Revealing novel biomarkers for diagnosing chronic kidney disease in pediatric patients.

Pediatric chronic kidney disease (CKD) is a clinical condition characterized by progressive renal function deterioration. CKD diagnosis is based on glomerular filtration rate, but its reliability is limited, especially at the early stages. New potential biomarkers (citrulline (CIT), symmetric dimethylarginine (SDMA), S-adenosylmethionine (SAM), n-butyrylcarnitine (nC4), cis-4-decenoylcarnitine, sphingosine-1-phosphate and bilirubin) in addition to creatinine (CNN) have been proposed for early diagnosis. To verify the clinical value of these biomarkers we performed a comprehensive targeted metabolomics study on a representative cohort of CKD and healthy pediatric patients. Sixty-seven children with CKD and forty-five healthy children have been enrolled in the study. Targeted metabolomics based on liquid chromatography-triple quadrupole mass spectrometry has been used for serum and plasma samples analysis. Univariate data analysis showed statistically significant differences (p < 0.05) in the concentration of CNN, CIT, SDMA, and nC4 among healthy and CKD pediatric patients. The predictive ability of the proposed biomarkers was also confirmed through specificity and sensitivity expressed in Receiver Operating Characteristic curves (AUC = 0.909). In the group of early CKD pediatric patients, AUC of 0.831 was obtained, improving the diagnostic reliability of CNN alone. Moreover, the models built on combined CIT, nC4, SDMA, and CNN allowed to distinguish CKD patients from healthy control regardless of blood matrix type (serum or plasma). Our data demonstrate potential biomarkers in the diagnosis of early CKD stages.

Avaliação da colpocitologia oncótica vaginal em reeducandas no Sistema Penitenciário do CPP do Butantan / Assessment of vaginal oncotic colpocytology in inmates at the CPP Butantan Penitentiary System

Introdução: O Brasil ocupa o sexto lugar entre os países mais populosos do mundo com 214 milhões de habitantes, dos quais 51,1% são mulheres. O câncer de colo representa uma das principais causas de morte feminina e inúmeros são os fatores de risco envolvidos na sua eclosão como, baixa escolaridade, raça negra, múltiplos parceiros sexuais e o mais importante, a infecção pelo vírus do HPV. As detentas exibem perfil altamente vulnerável para desenvolver o câncer de colo uterino Objetivos: caracterizar os achados colpocitológicos obtidos no exame de Papanicolaou em mulheres privadas de liberdade, do Centro de Progressão Penitenciária do Butantan (CPP do Butantan), bem como possíveis associações com características clínicas/epidemiológicas, exames colposcópicos/biópsias, sorologia para HIV e desfechos sobre colo uterino. Métodos: Em estudo retrospectivo foram analisados os prontuários e os resultados de 894 colpocitologias oncológicas realizadas nas reeducandas, a partir de mutirões no Centro Assistencial Cruz de Malta (CACM), em parceria com o CPP do Butantan. Métodos estatísticos: foram utilizados medidas-resumo, gráficos de barras, boxplot e para as análises inferenciais visando confirmar ou refutar as evidências encontradas na análise descritiva foram empregados o Qui-Quadrado de Pearson, Extensão do teste Exato de Fisher e Kruskal-Wallis. Resultados: O exame ginecológico mostrou 4% de lesões verrucosas anogenitais, a colpocitologia oncológica detectou 13,5% de alterações e a biópsia guiada pela colposcopia 78,5%. As bissexuais apresentaram maior prevalência de carcinomas e as reeducandas que ficaram mais tempo aguardando a colposcopia tiveram piora no diagnóstico. Conclusões: Reeducandas com lesões verrucosas expressaram maior frequência de LSIL, HIV e biópsias ampliadas do colo uterino. Ademais, entre as reeducandas foram constatadas nítidas falhas na educação e nos programas de prevenção do carcinoma de colo uterino.

Introduction: Brazil ranks sixth among the most populous countries in the world with 214 million inhabitants, of which 51,1% are women. Cervical cancer represents one of the main causes of female mortality, and there are several risk factors involved in its outbreak, such as having a low educational level, belonging to the black racial group, having multiple sexual partners, and most importantly, being infected with the HPV virus. Female Inmates have a highly vulnerable profile for developing cervical cancer. Objectives: To characterize the colpocytological findings obtained in the Pap smears tests in incarcerated women at the Butantan Penitentiary Progression Center (Butantan CPP) as well as possible associations with clinical/epidemiological characteristics, colposcopic/biopsy exams, HIV serology and the outcomes related to the cervix. Methods: A retrospective study which analyzed the medical records and results of 894 oncological colpocytologies conducted through a joint effort as part of a health campaign at Centro Assistencial Cruz de Malta (CACM) in partnership with the Butantan CPP. Statistical Methods: summary measures, bar graphs nad boxplots were used. For the inferential analysis the Pearsons Chi squared test, Fishers exact test extension, and Kruskal-Wallis tests were employed to confirm or refute the evidence found in the description analysis. Results: The gynecological examination showed 4% of anogenital verrucous lesions, the oncological colpocytology exams detected 13,5% of alterations, and the colposcopy guided biopsy showed 78,5% of alterations. Bisexual women had a higher prevalence of carcinomas and inmates who waited longer for the colposcopy test had a worse diagnosis. Conclusions: Inmates with verrucous lesions had a higher frequency of LSIL, HIV and expanded cervical biopsies. Furthermore, clear shortcomings in education, and cervical cancer prevention programs were identified among female inmates.

Função reprodutiva em portadoras de hiperplasia adrenal congênita: revisão narrativa da literatura / Reproductive health of patients with congenital adrenal hyperplasia: a narrative review

A hiperplasia adrenal congênita (HAC) pode cursar com redução da fertilidade na mulher. Entretanto, nos casos em que ocorre gestação, os recém-nascidos das por- tadoras de hiperplasia adrenal congênita exibem risco de hiperandrogenismo, com todas as suas consequências. A presente revisão atualiza o tema, considerando também as necessidades da assistência a essas pacientes. A busca identificou 294 artigos na base de dados MEDLINE/PubMed de 1961 a março/2023, e os resultados mostraram que as portadoras de hiperplasia adrenal congênita exibem significativa redução da fertilidade. Nos casos de interesse de gestação, as portadoras de hiper- plasia adrenal congênita devem fazer um planejamento reprodutivo, envolvendo a fase antenatal, o acompanhamento pré-natal especializado, o parto e o aleitamento.

Congenital adrenal hyperplasia may lead to reduced male and female fertility. Mo- reover, when the pregnancy occurs, the newborns of patients with congenital adrenal hyperplasia are at risk of hyperandrogenism with all its consequences. This review updates the theme and emphasizes assistance needs. The search identified 294 ar- ticles in the MEDLINE/PubMed database from 1961 to March/2023, and the results showed that patients with congenital adrenal hyperplasia truly exhibit a significant reduction in fertility. In cases of interest in pregnancy, patients with congenital adre- nal hyperplasia should carry out reproductive planning, involving the antenatal pha- se, specialized prenatal care, till delivery and breastfeeding.

Overview of SARS-COV-2 infection at the Butantan Penitentiary Progression Center / Panorama da infecção pelo SARS-COV-2 no Centro de Progressão Penitenciária do Butantan

ABSTRACT OBJECTIVE To estimate the prevalence of exposure to the SARS-CoV-2 virus among individuals living in restricted freedom. METHODS A seroprevalence survey was carried out with the population of the female penitentiary of the Centro de Progressão Penitenciária (CPP) in Butantan (municipality of São Paulo), between June 24 and August 20, 2020. During this period, according to the Secretariat of Penitentiary Administration (SAP), the positivity of rapid tests among inmates ranged from 65% to 78%. The evaluation method used in the study was the "One Step COVID-19" rapid test (chromatography), from the company Wondfo, also using the RT-PCR method in symptomatic participants to confirm the viral condition. The study population consisted of 879 female inmates and 170 employees of the institution. RESULTS The prevalence of total antibodies (IgG/IgM) against the SARS-CoV-2 virus in the total population of 1049 study participants was 6.1%; among the population of 879 inmates,a prevalence of 5.8% was observed, and among the institution's employees, 7.5%. CONCLUSIONS The prevalence of covid-19 at the Butantan CPP was low, which is due to the implementation of simple prevention measures at the institution, such as the use of masks (with appropriate changes), emphasis on hygiene, hand washing and social distancing, in addition to other strategies, such as suspending inmates' visits from relatives and friends and cutting back on elective medical appointments and outside work.

RESUMO OBJETIVO Estimar a prevalência da exposição ao vírus SARS-CoV-2 entre indivíduos vivendo em restrição de liberdade. MÉTODOS Foi realizado inquérito de soroprevalência com a população da penitenciária feminina do Centro de Progressão Penitenciária (CPP) do Butantan (município de São Paulo), entre 24 de junho e 20 de agosto de 2020. Nesse período, segundo a Secretaria de Administração Penitenciária (SAP), a positividade dos testes rápidos entre detentos variou de 65 a 78%. O método de avaliação utilizado no estudo foi o teste rápido "One Step COVID-19" (cromatografia), da empresa Wondfo, empregando-se também o método RT-PCR em participantes sintomáticos para confirmação do quadro viral. A população do estudo foi constituída por 879 reeducandas e 170 funcionários da instituição. RESULTADOS A prevalência de anticorpos totais (IgG/IgM) contra o vírus SARS-CoV-2 na população total de 1.049 participantes do estudo foi de 6,1%; entre a população de 879 reeducandas foi observada prevalência de 5,8% e entre os servidores da instituição, 7,5%. CONCLUSÃO Houve baixa prevalência de covid-19 no CPP do Butantan, o que se deve à implementação de medidas de prevenção simples na instituição, como o uso de máscaras (com trocas adequadas), ênfase na higiene, lavagem das mãos e distanciamento social, além de outras estratégias, como suspensão de visitas de familiares e amigos das reeducandas, cortes de consultas médicas eletivas e do trabalho externo.

Genome-wide promoter methylation profiling in a cellular model of melanoma progression reveals markers of malignancy and metastasis that predict melanoma survival.

The epigenetic changes associated with melanoma progression to advanced and metastatic stages are still poorly understood. To shed light on the CpG methylation dynamics during melanoma development, we analyzed the methylome profiles of a four-stage cell line model of melanoma progression: non-tumorigenic melanocytes (melan-a), premalignant melanocytes (4C), non-metastatic melanoma cells (4C11-), and metastatic melanoma cells (4C11+). We identified 540 hypo- and 37 hypermethylated gene promoters that together characterized a malignancy signature, and 646 hypo- and 520 hypermethylated promoters that distinguished a metastasis signature. Differentially methylated genes from these signatures were correlated with overall survival using TCGA-SKCM methylation data. Moreover, multivariate Cox analyses with LASSO regularization identified panels of 33 and 31 CpGs, respectively, from the malignancy and metastasis signatures that predicted poor survival. We found a concordant relationship between DNA methylation and transcriptional levels for genes from the malignancy (Pyroxd2 and Ptgfrn) and metastasis (Arnt2, Igfbp4 and Ptprf) signatures, which were both also correlated with melanoma prognosis. Altogether, this study reveals novel CpGs methylation markers associated with malignancy and metastasis that collectively could improve the survival prediction of melanoma patients.

Treatment adherence in tyrosinemia type 1 patients.

BACKGROUND: While therapeutic advances have significantly improved the prognosis of patients with hereditary tyrosinemia type 1 (HT1), adherence to dietary and pharmacological treatments is essential for an optimal clinical outcome. Poor treatment adherence is well documented among patients with chronic diseases, but data from HT1 patients are scarce. This study evaluated pharmacological and dietary adherence in HT1 patients both directly, by quantifying blood levels nitisinone (NTBC) levels and metabolic biomarkers of HT1 [tyrosine (Tyr), phenylalanine (Phe), and succinylacetone]; and indirectly, by analyzing NTBC prescriptions from hospital pharmacies and via clinical interviews including the Haynes-Sackett (or self-compliance) test and the adapted Battle test of patient knowledge of the disease. RESULTS: This observational study analyzed data collected over 4 years from 69 HT1 patients (7 adults and 62 children; age range, 7 months-35 years) who were treated with NTBC and a low-Tyr, low-Phe diet. Adherence to both pharmacological and, in particular, dietary treatment was poor. Annual data showed that NTBC levels were lower than recommended in more than one third of patients, and that initial Tyr levels were high (> 400 µM) in 54.2-64.4% of patients and exceeded 750 µM in 25.8% of them. Remarkably, annual normalization of NTBC levels was observed in 29.4-57.9% of patients for whom serial NTBC determinations were performed. Poor adherence to dietary treatment was more refractory to positive reinforcement: 36.2% of patients in the group who underwent multiple analyses per year maintained high Tyr levels during the entire study period, and, when considering each of the years individually this percentage ranged from 75 to 100% of them. Indirect methods revealed percentages of non-adherent patients of 7.3 and 15.9% (adapted Battle and Haynes tests, respectively). CONCLUSIONS: Despite initially poor adherence to pharmacological and especially dietary treatment among HT1 patients, positive reinforcement at medical consultations resulted in a marked improvement in NTBC levels, indicating the importance of systematic positive reinforcement at medical visits.

Análise da agressividade docente na cena pedagógica: implicações para a formação de professoras(es) / Teachers' aggressiveness analysis at pedagogical scene: implications for teachers' training / Análisis de la agresividad docente en la escena pedagógica: implicaciones para la formación

A partir da teoria psicanalítica laplancheana e winnicottiana da agressividade, objetivou-se analisar a agressividade de uma docente e seus efeitos na cena pedagógica através do estudo de caso de uma professora da Educação Infantil. Numa pesquisa qualitativa, recorrendo à triangulação entre observação, entrevista e grupo focal, tomou-se como unidade de análise a cena pedagógica (definida como o conjunto de interações entre docentes e discentes e dos significados intersubjetivos dessas interações nos vínculos envolvendo esses sujeitos). Constataram-se condutas docentes agressivas na interação com alunos da turma, o que levou à hipótese de que as dificuldades subjetivas da professora em lidar com a própria agressividade interferiam no manejo da agressividade discente. Considerando a subjetividade da docente, a participação da professora em formação docente continuada promovida durante a pesquisa viabilizou a tomada de consciência de novos arranjos relacionais entre a professora e as crianças de sua turma, favorecendo a qualidade do seu manejo.

From Laplanche's and Winnicott's psychoanalytic theories of aggressiveness, it was aimed to analyse the aggressiveness of a teacher and its effects on the pedagogical scene, through a case study about an Early Childhood Education teacher. In a qualitative research, resorting data triangulation between observation, interview and focus group, it was taken, as an analytical unit, the pedagogical scene (defined as the set of interactions between teachers and students, and the intersubjective meanings os these interactions considering the ties involving these subjects). Teacher's aggressive conducts were found on the interactions with her students, leading to the hypotheses: teacher's subjective difficulty in dealing with her own aggressiveness interfered on her management of students' aggressiveness. Considering the teacher's subjectivity, her participation on a teachers' continued qualification, promoted during the research, enabled the awareness of new relational arrangements between her and the children, favouring the quality of her management.

Basándose en la teoría psicoanalítica laplancheana y winnicottiana de la violencia, el objetivo fue analizar la agresividad de una docente y sus efectos en el escenario pedagógico, a través del estudio de caso de una maestra de Educación Infantil. En una investigación cualitativa, utilizando la triangulación entre observación, entrevista y grupo focal, se consideró como unidad de análisis el escenario pedagógico (definido como el conjunto de interacciones entre docentes y estudiantes, y los significados intersubjetivos de estas interacciones en los vínculos que se relacionan con estos sujetos). Se verificaron las conductas de maestros agresivos en la interacción con los estudiantes en la clase, lo que resultó llegar a la hipótesis de que las dificultades subjetivas de la docente para retener su propia violencia interferían en el manejo de la agresividad de los estudiantes. Respecto a la subjetividad del docente, la participación de la docente en la formación continua del profesorado promovida durante la investigación posibilitó la toma de conciencia de nuevos arreglos relacionales entre el docente y los niños de su clase, que favoreció la calidad de su estrategia de retención de la violencia.

Therapeutics of xeroderma pigmentosum: A PRISMA-compliant systematic review.

Xeroderma pigmentosum is a rare hereditary autosomal recessive genodermatosis. At present, there are many treatment options for xeroderma pigmentosum, covering medical/procedural, surgical and combined modalities. However, the quality of these interventions has not been assessed. Our study aimed to perform a systematic review of the literature regarding the treatment of xeroderma pigmentosum. Multiple medical databases were accessed with the Medical Subject Headings terms; "xeroderma pigmentosum," "therapeutics" and "surgical procedures, operative" from January 2000 to April 2019, including articles published in Portuguese, Spanish and English (PROSPERO-CRD42018114858). Two hundred and ninety-eight studies were found in the databases researched, of which, after applying the inclusion criteria, only 33 studies remained. The 33 complete articles were read by three of the authors, having been found: 16 reported medical/procedural and 17 reported surgical treatments. Only one clinical study presented a good level of evidence (EL: 2): a randomized clinical trial using a T4 endonuclease V (T4N5) liposome lotion which reduced the development of skin lesions in patients with xeroderma pigmentosum. Amongst surgical modalities, all studies presented low evidence level (EL: 4). Three illustrative cases are also presented, to emphasize the multiple number of times that surgical modalities may be required in these patients. The therapeutic modalities, both clinical and surgical, for xeroderma pigmentosum presented a low level of scientific evidence which did not allow meta-analysis. More therapeutic studies, both clinical and surgical, with better scientific evidence are needed.

Skin field cancerisation: A systematic review of the literature regarding its treatment.

INTRODUCTION: Skin neoplasms are the most frequent malignant lesions, increasing patient's morbidity when associated with skin field cancerisation. There is a need to understand the current therapies, both clinical and surgical. METHODS: A systematic review was performed according to the PRISMA guideline, registered in PROSPERO: CRD42018114826, including studies from 2012 to 2019. RESULTS: Seven hundred and eighty-two studies were found, of which 21 were included. Of these, 8 primary studies were randomised controlled trials: fractional CO2 laser-assisted photodynamic therapy (PDT) vs. PDT (no significance), daylight PDT vs. PDT (no significance, daylight PDT had less adverse effects), trichloroacetic acid peel vs. 5-aminolaevulinic acid PDT (clinical improvement of aminolaevulinic acid PDT), 5-Fluorouracil 0.5%/Salicylic Acid 10% vs. vehicle (clinical improvement of 5-Fluorouracil 0.5%/Salicylic Acid 10%), photolyase vs. sun filters (no significance), sunscreens vs. sunscreens plus DNA repair enzymes (DNA Repair Enzymes was more effective in reducing field cancerisation). Only one systematic review was included in which there was effectiveness of daylight PDT in the treatment of actinic keratoses. The other 12 included studies had a lower level of evidence including surgical studies. CONCLUSION: Clinical studies are more relevant in the treatment of the field cancerisation. There is a lack of surgical studies.

Caracterización de pacientes con osteoporosis tratadas con Vitamina D 100. 000 UI mensualmente / Characterization of patients with osteoporosis treated with Vitamin D 100,000 IU monthly

Introducción: La vitamina D en la piel tras la exposición solar se constituye en precursor y agente anabólico óseo que esti- mula el transporte activo de calcio a través de la mucosa intestinal. La Sociedad Europea de Aspectos Clínicos y Económicos de la osteoporosis y osteoartritis, recomienda que pacientes postmenopáusicas con niveles de 25 (OH) D menores de 50 nmol/L reciban suplementación entre 800 y 1000 UI diarias de vitamina D. Objetivo: Determinar en mujeres con osteoporosis el cambio porcentual de 25 (OH) D en sangre, con la administración de 100.000 UI. de vitamina D cápsulas una vez al mes, así como seguridad y grado de satisfacción con el tratamiento. Sujetos y métodos: Estudio observacional, descriptivo, longitudinal, en el que se incluyeron 44 mujeres que recibieron 100.000 UI de vitamina D una vez al mes por tres meses. Se realizó control de laboratorio pre y post-tratamiento a una sub- muestra no probabilística de 10 pacientes. Resultados: El 70% de casos refirió no tener comorbilidades. El valor inicial de vitamina D en la sub-muestra fue 23,5±10,1nmol/l; al final el promedio fue 27,2±9,6 nmol/l. Post-tratamiento los niveles de vitamina D aumentaron un 20% en más del 50% de casos. El 93% de casos no refirieron eventos adversos. Los eventos adversos reportados fueron gastro-intestinales, eventos ósteo-articulares y cefalea. La mayoría de casos reportaron encontrarse satisfechos con el tratamiento. Conclusión: El tratamiento fue muy bien tolerado, la mayoría de casos refirieron estar satisfechos con el tratamiento. Se observaron incrementos porcentuales significativos de 25 (OH) D en sangre luego de 12 semanas de tratamiento. Palabras clave: Vitamina D, osteoporosis, caracterización.

"Introduction: Vitamin D in the skin after sun exposure constitutes precursor and bone anabolic agent that stimulates the active transport of calcium through the intestinal mucosa. The European Society for Clinical and Economic Aspects of Os- teoporosis and Osteoarthritis, recommends that postmenopausal patients with 25 (OH) D levels less than 50 nmol / L receive supplementation between 800 and 1000 IU daily of vitamin D. Objective: Determine in women with osteoporosis the percentage change of 25 (OH) vitamin D in blood, with the adminis-tration of 100,000 IU of vitamin D caps once a month, as well as safety and degree of satisfaction with the treatment. Subjects and methods: Observational, descriptive and longitudinal study, which included 44 women who received 100,000 IU of vitamin D once a month for three months. Pre and Post-treatment laboratory control was performed on a non-proba- bilistic subsample of 10 patients. Results: The 70% of cases reported not having comorbidities. The initial value of vitamin D was 23.5 ± 10.1 nmol/l at the end the average was 27.2 ± 9.6 nmol/l in the subsample. Post-treatment increased Vit D. levels 20.4% in more than 50% of cases, 93% of cases did not report adverse events. The adverse events reported were gastro-intestinal, osteo-articular events and headache. The majority of cases reported being satisfied with the treatment. Conclusion: Treatment was very well tolerated, the majority of cases reported being satisfied with the treatment. Significant percentage increases of 25 (OH) D were observed in blood after 12 weeks of treatment. Key words: Vitamin D, osteoporosis, characterization."

Usefulness of urinary glycosaminoglycans assay for a mucopolysaccharidosis-specific screening.

BACKGROUND: Mucopolysaccharidoses (MPS), a group of inherited metabolic disorders characterized by the accumulation of glycosaminoglycans, can be diagnosed early through newborn screening programs. Establishing newborn screening in Morocco is a challenging task for multiple economic and social reasons. Screening in a Moroccan population using 1,9-dimethylmethylene blue urinary glycosaminoglycan (GAG) assays may allow for an earlier diagnosis of MPS. We studied the feasibility of implementing screening in Moroccan children as an alternative to national newborn screening. We determined the reference ranges for GAGs in the Moroccan population, their stability during transport, the effectiveness of this test as a screening procedure for MPS in patients, and its use as a screening test for MPS in the Imssouane region, where the rate of consanguineous marriage is 38%. METHODS: Using dimethylmethylene blue assays, urine samples of 47 MPS patients were analyzed, together with urine samples from healthy controls (n = 368, age ranging from 1 month to 25 years), and from Imssouane region children (n = 350, age ranging from 6 months to 24 month). Precision, linearity, recovery, limits, and stability were tested. RESULTS: Urinary GAGs reference values are age and ethnicity dependent. The validation parameters established displayed great precision and accuracy leading to recoveries according to internationally accepted values for bioanalytical methods. Urinary GAGs were stable for a maximum of 7 weeks at 40 °C. Screening of Imssouane children resulted in the detection of a 6-month-old child, diagnosed with MPS I. CONCLUSIONS: Our results demonstrate the usefulness of quantifying glycosaminoglycans for early screening of MPS.

Non-alcoholic fatty liver in hereditary fructose intolerance.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is characterized by fat accumulation affecting >5% of the liver volume that is not explained by alcohol abuse. It is known that fructose gives rise to NAFLD and it has been recently described that the ingestion of fructose in low amounts in aldolase B deficient mice is associated with the development of fatty liver. Therefore, it is reasonable that patients with HFI (Hereditary Fructose Intolerance) present fatty liver at diagnosis, but its prevalence in patients treated and with adequate follow-up is not well documented in the literature. The aim of this study is to analyze the association between HFI and NAFLD in treated patients. METHODS: A cross-sectional observational study was conducted. The population comprised 16 genetically diagnosed HFI patients aged from 3 years to 48 and in dietary treatment of fructose, sorbitol and sacarose exclusion at least for two years. Blood samples were obtained for analytical studies and anthropometric measurements of each patient were performed. RESULTS: Patients presented a Body Mass Index (BMI) of 17.9 ± 2.9 kg/m2. The HOMA index and Quick index were in normal range for our population. The S-adenosyl-methionine (SAM)/S-adenosyl-l-homocysteine (SAH) ratio was increased in the patients in whom this analysis was performed. By imaging techniques it was observed that 9 of the 16 patients presented fatty liver (7 by hepatic MRI). Of these 9 patients, only 3 presented hepatomegaly. 7 of 9 patients affected by the c.448G > C mutation had fatty infiltration, of which three of them presented in addition hepatomegaly. CONCLUSIONS: There is a high prevalence of fatty liver in HFI patients and it is not related to obesity and insulin resistance. The diagnosis of fatty liver in HFI patients and, above all, the identification of new therapeutic approaches, can positively impact the quality of life of these patients.

Large miRNA survival analysis reveals a prognostic four-biomarker signature for triple negative breast cancer.

Triple negative breast cancer (TNBC) is currently the only major breast tumor subtype without effective targeted therapy and, as a consequence, usually presents a poor outcome. Due to its more aggressive phenotype, there is an urgent clinical need to identify novel biomarkers that discriminate individuals with poor prognosis. We hypothesize that miRNAs can be used to this end because they are involved in the initiation and progression of tumors by altering the expression of their target genes. To identify a prognostic biomarker in TNBC, we analyzed the miRNA expression of a cohort composed of 185 patients diagnosed with TNBC using penalized Cox regression models. We identified a four-biomarker signature based on miR-221, miR-1305, miR-4708, and RMDN2 expression levels that allowed for the subdivision of TNBC into high- or low-risk groups (Hazard Ratio - HR = 0.32; 95% Confidence Interval - CI = 0.11-0.91; p = 0.03) and are also statistically associated with survival outcome in subgroups of postmenopausal status (HR = 0.19; 95% CI = 0.04-0.90; p= 0.016), node negative status (HR = 0.12; 95% CI = 0.01-1.04; p = 0.026), and tumors larger than 2cm (HR = 0.21; 95% CI = 0.05-0.81; p = 0.021). This four-biomarker signature was significantly associated with TNBC as an independent prognostic factor for survival.

Gene expression and promoter methylation of angiogenic and lymphangiogenic factors as prognostic markers in melanoma.

The high mortality rate of melanoma is broadly associated with its metastatic potential. Tumor cell dissemination is strictly dependent on vascularization; therefore, angiogenesis and lymphangiogenesis play an essential role in metastasis. Hence, a better understanding of the players of tumor vascularization and establishing them as new molecular biomarkers might help to overcome the poor prognosis of melanoma patients. Here, we further characterized a linear murine model of melanoma progression and showed that the aggressiveness of melanoma cells is closely associated with high expression of angiogenic factors, such as Vegfc, Angpt2, and Six1, and that blockade of the vascular endothelial growth factor pathway by the inhibitor axitinib abrogates their tumorigenic potential in vitro and in the in vivo chicken chorioallantoic membrane assay. Furthermore, analysis of The Cancer Genome Atlas data revealed that the expression of the angiogenic factor ANGPT2 (P-value = 0.044) and the lymphangiogenic receptor VEGFR-3 (P-value = 0.002) were independent prognostic factors of overall survival in melanoma patients. Enhanced reduced representation bisulfite sequencing-based methylome profiling revealed for the first time a link between abnormal VEGFC, ANGPT2, and SIX1 gene expression and promoter hypomethylation in melanoma cells. In patients, VEGFC (P-value = 0.031), ANGPT2 (P-value < 0.001), and SIX1 (P-value = 0.009) promoter hypomethylation were independent prognostic factors of shorter overall survival. Hence, our data suggest that these angio- and lymphangiogenesis factors are potential biomarkers of melanoma prognosis. Moreover, these findings strongly support the applicability of our melanoma progression model to unravel new biomarkers for this aggressive human disease.

CHD7 promotes glioblastoma cell motility and invasiveness through transcriptional modulation of an invasion signature.

Chromatin remodeler proteins exert an important function in promoting dynamic modifications in the chromatin architecture, performing a central role in regulating gene transcription. Deregulation of these molecular machines may lead to striking perturbations in normal cell function. The CHD7 gene is a member of the chromodomain helicase DNA-binding family and, when mutated, has been shown to be the cause of the CHARGE syndrome, a severe developmental human disorder. Moreover, CHD7 has been described to be essential for neural stem cells and it is also highly expressed or mutated in a number of human cancers. However, its potential role in glioblastoma has not yet been tested. Here, we show that CHD7 is up-regulated in human glioma tissues and we demonstrate that CHD7 knockout (KO) in LN-229 glioblastoma cells suppresses anchorage-independent growth and spheroid invasion in vitro. Additionally, CHD7 KO impairs tumor growth and increases overall survival in an orthotopic mouse xenograft model. Conversely, ectopic overexpression of CHD7 in LN-428 and A172 glioblastoma cell lines increases cell motility and invasiveness in vitro and promotes LN-428 tumor growth in vivo. Finally, RNA-seq analysis revealed that CHD7 modulates a specific transcriptional signature of invasion-related target genes. Further studies should explore clinical-translational implications for glioblastoma treatment.

Effects of the amino acid derivatives, ß-hydroxy-ß-methylbutyrate, taurine, and N-methyltyramine, on triacylglycerol breakdown in fat cells.

Various amino acid (AA) metabolites are used as supplements to facilitate metabolic control and enhance responsiveness of insulin-sensitive tissues. ß-hydroxy-ß-methylbutyrate (HMB) is a leucine metabolite proposed to prevent muscle wasting and to mitigate insulin resistance. Taurine, commonly added to energizing drinks, is a metabolite of methionine and cysteine present in bile juice, and proposed to be involved in lipid digestion and to be pro-lipolytic in adipocytes. N-methyltyramine (NMT) is a phenylalanine metabolite found in orange juices at 0.1-3 ppm while its effects on lipid mobilization remain controversial. Here, the putative lipolytic effects of these AA metabolites were studied and it was tested whether they could enhance insulin antilipolytic response in adipocytes. Release of glycerol and non-esterified fatty acids (NEFAs) was measured after a 2-h incubation of adipocytes obtained from control and diet-induced obese mice or from obese patients. In mouse, none of the tested AA derivatives was lipolytic from 1 µM to 1 mM. These compounds did not improve insulin antilipolytic effect or isoprenaline lipolytic action, except for 1 mM NMT that impaired triacylglycerol breakdown in obese mice. In human adipocytes, HMB and taurine were not lipolytic, while NMT weakly activated glycerol and NEFA release at 1 mM. However, 100 µM NMT impaired isoprenaline-stimulated lipolysis in a manner that was hardly added to insulin antilipolytic effect. Since none of these AA derivatives acutely helped or replaced insulin antilipolytic effect in adipocytes, the present in vitro observations do not support their proposed insulin-sensitizing properties. Moreover, NMT, HMB, and taurine were not notably lipolytic.

The Dietary Antioxidant Piceatannol Inhibits Adipogenesis of Human Adipose Mesenchymal Stem Cells and Limits Glucose Transport and Lipogenic Activities in Adipocytes.

Phenolic compounds are among the most investigated herbal remedies, as is especially the case for resveratrol. Many reports have shown its anti-aging properties and the ability to reduce obesity and diabetes induced by high-fat diet in mice. However, such beneficial effects hardly translate from animal models to humans. The scientific community has therefore tested whether other plant phenolic compounds may surpass the effects of resveratrol. In this regard, it has been reported that piceatannol reproduces in rodents the anti-obesity actions of its parent polyphenol. However, the capacity of piceatannol to inhibit adipocyte differentiation in humans has not been characterized so far. Here, we investigated whether piceatannol was antiadipogenic and antilipogenic in human preadipocytes. Human mesenchymal stem cells (hMSC), isolated from adipose tissues of lean and obese individuals, were differentiated into mature adipocytes with or without piceatannol, and their functions were explored. Fifty µM of piceatannol deeply limited synthesis/accumulation of lipids in both murine and hMSC-derived adipocytes. Interestingly, this phenomenon occurred irrespective of being added at the earlier or later stages of adipocyte differentiation. Moreover, piceatannol lowered glucose transport into adipocytes and decreased the expression of key elements of the lipogenic pathway (PPARγ, FAS, and GLUT4). Thus, the confirmation of the antiadipogenic properties of piceatanol in vitro warrants the realization of clinical studies for the application of this compound in the treatment of the metabolic complications associated with obesity.

Assessment of length of maternal cervix between 18 and 24 weeks of gestation in a low-risk brazilian population / Avaliação do comprimento do colo uterino materno entre 18 e 24 semanas de gestação em uma população brasileira de baixo risco

Abstract Purpose To determine cervical biometry in pregnant women between 18 and 24 weeks of gestation and the ideal mode of measurement of cervical length in cases of curved and straight cervical morphology. Methods The uterine cervices of 752 low-risk pregnant women were assessed using transvaginal ultrasound in a prospective cross-sectional study. In women with straight uterine cervices, cervical biometry was performed in a continuous manner. In women with curved uterine cervices, the biometry was performed using both the continuous and segmented techniques (in segments joining the cervical os). Polynomial regression models were created to assess the correlation between the cervical length and gestational age. The paired Student t-test was used to comparemeasuring techniques. Results The cervical biometry results did not vary significantly with the gestational age and were best represented by linear regression (R2 = 0.0075 with the continuous technique, and R2 = 0.0017 with the segmented technique). Up to the 21st week of gestation, there was a predominance of curved uterine cervix morphology (58.9%), whereas the straight morphology predominated after this gestational age (54.2%). There was a significant difference between the continuous and the segmented measuring methods in all the assessed gestational ages (p < 0.001). Conclusion Cervical biometry in pregnant women between 18 and 24 weeks was represented by a linear regression, independently of the measuring mode. The ideal measuring technique was the transvaginal ultrasound performed at a gestational age 21 weeks.

Resumo Objetivo Determinar a biometria cervical em gestantes entre a 18ª e 24ª semanas, e ainda a forma ideal de mensuração do comprimento do colo uterino em casos de morfologias curva e reta. Métodos Foram realizadas avaliações ultrassonográficas via vaginal dos colos uterinos de 752 gestantes de baixo risco em um estudo prospectivo transversal. Nos colos uterinos retos a biometria cervical foi feita de forma contínua, enquanto nos colos uterinos curvos, a biometria foi realizada de duas formas, contínua e fracionada (em segmentos unindo os orifícios do colo). Para avaliar a correlação entre o comprimento do colo uterino e a idade gestacional, foram criados modelos de regressão polinomial. Para se comparar a técnicas de medida do colo uterino, utilizou-se o teste t-Student pareado. Resultados A biometria do colo uterino não variou de forma significativa com a idade gestacional, sendo melhor representada por uma regressão linear (R2 = 0,0075 na forma contínua, e R2 = 0,0017 na forma fracionada, respectivamente). Observamos que até a 21ª semana houve predominância de colos curvos (58,9%), porém após esta idade gestacional a morfologia retilínea predominou (54,2%). Houve diferença estatisticamente significativa entre a forma de mensuração contínua e fracionada em todas as idades gestacionais avaliadas (p < 0,001). Conclusão A expressão da biometria cervical em gestantes entre 18 e 24 semanas é praticamente uma reta, independente da forma de mensuração. A forma ideal de medida é por ultrassonografia transvaginal realizada em idade gestacional 21 semanas.

Assessment of Length of Maternal Cervix between 18 and 24 weeks of Gestation in a Low-Risk Brazilian Population.

Purpose To determine cervical biometry in pregnant women between 18 and 24 weeks of gestation and the ideal mode of measurement of cervical length in cases of curved and straight cervical morphology. Methods The uterine cervices of 752 low-risk pregnant women were assessed using transvaginal ultrasound in a prospective cross-sectional study. In women with straight uterine cervices, cervical biometry was performed in a continuous manner. In women with curved uterine cervices, the biometry was performed using both the continuous and segmented techniques (in segments joining the cervical os). Polynomial regression models were created to assess the correlation between the cervical length and gestational age. The paired Student t-test was used to compare measuring techniques. Results The cervical biometry results did not vary significantly with the gestational age and were best represented by linear regression (R2 = 0.0075 with the continuous technique, and R2 = 0.0017 with the segmented technique). Up to the 21st week of gestation, there was a predominance of curved uterine cervix morphology (58.9%), whereas the straight morphology predominated after this gestational age (54.2%). There was a significant difference between the continuous and the segmented measuring methods in all the assessed gestational ages (p < 0.001). Conclusion Cervical biometry in pregnant women between 18 and 24 weeks was represented by a linear regression, independently of the measuring mode. The ideal measuring technique was the transvaginal ultrasound performed at a gestational age ≥21 weeks.

Objetivo Determinar a biometria cervical em gestantes entre a 18ª e 24ª semanas, e ainda a forma ideal de mensuração do comprimento do colo uterino em casos de morfologias curva e reta. Métodos Foram realizadas avaliações ultrassonográficas via vaginal dos colos uterinos de 752 gestantes de baixo risco em um estudo prospectivo transversal. Nos colos uterinos retos a biometria cervical foi feita de forma contínua, enquanto nos colos uterinos curvos, a biometria foi realizada de duas formas, contínua e fracionada (em segmentos unindo os orifícios do colo). Para avaliar a correlação entre o comprimento do colo uterino e a idade gestacional, foram criados modelos de regressão polinomial. Para se comparar a técnicas de medida do colo uterino, utilizou-se o teste t-Student pareado. Resultados A biometria do colo uterino não variou de forma significativa com a idade gestacional, sendo melhor representada por uma regressão linear (R2 = 0,0075 na forma contínua, e R2 = 0,0017 na forma fracionada, respectivamente). Observamos que até a 21ª semana houve predominância de colos curvos (58,9%), porém após esta idade gestacional a morfologia retilínea predominou (54,2%). Houve diferença estatisticamente significativa entre a forma de mensuração contínua e fracionada em todas as idades gestacionais avaliadas (p < 0,001). Conclusão A expressão da biometria cervical em gestantes entre 18 e 24 semanas é praticamente uma reta, independente da forma de mensuração. A forma ideal de medida é por ultrassonografia transvaginal realizada em idade gestacional ≥21 semanas.

No princípio é o ludens: integração do self do bebê através do brincar em creche / Al principio es el ludens: integración del self del bebé a través del jugar en la guardería / In the beginning is ludens: integration of the infant's self through playing at nursery school

Objetiva-se analisar o processo de integração do self do bebê em seu brincar. Trata-se de pesquisa descritiva, qualitativa, etnográfica, cujos dados foram coletados por observação participante em 72 horas ao longo de dois meses, com 12 lactentes envolvidos em recreação em creche pública. Considerando movimento, comunicação e expressão de intencionalidade, as brincadeiras dos bebês foram examinadas para identificar criatividade em ações fluentes, focalizadas e constantes. Esses sujeitos escolheram objetos inanimados para brincar, do que se inferiu sentirem necessidade de manipulação e posse. As ações dos bebês foram interpretadas, segundo a teoria de Winnicott sobre o desenvolvimento psíquico, como evidência de um estado de quase alheamento, levando a concluir que experimentaram o brincar como atividade que concorreu para integrarem seus selves como unidade, integrando-se também a seu entorno ambiental. Logo, o brincar merece mais compreensão e valorização por profissionais da Educação Infantil(AU)

This article analyzes the process of integration of the infant's self when playing. It is a descriptive, qualitative, ethnographic research. Data were collected with 12 nurslings from a Public Nursery School for 72 hours during recreation time. Considering their movements, communication, and expressed intentionality, infants' play was examined in order to identify creativeness in frequent, fluent and focused actions. Those subjects choose inanimate objects to play with, which allows inferring their need for possessing and manipulating objects. According to Winnicott's theory, their actions were interpreted as evidence of as a state of almost complete absent-mindedness, which suggests that they experienced playing as an activity integrating their selves as oneness, also integrating with their environments. Therefore, playing deserves understanding and appreciation by professionals at Nursery Schools(AU)

El texto analiza el proceso de integración del self del bebé en el acto de jugar. Esta es una investigación descriptiva, cualitativa, etnográfica, cuyos datos fueron recolectados mediante observación participativa, durante 72 horas y a lo largo de dos meses, con 12 lactantes en una guardería pública durante la recreación. Considerando movimiento, comunicación y expresión de intencionalidad, los juegos de los bebés fueron examinados con el fin de identificar creatividad en las acciones espontáneas, enfocadas y constantes. Los sujetos escogieron objetos inanimados para jugar, lo que permite inferir la necesidad de posesión y manipulación. Las acciones de los bebés fueron interpretadas según la teoría de Winnicott sobre el desarrollo psíquico, como evidencia de un estado de casi enajenación, lo que lleva a concluir que los bebés experimentaron el jugar como actividad que contribuyó a integrar sus selfs como unidad, integrándose también a su entorno ambiental. Se concluye que el jugar merece más comprensión y valorización por parte de los profesionales de la Educación Infantil(AU)