Beyond Boolean networks, a multi-valued approach.

Boolean networks can be viewed as functions on the set of binary strings of a given length, described via logical rules. They were introduced as dynamic models into biology, in particular as logical models of intracellular regulatory networks involving genes, proteins, and metabolites. Since genes can have several modes of action, depending on their expression levels, binary variables are often not sufficiently rich, requiring the use of multi-valued networks instead. The steady state analysis of Boolean networks is computationally complex, and increasing the number of variable values beyond $2$ adds substantially to this complexity, and no general methods are available beyond simulation. The main contribution of this paper is to give an algorithm to compute the steady states of a multi-valued network that has a complexity that, in many cases, is essentially the same as that for the case of binary values. Our approach is based on a representation of multi-valued networks using multi-valued logic functions, providing a biologically intuitive representation of the network. Furthermore, it uses tools to compute lattice points in rational polytopes, tapping a rich area of algebraic combinatorics as a source for combinatorial algorithms for Boolean network analysis. An implementation of the algorithm is provided.

Efecto de la suplementación con vitamina D en los efectos secundarios musculoesqueléticos relacionados con los inhibidores de la aromatasa para el cáncer de mama: cohorte B-ABLE / Effect of vitamin D supplementation on aromatase inhibitor-related musculoskeletal side effects for breast cancer: B-ABLE cohort

Objetivo: Evaluar el efecto de la suplementación con vitamina D en las complicaciones musculoesqueléticas relacionadas con el tratamiento con inhibidores de la aromatasa (IA) en pacientes con cáncer de mama. Material y métodos: Estudio observacional prospectivo de mujeres en tratamiento con IA, reclutadas en la cohorte B-ABLE. Las pacientes con niveles séricos iniciales de 25(OH)D (25-hidroxivitamina D) <30 ng/ml recibieron una dosis de 16.000 UI de calcifediol oral cada 2 semanas. La artralgia y la pérdida ósea relacionadas con los IA se evaluaron a los 3 meses y al año de seguimiento, respectivamente. Los análisis de asociación del status de vitamina D a los 3 meses con eventos musculoesqueléticos se realizaron mediante modelos de regresión lineal multivariante ajustados. Además, se evaluó la asociación del dolor incidente, definido como pacientes sin dolor articular inicial, pero con una escala visual analógica (EVA) >0 a los 3 meses, mediante regresión logística. Resultados: La suplementación con vitamina D al inicio del tratamiento con IA disminuyó el riesgo tanto de artralgia incidente como de su empeoramiento. El umbral efectivo de 25(OH)D en suero para reducir el dolor articular se estableció en 40 ng/ml. Sin embargo, este umbral no se relacionó significativamente con los cambios óseos al año de seguimiento. No obstante, los niveles de vitamina D se correlacionaron inversamente con la pérdida ósea de la columna lumbar (CL) (β=0,177% [IC 95%: 0,014 a 0,340]). Conclusiones: La administración de suplementos de vitamina D con el objetivo de alcanzar niveles séricos de 25OHD de al menos 40 ng/ml es protectora para la artralgia. Los niveles de vitamina D a los tres meses podrían predecir el riesgo de pérdida ósea en CL al año de tratamiento con IA. Por lo tanto, se recomiendan dosis altas de vitamina D en estas pacientes, que son más propensas a sufrir afecciones musculoesqueléticas. (AU)

Objetive: To assess the effect of vitamin D supplementation on musculoskeletal complications related to aromatase inhibitor (AI) treatment in patients with breast cancer. Material and methods: Prospective observational study of women undergoing AI treatment, recruited in the B-ABLE cohort. Patients with baseline serum 25 (OH) D (25-hydroxyvitamin D) levels <30 ng/ml received a 16,000 IU dose of oral calcifediol every 2 weeks. Arthralgia and bone loss related to AIs were assessed at 3 months and 1 year of followup, respectively. The association analyzes of vitamin D status at 3 months with musculoskeletal events were carried out using adjusted multivariate linear regression models. In addition, the association of incident pain, defined as patients without initial joint pain, but with a visual analog scale (VAS) >0 at 3 months, was evaluated using logistic regression. Results: Vitamin D supplementation at the start of AI treatment decreased the risk of both incident arthralgia and its worsening. The effective threshold of 25 (OH) D in serum to reduce joint pain was established at 40 ng/ml. However, this threshold was not significantly related to bone changes at one year of follow-up. However, vitamin D levels were inversely correlated with lumbar spine bone loss (LS) (β=0.177% [95% CI: 0.014 to 0.340]). Conclusions: Vitamin D supplementation aimed at achieving serum 25(OH)D levels of at least 40 ng/ml is protective for arthralgia. Vitamin D levels at three months could predict the risk of bone loss in LS at one year of AI treatment. Therefore, high doses of vitamin D are recommended in these patients, who are more prone to musculoskeletal conditions. (AU)

Análisis descriptivo y comparativo de los saques de esquina. UEFA Euro 2012 / Análise descritiva e comparativa das cobranças de escanteios. UEFA Euro 2012 / Descriptive and comparative analysis of the corners. UEFA Euro 2012

Objetivo. Alcanzar un conocimiento más profundo (y con el soporte empírico adecuado) de los saques de esquina en el fútbol de máximo nivel. Se pretende conocer la incidencia real de este tipo de acciones durante los partidos, así como describir cuáles son las prácticas habituales. A continuación, se pretende identificar aquellas variables que puedan estar asociadas a la eficacia de estas acciones. Método. Se plantean dos tipos de aproximaciones complementarias en el análisis de los datos: una de carácter univariada, y otra bivariada. A nivel univariado se trata de describir cuáles son las características de la ejecución de estas acciones (número, forma de ejecución…). A nivel bivariado, mediante la realización de tablas de contingencia (acompañadas del contraste Chi-cuadrado y medidas de asociación) se intentará identificar aquellas variables que puedan estar asociadas a la eficacia alcanzada. Resultados. Después del registro de 345 saques de esquina ejecutados durante la Eurocopa 2012, los resultados indican una baja eficacia en el remate de este tipo de acciones. En cambio, los goles que proceden de saque de esquina sí presentan una transcendencia importante en el resultado final. Para alcanzar el éxito en este tipo de acciones, deben intervenir entre tres y cuatro atacantes y producirse una organización ofensiva dinámica. Conclusiones. Los datos empíricos disponibles han puesto en valor la necesidad de un trabajo táctico más refinado de estas acciones, basado en asociaciones entre los jugadores y movimientos de engaño (AU)

Objetivo. Chegar a um conhecimento mais profundo (e com suporte empírico adequado) das cobranças de escanteios no futebol de alto nível. Destina-se a determinar a incidência real deste tipo de ação durante as partidas, assim como descrever quais são as práticas habituais. A seguir, se pretende identificar as variáveis que podem estar associados com a eficácia destas ações. Método. Surgem dois tipos de abordagens complementares na análise de dados: uma de caráter univariada e outra bivariada. A univariada trata-se de descrever quais são as características da execução destas ações (número, forma de execução …). A bivariada, mediante a realização de tabelas de contingência (acompanhada do contraste qui-quadrado e medidas de associação) tentará identificar as variáveis que podem estar associados com a eficiência alcançada. Resultados. Após o registro de 345 cobranças de escanteios executadas durante a Eurocopa 2012, os resultados indicam uma baixa eficiência na finalização de tais ações. Entretanto, os objetivos que precedem de cobranças de escanteios têm uma transcendência importante no resultado final. Para alcançar sucesso neste tipo de ação, devem intervir entre três e quatro atacantes e produzir uma organização ofensiva dinâmica. Conclusões. Os dados empíricos disponíveis foram postos em valor a necessidade de um trabalho tático mais refinado destas ações, baseados em associações entre os jogadores e os movimentos de engano (AU)

Objective. Reaching a deeper knowledge (and with proper empirical support) of the corners in the top-level football. It is intended to determine the real impact of this type of actions during matches and describe what the current practices are. Then, it is intended to identify those variables that may be associated with the effectiveness of these actions. Method. Two complementary approaches arise in the analysis of data: one univariate and other bivariate. At univariate level, it comes to describe what are the characteristics of the execution of these actions (number, form of execution…). At bivariate level, by making contingency tables (accompanied by Chi-square contrast and association measures) it will try to identify those variables that may be associated with the achieved efficiency. Results. After registration of 345 corners executed during Euro 2012, the results indicate a low efficiency in the auction of such actions. Instead, the goals coming from corner have an important significance in the final result. To succeed in this kind of actions should intervene between three and four attackers and a dynamic offensive organization should occur. Conclusions. The empirical data available have been worth the need for a more refined tactical work of these actions, based on partnerships between players and movements of trick (AU)

A new ELISA for determination of potency in snake antivenoms.

A competitive ELISA for potency determination of bothropic equine antivenom was developed and compared to the conventional in vivo ED(50) assay, with the aim of partially substituting the in vivo assay in the monitoring of antivenom immunoglobulin levels. On this purpose, blood samples were taken at different times during and after the immunization protocol of the lot of horses used for production of snake antivenom at the Instituto de Higiene, Uruguay. Both the competitive ELISA and the ED(50) assay were performed on those samples. In addition, a group of five commercial pepsin-digested antivenoms were tested by both methods. A significant (P<0.001) correlation (Pearson's r=0.957) was found between the ELISA titres and the corresponding ED(50) values, indicating that the in vitro test can estimate the neutralizing antibody capacity of the sera as well as the in vivo assay. By means of this new ELISA, it was found that the immunized animals maintained good venom antibody titres, in the order of 20-50% of the maximum achieved, even 10 month after the end of the immunization schedule. The main advantage of our ELISA design is its ability to correctly estimate the neutralization capacity of crude hyperimmune plasma and antivenom sera independently of their antibody composition in terms of whole IgG or F(ab')(2) fragment.

Dissociation of ERK and Akt signaling in endothelial cell angiogenic responses to beta-amyloid.

Cerebrovascular deposits of beta-amyloid (Abeta) peptides are found in Alzheimer's disease and cerebral amyloid angiopathy with stroke or dementia. Dysregulations of angiogenesis, the blood-brain barrier and other critical endothelial cell (EC) functions have been implicated in aggravating chronic hypoperfusion in AD brain. We have used cultured ECs to model the effects of beta-amyloid on the activated phosphorylation states of multifunctional serine/threonine kinases since these are differentially involved in the survival, proliferation and migration aspects of angiogenesis. Serum-starved EC cultures containing amyloid-beta peptides underwent a 2- to 3-fold increase in nuclear pyknosis. Under growth conditions with sublethal doses of beta-amyloid, loss of cell membrane integrity and inhibition of cell proliferation were observed. By contrast, cell migration was the most sensitive to Abeta since inhibition was significant already at 1 muM (P = 0.01, migration vs. proliferation). In previous work, intracellular Abeta accumulation was shown toxic to ECs and Akt function. Here, extracellular Abeta peptides do not alter Akt activation, resulting instead in proportionate decreases in the phosphorylations of the MAPKs: ERK1/2 and p38 (starting at 1 microM). This inhibitory action occurs proximal to MEK1/2 activation, possibly through interference with growth factor receptor coupling. Levels of phospho-JNK remained unchanged. Addition of PD98059, but not LY294002, resulted in a similar decrease in activated ERK1/2 levels and inhibition of EC migration. Transfection of ERK1/2 into Abeta-poisoned ECs functionally rescued migration. The marked effect of extracellular Abeta on the migration component of angiogenesis is associated with inhibition of MAPK signaling, while Akt-dependent cell survival appears more affected by cellular Abeta.

An attenuated Salmonella Enteritidis strain derivative of the main genotype circulating in Uruguay is an effective vaccine for chickens.

We have recently reported that Salmonella enterica serovar Enteritidis (S. Enteritidis) strains circulating in Uruguay, are unevenly distributed among different genetic subtypes, with a predominant genotype that is a common contaminant of poultry-derived food and that accounts for the vast majority of human cases of food-borne disease. Herein, we describe the construction of a genetically-defined aroC derivative (LVR02) of a local strain of S. Enteritidis belonging to the major genetic type. We demonstrated the attenuation and the immunogenicity of that strain in a mouse model, and evaluated it as a vaccine for commercial layer chickens. LVR02 proved to be stable, attenuated, innocuous, immunogenic and to induce protective immunity against a S. Enteritidis challenge when used for oral vaccination. A single oral dose of LVR02 administered to newly hatched chickens induced protection against oral challenge with the parental virulent strain, preventing systemic and persistent intestinal infection and significantly reducing the shedding of the challenge strain in birds' feces. A second vaccine dose at 15 days post-hatching boosted the immunogenicity of the vaccine, and strengthened the protection achieved with a single dose. This strain may represent the basis of a live vaccine to be included in national control programs to reduce circulation of this pathogen in the country.

Calcium dyshomeostasis in beta-amyloid and tau-bearing skeletal myotubes.

The relative scarcity of inclusion-affected muscle cells or markers of cell death in inclusion body myositis (IBM) is in distinction to the specific and early intracellular deposition of several Alzheimer's Disease (AD)-related proteins. The current study examined the possible correlation between myotube beta-amyloid and/or Tau accumulations and a widespread mishandling of intracellular muscle calcium concentration that could potentially account for the unrelenting weakness in affected patients. Cultured myogenic cells (C(2)C(12)) expressed beta-amyloid-42 (Abeta(42)) and fetal Tau peptides, as human transgenes encoded by herpes simplex virus, either individually or concurrently. Co-expression of Abeta(42) in C(2)C(12) myotubes resulted in hyperphosphorylation of Tau protein that was not observed when Tau was expressed alone. Resting calcium concentration and agonist-induced RyR-mediated Ca(2+) release were examined using calcium-specific microelectrodes and Fluo-4 epifluorescence, respectively. Co-expression of Abeta(42) and Tau cooperatively elevated basal levels of myoplasmic-free calcium, an effect that was accompanied by depolarization of the plasma membrane. Sarcoplasmic reticulum (SR) calcium release, induced by KCl depolarization, was not affected by Abeta(42) or Tau. In contrast, expression of Abeta(42), Tau, or Abeta(42) together with Tau resulted in enhanced sensitivity of ryanodine receptors to activation by caffeine. Notably, expression of beta-amyloid, alone, was sufficient to result in an increased sensitivity to direct activation by caffeine. Current results indicate that amyloid proteins cooperate to raise resting calcium levels and that these effects are associated with a passive SR Ca(2+) leak and Tau hyperphosphorylation in skeletal muscle.

Intranasal immunization with a colloid-formulated bacterial extract induces an acute inflammatory response in the lungs and elicits specific immune responses.

Nonspecific stimulation of lung defenses by repeated oral administration of immunomodulators, such as bacterial extracts, has shown potential for the prevention of respiratory tract infections. Here, we show that intranasal (i.n.) immunization with a bacterial extract formulated as a colloid induces an acute inflammatory response in the lungs characterized by increased production of CCL and CXCL chemokines and a major influx of dendritic cells (DCs) and neutrophils, with a higher proportion of DCs showing an activated phenotype (high CD80/CD86 expression). Cytokine levels measured in bronchoalveolar-lavage samples showed a small increase in the production of tumor necrosis factor alpha and similar levels of the other cytokines measured (interleukin 10 [IL-10], IL-12, and gamma interferon [IFN-gamma]) in immunized mice compared with control mice. However, the recall response of primed animals after antigenic challenge induced increased expression of IL-12 and IFN-gamma mRNAs in lung homogenates. Overall, all these effects were not due to the lipopolysaccharide content in the bacterial extract. Furthermore, we found that three i.n. doses administered 2 to 3 weeks apart were enough to elicit long-lasting specific serum immunoglobulin G (IgG) and secretory IgA antibody responses. Assessment of IgG subclasses showed a balanced pattern of IgG1-IgG2a responses. The serum total IgE concentrations were also elevated in immunized mice 2 weeks after the third dose, but they significantly decreased soon afterwards. Our results suggest that simple formulations of bacterial extracts administered i.n. are highly immunogenic, eliciting local and systemic immune responses, and may serve as the basis for cost-effective immunotherapies for the prevention and treatment of respiratory infections.

NERF2, a member of the Ets family of transcription factors, is increased in response to hypoxia and angiopoietin-1: a potential mechanism for Tie2 regulation during hypoxia.

Vascular endothelial growth factor (VEGF) and angiopoietins regulate endothelial cell survival and migration and are essential for angiogenesis. Considerable progress has been made towards understanding hypoxia-mediated regulation of VEGF and its receptors. In contrast, little is known about the regulation of angiopoietins and their receptors in hypoxic cells. Using RT-PCR, RNAase protection assay, and Western blotting, we found that Tie1 and Tie2 mRNA and protein levels increased in response to hypoxia in human umbilical vein endothelial cells. Previously, we have shown that NERF2, a member of Ets family of transcription factors that is specifically expressed in endothelial cells, binds to the promoter region of Tie2 and transactivates Tie2 expression. In this study, we show that expression of NERF2 was increased under hypoxia and that this increase temporally correlated with the increase in Tie2 expression. Hypoxia-induced expression of NERF2 and Tie2 was blocked by angiopoietin-2, a competitive inhibitor of angiopoietin-1, and by recombinant soluble extracellular domain of Tie2 but not by VEGF-neutralizing antibodies. In addition, angiopoietin-1 directly induced expression of NERF2 in quiescent cells. These novel findings suggest that angiopoietin-1 regulates expression of NERF2 and its own receptor in hypoxic cells.

Adenocarcinoma de pulmón asociado a mixoma auricular derecho / Adenocarcinoma of the lung and right atrial myxoma

Varón de 68 años de edad, diagnosticado de adenocarcinoma de pulmón y mixoma auricular derecho, al realizar una radiografía de tórax en un preoperatorio por enfermedad de Dupuytren bilateral. El interés de este caso vendría, por su diagnostico diferencial, por su manejo, por la posible asociación entre ambos tumores (1), y por la escasez de publicaciones encontradas (AU)

Colecistitis aguda, shock séptico y tuberculosis miliar / Acute cholecystitis, septic shock and miliary tuberulosis

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[Lung adenocarcinoma associated with myxoma of the right atrium]. / Adenocarcinoma de pulmón asociado a mixoma auricular derecho.

A 68 year-old man, was fond to have both an adenocarcinoma of the lung and a right atrial myxoma during a preoperative Dupuytren disease chest x-ray. The following case is being reported for to discuss diagnosis, to discuss management, for the feasible association between diseases and the few previous reports in the English-language literature.