Ectophosphatase activity in the triple-negative breast cancer cell line MDA-MB-231.

Breast cancer is one of the most common cancers in the female population worldwide, and its development is thought to be associated with genetic mutations that lead to uncontrolled and accelerated growth of breast cells. This abnormal behavior requires extra energy, and indeed, tumor cells display a rewired energy metabolism compared to normal breast cells. Inorganic phosphate (Pi) is a glycolytic substrate of glyceraldehyde-3-phosphate dehydrogenase and has an important role in cancer cell proliferation. For cells to obtain Pi, ectoenzymes in the plasma membrane with their catalytic site facing the extracellular environment can hydrolyze phosphorylated molecules, and this is an initial and possibly limiting step for the uptake of Pi by carriers that behave as adjuvants in the process of energy harvesting and thus partially contributes to tumor energy requirements. In this study, the activity of an ectophosphatase in MDA-MB-231 cells was biochemically characterized, and the results showed that the activity of this enzyme was higher in the acidic pH range and that the enzyme had a Km = 4.5 ± 0.5 mM para-nitrophenylphosphate and a Vmax = 2280 ± 158 nM × h-1 × mg protein-1 . In addition, classical acid phosphatase inhibitors, including sodium orthovanadate, decreased enzymatic activity. Sodium orthovanadate was able to inhibit ectophosphatase activity while also inhibiting cell proliferation, adhesion, and migration, which are important processes in tumor progression, especially in metastatic breast cancer MDA-MB-231 cells that have higher ectophosphatase activity than MCF-7 and MCF-10 breast cells.

Corrigendum: Metabolic Reprogramming During Multidrug Resistance in Leukemias.

[This corrects the article DOI: 10.3389/fonc.2018.00090.].

Osmolyte Induced Tumorigenesis and Metastasis: Interactions With Intrinsically Disordered Proteins.

In spite of a great deal of work, the biochemical mechanisms underlying tumorigenesis and metastasis are not yet fully understood. Specifically regarding metastasis many authors consider that malignancy is caused by the accumulation of mutations. However, evidence is gathering to show that tumors are composed of heterogeneous cell populations subjected to selective pressures. In this micro evolutionary scenario, intra- and extra-cellular selective pressures will determine which subpopulations of tumor cells will thrive and be able to dissociate from the tumor as autonomous metastatic cells. We propose here that alteration of conformations of transcription factors confer novel non-canonical functions that may induce oncogenesis and metastasis in a mutation independent manner. We argue that the functional plasticity of transcription factors is due to intrinsically disordered domains (IDRs) of proteins. IDRs prevent spontaneous folding of proteins into well-defined three-dimensional structures. Because most transcription factors contain IDRs, each could potentially interact with many ligands. This high degree of functional pleiotropy would then be ultimately responsible for the metastatic phenotype. The conformations of proteins can be altered by chemical chaperones collectively known as osmolytes. Osmolytes are small organic molecules permeable through biological membranes that can accumulate in cells, increase the thermodynamic stability of proteins, modulate enzyme activity and prevent protein aggregation. Thus, by modifying IDRs, osmolytes could subvert the homeostatic regulatory network of cells. Untargeted metabolomic analysis of oral cancer cells showed that those with the greatest metastatic potential contained several osmolytes that were absent in the non-metastatic cells. We hypothesize that high concentrations of osmolytes might promote conformational alterations of transcription factors that favor metastatic behavior. This hypothesis is eminently testable by investigating whether: (a) the intracellular microenvironment of metastatic cells differs from non-metastatic cells and whether osmolytes are responsible for this change and (b) high intracellular concentrations of osmolytes are sufficient to induce structural modifications in regulatory protein so as to establish novel interactive networks that will constitute the metastatic phenotype. Synthetic cell penetrating peptides mimicking IDRs could act as sensitive probes. By exposing the peptides to the microenvironments of living tumor and metastatic tumor cells one should be able to compare the chemical shifts as revealed by spectra obtained by nuclear magnetic resonance (NMR).

Metabolic Reprogramming During Multidrug Resistance in Leukemias.

Cancer outcome has improved since introduction of target therapy. However, treatment success is still impaired by the same drug resistance mechanism of classical chemotherapy, known as multidrug resistance (MDR) phenotype. This phenotype promotes resistance to drugs with different structures and mechanism of action. Recent reports have shown that resistance acquisition is coupled to metabolic reprogramming. High-gene expression, increase of active transport, and conservation of redox status are one of the few examples that increase energy and substrate demands. It is not clear if the role of this metabolic shift in the MDR phenotype is related to its maintenance or to its induction. Apart from the nature of this relation, the metabolism may represent a new target to avoid or to block the mechanism that has been impairing treatment success. In this mini-review, we discuss the relation between metabolism and MDR resistance focusing on the multiple non-metabolic functions that enzymes of the glycolytic pathway are known to display, with emphasis with the diverse activities of glyceraldehyde-3-phosphate dehydrogenase.

Suppression of MAGE-A10 alters the metastatic phenotype of tongue squamous cell carcinoma cells.

MAGE-A10 is a member of the MAGE protein family (melanoma associated antigen) which is overexpressed in cancer cells. Although MAGE-A10 has been characterized for some time and is generally associated to metastasis its function remains unknown. Here we describe experiments using as models oral squamous cell carcinoma (OSCC) cell lines displaying increasing metastatic potential (LN1 and LN2). These cell lines were transduced with lentivirus particles coding for short hairpin against MAGE-A10 mRNA. Repression of MAGE-A10 expression in LN2 cells altered their morphology and impaired growth of LN1 and LN2 cell lines. Furthermore, repression of MAGE-A10 expression increased cell-cell and cell matrix adhesion. Furthermore shMAGEA10 cells were shown to assemble aberrantly on a 3D culture system (microspheroids) when compared to cells transduced with the control scrambled construct. Cell migration was inhibited in knocked down cells as revealed by two different migration assays, wound healing and a phagokinetic track motility assay. In vitro invasion assay using a leiomyoma tissue derived matrix (myogel) showed that shMAGEA10 LN1 and shMAGEA10 LN2 cells displayed a significantly diminished ability to penetrate the matrices. Concomitantly, the expression of E-cadherin, N-cadherin and vimentin genes was analyzed. shMAGEA10 activated the expression of E-cadherin and repression N-cadherin and vimentin transcription. Taken together the results indicate that MAGE-A10 exerts its effects at the level of the epithelial-mesenchymal transition (EMT) presumably by regulating the expression of adhesion molecules.

International incidence and mortality trends of liver cancer: a global profile.

We examined the global incidence and mortality rates of liver cancer, and evaluated the association between incidence/mortality and socioeconomic development (Human Development Index [HDI] and Gross Domestic Product [GDP]) using linear regression analysis. The average annual percent change (AAPC) of the trends was evaluated from join-point regression analysis. The global incidence of liver cancer varied widely by nine-fold, and was negatively correlated with HDI (men: r = -0.232, p = 0.003; women: r = -0.369, p < 0.001) and GDP per capita (men: r = -0.164, p = 0.036; women: r = -0.212, p = 0.007). Its mortality showed a similarly negative correlation with both indices. The greatest incidence rise in men was observed in Poland (AAPC = 17.5, 95% C.I. = 5.6, 30.9) and Brazil (AAPC = 13.2, 95% C.I. = 5.9, 21.0), whereas Germany (AAPC = 6.6, 95% C.I = 2.0, 11.5) and Norway (AAPC = 6.5, 95% C.I. = 3.2, 10.0) had the greatest increase in women. The mortality rates paralleled the incidence rates in most countries. For mortality, Malta (AAPC = 11.5, 95% C.I. = 3.9, 19.8), Australia (AAPC = 6.8, 95% C.I. = 2.2, 11.5) and Norway (APCC = 5.6, 95% C.I. = 2.8, 8.5) reported the biggest increase among men; whilst Australia (AAPC = 13.4, 95% C.I. = 7.8, 19.4) and Singapore (AAPC = 7.7, 95% C.I. = 4.1, 11.5) showed the most prominent rise among women. These epidemiological data identified countries with potentially increasing trends of liver cancer for preventive actions.

Enhanced OXPHOS, glutaminolysis and ß-oxidation constitute the metastatic phenotype of melanoma cells.

Tumours display different cell populations with distinct metabolic phenotypes. Thus, subpopulations can adjust to different environments, particularly with regard to oxygen and nutrient availability. Our results indicate that progression to metastasis requires mitochondrial function. Our research, centered on cell lines that display increasing degrees of malignancy, focused on metabolic events, especially those involving mitochondria, which could reveal which stages are mechanistically associated with metastasis. Melanocytes were subjected to several cycles of adhesion impairment, producing stable cell lines exhibiting phenotypes representing a progression from non-tumorigenic to metastatic cells. Metastatic cells (4C11+) released the highest amounts of lactate, part of which was derived from glutamine catabolism. The 4C11+ cells also displayed an increased oxidative metabolism, accompanied by enhanced rates of oxygen consumption coupled to ATP synthesis. Enhanced mitochondrial function could not be explained by an increase in mitochondrial content or mitochondrial biogenesis. Furthermore, 4C11+ cells had a higher ATP content, and increased succinate oxidation (complex II activity) and fatty acid oxidation. In addition, 4C11+ cells exhibited a 2-fold increase in mitochondrial membrane potential (ΔΨmit). Consistently, functional assays showed that the migration of cells depended on glutaminase activity. Metabolomic analysis revealed that 4C11+ cells could be grouped as a subpopulation with a profile that was quite distinct from the other cells investigated in the present study. The results presented here have centred on how the multiple metabolic inputs of tumour cells may converge to compose the so-called metastatic phenotype.

Understanding the cancer cell phenotype beyond the limitations of current omics analyses.

Efforts to understand the mechanistic principles driving cancer metabolism and proliferation have been lately governed by genomic, transcriptomic and proteomic studies. This paper analyzes the caveats of these approaches. As molecular biology's central dogma proposes a unidirectional flux of information from genes to mRNA to proteins, it has frequently been assumed that monitoring the changes in the gene sequences and in mRNA and protein contents is sufficient to explain complex cellular processes. Such a stance commonly disregards that post-translational modifications can alter the protein function/activity and also that regulatory mechanisms enter into action, to coordinate the protein activities of pathways/cellular processes, in order to keep the cellular homeostasis. Hence, the actual protein activities (as enzymes/transporters/receptors) and their regulatory mechanisms ultimately dictate the final outcomes of a pathway/cellular process. In this regard, it is here documented that the mRNA levels of many metabolic enzymes and transcriptional factors have no correlation with the respective protein contents and activities. The validity of current clinical mRNA-based tests and proposed metabolite biomarkers for cancer detection/prognosis is also discussed. Therefore, it is proposed that, to achieve a thorough understanding of the modifications undergone by proliferating cancer cells, it is mandatory to experimentally analyze the cellular processes at the functional level. This could be achieved (a) locally, by examining the actual protein activities in the cell and their kinetic properties (or at least kinetically characterize the most controlling steps of the pathway/cellular process); (b) systemically, by analyzing the main fluxes of the pathway/cellular process, and how they are modulated by metabolites, all which should contribute to comprehending the regulatory mechanisms that have been altered in cancer cells. By adopting a more holistic approach it may become possible to improve the design of therapeutic strategies that would target cancer cells more specifically.

Componentes principais das características de carcaças de bovinos anelorados e fontes de variação em lesões / Principal components of carcass characteristics in zebu cattle and variation factors for injuries

Objetivou-se levantar e avaliar os componentes principais das características de carcaças de bovinos anelorados e fontes de variação em lesões. Utilizou-se um banco de dados com informações de 15.002 carcaças de bovinos anelorados. As variáveis levantadas foram peso da carcaça quente, conformação da carcaça, escore de gordura subcutânea, condição sexual, número de dentes incisivos, lesões e distância percorrida da propriedade rural ao abatedouro. Também foi considerado o sistema de terminação dos bovinos por meio da comunicação pessoal do técnico responsável pelo rebanho. Para entender o relacionamento das variáveis descritas, utilizaram-se a correlação dos componentes principais e as variáveis originais, os planos fatoriais, o círculo unitário, a análise de cluster e testes não-paramétricos. O escore de gordura subcutânea, a condição sexual, o peso da carcaça quente, o número de dentes e a propriedade rural, compuseram 68,26% da variação total. A conformação das carcaças e o sistema de terminação explicaram uma baixa parcela da variabilidade. As variáveis: propriedade rural (distância percorrida), número de dentes incisivos, sistema de terminação e escore de gordura subcutânea, influenciaram o número de carcaças com lesões. A condição sexual, o peso da carcaça quente e a conformação da carcaça não alteraram a proporção de carcaças com lesões.

This study was made in order to evaluate the principal components of carcass characteristics in Zebu cattle and variation factors for injuries. We used a database with information from 15,002 carcasses of Zebu cattle. The variables studied were hot carcass weight, carcass conformation, fat thickness score, sexual condition, number of teeth, injuries and distance from the farm to the slaughterhouse. We also raised the finishing system of cattle through information obtained from the technician responsible for the herd. To understand the relationship of the variables, we used the correlation of the principal components and original variables, the factorial plans, the unit circle, cluster analysis and non-parametric tests. The fat thickness score, sexual condition, hot carcass weight, the number of teeth, and farm comprised 68.26% of the total variability. The carcasses conformation and the finishing system explained a low proportion of the variability. Variables as farm, number of teeth, finishing system and fat thickness score influenced the number of injuried carcasses. The sexual condition, hot carcass weight and carcass conformation did not change the proportion of injuried carcasses.

Componentes principais das características de carcaças de bovinos anelorados e fontes de variação em lesões / Principal components of carcass characteristics in Zebu cattle and variation factors for injuries

Objetivou-se levantar e avaliar os componentes principais das características de carcaças de bovinos anelorados e fontes de variação em lesões. Utilizou-se um banco de dados com informações de 15.002 carcaças de bovinos anelorados. As variáveis levantadas foram peso da carcaça quente, conformação da carcaça, escore de gordura subcutânea, condição sexual, número de dentes incisivos, lesões e distância percorrida da propriedade rural ao abatedouro. Também foi considerado o sistema de terminação dos bovinos por meio da comunicação pessoal do técnico responsável pelo rebanho. Para entender o relacionamento das variáveis descritas, utilizaram-se a correlação dos componentes principais e as variáveis originais, os planos fatoriais, o círculo unitário, a análise de cluster e testes não-paramétricos. O escore de gordura subcutânea, a condição sexual, o peso da carcaça quente, o número de dentes e a propriedade rural, compuseram 68,26% da variação total. A conformação das carcaças e o sistema de terminação explicaram uma baixa parcela da variabilidade. As variáveis: propriedade rural (distância percorrida), número de dentes incisivos, sistema de terminação e escore de gordura subcutânea, influenciaram o número de carcaças com lesões. A condição sexual, o peso da carcaça quente e a conformação da carcaça não alteraram a proporção de carcaças com lesões.(AU)

This study was made in order to evaluate the principal components of carcass characteristics in Zebu cattle and variation factors for injuries. We used a database with information from 15,002 carcasses of Zebu cattle. The variables studied were hot carcass weight, carcass conformation, fat thickness score, sexual condition, number of teeth, injuries and distance from the farm to the slaughterhouse. We also raised the finishing system of cattle through information obtained from the technician responsible for the herd. To understand the relationship of the variables, we used the correlation of the principal components and original variables, the factorial plans, the unit circle, cluster analysis and non-parametric tests. The fat thickness score, sexual condition, hot carcass weight, the number of teeth, and farm comprised 68.26% of the total variability. The carcasses conformation and the finishing system explained a low proportion of the variability. Variables as farm, number of teeth, finishing system and fat thickness score influenced the number of injuried carcasses. The sexual condition, hot carcass weight and carcass conformation did not change the proportion of injuried carcasses.(AU)

Structure-based analysis of A19D, a variant of transthyretin involved in familial amyloid cardiomyopathy.

Transthyretin (TTR) is a tetrameric beta-sheet-rich protein. Its deposits have been implicated in four different amyloid diseases. Although aggregation of the wild-type sequence is responsible for the senile form of the disease, more than one hundred variants have been described thus far, most of which confer a more amyloidogenic character to TTR, mainly because they compromise the stability of the protein in relation to monomer formation, which upon misfolding is intrinsically aggregation-prone. We report the case of a Brazilian patient suffering from a severe cardiomyopathy who carries a rare mutation in exon 2 of the TTR gene that results in an Ala to Asp substitution at position 19 (A19D). The putative pathogenic mechanisms of this variant were analyzed in silico. We constructed a structural model for the A19D tetramer from which its thermodynamic stability was compared to that displayed by the V30M (more amyloidogenic than WT-TTR) and T119M (non-amyloidogenic) variants. The FoldX force field predicted that A19D and V30M are 10.88 and 8.07 kCal/mol less stable than the WT-TTR, while T119M is 5.15 kCal/mol more stable, which is consistent with the aggregation propensities exhibited by these variants. We analyzed the step in which the tetramer-dimer-monomer-unfolded monomer equilibrium might contribute the most to the increased or decreased amyloidogenicity in each variant. Our results suggest that the concentration of four non-native negative charges occur inside thyroxine-binding channels, and the loss of contacts at both the tetrameric and dimeric interfaces would account for an overall decreased stability of the tetramer and the consequent enhanced amyloidogenicity of the A19D variant. As far as we know, this is the first description of a non-V30M mutation in Brazil.

The 2-oxoglutarate supply exerts significant control on the lysine synthesis flux in Saccharomyces cerevisiae.

To determine the extent to which the supply of the precursor 2-oxoglutarate (2-OG) controls the synthesis of lysine in Saccharomyces cerevisiae growing exponentially in high glucose, top-down elasticity analysis was used. Three groups of reactions linked by 2-OG were defined. The 2-OG supply group comprised all metabolic steps leading to its formation, and the two 2-OG consumer groups comprised the enzymes and transporters involved in 2-OG transformation into lysine and glutamate and their further utilization for protein synthesis and storage. Various 2-OG steady-state concentrations that produced different fluxes to lysine and glutamate were attained using yeast mutants with increasing activities of Krebs cycle enzymes and decreased activities of Lys synthesis enzymes. The elasticity coefficients of the three enzyme groups were determined from the dependence of the amino acid fluxes on the 2-OG concentration. The respective degrees of control on the flux towards lysine (flux control coefficients) were determined from their elasticities, and were 1.1, 0.41 and -0.52 for the 2-OG producer group and the Lys and Glu branches, respectively. Thus, the predominant control exerted by the 2-OG supply on the rate of lysine synthesis suggests that over-expression of 2-OG producer enzymes may be a highly effective strategy to enhance Lys production.

Identification of a new Schistosoma mansoni SMYB1 partner: putative roles in RNA metabolism.

SMYB1 is a Schistosoma mansoni protein highly similar to members of the Y-box binding protein family. Similar to other homologues, SMYB1 is able to bind double- and single-stranded DNA, as well as RNA molecules. The characterization of proteins involved in the regulation of gene expression in S. mansoni is of great importance for the understanding of molecular events that control morphological and physiological changes in this parasite. Here we demonstrate that SMYB1 is located in the cytoplasm of cells from different life-cycle stages of S. mansoni, suggesting that this protein is probably acting in mRNA metabolism in the cytoplasm and corroborating previous findings from our group that showed its ability to bind RNA. Protein-protein interactions are important events in all biological processes, since most proteins execute their functions through large supramolecular structures. Yeast two-hybrid screenings using SMYB1 as bait identified a partner in S. mansoni similar to the SmD3 protein of Drosophila melanogaster (SmRNP), which is important in the assembly of small nuclear ribonucleoprotein complexes. Also, pull-down assays were conducted using immobilized GST-SMYB1 proteins and confirmed the SMYB1-SmRNP interaction. The interaction of SMYB1 with a protein involved in mRNA processing suggests that it may act in processes such as turnover, transport and stabilization of RNA molecules.

Prevalence of dental anomalies in patients with cleft lip and palate, Paraiba, Brazil: clinic and radiographic study.

The aim of this study is to investigate the prevalence of dental anomalies in a group of individuals with different types of clefts attending the reference service in orthodontics for the care of patients with clefts in Paraiba state, northeastern Brazil. This was a cross-sectional, observational study. Two previously trained examiners (kappa = 0.89) performed the clinical examination of 76 patients with post and incisive transforamen unilateral or bilateral clefts, of both sexes, aged 4 to 32 years, and the analysis of periapical and panoramic radiographs from archived records of these patients. Only the upper front teeth were evaluated. Data were processed by descriptive statistics and subjected to statistical Chi-square test considered significant at 5%. Among the patients evaluated, males (57.9%) and left unilateral transforamen clefts (40.8%) were prevalent. Of the total 76 patients examined, 56 (73.68%) had at least one dental anomaly, the most frequent being agenesis (31.6%) and conical teeth (28.9%). The presence of anomalies differed significantly between the cleft and the contralateral sides (p<0.00001). The diagnosis and treatment of patients with clefts should therefore receive more attention. It is suggested that clinical and radiographic examination be performed together with careful planning and implementation of specialist services in an effort to provide early and adequate detection and treatment.

Spatio-temporal biodiversity of soft bottom macrofaunal assemblages in shallow coastal waters exposed to episodic hypoxic events.

The Humboldt Current System (HCS) has one of the three most important oxygen minimum zones (OMZ) of the global ocean. Several studies have looked at the macrofaunal benthic assemblages inhabiting the continental shelf and shallow bays off central-southern Chile associated with low oxygen areas, but little is known about open coast macrofaunal communities within this zone, which are frequently subjected to the low oxygen conditions of Equatorial Subsurface Waters (ESSW). In order to assess local and mesoscale coastal macrofauna dynamics, the sampling area (ca. 40 linear km) was divided into seven local zones (Cobquecura, southern Cobquecura, northern Itata, Itata River mouth, external, southern Itata, and Coliumo). Eight oceanographic cruises were carried out between May 2006 and February 2008 covering 16 coastal sampling sites, between 36°07'S and 36°30'S. The macrofaunal assemblage was dominated by polychaetes, crustaceans, and mollusks. Our results suggest a high degree of temporal faunal stability on the mesoscale in soft bottom communities along the open coast, given the persistence of a faunal assemblage dominated by organisms tolerant of low oxygen conditions. While there is some local variability in community attributes, the main structuring factor for soft bottom communities in the shallow coastal area off central-southern Chile is the seasonal intrusion of low oxygen ESSW.

Estrés en dos cohortes de estudiantes de medicina de la Escuela Luis Razetti-Universidad Central de Venezuela / Stress in two cohorts of medical students from the Escuela Luis Razetti-Universidad Central de Venezuela

El estrés es un proceso de interacción entre eventos del entorno biopsicosocial. Los síntomas relacionados con este, en estudiantes de medicina, puede variar a lo largo de su carrera. Se comparó la prevalencia de estrés en estudiantes de 1º a 5º año, con el objetivo de establacer si existen diferencias significativas entre ellos. La presente fue una investigación de corte transversal observacional, no experimental. El universo fue de 481 individuos (cohortes 2009-2010). En mayo 2010 se tomó una muestra probabilística, aleatoria simple, estratificada, de 116 estudiantes de 1º año y 88 de 5º año de la Escuela Luis Razetti (total 204,42% del universo). El instrumento de evaluación fue una encuesta que constaba de datos generales, Escala de Depresión, Ansiedad y Estrés (EDAS-21) y Estratificación Social de Graffar-Méndez-Castellano. Se utilizó el programa SPSS v.10.0 para el análisis de datos, nivel de confianza 95%. Respecto a la puntuación total del EDAS-21, delos estudiantes evaluados, 64,8% presentaron estrés normal y 6,7% estrés muy severo. La prevalencia de estrés de leve a muy severo en estudiantes de 1º fue significativamente mayor que de la de los de 5º año (42,7% vs. 27,8%; P<0,05). Se encontraron diferencias significativas en la frecuencia de estrés entre los estudiantes de 1º y 5º año, siendo mayor en los de 1º; lo cual puede deberse, dentro de otros factores, a la adaptación ante situaciones que generan estrés en los mismos a lo largp de su carrera

stress is considered as an interactive process between biopsychosocial events, symptoms related to it, in medical students, may vary along their careers. Stress prevalence was compared between 1º and 5º year students, to establish if significant differences exist or not. This was a cross-sectional, observational, non-experimental research. The universe was 481 individuals (cohort 2009-2010). In may 2010 a probabilistic, simple random, stratified sample of 116 students of 1º year and 88 of 5º at the School Luis Razetti was taken (total 204,42% of the universe). The evaluation instrument was a survey form consisting on general information, Depression, Anxiety and Stress Scale (DASS-21) and the Graffar-Méndez-Castellano Social Stratification. The Software SPSS v.10.0, with a 95% confidence level, was used for data analyses. Regarding the total DASS-21 score, from the evaluated students, 64.8% presented normal stress levels and 6.7% very severe stress levels. The Low to very severe stress levels prevalence in 1st year students was significantly higher than that presented in 5th year students (42.7% vs. 27,8%; P<0.05). Significant differences on stress frequency were evidenced between 1º and 5º year students, being higher in 1º year students; wich can be due, among other factors, to the adaptacion, ocurred along the years, to situacions that generate stress on their careers

Mortalidad infantil por enfermedades infecciosas intestinales en Venezuela, 1996-2008 / Infant mortality due to intestinal infectious diseases in Venezuela, 1996-2008

Objetivo: Estudio de la Mortalidad por Enfermedades Infecciosas Intestinales (CIE-10: A00-A09) (EII) en los menores de 1 año en Venezuela según tiempo, persona, etiología y lugar durante 1996-2008. Materiales y métodos utilizados: Las fuentes son los Anuarios de Mortalidad del Min. Salud y del Instituto Nacional de Estadística. Análisis en números absolutos y cálculos de tasas específicas de menores de 1 año según sexo, etiología, entidad federal y tiempo, promedios, razones y proporciones. Correlación de Pearson entre tasa de mortalidad infantil por EII con Índice de Desarrollo Humano (IDH) (p < 0,05). Análisis con Microsoft Excel 2010 y SPSS.13.00. Resultados: Las muertes disminuyeron mucho, las tasas del primer trienio pasan de 3,18 por mil a 0,66; cayeron casi 5 veces. El índice de masculinidad es 1,33; estable en el lapso. Las EII son diarreas y gastroenteritis de presunto origen infeccioso; bacterianas (94,3%): Salmonella, Shigella e intoxicaciones intestinales bacterianas (1,5%); amebiasis y protozoarios (3,8%); el resto virales (0,05%). Las tasas varían en extremo por entidades federales. El último trienio, Delta Amacuro alcanza una tasa de 6,45; 10 veces por arriba de la tasa nacional, seguido a distancia por Zulia 2,64; Amazonas 2,28 y Apure 2,03. Se encontró una correlación de Pearson moderada (-0,416; p=0,03) inversamente proporcional entre la tasa de mortalidad y el IDH. Conclusiones: La mortalidad infantil por EII está descendiendo mucho en cifras absolutas y relativas. Es necesario mejorar el diagnóstico etiológico. Los estados con mayor población rural e indígena tienen las tasas más elevadas; abordando sanitariamente estos, tendríamos un gran impacto en la carga de muertes.

Objective: Study of the Mortality for Infectious Intestinal Diseases (IID) in 1-year-old minors in Venezuela according to time, person, etiology and place during 1996-2008. Materials and Used Methods: The sources are the Yearbooks of Mortality of the Min. and the National Institute of Statistics.Analysis are presented in absolute and relative numbers and calculations of specific rates of 1-year-old minors accordingto sex, etiology, federal entity and time, averages, rates and proportions. Pearson Correlation between rate of infant mortality for IID with Index of Human Development (IDH) (p<0.05). Analysis with Microsoft Excel 2010 and SPSS.13.00. Results: The deaths diminished very much, the rates of the first triennium dropped from 3.18 for thousand to 0.66; rates fell almost 5 times. The index of masculinity is 1.33, timelystable. The IID (94.3%) are diarrheas and gastroenteritis of presumable infectious origin; bacterial: Salmonella, Shigella and intestinal bacterial poisonings (1.5%); amebiasis and protozoans (3.8%); the rest viral (0.05%). The rates change much among the states. The last triennium, Delta Amacuroreaches a rate of 6.45, 10 times over of the national rate, followed distantly by Zulia 2.64, Amazonas 2.28 and Apure 2.03. There was a moderate correlation (-0.416; p=0.03) inversely proportional between the rate of mortality and the IDH. Conclusions: The infant mortality for IID is descending very much in absolute and relative numbers. It is necessary to improve the etiological diagnosis. States with high proportion of rural and indigenous population have the highest rates; tackling sanitarily these states, would have a great impact inthe load of deaths.

The short chain fatty acid sodium butyrate regulates the induction of CD1a in developing dendritic cells.

Dendritic cells (DCs) are professional antigen-presenting cells with attributes for priming/activating T cells and mediating immune responses. Considering the importance of DCs in the initiation of immune responses, it will be of interest to study their mechanisms of regulation. Histone-modifying enzymes, such as histone deacetylases (HDACs), are critical in controlling chromatin organization. The aim of our study was to investigate DC differentiation under the influence of sodium butyrate (NaB), a short chain fatty acid that is a histone deacetylase inhibitor. Monocytes from healthy individuals were differentiated into immature DCs with IL-4 and GM-CSF in the presence or absence of NaB. DC differentiation was evaluated by CD14 and CD1a expression by flow cytometry. We observed that monocytes stimulated to differentiate in the presence of NaB displayed colony formation and dendritic cell morphology, lost CD14 and showed decreased secretion of IL-1ß. The acquisition of CD1a, however, was impaired. Being a natural short chain fatty acid, NaB may regulate CD1a acquisition independently of its HDAC inhibitory activity. We observed that the addition of peroxisome proliferator-activated receptor γ (PPAR-γ) antagonist (GW9662) did not reverse NaB effect, suggesting this was not the pathway involved. On the other hand, CD1a can also be induced by toll like receptors 2 (TLR 2) agonists, such as Pam3Cys, and NaB inhibited this effect. Our data suggest that the histone deacetylase inhibitor NaB instead of impairing DC differentiation inhibits the acquisition of CD1a induced both by cytokines and by TLR 2 agonist stimulus. Furthermore, this occurs at the transcriptional level as NaB led to a decrease in mRNA levels of CD1a and upregulation of CD1d.