCLUSIONS: The high-throughput comet assay represents a sensitive tool for monitoring discrete changes in DNA integrity and assessing the viability status in plant germplasm processed for long-term storage.

How can environmental conditions influence dicofol genotoxicity on the edible Asiatic clam, Meretrix meretrix?

Genotoxic effects of dicofol on the edible clam Meretrix meretrix were investigated through a mesocosm experiment. Individuals of M. meretrix, were exposed to environmental concentration (D1 = 50 ng/L) and supra-environmental concentration (D2 = 500 ng/L) of dicofol for 15 days, followed by the same depuration period. DNA damage (i.e., strand breaks and alkali-labile sites) was evaluated at day 1, 7 and 15, during uptake and depuration, using Comet assay (alkaline version) and nuclear abnormalities (NAs) as genotoxicity biomarkers. The protective effects of dicofol against DNA damage induced by ex vivo hydrogen peroxide (H2O2) exposure were also assessed. Comet assay results revealed no significant DNA damages under dicofol exposure, indicating 1) apparent lack of genotoxicity of dicofol to the tested conditions and/or 2) resistance of the animals due to optimal adaptation to stress conditions. Moreover, ex vivo H2O2 exposure showed an increase in the DNA damage in all the treatments without significant differences between them. However, considering only the DNA damage induced by H2O2 during uptake phase, D1 animals had significantly lower DNA damage than those from other treatments, revealing higher protection against a second stressor. NAs data showed a decrease in the % of cells with polymorphic, kidney shape, notched or lobbed nucleus, along the experiment. The combination of these results supports the idea that the clams used in the experiment were probably collected from a stressful environment (in this case Pearl River Delta region) which could have triggered some degree of adaptation to those environmental conditions, explaining the lack of DNA damages and highlighting the importance of organisms' origin and the conditions that they were exposed during their lives.

Vestibular recruitment: new application for an old concept.

INTRODUCTION: Vestibular recruitment is a sign of hyperexcitability of central vestibular neurons and may be characteristic of peripheral vestibular damage. OBJECTIVE: To define the post-caloric recruitment index and its ability to predict the stage of vestibular compensation and peripheral lesion. METHODS: First of all, we demonstrated that larger values in the cold post-caloric stimulation compared to warm stimulation were equivalent to vestibular recruitment observed during the sinusoidal harmonic acceleration test. In the next step, patients with vestibular complaints and asymptomatic controls were submitted to the caloric test. We calculated post-caloric recruitment index for the control group. Among the study group, we analyzed the relation between post-caloric recruitment and unilateral weakness as well as the types of vestibular diagnoses. RESULTS: Mean post-caloric recruitment was 17.06% and 33.37% among the control and study group, respectively. The ratio between post-caloric recruitment and unilateral weakness was 1.3 in the study group. Among recruiting subjects, no significant difference of unilateral weakness from the lesioned or healthy side was observed. We found no differences in vestibular diagnoses between recruiting and non-recruiting subjects. CONCLUSION: Post-caloric recruitment index identified asymmetric vestibular tonus and central compensation. The normal value was established at 17.06%.

Vestibular recruitment: new application for an old concept / Recrutamento vestibular: nova aplicação para um conceito antigo

Abstract Introduction Vestibular recruitment is a sign of hyperexcitability of central vestibular neurons and may be characteristic of peripheral vestibular damage. Objective To define the post-caloric recruitment index and its ability to predict the stage of vestibular compensation and peripheral lesion. Methods First of all, we demonstrated that larger values in the cold post-caloric stimulation compared to warm stimulation were equivalent to vestibular recruitment observed during the sinusoidal harmonic acceleration test. In the next step, patients with vestibular complaints and asymptomatic controls were submitted to the caloric test. We calculated post-caloric recruitment index for the control group. Among the study group, we analyzed the relation between post-caloric recruitment and unilateral weakness as well as the types of vestibular diagnoses. Results Mean post-caloric recruitment was 17.06% and 33.37% among the control and study group, respectively. The ratio between post-caloric recruitment and unilateral weakness was 1.3 in the study group. Among recruiting subjects, no significant difference of unilateral weakness from the lesioned or healthy side was observed. We found no differences in vestibular diagnoses between recruiting and non-recruiting subjects. Conclusion Post-caloric recruitment index identified asymmetric vestibular tonus and central compensation. The normal value was established at 17.06%.

Resumo Introdução O recrutamento vestibular é um sinal de hiperexcitabilidade dos neurônios vestibulares centrais e pode ser característico de lesão vestibular periférica. Objetivo Definir o índice de recrutamento pós‐calórico e sua capacidade de predizer o estágio de compensação vestibular e lesão periférica. Método Em primeiro lugar, demonstramos que valores maiores na estimulação pós‐calórica fria em relação à estimulação quente foram equivalentes ao recrutamento vestibular observado durante o teste de aceleração harmônica sinusoidal. Na etapa seguinte, os pacientes com queixas vestibulares e controles assintomáticos foram submetidos à prova calórica. Calculamos o índice de recrutamento pós calórico para o grupo controle. No grupo de estudo, analisamos a relação entre o recrutamento pós‐calórico e predomínio labiríntico, bem como os tipos de diagnósticos vestibulares. Resultados O recrutamento pós‐calórico médio foi de 17,06% e 33,37% nos grupos controle e estudo, respectivamente. A razão entre o recrutamento pós‐calórico e o predominício labiríntico foi de 1,3 no grupo de estudo. Nos sujeitos com recrutamento, não foi observada diferença significativa de predominício labiríntico do lado lesionado ou saudável. Não encontramos diferenças de diagnóstico vestibular entre sujeitos com recrutamento e sem recrutamento. Conclusão O índice de recrutamento pós‐calórico identificou tônus vestibular assimétrico e compensação central. O valor normal foi estabelecido em 17,06%.

Intensidade de los sintomas de fatiga vocal y parâmetros acústicos de las professoras antes y después de la carga vocal / The intensity of vocal fatigue symptoms and acoustic parameters of teachers before and after vocal loading / Intensidade dos sintomas da fadiga vocal e parâmetros acústicos de professoras antes e após exposição vocal

Introdução: A fadiga vocal é um conjunto de sintomas vocais manifestados após o uso prolongado e/ou intenso da voz, algo amplamente observado em professores. Objetivo: descrever e comparar os parâmetros acústicos e de autopercepção dos sinais e sintomas da fadiga vocal antes e após a exposição vocal pelo professor no ambiente ocupacional. Método: 30 mulheres, com média de idade de 40,37 anos, professoras do ensino público que foram submetidas à extração dos parâmetros acústicos e autoavaliação da intensidade dos sintomas da fadiga vocal antes e depois do uso vocal em sala de aula. Foi utilizado o programa Advanced Mult-Dimensional Voice Programm (MDVP-Adv) na análise acústica. Resultados: apenas a medida de ruído (SPI) demostrou-se significante (p=0.02) nos parâmetros acústicos. Os sintomas de rouquidão, falhas na voz, ardência/ queimação na garganta, cansaço para manter a fala apresentaram aumento após o uso da voz ocupacional. Conclusão: houve diminuição da taxa de soprosidade (SPI) e aumento de alguns sintomas da fadiga vocal após o uso prolongado da voz no ambiente ocupacional por professoras.

Introduction: Vocal fatigue is a set of vocal symptoms manifested after prolonged and/or intense vocal use that is frequently observed in teachers. Objective: to describe and compare acoustic parameters and self-perception of vocal fatigue symptoms before and after a vocal exposure by the teacher in the occupational environment. Methods: 30 women, with an average of 40.37 years old, public school teachers, were submitted to the recording of acoustic parameters and self-perception evaluation of the intensity of vocal fatigue symptoms before and after vocal use in the classroom. The Advanced Mult-Dimensional Voice Programm (MDVP-Adv) was used to extract acoustic parameters. Results: only the SPI parameter of noise showed a significant decrease after vocal use (p=0.02). Symptoms of hoarseness, vocal failures, sore/ burning throat, tiredness to maintain speech increased after occupational voice use. Conclusion: after occupational voice use, the SPI breathiness rate decreased and the vocal fatigue symptoms increased.

Introducción: La fatiga vocal es um conjunto de sintomas vocales que se manifiestan tras um uso vocal prolongado y /o intenso, ampliamente observado en los profesores.Objetivo: describir y comparar los parâmetros acústicos y la autopercepción de los sintomas de fatiga vocal antes y después de uma exposición vocal por parde del professor em el entorno ocupacional. Métodos: 30 mujeres, com um promedio de 40.37 años, los maestros de escuelas públicas fueron sometidos a extracción de parámetros acústicos y autopercépcion de la intensidad de los síntomas de fatiga vocal antes y después del uso vocal en el aula. Se utilizó el Advanced Mult-Dimensional Voice Programm (MDVP-Adv) para extraer los parâmetros acústicos. Resultados: el parâmetro de ruído SPI mostro uma disminución significativa después del uso vocal (p=0.02). Los sintomas de ronquera, fallas vocales, dolor de garganta/ ardor, cansancio para mantener el habla aumentaron después del uso de la voz ocupacional. Conclusión: después del uso ocupacional de la voz, el SPI disminuyó y los sintomas de fatiga vocal aumentaron.

Fucoxanthin Holds Potential to Become a Drug Adjuvant in Breast Cancer Treatment: Evidence from 2D and 3D Cell Cultures.

Fucoxanthin (Fx) is a carotenoid derived from marine organisms that exhibits anticancer activities. However, its role as a potential drug adjuvant in breast cancer (BC) treatment is still poorly explored. Firstly, this study investigated the cytotoxic effects of Fx alone and combined with doxorubicin (Dox) and cisplatin (Cis) on a panel of 2D-cultured BC cell lines (MCF7, SKBR3 and MDA-MB-231) and one non-tumoral cell line (MCF12A). Fucoxanthin induced cytotoxicity against all the cell lines and potentiated Dox cytotoxic effects towards the SKBR3 and MDA-MB-231 cells. The combination triggering the highest cytotoxicity (Fx 10 µM + Dox 1 µM in MDA-MB-231) additionally showed significant induction of cell death and genotoxic effects, relative to control. In sequence, the same combination was tested on 3D cultures using a multi-endpoint approach involving bioactivity assays and microscopy techniques. Similar to 2D cultures, the combination of Fx and Dox showed higher cytotoxic effects on 3D cultures compared to the isolated compounds. Furthermore, this combination increased the number of apoptotic cells, decreased cell proliferation, and caused structural and ultrastructural damages on the 3D models. Overall, our findings suggest Fx has potential to become an adjuvant for Dox chemotherapy regimens in BC treatment.

Avaliação da mortalidade no pós-operatório de fraturas de fêmur em idosos com comorbidades prévias / Evaluation of postoperative mortality of femoral fractures in elderly with previous comorbidities

Introdução: Queda é o acidente que ocorre com maior frequência no idoso, sendo a principal causa de morte naqueles com mais de 65 anos. As fraturas do quadril ocupam um papel de grande importância, gerando grande problema de ordem clínica envolvendo pacientes e familiares e de ordem econômica para a sociedade. Objetivo: Coletar dados de questionário da admissão e correlacionar a presença de comorbidades prévias a mortalidade em 30 dias do pós-cirurgia. Métodos: Estudo retrospectivo observacional não randomizado com 216 pacientes com fraturas cirúrgicas do quadril com 61 anos ou mais de idade atendidos no setor de emergência do Centro Hospitalar São Lucas na cidade de Niterói, RJ, no período de 30/03/2016 a 20/03/2018. Resultados: A incidência de óbito após a cirurgia do quadril é igual a 6,9% no primeiro mês. O paciente com fratura no quadril tem comorbidades cardiovasculares (75,9%). O óbito está associado à comorbidade hepática em 13,3% e ao baixo peso em 33,3%. O fato de ter duas ou mais comorbidades não está significativamente associado ao óbito. Conclusão: As comorbidades hepáticas, o baixo peso e a presença de disfunções cardiovasculares são importantes preditores prognósticos na mortalidade do paciente com mais de 61 anos após cirurgia de fratura do fêmur no primeiro mês. (AU)

Introduction: Falls are the leading cause of accidents and death in those aged 65 and above. The high incidence of these injuries impact patients, their families and it represents an economic problem for society. Objective: Collect data from the admission survey and correlate previous comorbidities to mortality in 30 days after surgery. Methods: Retrospective observational non-randomized study. 216 patients were included, aged 61 years or older, who were admitted at the emergency department of the Centro Hospitalar São Lucas in Niterói city, Rio de Janeiro. All the participants were candidates of hip fracture surgery between 03/30/2016 and 03/20/2018. Results: The mortality after hip surgery was 6.9% in the first month. Patients who underwent hip surgery had, previously, cardiovascular diseases (75.9%). Death was associated with liver comorbidity in 13.3% and low weight in 33.3%. The fact of having two or more comorbidities was not associated with death. Conclusion: Liver and cardiovascular diseases and low weight are important prognostic predictors in mortality of patients over 61 years of age after femoral fracture surgery in the first month. (AU)

Cytotoxicity of Seaweed Compounds, Alone or Combined to Reference Drugs, against Breast Cell Lines Cultured in 2D and 3D.

Seaweed bioactive compounds have shown anticancer activities in in vitro and in vivo studies. However, tests remain limited, with conflicting results, and effects in combination with anticancer drugs are even scarcer. Here, the cytotoxic effects of five seaweed compounds (astaxanthin, fucoidan, fucosterol, laminarin, and phloroglucinol) were tested alone and in combination with anticancer drugs (cisplatin-Cis; and doxorubicin-Dox), in breast cell lines (three breast cancer (BC) subtypes and one non-tumoral). The combinations revealed situations where seaweed compounds presented potentiation or inhibition of the drugs' cytotoxicity, without a specific pattern, varying according to the cell line, concentration used for the combination, and drug. Fucosterol was the most promising compound, since: (i) it alone had the highest cytotoxicity at low concentrations against the BC lines without affecting the non-tumoral line; and (ii) in combination (at non-cytotoxic concentration), it potentiated Dox cytotoxicity in the triple-negative BC cell line. Using a comparative approach, monolayer versus 3D cultures, further investigation assessed effects on cell viability and proliferation, morphology, and immunocytochemistry targets. The cytotoxic and antiproliferative effects in monolayer were not observed in 3D, corroborating that cells in 3D culture are more resistant to treatments, and reinforcing the use of more complex models for drug screening and a multi-approach that should include histological and ICC analysis.

GHR and IGF2R genes may contribute to normal variations in craniofacial dimensions: Insights from an admixed population.

INTRODUCTION: This study aimed to determine whether single nucleotide polymorphisms in the growth hormone receptor (GHR) and insulin-like growth factor 2 receptor (IGF2R) genes are associated with different craniofacial phenotypes. METHODS: A total of 596 orthodontic and 98 orthognathic patients from 4 cities in Brazil were included for analyses. Angular and linear cephalometric measurements were obtained, and phenotype characterizations were performed. Genomic DNA was collected from buccal cells and single nucleotide polymorphisms in GHR (rs2910875, rs2973015, rs1509460) and IGF2R (rs2277071, rs6909681, rs6920141) were genotyped by polymerase chain reactions using TaqMan assay. Genotype-phenotype associations were assessed in the total sample (statistical significance was set at P <8.333 × 10-3) and by a meta-analytic approach implemented to calculate the single effect size measurement for the different cohorts. RESULTS: Rare homozygotes for the GHR rs2973015 showed increased measurements for the lower anterior facial height (ANS-Me) and mandibular sagittal lengths (Co-Gn and Go-Pg). In contrast, common homozygotes for the IGF2R rs6920141 presented reduced measurements for these dimensions (ANS-Me and Go-Pg). Furthermore, the less common homozygotes for IGF2R rs2277071 had reduced maxillary sagittal length (Ptm'-A'). The meta-analytical approach replicated the associations of rs2973015 with ANS-Me, rs2277071 with Ptm'-A', and rs6920141 with Go-Pg. CONCLUSIONS: Our results provide further evidence that GHR contributes to the determination of mandibular morphology. In addition, we report that IGF2R is a possible gene associated with variations in craniofacial dimensions. Applying meta-analytical approaches to genetic variation data originating from likely underpowered samples may provide additional insight regarding genotype and/or phenotype associations.

Association between craniofacial morphological patterns and tooth agenesis-related genes.

BACKGROUND: The aim of the present study was to assess if genetic polymorphisms in tooth agenesis (TA)-related genes are associated with craniofacial morphological patterns. METHODS: This cross-sectional, multi-center, genetic study evaluated 594 orthodontic Brazilians patients. The presence or absence of TA was determined by analysis of panoramic radiography. The patients were classified according to their skeletal malocclusion and facial growth pattern by means of digital cephalometric analysis. Genomic DNA was extracted from squamous epithelial cells of buccal mucosa and genetic polymorphisms in MSX1 (rs1042484), PAX9 (rs8004560), TGF-α (rs2902345), FGF3 (rs1893047), FGF10 (rs900379), and FGF13 (rs12838463, rs5931572, and rs5974804) were genotyped by polymerase chain reaction using TaqMan chemistry and end-point analysis. RESULTS: Genotypes (p = 0.038) and allele (p = 0.037) distributions for the FGF3 rs1893047 were significantly different according to the skeletal malocclusion. Carrying at least one G allele increased in more than two times the chance of presenting skeletal class III malocclusion (OR = 2.21, CI 95% = 1.14-4.32; p = 0.017). There was no association between another skeletal craniofacial pattern and some polymorphism assessed in the present study. CONCLUSION: Our results suggest that the genetic polymorphism rs1893047 in FGF3 might contribute to variations in the craniofacial sagittal pattern.

Bioactive Compounds from Seaweed with Anti-Leukemic Activity: A Mini-Review on Carotenoids and Phlorotannins.

Chronic Myeloid Leukemia (CML) represents 15-20% of all new cases of leukemia and is characterized by an uncontrolled proliferation of abnormal myeloid cells. Currently, the first-line of treatment involves Tyrosine Kinase Inhibitors (TKIs), which specifically inhibits the activity of the fusion protein BCR-ABL. However, resistance, mainly due to mutations, can occur. In the attempt to find more effective and less toxic therapies, several approaches are taken into consideration such as research of new anti-leukemic drugs and "combination chemotherapy" where different drugs that act by different mechanisms are used. Here, we reviewed the molecular mechanisms of CML, the main mechanisms of drug resistance and current strategies to enhance the therapeutic effect of TKIs in CML. Despite major advances in CML treatment, new, more potent anticancer drugs and with fewer side effects are needed. Marine organisms, and particularly seaweed, have a high diversity of bioactive compounds with some of them having anticancer activity in several in vitro and in vivo models. The state-of-art suggests that their use during cancer treatment may improve the outcome. We reviewed here the yet few data supporting anti-leukemic activity of some carotenoids and phlorotannins in some leukemia models. Also, strategies to overcome drug resistance are discussed, particularly the combination of conventional drugs with natural compounds.

Can marine-derived fungus Neosartorya siamensis KUFA 0017 extract and its secondary metabolites enhance antitumor activity of doxorubicin? An in vitro survey unveils interactions against lung cancer cells.

Doxorubicin (Dox) is one of the most successful anticancer drugs in use. However, chemoresistance is one of the main limitations that patients face. Therefore, development of new strategies to improve the efficacy of Dox is needed. Marine-derived fungi are especially promising sources of new anticancer compounds. In this work, antitumor activity of crude ethyl extract of the cultures of the marine-derived fungus Neosartorya siamensis KUFA 0017 (NS), combined with Dox, was evaluated in six cancer cell lines. To evaluate possible mechanisms involved in the eventual improvement of Dox's cytotoxicity by NS extract, effects on DNA damage, cell death, ultrastructural modifications, and intracellular accumulation of Dox were assessed. The NS extract demonstrated a significant enhancement of Dox's cytotoxic activity in A549 cells, inducing DNA damage, cell death, and intracellular accumulation of Dox. Additionally, the cytotoxic effect of eight compounds, isolated from this extract, that is, 2,4-dihydroxy-3-methylacetophenone-(C1), nortryptoquivaline-(C2), chevalone C-(C3), tryptoquivaline H-(C4), fiscalin A-(C5), epi-fiscalin-C (C6), epi-neofiscalin A-(C7), and epi-fiscalin A-(C8), alone and combined with Dox was also evaluated in lung cancer cells. The cytotoxic effect of Dox was potentiated by all the isolated compounds (except C1) in A549 cells. Therefore, we concluded that NS extract potentiated cytotoxicity by inhibiting cell proliferation, increasing intracellular accumulation of Dox, and inducing cell death (possibly by an autophagic process). The isolated compounds also enhanced the activity of Dox, supporting the potential of this sort of combination. These data call for further studies to characterize drug interactions and underlying mechanisms.

Clinical orofacial and myofunctional manifestations in an adolescent with Noonan Syndrome: a case report / Manifestações clínicas e miofuncionais orofaciais em adolescente com a Síndrome de Noonan: relato de caso

ABSTRACT Noonan syndrome is an autosomal dominant genetic disease with different manifestations, including Speech, Language and Hearing Sciences ones. The authors describe the orofacial and myofunctional manifestations of an adolescent diagnosed with Noonan syndrome, by consulting the Speech, Language and Hearing Sciences record of a 17-year-old male patient, who underwent screening and speech therapy evaluation with a confirmed genetic diagnosis of Noonan syndrome. The results were qualitatively analyzed. The patient had a long facial type, with a disproportion between the lower and middle thirds of the face, ogival palate, and Mallampati class IV. A deficit in mobility and sensitivity of phonoarticulatory organs was also identified, absence of pathological oral and gag reflexes, decreased lip tone and tongue tension, increased speed chewing and inefficient grinding, functional swallowing for assessed consistencies, mild verbal and nonverbal apraxia, and moderate dysarthria. The results confirmed the presence of alterations in the speech-language organs, proving the relevance of the Speech, Language and Hearing Sciences evaluation in Noonan Syndrome, to allow adequate follow-up and treatment.

RESUMO A síndrome de Noonan é uma doença genética autossômica dominante com diferentes manifestações, incluindo as fonoaudiológicas. Os autores descrevem as manifestações miofuncionais orofaciais de um adolescente com diagnóstico de síndrome de Noonan, por meio de consulta ao prontuário fonoaudiológico de um paciente do sexo masculino, dezessete anos, que foi submetido à triagem e avaliação fonoaudiológicas com diagnóstico genético confirmado de síndrome de Noonan. Os resultados foram analisados qualitativamente. O paciente apresentou tipologia facial longa, com desproporção entre os terços inferior e médio da face, palato ogival e Mallampati classe IV. Também foi identificado déficit na mobilidade e sensibilidade dos órgãos fonoarticulatórios, ausência de reflexos orais patológicos e de gag, diminuição de tônus de lábios e de tensão de língua, mastigação com velocidade aumentada e trituração ineficiente, deglutição funcional para as consistências avaliadas, apraxia verbal e não verbal leve, disartria moderada. Os resultados confirmam a presença de alterações morfofuncionais relacionadas aos órgãos fonoarticulatórios, comprovando a relevância da avaliação fonoaudiológica na Síndrome de Noonan, de forma a possibilitar o acompanhamento e tratamento adequados.

Cytotoxic and Antiproliferative Effects of Preussin, a Hydroxypyrrolidine Derivative from the Marine Sponge-Associated Fungus Aspergillus candidus KUFA 0062, in a Panel of Breast Cancer Cell Lines and Using 2D and 3D Cultures.

Preussin, a hydroxyl pyrrolidine derivative isolated from the marine sponge-associated fungus Aspergillus candidus KUFA 0062, displayed anticancer effects in some cancer cell lines, including MCF7. Preussin was investigated for its cytotoxic and antiproliferative effects in breast cancer cell lines (MCF7, SKBR3, and MDA-MB-231), representatives of major breast cancers subtypes, and in a non-tumor cell line (MCF12A). Preussin was first tested in 2D (monolayer), and then in 3D (multicellular aggregates), cultures, using a multi-endpoint approach for cytotoxicity (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), resazurin and lactate dehydrogenase (LDH)) and proliferative (5-bromo-2'-deoxyuridine (BrdU)) assays, as well as the analysis of cell morphology by optical/electron microscopy and immunocytochemistry for caspase-3 and ki67. Preussin affected cell viability and proliferation in 2D and 3D cultures in all cell lines tested. The results in the 3D culture showed the same tendency as in the 2D culture, however, cells in the 3D culture were less responsive. The effects were observed at different concentrations of preussin, depending on the cell line and assay method. Morphological study of preussin-exposed cells revealed cell death, which was confirmed by caspase-3 immunostaining. In view of the data, we recommend a multi-endpoint approach, including histological evaluation, in future assays with the tested 3D models. Our data showed cytotoxic and antiproliferative activities of preussin in breast cancer cell lines in 2D and 3D cultures, warranting further studies for its anticancer potential.

Cytotoxic activity of the seaweed compound fucosterol, alone and in combination with 5-fluorouracil, in colon cells using 2D and 3D culturing.

Colorectal cancer (CRC) is one of the most frequently occurring carcinomas which require effective therapies. Fucosterol is a sterol present in marine brown seaweeds with several biological activities. However, the influence of fucosterol in CRC remains to be determined. Thus, the aim of this study was to examine the anticancer activity of fucosterol alone and in combination with 5-fluorouracil (5-Fu) on two human CRC cell lines (HCT116 and HT29) and compared with cytotoxicity in one normal colon fibroblast cell line (CCD-18co) in monolayer (2D). The effect of fucosterol alone or in combination with 5-Fu was further assessed using HT29 multicellular spheroids (3D). Data demonstrated that fucosterol alone or combined with 5-Fu decreased cell viability in HT29 cells in 2D cultures without inducing cytotoxic in normal colon cells. The combination, fucosterol, and 5-Fu, also inhibited cell proliferation, clonogenic potential and cell migration without producing cell death in 2D. In multicellular spheroids, the combination fucosterol plus 5-Fu at the same concentrations used in 2D was not effective demonstrating that under the tested conditions the 3D model was more resistant than the 2D model. Taken together, these findings suggest that fucosterol might be a promising alternative to enhance the cytotoxic and anti-invasive actions of 5-Fu in colon cancer cells without consequent major adverse effects in normal cells. Our results also reinforce the need to include more complex 3D culture models in the initial stages of drug screening.

Tooth agenesis-related GLI2 and GLI3 genes may contribute to craniofacial skeletal morphology in humans.

OBJECTIVE: The present cross-sectional, multi-centre, genetic study aimed to determine, whether single nucleotide polymorphisms (SNPs) in tooth agenesis (TA)-associated GLI2 and GLI3 genes contribute to the development of craniofacial skeletal morphology in humans. DESIGN: Orthodontic patients from an ethnically heterogeneous population were selected for the present study (n = 594). The presence or absence of TA was determined by analysis of panoramic radiography and dental records. The subjects were classified according to their skeletal malocclusion and facial growth pattern by means of digital cephalometric analysis. Genomic DNA was extracted from squamous epithelial cells of the buccal mucosa and SNPs in GLI2 (rs3738880, rs2278741) and GLI3 (rs929387, rs846266) were analysed by polymerase chain reaction using TaqMan chemistry and end-point analysis. RESULTS: Class II skeletal malocclusion presented a significantly lower frequency of TA (P < 0.05). Subjects without TA showed significantly higher ANB angles (P < 0.05). Genotype and/or allele distributions of the SNPs in GLI2 (rs3738880, rs2278741) and GLI3 (rs846266) were associated with the presence of TA (P < 0.05). The SNPs rs3738880, rs2278741 and rs929387 were also associated with some type of skeletal malocclusion (P < 0.05), but not with the facial growth pattern (P > 0.05). The G allele for TA-related GLI2 rs3738880 was strongly linked to the presence of Class III skeletal malocclusion (OR = 2.03; 95% CI = 1.37-3.03; P<3125 × 10-6). GLI2 rs2278741 C allele was overrepresented in individuals without TA, suggesting it as a protective factor for this dental phenotype (OR = 0.43; 95% CI = 0.24-0.78; P<625 × 10-5). CONCLUSION: The present study suggests that SNPs in TA-associated GLI2 and GLI3 genes may also play a role in the development of skeletal malocclusions. rs3738880 and rs2278741 in GLI2 seems to contribute to the genetic background for skeletal Class III and TA, respectively. TA could be an additional predictor of craniofacial morphology in some cases. Further research replicating the reported associations should be performed.

Genetic variants in ACTN3 and MYO1H are associated with sagittal and vertical craniofacial skeletal patterns.

OBJECTIVE: This study aimed to evaluate the association of genetic variants inACTN3 and MYO1H with craniofacial skeletal patterns in Brazilians. DESIGN: This cross-sectional study enrolled orthodontic and orthognathic patients selected from 4 regions of Brazil. Lateral cephalograms were used and digital cephalometric tracings and analyzes were performed for craniofacial phenotype determination. Participants were classified according to the skeletal malocclusion in Class I, II or III; and according to the facial type in Mesofacial, Dolichofacial or Brachyfacial. Genomic DNA was extracted from saliva samples containing exfoliated buccal epithelial cells and analyzed for genetic variants inACTN3 (rs678397 and rs1815739) and MYO1H (rs10850110) by real-time PCR. Chi-square or Fisher's exact tests were used for statistical analysis (α = 5%). RESULTS: A total of 646 patients were included in the present study. There was statistically significant association of the genotypes and/or alleles distributions with the skeletal malocclusion (sagittal skeletal pattern) and facial type (vertical pattern) for the variants assessed inACTN3 (P < 0.05). For the genetic variant evaluated in MYO1H, there was statistically significant difference between the genotypes frequencies for skeletal Class I and Class II (P < 0.05). The reported associations were different depending on the region evaluated. CONCLUSION: ACTN3 and MYO1H are associated with sagittal and vertical craniofacial skeletal patterns in Brazilian populations.