A New Murine Undernutrition Model Based on Complementary Feeding of Undernourished Children Causes Damage to the Morphofunctional Intestinal Epithelium Barrier.

BACKGROUND: Complementary feeding is critical in establishing undernutrition. However, experimental undernourished diets do not represent the amount of nutrients in the complementary diets of undernourished children. OBJECTIVES: To develop, validate, and evaluate the impact of a new murine model of undernutrition on the intestinal epithelium, based on the complementary diet of undernourished children from 7 countries with low-socioeconomic power belonging to the Malnutrition-Enteric Diseases (MAL-ED) cohort study. METHODS: We used the difference in the percentage of energy, macronutrients, fiber and zinc in the complementary diet of children without undernutrition compared with stunting (height-for-age Z-score < -2) for the MAL-ED diet formulation. Subsequently, C57BL/6 mice were fed a control diet (AIN-93M diet) or MAL-ED diet for 28 d. Weight was measured daily; body composition was measured every 7 d; lactulose:mannitol ratio (LM) and morphometry were evaluated on days 7 and 28; the cotransport test and analysis of intestinal transporters and tight junctions were performed on day 7. RESULTS: The MAL-ED diet presented -8.03% energy, -37.46% protein, -24.20% lipid, -10.83% zinc, +5.93% carbohydrate, and +45.17% fiber compared with the control diet. This diet rapidly reduced weight gain and compromised body growth and energy reserves during the chronic period (P < 0.05). In the intestinal epithelial barrier, this diet caused an increase in the LM (P < 0.001) and reduced (P < 0.001) the villous area associated with an increase in FAT/CD36 in the acute period and increased (P < 0.001) mannitol excretion in the chronic period. CONCLUSIONS: The MAL-ED diet induced undernutrition in mice, resulting in acute damage to the integrity of the intestinal epithelial barrier and a subsequent increase in the intestinal area during the chronic period. This study introduces the first murine model of undernutrition for the complementary feeding phase, based on data from undernourished children in 7 different countries.

Cytokines, chemokines, and cells growth factors in patients with mild to moderate SARS-CoV-2 infection: A case-control study.

Several biomarkers have been evaluated as predictors of severity or in directing the treatment of COVID-19, however there are no conclusive results. In this study, we evaluated serum levels of cytokines, chemokines, and cell growth factors in association with the pathobiology of mild to moderate SARS-CoV-2 infection. Serum levels of SARS-CoV-2 infected patients (n = 113) and flu symptoms individuals negative for SARS-CoV-2 (n = 58), tested by the RT-qPCR test-nasal swab were compared to healthy controls (n = 53). Results showed that the proinflammatory cytokines IL-1ß, MCP-3, TNF-α, and G-CSF were increased in symptomatic patients and the cytokines IL-6 and IL-10 were associated with patients positive for SARS-CoV-2 when compared to healthy controls. Symptoms associated with COVID-19 were fever, anosmia, ageusia, and myalgia. For patients without SARS-CoV-2 infection, their major symptom was sore throat. The pathobiology of mild to moderate SARS-CoV-2 infection was associated with increasing proinflammatory cytokines and a pleiotropic IL-6 and anti-inflammatory IL-10 cytokines compared to healthy controls. Thus, knowledge about the pathophysiology and the involvement of biomarkers in the mild to moderate profile of the disease should be evaluated. Monitoring these biomarkers in patients with mild to moderate disease can help establish adequate treatment and prevention strategies for long-term COVID-19.

[8] and [10]-Gingerol reduces urothelial damage in ifosfamide-induced hemorrhagic cystitis via JAK/STAT/FOXO signaling pathway via IL-10.

Acrolein is the main toxic metabolite of ifosfamide (IFO) that causes urothelial damage by oxidative stress and inflammation. Here, we investigate the molecular mechanism of action of gingerols, Zingiber officinale bioactive molecules, as an alternative treatment for ifosfamide-induced hemorrhagic cystitis. Female Swiss mice were randomly divided into 5 groups: control; IFO; IFO + Mesna; and IFO + [8]- or [10]-gingerol. Mesna (80 mg/kg, i.p.) was given 5 min before, 4 and 8 h after IFO (400mg/kg, i.p.). Gingerols (25 mg/kg, p.o.) were given 1 h before and 4 and 8 h after IFO. Animals were euthanized 12 h after IFO injection. Bladders were submitted to macroscopic and histological evaluation. Oxidative stress and inflammation were assessed by malondialdehyde (MDA) or myeloperoxidase assays, respectively. mRNA gene expression was performed to evaluate mesna and gingerols mechanisms of action. Mesna was able to protect bladder tissue by activating NF-κB and NrF2 pathways. However, we demonstrated that gingerols acted as an antioxidant and anti-inflammatory agent stimulating the expression of IL-10, which intracellularly activates JAK/STAT/FOXO signaling pathway.

Consumption of a multi-deficient diet causes dynamic changes in the intestinal morphofunctional barrier, body composition and impaired physical development in post-weaning mice.

Few studies have focused on nutrient-deficient diets and associated pathobiological dynamics of body composition and intestinal barrier function. This study evaluated the impact of a nutrient-deficient diet on physical development and intestinal morphofunctional barrier in mice. C57BL/6 (21 days of age) mice were fed a Northeastern Brazil regional basic diet (RBD) or a control diet for 21 d. The animals were subjected to bioimpedance analysis, lactulose test, morphometric analysis and quantitative reverse transcription-PCR to evaluate tight junctions and intestinal transporters. RBD feeding significantly reduced weight (P < 0·05) from day 5, weight gain from day 3 and tail length from day 14. The intake of RBD reduced total body water, extracellular fluid, fat mass and fat-free mass from day 7 (P < 0·05). RBD induced changes in the jejunum, with an increase in the villus:crypt ratio on day 7, followed by reduction on days 14 and 21 (P < 0·05). Lactulose:mannitol ratio increased on day 14 (P < 0·05). Changes in intestinal barrier function on day 14 were associated with reductions in claudin-1 and occludin, and on day 21, there was a reduction in the levels of claudin-2 and occludin. SGLT-1 levels decreased on day 21. RBD compromises body composition and physical development with dynamic changes in intestinal barrier morphofunctional. RBD is associated with damage to intestinal permeability, reduced levels of claudin-1 and occludin transcripts and return of bowel function in a chronic period.

Elevated IL-18 predicts poor prognosis in critically ill COVID-19 patients at a Brazilian hospital in 2020-21.

Background: A dysregulated inflammatory response contributes to decline in patients with COVID-19. This cross-sectional study evaluated biomarkers of unvaccinated patients admitted to the intensive care unit of a hospital in Fortaleza, Brazil. Methods: Twenty cytokines were quantified upon hospital admission; clinical and laboratory data were analyzed, as well as sociodemographic data, to search for an association with clinical outcomes, including fatal (n = 40) or recovered cases (n = 38). Results: Fatal cases exhibited significantly higher levels of IL-18 (p = 0.009); deceased patients were older (p = 0.0001), had a lower number of platelets (p = 0.0063) and higher neutrophil-lymphocyte ratio (p = 0.0230) than those who recovered. Conclusion: These findings indicate that IL-18 is a possible marker to predict poor prognosis in critically ill patients with COVID-19.

Using deep learning to predict outcomes of legal appeals better than human experts: A study with data from Brazilian federal courts.

Legal scholars have been trying to predict the outcomes of trials for a long time. In recent years, researchers have been harnessing advancements in machine learning to predict the behavior of natural and social processes. At the same time, the Brazilian judiciary faces a challenging number of new cases every year, which generates the need to improve the throughput of the justice system. Based on those premises, we trained three deep learning architectures, ULMFiT, BERT, and Big Bird, on 612,961 Federal Small Claims Courts appeals within the Brazilian 5th Regional Federal Court to predict their outcomes. We compare the predictive performance of the models to the predictions of 22 highly skilled experts. All models outperform human experts, with the best one achieving a Matthews Correlation Coefficient of 0.3688 compared to 0.1253 from the human experts. Our results demonstrate that natural language processing and machine learning techniques provide a promising approach for predicting legal outcomes. We also release the Brazilian Courts Appeal Dataset for the 5th Regional Federal Court (BrCAD-5), containing data from 765,602 appeals to promote further developments in this area.

Detection of SARS-CoV-2 in different human biofluids using the loop-mediated isothermal amplification assay: A prospective diagnostic study in Fortaleza, Brazil.

We adopted the reverse-transcriptase-loop-mediated isothermal amplification (RT-LAMP) to detect severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) in patient samples. Two primer sets for genes N and Orf1ab were designed to detect SARS-CoV-2, and one primer set was designed to detect the human gene Actin. We collected prospective 138 nasopharyngeal swabs, 70 oropharyngeal swabs, 69 salivae, and 68 mouth saline wash samples from patients suspected to have severe acute respiratory syndrome (SARS) caused by SARS-CoV-2 to test the RT-LAMP in comparison with the gold standard technique reverse-transcription quantitative polymerase chain reaction  (RT-qPCR). The accuracy of diagnosis using both primers, N5 and Orf9, was evaluated. Sensitivity and specificity for diagnosis were 96% (95% confidence interval [CI]: 87-99) and 85% (95% CI: 76-91) in 138 samples, respectively. Accurate diagnosis results were obtained only in nasopharyngeal swabs processed via extraction kit. Accurate and rapid diagnosis could aid coronavirus disease 2019 (COVID-19) pandemic management by identifying, isolating, and treating patients rapidly.

O significado do uso de telas entre adolescentes: causas e consequências / El significado del uso de pantallas entre adolescentes: causas y consecuencias / The signification of the use of screens among adolescents: causes and consequences

RESUMO Objetivo: compreender o significado do uso de telas atribuído pelos adolescentes. Métodos: o presente estudo foi descritivo exploratório, com abordagem qualitativa e referencial teórico-metodológico do interacionismo simbólico. Participaram adolescentes de uma escola pública mineira. Os dados foram coletados através de entrevistas e grupos focais realizados de forma online e analisados conforme a análise temática no período deagosto a dezembro de 2020. Resultados: participaram oito adolescentescom idades entre 14 e 17 anos, que cursavam o ensino médioe relataram que a tela mais usada foi o celular. Os significados atribuídos ao uso de telas estiveram relacionados à possibilidade de interação e praticidade por possibilitar a realização de várias atividades. Houve o reconhecimento que, diante do uso excessivo, é preciso ter momento distante da tela. Após a análise foram desveladas três categorias: 1. Tela é diversidade 2. Tela é interação, 3. É bom parar um pouco. Considerações finais: a pesquisa mostrou que distanciar-se das telas é difícil e que a presença de profissionais da saúde, particularmente relacionados à saúde do adolescente, pode ajudá-los a encontrar alternativas para usar as telas com redução das consequências negativas.

RESUMEN Objetivo: comprender el significado del uso de pantallas asignado por los adolescentes. Métodos: el presente estudio fue descriptivo exploratorio, con abordaje cualitativo y referencial teórico-metodológico del interaccionismo simbólico. Participaron adolescentes de una escuela pública de Minas Gerais-Brasil. Los datos fueron recolectados a través de entrevistas y grupos focales realizados en forma online y analizados conforme el análisis temático en el período de agosto a diciembre de 2020. Resultados: participaron ocho adolescentes con edades entre 14 y 17 años, que cursaban la enseñanza secundaria y relataron que la pantalla más usada fue el celular. Los significados atribuidos al uso de pantallas estuvieron relacionados a la posibilidad de interacción y practicidad por posibilitar la realización de varias actividades. Hubo el reconocimiento de que, ante el uso excesivo, es necesario tener momento alejado de la pantalla. Después del análisis surgieron tres categorías: 1. La pantalla es diversidad; 2. La pantalla es interacción; 3. Es bueno detenerse un poco. Consideraciones finales: la investigación ha demostrado que distanciarse de las pantallas es difícil y que la presencia de profesionales de la salud, particularmente involucrados con la salud del adolescente, puede ayudarles a encontrar alternativas para usar las pantallas con reducción de las consecuencias negativas.

ABSTRACT Objective: to understand the signification of the use of screens attributed by adolescents. Methods: the current study was descriptive and exploratory, with a qualitative approach and theoretical-methodological framework of symbolic interactionism. Adolescents from a public school in Minas Gerais participated in it. Data were collected through interviews and focus groups carried out online and analyzed according to thematic analysis in the period from August to December 2020. Results: it had the participation of eight adolescents aged between 14 and 17 years, who attended high school and reported that the most used screen was the cell phone. The significations attributed to the use of screens were related to the possibility of interaction and practicality for allowing the performance of various activities. There was recognition that, in the face of excessive use, it is necessary to have a moment away from the screen. After the analysis, three categories were revealed: 1. Screen is diversity 2. Screen is interaction, 3. It is good to stop for a while. Final considerations: research has shown that distance from screens is difficult and the presence of health professionals, particularly related to adolescent health, can help them to find alternatives to use screens with reduced negative consequences.

Retinoids delay cell cycle progression and promote differentiation of intestinal epithelial cells exposed to nutrient deprivation.

OBJECTIVE: Vitamin A is commonly recommended as a treatment for diarrhea and undernutrition; however, little is known about the underlying cellular mechanisms. The aim of this study was to investigate the modulation of cell cycle by vitamin A derivatives (retinyl palmitate or retinol) in undernourished intestinal epithelial crypts (IEC-6). METHODS: IEC-6 cells were exposed to nutrient deprivation (no serum and no glutamine) and supplemented with retinyl palmitate or retinol at a range of 2 to 20 µM. Proliferation, apoptosis/necrosis, cell cycle process, and gene transcription were assessed. RESULTS: Nutrient deprivation for 6, 12, 24, or 48 h decreased cell proliferation, and retinyl palmitate further decreased it after 24 and 48 h. Apoptosis rates were reduced by undernourishment and further reduced by retinyl palmitate after 48 h; whereas necrosis rates were unaltered. Undernourishment induced overall cell quiescence, increased percentage of cells in G0/G1 phase and decreased percentage of cells in S phase after 12 h and in G2/M phases at 6, 12, and 24 h after treatment. Both retinoids also showed cell quiescence induction with less cells in G2/M phases after 48 h, whereas only retinol showed significant modulation of G0/G1 and S phases. Both retinoids also increased markers of cell differentiation Fabp and Iap gene transcriptions in about fivefold rates after 42 h. Furthermore, specific gene transcriptions related to MAP kinase signaling pathway regulation of cell differentiation and cell cycle regulation were triggered by retinoids in undernourished IEC-6, with higher levels of expression for Atf2 and C-jun genes. CONCLUSIONS: These findings indicated that both vitamin A derivatives induce further survival mechanisms in undernourished intestinal epithelial crypt cells. These mechanisms include increased cell quiescence, decreased apoptosis, increased cell differentiation, and transcription of genes related to MAP kinase signaling pathway.

MANF is neuroprotective against ethanol-induced neurodegeneration through ameliorating ER stress.

Fetal alcohol spectrum disorders (FASD) are a spectrum of developmental disorders caused by prenatal alcohol exposure. Neuronal loss or neurodegeneration in the central nervous system (CNS) is one of the most devastating features in FASD. It is imperative to delineate the underlying mechanisms to facilitate the treatment of FASD. Endoplasmic reticulum (ER) stress is a hallmark and an underlying mechanism of many neurodegenerative diseases, including ethanol-induced neurodegeneration. Mesencephalic astrocyte-derived neurotrophic factor (MANF) responds to ER stress and has been identified as a protein upregulated in response to ethanol exposure during the brain development. To investigate the role of MANF in ethanol-induced neurodegeneration and its association with ER stress regulation, we established a CNS-specific Manf knockout mouse model and examined the effects of MANF deficiency on ethanol-induced neuronal apoptosis and ER stress using a third-trimester equivalent mouse model. We found MANF deficiency exacerbated ethanol-induced neuronal apoptosis and ER stress and that blocking ER stress abrogated the harmful effects of MANF deficiency on ethanol-induced neuronal apoptosis. Moreover, using an animal model of ER-stress-induced neurodegeneration, we demonstrated that MANF deficiency potentiated tunicamycin (TM)-induced ER stress and neurodegeneration. A whole transcriptome RNA sequencing also supported the functionality of MANF in ER stress modulation and revealed targets that may mediate the ER stress-buffering capacity of MANF. Collectively, these results suggest that MANF is a neurotrophic factor that can protect neurons against ethanol-induced neurodegeneration by ameliorating ER stress.

Predição da adesão ao tratamento e qualidade de vida de pacientes com transtorno bipolar / Predicción de la adherencia al tratamiento y la calidad de vida en pacientes con trastorno bipolar / Prediction of treatment adherence and quality of life in patients with bipolar disorder

Objetivo: Descrever a predição de adesão ao tratamento e a percepção de qualidade de vida de pacientes com transtorno bipolar. Métodos: Estudo transversal realizado com 35 pacientes de um Centro de Atenção Psicossocial III. Foi utilizada uma escala de avaliação da predição da adesão ao tratamento e outra, para avaliar a qualidade de vida dos pacientes, realizou-se análise descritiva dos dados. Resultados: Observou-se maior predição de adesão nos aspectos relacionados à aliança terapêutica com os profissionais (91,4%); dificuldade em seguir o tratamento e efeitos adversos da medicação impactaram negativamente (91,4%). A maioria (77,2%) apresentou média de qualidade de vida regular. A qualidade de vida foi melhor no domínio relações sociais (31,5%) e pior no domínio meio ambiente (25,7%). Conclusão: É necessário construir estratégias de cuidado, pela Enfermagem, que minimizem os desconfortos da medicação e que promovam a reabilitação psicossocial, com o intuito de potencializar a adesão e promover a qualidade de vida dos pacientes.

Objective: To describe the prediction of treatment adherence and quality of life of patients with bipolar disorder. Methods: cross- sectional study with 35 patients from a Psychosocial Care Center III. Scales were used to assess the prediction of treatment adherence and the quality of life of the patients. Results: there was a higher prediction of adherence in aspects related to therapeutic alliance with professionals (91.4%), while difficulty in following treatment and adverse effects of medication caused a negatively impact (91.4%). Most (77.2%) had an average of regular quality of life. Quality of life was better in the social relations domain (31.5%) and worse in the environment domain (25.7%). Conclusion: it is necessary to build nursing care strategies that minimize medication discomfort and promote psychosocial rehabilitation, in order to enhance adherence and promote patients' quality of life.

Objetivo: describir la predeción de la adherencia al tratamiento y la calidad de vida de los pacientes con trastorno bipolar. Métodos: estudio transversal realizado con 35 pacientes de un Centro de Atención Psicosocial III. Se utilizaron escalas para la evaluación de la predicción de la adherencia al tratamiento y otra para evaluar la calidad de vida de los pacientes, se realizó el análisis descriptivo de los datos. Resultados: se observó mayor predicción de adherencia en los aspectos relacionados a la alianza terapéutica con los profesionales (91,4%); dificultad para seguir el tratamiento y efectos adversos de la medicación impactaron negativamente (91,4%). La mayoría (77,2%) presentó promedio de calidad de vida regular. La calidad de vida fue mejor en el dominio de relaciones sociales (31,5%), y peor en el dominio de medio ambiente (25,7%). Conclusión: es necesario desarrollar estrategias de atención de enfermería que minimicen la incomodidad de los medicamentos y promuevan la rehabilitación psicosocial, para mejorar la adherencia y promover la calidad de vida de los pacientes.

Deubiquitinase USP7-mediated MCL-1 up-regulation enhances Arsenic and Benzo(a)pyrene co-exposure-induced Cancer Stem Cell-like property and Tumorigenesis.

Rationale: MCL-1 is up-regulated in cancer and a target for cancer treatment. How MCL-1 is up-regulated and whether MCL-1 up-regulation plays a role in tumorigenic process is not well-known. Arsenic and benzo(a)pyrene (BaP) are well-recognized lung carcinogens and we recently reported that arsenic and BaP co-exposure acts synergistically in inducing cancer stem cell (CSC)-like property and lung tumorigenesis. This study was performed to further investigate the underlying mechanism focusing on the role of MCL-1. Methods: The spheroid formation assay and nude mouse tumorigenesis assay were used to determine the CSC-like property and tumorigenicity of arsenic plus BaP co-exposure-transformed human bronchial epithelial BEAS-2B cells, respectively. Biochemical, pharmacological and genetic approaches were used to manipulate gene expressions, dissect signaling pathways and determine protein-protein interactions. Both loss-of-function and gain-of-function approaches were used to validate the role of MCL-1 in arsenic plus BaP co-exposure-enhanced CSC-like property and tumorigenicity. Results: Arsenic plus BaP co-exposure-transformed cells express significantly higher protein levels of MCL-1 than the passage-matched control, arsenic or BaP exposure alone-transformed cells. Knocking down MCL-1 levels in arsenic plus BaP co-exposure-transformed cells significantly reduced their apoptosis resistance, CSC-like property and tumorigenicity in mice. Mechanistic studies revealed that arsenic plus BaP co-exposure up-regulates MCL-1 protein levels by synergistically activating the PI3K/Akt/mTOR pathway to increase the level of a deubiquitinase USP7, which in turn reduces the level of MCL-1 protein ubiquitination and prevents its subsequent proteasome degradation. Conclusions: The deubiquitinase USP7-mediated MCL-1 up-regulation enhances arsenic and BaP co-exposure-induced CSC-like property and tumorigenesis, providing the first evidence demonstrating that USP7 stabilizes MCL-1 protein during the tumorigenic process.

Integrin α4 up-regulation activates the hedgehog pathway to promote arsenic and benzo[α]pyrene co-exposure-induced cancer stem cell-like property and tumorigenesis.

Arsenic and benzo[α]pyrene (BaP) are widespread carcinogens and important etiology factors for lung cancer. Moreover, arsenic and BaP co-exposure displays a significantly stronger effect in inducing lung cancer than arsenic or BaP exposure alone. This study was performed to investigate the basic mechanism of the synergistic carcinogenic effect of arsenic and BaP co-exposure. It was found that integrin α4 (ITGA4) expression levels are significantly up-regulated and the Hedgehog pathway is highly activated in arsenic plus BaP co-exposure-transformed human bronchial epithelial cells. Either ITGA4 downregulation or Hedgehog pathway inhibition in the co-exposure-transformed cells significantly reduced their cancer stem cell (CSC)-like property and tumorigenicity. It was determined that ITGA4 downregulation leads to the inhibition of the Hedgehog pathway activation, which is achieved by increasing suppressor of fused (SUFU) protein stability through reducing the PI3K/Akt signaling. Moreover, stably overexpressing SUFU in the co-exposure-transformed cells significantly reduces their CSC-like property and tumorigenicity. These findings indicate that ITGA4 up-regulation activates the Hedgehog pathway to enhance the CSC-like property and tumorigenicity of arsenic and BaP co-exposure-transformed cells, offering new mechanistic insight for the synergistic carcinogenic effect of arsenic and BaP co-exposure.

A Positive Feedback Loop Between c-Myc Upregulation, Glycolytic Shift, and Histone Acetylation Enhances Cancer Stem Cell-like Property and Tumorigenicity of Cr(VI)-transformed Cells.

Chronic hexavalent chromium [Cr(VI)] exposure causes lung cancer and other types of cancer; however, the mechanism of Cr(VI) carcinogenesis remains to be clearly defined. Our recent study showed that chronic Cr(VI) exposure upregulates the proto oncogene c-Myc expression, which contributes significantly to Cr(VI)-induced cell transformation, cancer stem cell (CSC)-like property and tumorigenesis. c-Myc is a master regulator of cancer cell abnormal metabolism and accumulating evidence suggests that metabolism dysregulation plays an important role in both cancer development and progression. However, little is known about the role of metabolism dysregulation in Cr(VI) carcinogenesis. This study was performed to investigate the potential role and mechanism of metabolism dysregulation in Cr(VI) carcinogenesis. It was found that Cr(VI)-transformed cells display glycolytic shift, which depends on the upregulation of c-Myc. The glycolytic shift in Cr(VI)-transformed cells led to increased production of acetyl coenzyme A (acetyl-CoA) and elevation of histone acetylation. This, in turn, upregulated the expression of an acetyl-CoA producing key enzyme ATP citrate lyase and c-Myc, forming a positive feedback loop between the upregulation of c-Myc expression, glycolytic shift and increased histone acetylation. It was further determined that glucose depletion not only reverses the glycolytic shift in Cr(VI)-transformed cells, but also significantly reduces their growth, CSC-like property and tumorigenicity. These findings indicate that glycolytic shift plays an important role in maintaining malignant phenotypes of Cr(VI)-transformed cells, suggesting that metabolism dysregulation is critically involved in Cr(VI) carcinogenesis.

Transtorno Afetivo Bipolar: avaliação da satisfação dos pacientes, familiares e profissionais com o tratamento / Bipolar affective disorder: assessment of patient, family and professional satisfaction with treatment

Objetivo: Avaliar as perspectivas da satisfação dos pacientes acometidos por transtorno afetivo bipolar, seus familiares e profissionais da saúde. Metodologia: Estudo transversal com 80 indivíduos de um Centro de Atenção Psicossocial III da região Centro Oeste de Minas Gerais. Foram realizadas entrevistas, usando as Escalas de Avaliação da Satisfação com os Serviços de Saúde Mental. Resultados: Os índices de satisfação apresentaram-se maiores entre pacientes, especialmente no domínio Acolhida e ajuda recebida no serviço [escore 4,66; n = 30 (83,3%)]. Entre os familiares, o maior índice de satisfação foi no domínio Resultados do tratamento [escore 4,66; n = 27 (79,4%)]. O destaque dos profissionais foi na insatisfação, referente ao domínio Condições de trabalho [escore 2,85; n = 7 (70%)]. Conclusão: Constatou-se que os pacientes estão satisfeitos com o serviço e suas perspectivas de satisfação são as maiores, seguidos dos familiares e profissionais. (AU)

Objective: To evaluate the perspectives of satisfaction of patients affected by bipolar affective disorder, their families and health professionals. Methodology: Cross-sectional study with 80 individuals from a Psychosocial Care Center III in the Midwest region of Minas Gerais. Interviews were conducted using the Satisfaction Rating Scales with Mental Health Services. Results: Satisfaction rates were higher among patients, especially in the domain Welcoming and help received at the service [score 4.66; n = 30 (83.3%)]. Among family members, the highest satisfaction rate was in the treatment results domain [score 4.66; n = 27 (79.4%)]. The highlight of the professionals was dissatisfaction, referring to the domain Working conditions [score 2.85; n = 7 (70%)]. Conclusion: It was found that patients are satisfied with the service and their satisfaction prospects are the highest, followed by family members and professionals. (AU)

Objetivo: evaluar las perspectivas de satisfacción de los pacientes afectados por el trastorno afectivo bipolar, sus familias y profesionales de la salud. Metodología: Estudio transversal con 80 personas de un Centro de Atención Psicosocial III en la región del Medio Oeste de Minas Gerais. Las entrevistas se realizaron utilizando las escalas de calificación de satisfacción con los servicios de salud mental. Resultados: las tasas de satisfacción fueron más altas entre los pacientes, especialmente en el dominio de bienvenida y la ayuda recibida en el servicio [puntuación 4.66; n = 30 (83,3%)]. Entre los miembros de la familia, la tasa de satisfacción más alta se encontraba en el dominio de resultados del tratamiento [puntuación 4.66; n = 27 (79,4%)]. Lo más destacado de los profesionales fue la insatisfacción, refiriéndose al dominio Condiciones de trabajo [puntaje 2.85; n = 7 (70%)]. Conclusion: Se encontró que los pacientes están satisfechos con el servicio y sus perspectivas de satisfacción son las más altas, seguidas por los familiares y profesionales. (AU)

Constitutive Activation of NAD-Dependent Sirtuin 3 Plays an Important Role in Tumorigenesis of Chromium(VI)-Transformed Cells.

Chronic exposure of human bronchial epithelial BEAS-2B cells to hexavalent chromium [Cr(VI)] causes malignant cell transformation. Sirtuin-3 (SIRT3) regulates mitochondrial adaptive response to stress, such as metabolic reprogramming and antioxidant defense mechanisms. In Cr(VI)-transformed cells, SIRT3 was upregulated and mitochondrial adenosine triphosphate (ATP) production and proton leak were reduced. Knockdown of SIRT3 by its shRNA further decreased mitochondrial ATP production, proton leak, mitochondrial mass, and mitochondrial membrane potential, indicating that SIRT3 positively regulates mitochondrial oxidative phosphorylation and maintenance of mitochondrial integrity. Mitophagy is critical to maintain proper cellular functions. In Cr(VI)-transformed cells expressions of Pink 1 and Parkin, two mitophagy proteins, were elevated, and mitophagy remained similar as that in passage-matched normal BEAS-2B cells, indicating that in -Cr(VI)-transformed cells mitophagy is suppressed. Knockdown of SIRT3 induced mitophagy, suggesting that SIRT3 plays an important role in mitophagy suppression of Cr(VI)-transformed cells. In Cr(VI)-transformed cells, nuclear factor (erythroid-derived 2)-like 2 (Nrf2) was constitutively activated, and protein levels of p62 and p-p62Ser349 were elevated. Knockdown of SIRT3 or treatment with carbonyl cyanide m-chlorophenyl hydrazone (CCCP) decreased the binding of p-p62Ser349 to Keap1, resulting in increased binding of Keap1 to Nrf2 and consequently reduced Nrf2 activation. The results from CHIP assay showed that in Cr(VI)-transformed cells binding of Nrf2 to antioxidant response element (ARE) of SIRT3 gene promoter was dramatically increased. Knockdown of SIRT3 suppressed cell proliferation and tumorigenesis of Cr(VI)-transformed cells. Overexpression of SIRT3 in normal BEAS-2B cells exhibited mitophagy suppression phenotype and increased cell proliferation and tumorigenesis. The present study demonstrated that upregulation of SIRT3 causes mitophagy suppression and plays an important role in cell survival and tumorigenesis of Cr(VI)-transformed cells.

Alanyl-glutamine Protects Against Damage Induced by Enteroaggregative Escherichia coli Strains in Intestinal Cells.

BACKGROUND: Enteroaggregative Escherichia coli (EAEC) is an important pathogen causing enteric infections worldwide. This pathotype is linked to malnutrition in children from developing countries. Alanyl-glutamine (Ala-Gln) is an immune modulator nutrient that acts during intestinal damage and/or inflammation. This study investigated the effect of EAEC infection and Ala-Gln on cell viability, cell death, and inflammation of intestinal epithelium cells (IEC-6). METHODS: Cells were infected with an EAEC prototype 042 strain, an EAEC wild-type strain isolated from a Brazilian malnourished child, and a commensal E coli HS. Gene transcription and protein levels of caspases-3, -8, and -9 and cytokine-induced neutrophil chemoattractant 1 (CINC-1/CXCL1) were evaluated using RT-qPCR, western blot analysis, and ELISA. RESULTS: Infections with both EAEC strains decreased cell viability and induced apoptosis and necrosis after 24 hours. Ala-Gln supplementation increased cell proliferation and reduced cell death in infected cells. Likewise, EAEC strain 042 significantly increased the transcript levels of caspases-3, -8, and -9 when compared to the control group, and Ala-Gln treatment reversed this effect. Furthermore, EAEC induced CXCL1 protein levels, which were also reduced by Ala-Gln supplementation. CONCLUSION: These findings suggest that EAEC infection promotes apoptosis, necrosis, and intestinal inflammation with involvement of caspases. Supplementation of Ala-Gln inhibits cell death, increases cell proliferation, attenuates mediators associated with cell death, and inflammatory pathways in infected cells.

New developments in mechanisms of prostate cancer progression.

Prostate cancer is the most prevalent type of cancer in men. The etiology of prostate cancer development and the mechanisms underlying androgen-independent progression remains to be further investigated. There are many known targets for prostate cancer therapy including the androgen receptor (AR) axis, but resistance eventually develops in advanced disease suggesting the need to better understand mechanisms of resistance and consideration of multi-targeted therapy. Mechanisms contributing to resistance may include gene amplifications, gene mutations, AR splice variants, and changes in expression of androgen receptor co-regulatory proteins. Given the limitations of approved therapies, further study of additional potential targets is warranted. This review focuses on the roles of autophagy pathway, p62, Yes-associated protein (YAP), cancer stem cells, and epigenetics. Therapies targeting these potential mechanisms of resistance may interact with currently approved therapies either additively or synergistically. Thus, the study of combination therapy against multiple targets may be critically important to achieve more impact against lethal forms of prostate cancer resistant to all approved current therapies.

Oxidative Stress and Metabolic Reprogramming in Cr(VI) Carcinogenesis.

Cr(VI)-containing compounds are well-established lung carcinogens. Chronic exposure of the normal human epithelial cells is able to induce malignant cell transformation, the first stage of metal carcinogenesis. These Cr(VI)-transformed cells exhibit increased level of antioxidants, reduced capacity of generating reactive oxygen species (ROS), and development of apoptosis resistance, promoting tumorigenesis of Cr(VI)-transformed cells, the second stage of metal carcinogenesis. The mechanism of Cr(VI) induced carcinogenesis is still under investigation. Recent studies indicate that ROS play a positive role in the first stage while a negative role in the second stage. Transformed cells adapt metabolism to support tumor initiation and progression. Altered metabolic activities directly participate in the process of cell transformation or support a large requirement for nucleotides, amino acids, and lipids for tumor growth. In malignantly Cr(VI)-transformed cells, mitochondrial oxidative phosphorylation is defective, and pentose phosphate pathway, glycolysis, and glutaminolysis are upregulated. These metabolic reprogramming supports rapid cell proliferation and contributes to tumorigenesis of Cr(VI)-transformed cells. This article summarizes the current progress in the studies of metabolic reprogramming and Cr(VI) carcinogenesis with emphasis on the metabolic enzymes and oxidative stress related major oncogenic pathways.

Prevalence and virulence gene profiling of enteroaggregative Escherichia coli in malnourished and nourished Brazilian children.

The impact of enteroaggregative E. coli (EAEC) infection on childhood malnutrition and inflammation has been suggested, regardless of diarrhea. We investigated whether EAEC and its virulence-related genes (VRGs) are associated with malnutrition in a case-control study. Children aged 6-24 months from Brazil were enrolled as malnourished if weight-for-age Z-score (WAZ) ≤ -2 and nourished if WAZ > -1. Stools were cultured and examined for E. coli. DNA was extracted from fecal isolates and tested for EAEC by polymerase chain reaction (PCR). Positive samples were analyzed by 5 multiplex PCRs to identify 20 EAEC VRGs. Biomarkers of intestinal barrier function and inflammation were measured. The prevalence of EAEC was 39.94%. Samples that presented both aaiC and aatA genes were associated with malnutrition (P = 0.045). A high prevalence of VRGs was observed and the aafC gene was significantly associated with malnourished (P = 0.0101). Strains lacking aar and pic genes were associated with malnutrition (P = 0.018), while the concomitant presence of aar, pic, agg4A, and capU genes was associated with nourished (P = 0.031). These data reinforce the EAEC impact on malnutrition, the importance of aar as negative regulator and the great contribution of AAF/II fimbria for the pathobiology of EAEC.