Mathematical model of interaction Escherichia coli and Coliphages.

We propose a mathematical model based in ordinary differential equations between bacterial pathogen and Bacteriophages to describe the infection dynamics of these populations, for which we use a nonlinear function with an inhibitory effect. We study the stability of the model using the Lyapunov theory and the second additive compound matrix and perform a global sensitivity analysis to elucidate the most influential parameters in the model, besides we make a parameter estimation using growth data of Escherichia coli (E.coli) bacteria in presence of Coliphages (bacteriophages that infect E.coli) with different multiplicity of infection. We found a threshold that indicates whether the bacteriophage concentration will coexist with the bacterium (the coexistence equilibrium) or become extinct (phages extinction equilibrium), the first equilibrium is locally asymptotically stable while the other is globally asymptotically stable depending on the magnitude of this threshold. Beside we found that the dynamics of the model is particularly affected by infection rate of bacteria and Half-saturation phages density. Parameter estimation show that all multiplicities of infection are effective in eliminating infected bacteria but the smaller one leaves a higher number of bacteriophages at the end of this elimination.

Design of Optimal Coils for Deep Transcranial Magnetic Stimulation.

In this work, a stream function inverse boundary element method (IBEM) has been used for designing different deep transcranial magnetic stimulation (dTMS)coils to activate the prefrontal cortex and the temporal lobe have been set as the target regions. In addition, the performances of these coils have been described and the electric field induced by them has been obtained by using a computational forward technique. These results show that the stream function IBEM is an ideal approach to design optimal dTMS coils capable of producing deep stimulation in the target brain regions. Clinical relevance - The design problem proposed here can be used to produce efficient dTMS stimulators for neurological disorders, which can overcome some of the currently existing limitations of the most common devices employed in TMS.

Design of coils for lateralized TMS on mice.

OBJECTIVE: Translational studies on animals play a vital role in the advancement of transcranial magnetic stimulation (TMS) as clinical technique. Nonetheless the relevance of these procedures is frequently limited by the lack of TMS systems specifically designed for small animals capable of producing comparable stimulation conditions to those found in human TMS. In this work, we propose to take advantage of the versatility of recently introduced TMS coil design methods to produce optimal rodent-specific TMS stimulators. APPROACH: A stream function inverse boundary element method (IBEM) has been used for producing three small sized mice-specific TMS coils of different geometries. They have been created for unilateral hemispheric stimulation of the rodent brain, and several constraints have been considered in the design process to satisfy essential performance requirements, such as minimum stored magnetic energy, minimum power dissipation, optimised maximum current density or minimization of the undesired electric field induced in non-target regions. In order to validate the presented strategy, three prototype coils have been built. The performance of each prototype has also been numerically investigated, where the electric field induced in a mouse model has been found by using an existing computational forward technique. MAIN RESULTS: Stream function IBEM represents an ideally suited approach for designing specific TMS coils for small animals, capable of fulfilling many essential functional and technical requirements. The prototypes produced in this work focally stimulate the right hemisphere of the mouse brain, and so they can be successfully used in lateralized TMS experiments. SIGNIFICANCE: The design scheme proposed here can be used to produce efficient TMS stimulators for small animals, which can overcome some of the existing limitations found when producing more reliable translational experiments.

Design of TMS coils with reduced Lorentz forces: application to concurrent TMS-fMRI.

OBJECTIVE: Interleaving TMS (transcranial magnetic stimulation) with fMRI (functional Magnetic Resonance Imaging) is a promising technique to study functional connectivity in the human brain, but its development is being restricted by technical limitations, such as that due to the interaction of the TMS current pulses with the magnetic fields of an MRI scanner. In this work, a TMS coil design method capable of controlling Lorentz forces experienced by the coil in the presence of static magnetic fields is presented. APPROACH: The suggested approach is based on an existing inverse boundary element method (IBEM) for TMS coil design, in which new electromagnetic computational models of the Lorentz forces have been included to be controlled in the design process. MAIN RESULTS: To demonstrate the validity of this technique, it has been used for the design and simulation of TMS coils wound on rectangular flat, spherical and hemispherical surfaces with improved mechanical stability. The obtained results confirm that TMS coils with reduced Lorentz forces inside the static main field of an MRI scanner can be produced, which is achieved to the detriment of other coil performance parameters. SIGNIFICANCE: The proposed approach provides an efficient tool to design TMS stimulators of a wide range of coil geometries with improved mechanical stability, which can be extremely useful to overcome current limitations for interleaved TMS-fMRI.

[Changes attributed to a program based on the action-training of health agents. What do the associations say?] / Cambios atribuidos a un programa basado en la formación-acción de agentes de salud ¿Qué dicen las asociaciones?

OBJECTIVE: Interventions aimed at improving health must take into account the health inequalities and the target the population in need. The mihsalud program (Women, Children and Men creating health) promotes health in vulnerable populations through engaging and collaborating with the local third sector. The objective of the study was to describe the changes attributed to the mihsalud programme and the process of action-training of community-based health volunteers (ASBC in Spanish) as perceived by the local organizations where they work or volunteer. METHODS: Qualitative descriptive study through semi-structured interviews with representatives of organizations that trained ASBC during 2012 in Valencia. Twelve semi-structured interviews were conducted with representatives of organizations which had trained some of their volunteers to become ASBC during the 2012 action-training session. The interviews were transcribed verbatim and analysed with the programme for qualitative analysis Nvivo. Themathic analysis was performed: transcripts were coded line by line from an inductive perspective. RESULTS: Three main categories were identified: 1) The role of the ASBC: The associations recognise the role of the ASBC among their peers and the importance of the training received in the program; 2) Perceived changes: The associations recognize having a broader vision of health, identify the role of the figure ASBC that coordinates with health professionals in their health area and networking with other associations that were previously unknown; 3) Challenges and opportunities: Lack of support for the continuity of projects with ASBC due to the precariousness of small organisations and coordination with services, recognition at the local level and promotion of participation and interculturality through ASBC and their peers. CONCLUSIONS: The organizations recognize that the program and ASBC have made collaboration with health sector possible, have promoted health among their peers and have encouraged networking with other organizations and areas.

OBJETIVO: Las intervenciones dirigidas a mejorar la salud deben tener en cuenta las desigualdades de la población y orientarse a la población más necesitada. El programa mihsalud (Mujeres, Infancia y Hombres construyendo salud) promueve la salud en poblaciones en situación de vulnerabilidad implicando al ámbito asociativo. El objetivo del estudio fue describir los cambios atribuidos al programa mihsalud y al proceso de formaciónacción de agentes de salud de base comunitaria (ASBC) por parte de las asociaciones a las que pertenecen. METODOS: Estudio descriptivo cualitativo mediante entrevistas semiestructuradas a representantes de asociaciones participantes que formaron ASBC durante 2012 en Valencia. Se realizaron 12 entrevistas semiestructuradas con representantes de asociaciones que formaron ASBC tras 4 años de la formación. Las entrevistas se transcribieron verbatim y se analizaron con el programa para análisis cualitativo "Nvivo (análisis temático)": Las transcripciones se codificaron línea por línea con perspectiva inductiva. RESULTADOS: Se agruparon en tres categorías principales: 1) Reconocimiento del rol del ASBC: Las asociaciones reconocieron el rol del ASBC entre sus iguales y la importancia de la formación recibida; 2) Cambios percibidos: Las asociaciones reconocieron tener una visión más amplia sobre la salud, identificaron el rol del ASBC que se coordina con los profesionales sanitarios de su zona de salud y el trabajo en red con otras asociaciones que antes desconocían; 3) Dificultades y oportunidades: La falta de apoyo para la continuidad de los proyectos vinculados con ASBC por la precariedad de las asociaciones pequeñas; y la coordinación con los servicios, el reconocimiento a nivel local y el fomento de la participación e interculturalidad a través de ASBC y sus iguales. CONCLUSIONES: Las asociaciones reconocen que el programa y ASBC han hecho posible la colaboración con recursos sanitarios, han promocionado la salud entre sus iguales y han fomentado el trabajo en red.

Cambios atribuidos a un programa basado en la formación-acción de agentes de salud ¿Qué dicen las asociaciones? / Changes attributed to a program based on the action-training of health agents. What do the associations say?

Fundamentos: Las intervenciones dirigidas a mejorar la salud deben tener en cuenta las desigualdades de la población y orientarse a la población más necesitada. El programa mihsalud (Mujeres, Infancia y Hombres construyendo salud) promueve la salud en poblaciones en situación de vulnerabilidad implicando al ámbito asociativo. El objetivo del estudio fue describir los cambios atribuidos al programa mihsalud y al proceso de formación-acción de agentes de salud de base comunitaria (ASBC) por parte de las asociaciones a las que pertenecen. Método: Estudio descriptivo cualitativo mediante entrevistas semiestructuradas a representantes de asociaciones participantes que formaron ASBC durante 2012 en Valencia. Se realizaron 12 entrevistas semiestructuradas con representantes de asociaciones que formaron ASBC tras 4 años de la formación. Las entrevistas se transcribieron verbatim y se analizaron con el programa para análisis cualitativo "Nvivo (análisis temático) ": Las transcripciones se codificaron línea por línea con perspectiva inductiva. Resultados: Se agruparon en tres categorías principales: 1) Reconocimiento del rol del ASBC: Las asociaciones reconocieron el rol del ASBC entre sus iguales y la importancia de la formación recibida; 2) Cambios percibidos: Las asociaciones reconocieron tener una visión más amplia sobre la salud, identificaron el rol del ASBC que se coordina con los profesionales sanitarios de su zona de salud y el trabajo en red con otras asociaciones que antes desconocían; 3) Dificultades y oportunidades: La falta de apoyo para la continuidad de los proyectos vinculados con ASBC por la precariedad de las asociaciones pequeñas; y la coordinación con los servicios, el reconocimiento a nivel local y el fomento de la participación e interculturalidad a través de ASBC y sus iguales. Conclusiones: Las asociaciones reconocen que el programa y ASBC han hecho posible la colaboración con recursos sanitarios, han promocionado la salud entre sus iguales y han fomentado el trabajo en red

Background: Interventions aimed at improving health must take into account the health inequalities and the target the population in need. The mihsalud program (Women, Children and Men creating health) promotes health in vulnerable populations through engaging and collaborating with the local third sector. The objective of the study was to describe the changes attributed to the mihsalud programme and the process of action-training of community-based health volunteers (ASBC in Spanish) as perceived by the local organizations where they work or volunteer. Methods: Qualitative descriptive study through semi-structured interviews with representatives of organizations that trained ASBC during 2012 in Valencia. Twelve semi-structured interviews were conducted with representatives of organizations which had trained some of their volunteers to become ASBC during the 2012 action-training session. The interviews were transcribed verbatim and analysed with the programme for qualitative analysis Nvivo. Themathic analysis was performed: transcripts were coded line by line from an inductive perspective. Results: Three main categories were identified: 1) The role of the ASBC: The associations recognise the role of the ASBC among their peers and the importance of the training received in the program; 2) Perceived changes: The associations recognize having a broader vision of health, identify the role of the figure ASBC that coordinates with health professionals in their health area and networking with other associations that were previously unknown; 3) Challenges and opportunities: Lack of support for the continuity of projects with ASBC due to the precariousness of small organisations and coordination with services, recognition at the local level and promotion of participation and interculturality through ASBC and their peers. Conclusions: The organizations recognize that the program and ASBC have made collaboration with health sector possible, have promoted health among their peers and have encouraged networking with other organizations and areas

Molecular mechanism of sphingosine-1-phosphate action in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a lethal muscle-wasting disease. Studies in Drosophila showed that genetic increase of the levels of the bioactive sphingolipid sphingosine-1-phosphate (S1P) or delivery of 2-acetyl-5-tetrahydroxybutyl imidazole (THI), an S1P lyase inhibitor, suppresses dystrophic muscle degeneration. In the dystrophic mouse (mdx), upregulation of S1P by THI increases regeneration and muscle force. S1P can act as a ligand for S1P receptors and as a histone deacetylase (HDAC) inhibitor. Because Drosophila has no identified S1P receptors and DMD correlates with increased HDAC2 levels, we tested whether S1P action in muscle involves HDAC inhibition. Here we show that beneficial effects of THI treatment in mdx mice correlate with significantly increased nuclear S1P, decreased HDAC activity and increased acetylation of specific histone residues. Importantly, the HDAC2 target microRNA genes miR-29 and miR-1 are significantly upregulated, correlating with the downregulation of the miR-29 target Col1a1 in the diaphragm of THI-treated mdx mice. Further gene expression analysis revealed a significant THI-dependent decrease in inflammatory genes and increase in metabolic genes. Accordingly, S1P levels and functional mitochondrial activity are increased after THI treatment of differentiating C2C12 cells. S1P increases the capacity of the muscle cell to use fatty acids as an energy source, suggesting that THI treatment could be beneficial for the maintenance of energy metabolism in mdx muscles.

Increased sphingosine-1-phosphate improves muscle regeneration in acutely injured mdx mice.

BACKGROUND: Presently, there is no effective treatment for the lethal muscle wasting disease Duchenne muscular dystrophy (DMD). Here we show that increased sphingosine-1-phoshate (S1P) through direct injection or via the administration of the small molecule 2-acetyl-4(5)-tetrahydroxybutyl imidazole (THI), an S1P lyase inhibitor, has beneficial effects in acutely injured dystrophic muscles of mdx mice. METHODS: We treated mdx mice with and without acute injury and characterized the histopathological and functional effects of increasing S1P levels. We also tested exogenous and direct administration of S1P on mdx muscles to examine the molecular pathways under which S1P promotes regeneration in dystrophic muscles. RESULTS: Short-term treatment with THI significantly increased muscle fiber size and extensor digitorum longus (EDL) muscle specific force in acutely injured mdx limb muscles. In addition, the accumulation of fibrosis and fat deposition, hallmarks of DMD pathology and impaired muscle regeneration, were lower in the injured muscles of THI-treated mdx mice. Furthermore, increased muscle force was observed in uninjured EDL muscles with a longer-term treatment of THI. Such regenerative effects were linked to the response of myogenic cells, since intramuscular injection of S1P increased the number of Myf5nlacz/+ positive myogenic cells and newly regenerated myofibers in injured mdx muscles. Intramuscular injection of biotinylated-S1P localized to muscle fibers, including newly regenerated fibers, which also stained positive for S1P receptor 1 (S1PR1). Importantly, plasma membrane and perinuclear localization of phosphorylated S1PR1 was observed in regenerating muscle fibers of mdx muscles. Intramuscular increases of S1P levels, S1PR1 and phosphorylated ribosomal protein S6 (P-rpS6), and elevated EDL muscle specific force, suggest S1P promoted the upregulation of anabolic pathways that mediate skeletal muscle mass and function. CONCLUSIONS: These data show that S1P is beneficial for muscle regeneration and functional gain in dystrophic mice, and that THI, or other pharmacological agents that raise S1P levels systemically, may be developed into an effective treatment for improving muscle function and reducing the pathology of DMD.

Drosophila as a starting point for developing therapeutics for the rare disease Duchenne Muscular Dystrophy.

Progress into developing therapeutics for rare diseases can be accelerated for those diseases that can be modeled in genetically tractable organisms. Here we comment on one disease, Duchenne Muscular Dystrophy (DMD), modeled in Drosophila that brought together disparate lines of research toward the goal of developing a therapeutic. Though the bioactive lipid sphingosine 1-phosphate (S1P) has been implicated in many anabolic processes in many cell types and tissues, including muscle, this work confirmed the therapeutic potential of assessing this pathway for DMD. Genetic dissection of sphingolipid metabolism showed the suppression of muscle structural and functional defects in flies. Moreover, improvement of muscle defects using known pharmacological agents that raise S1P levels in vivo highlight the potential of Drosophila as a drug-screening tool for DMD. We and others have extended S1P studies into the mouse model of DMD and have shown a partial amelioration of symptoms associated with DMD. Translation of this work to mammals makes the sphingolipid metabolism pathway a promising target for further drug development that may benefit the human condition.

Genetic elevation of sphingosine 1-phosphate suppresses dystrophic muscle phenotypes in Drosophila.

Duchenne muscular dystrophy is a lethal genetic disease characterized by the loss of muscle integrity and function over time. Using Drosophila, we show that dystrophic muscle phenotypes can be significantly suppressed by a reduction of wunen, a homolog of lipid phosphate phosphatase 3, which in higher animals can dephosphorylate a range of phospholipids. Our suppression analyses include assessing the localization of Projectin protein, a titin homolog, in sarcomeres as well as muscle morphology and functional movement assays. We hypothesize that wunen-based suppression is through the elevation of the bioactive lipid Sphingosine 1-phosphate (S1P), which promotes cell proliferation and differentiation in many tissues, including muscle. We confirm the role of S1P in suppression by genetically altering S1P levels via reduction of S1P lyase (Sply) and by upregulating the serine palmitoyl-CoA transferase catalytic subunit gene lace, the first gene in the de novo sphingolipid biosynthetic pathway and find that these manipulations also reduce muscle degeneration. Furthermore, we show that reduction of spinster (which encodes a major facilitator family transporter, homologs of which in higher animals have been shown to transport S1P) can also suppress dystrophic muscle degeneration. Finally, administration to adult flies of pharmacological agents reported to elevate S1P signaling significantly suppresses dystrophic muscle phenotypes. Our data suggest that localized intracellular S1P elevation promotes the suppression of muscle wasting in flies.

Dystroglycan and mitochondrial ribosomal protein L34 regulate differentiation in the Drosophila eye.

Mutations that diminish the function of the extracellular matrix receptor Dystroglycan (DG) result in muscular dystrophies, with associated neuronal migration defects in the brain and mental retardation e.g. Muscle Eye Brain Disease. To gain insight into the function of DG in the nervous system we initiated a study to examine its contribution to development of the eye of Drosophila melanogaster. Immuno-histochemistry showed that DG is concentrated on the apical surface of photoreceptors (R) cells during specification of cell-fate in the third instar larva and is maintained at this location through early pupal stages. In point mutations that are null for DG we see abortive R cell elongation during differentiation that first appears in the pupa and results in stunted R cells in the adult. Overexpression of DG in R cells results in a small but significant increase in their size. R cell differentiation defects appear at the same stage in a deficiency line Df(2R)Dg(248) that affects Dg and the neighboring mitochondrial ribosomal gene, mRpL34. In the adult, these flies have severely disrupted R cells as well as defects in the lens and ommatidia. Expression of an mRpL34 transgene rescues much of this phenotype. We conclude that DG does not affect neuronal commitment but functions R cell autonomously to regulate neuronal elongation during differentiation in the pupa. We discuss these findings in view of recent work implicating DG as a regulator of cell metabolism and its genetic interaction with mRpL34, a member of a class of mitochondrial genes essential for normal metabolic function.

Genetic modifier screens reveal new components that interact with the Drosophila dystroglycan-dystrophin complex.

The Dystroglycan-Dystrophin (Dg-Dys) complex has a capacity to transmit information from the extracellular matrix to the cytoskeleton inside the cell. It is proposed that this interaction is under tight regulation; however the signaling/regulatory components of Dg-Dys complex remain elusive. Understanding the regulation of the complex is critical since defects in this complex cause muscular dystrophy in humans. To reveal new regulators of the Dg-Dys complex, we used a model organism Drosophila melanogaster and performed genetic interaction screens to identify modifiers of Dg and Dys mutants in Drosophila wing veins. These mutant screens revealed that the Dg-Dys complex interacts with genes involved in muscle function and components of Notch, TGF-beta and EGFR signaling pathways. In addition, components of pathways that are required for cellular and/or axonal migration through cytoskeletal regulation, such as Semaphorin-Plexin, Frazzled-Netrin and Slit-Robo pathways show interactions with Dys and/or Dg. These data suggest that the Dg-Dys complex and the other pathways regulating extracellular information transfer to the cytoskeletal dynamics are more intercalated than previously thought.

Agrobacterium type IV secretion is a two-step process in which export substrates associate with the virulence protein VirJ in the periplasm.

Type IV secretion systems are virulence determinants in many bacteria and share extensive homology with many conjugal transfer systems. Although type IV systems and their homologues have been studied widely, the mechanism by which substrates are secreted remains unclear. In Agrobacterium, we show that type IV secretion substrates that lack signal peptides form a soluble complex in the periplasm with the virulence protein VirJ. Additionally, these proteins co-precipitate with constituents of the type IV transporter: the VirB pilus and the VirD4 protein. Our findings suggest that the substrate proteins localized to the periplasm may associate with the pilus in a manner that is mediated by VirJ, and suggest a two-step process for type IV secretion in Agrobacterium. Our analyses of protein-protein interactions in a variety of mutant backgrounds indicate that substrates are probably secreted independently of one another.

Situación de Salud de los Trabajadores en Bolivia y Propuesta de un Plan Nacional de Salud Ocupacional / Health situation of workman of Bolivia and propalal of a National Plan of Occupational Health

El presente informe trata precisamente de analizar la naturaleza, la importancia de las implicaciones de esa problemática, para luego, en su mérito, plantear las soluciones que consideramos pertinentes. La importancia social, económica y política del trabajo es objeto de la mas grande atención en todos los países, por cuanto una de las funciones más importantes del trabajo consiste en producir y distribuir bienes y servicios de los cuales se beneficia el propio trabajador.