A multi-target antisense approach against PDE4 and PDE7 reduces smoke-induced lung inflammation in mice

<p>Abstract</p> <p>Background</p> <p>Recent development in the field of COPD has focused on strategies aimed at reducing the underlying inflammation through selective inhibition of the phosphodiesterase type IV (PDE4) isoform. Although the anti-inflammatory and bronchodilator activity of selective PDE4 inhibitors has been well documented, their low therapeutic ratio and dose-dependent systemic side effects have limited their clinical utility. This study examined the effect of 2'-deoxy-2'-Fluoro-β-D-Arabinonucleic Acid (FANA)-containing antisense oligonucleotides (AON) targeting the mRNA for the PDE4B/4D and 7A subtypes on lung inflammatory markers, both <it>in vitro </it>and <it>in vivo</it>.</p> <p>Methods</p> <p>Normal human bronchial epithelial (NHBE) cells were transfected with FANA AON against PDE4B/4D and 7A alone or in combination. mRNA levels for target PDE subtypes, as well as secretion of pro-inflammatory chemokines were then measured following cell stimulation. Mice were treated with combined PDE4B/4D and 7A AON via endo-tracheal delivery, or with roflumilast via oral delivery, and exposed to cigarette smoke for one week. Target mRNA inhibition, as well as influx of inflammatory cells and mediators were measured in lung lavages. A two-week smoke exposure protocol was also used to test the longer term potency of PDE4B/4D and 7A AONs.</p> <p>Results</p> <p>In NHBE cells, PDE4B/4D and 7A AONs dose-dependently and specifically inhibited expression of their respective target mRNA. When used in combination, PDE4B/4D and 7A AONs significantly abrogated the cytokine-induced secretion of IL-8 and MCP-1 to near baseline levels. In mice treated with combined PDE4B/4D and 7A AONs and exposed to cigarette smoke, significant protection against the smoke-induced recruitment of neutrophils and production of KC and pro-MMP-9 was obtained, which was correlated with inhibition of target mRNA in cells from lung lavages. In this model, PDE AONs exerted more potent and broader anti-inflammatory effects against smoke-induced lung inflammation than roflumilast. Moreover, the protective effect of PDE4B/4D and 7A AON was maintained when a once-weekly treatment schedule was used.</p> <p>Conclusion</p> <p>These results indicate that inhaled AON against PDE4B/4D and 7A have unique effects on biomarkers that are believed to be important in the pathophysiology of COPD, which supports further development as a potential therapy in this disease.</p

Integración económica en el mundo globalizado de las comunidades indígenas a través del modelo cooperativo

El presente trabajo es resultado de la investigación del Comité Académico “Comunidades indígenas y cooperativismo”, en el que se conjuntan el estudio de cinco realidades autóctonas de América. El encuentro de diversas realidades, desde la etnia Innu de Québec, pasando por la comunidad Otomí de México, la etnia Páez de Colombia, hasta el otro extremo del continente con los Aymarás en Chile y los Kollas en Argentina, conducen a desarrollar un rico conglomerado de particularidades culturales con un denominador común, en todas ellas, se han desarrollado distintas experiencias basadas en el modelo cooperativista como opción para su desarrollo. El estudio de caso permitió evaluar la aplicabilidad del modelo cooperativo como estrategia de etnodesarrollo para las comunidades indígenas en América. La investigación que aquí se presenta abre nuevas líneas de debate en torno al tema, pues como un modelo integrado e integrante, devela el potencial de una filosofía que, a través de la educación se abre a las culturas promoviéndolas. La transformación que subyace en las experiencias estudiadas posee el potencial de ser la respuesta a los embates de la globalización que excluye a las minorías indígenas provocando la desaparición de sus culturas.The present work is the result of the investigation of the Academic Committee “Comunidades indígenas y cooperativismo” (Indigenous Communities and Economical Cooperative system), in which we find the study of five indigenous realities from the north to the south of America. From the Quebec Innus’ ethnic group to the Mexican Otomi community, from the Colombian Páez ethnic group to, at the other end of the continent, the Chilean Aymarás and the Argentinian Kollas, The encounter of diverse realities allowed us to acknowledge a rich group of cultural features with a common denominator: the cooperative model as an option for their development. The method of case study allowed us to assess the applicability of the cooperative model as a strategy for the ethno‐development of indigenous communities in America. The work which we now present, result in new lines of debate around a model integrated and integrating to the particular philosophical functionalities which, through education, opens up to cultures and in fact even promotes them. The transformation that underlies the experiences that have been studied could reveal itself to be a valuable response to the forces of globalization that exclude the indigenous minority and cause the disappearance of their cultures.Facultad de Ciencias Económica

Integración económica en el mundo globalizado de las comunidades indígenas a través del modelo cooperativo

El presente trabajo es resultado de la investigación del Comité Académico “Comunidades indígenas y cooperativismo”, en el que se conjuntan el estudio de cinco realidades autóctonas de América. El encuentro de diversas realidades, desde la etnia Innu de Québec, pasando por la comunidad Otomí de México, la etnia Páez de Colombia, hasta el otro extremo del continente con los Aymarás en Chile y los Kollas en Argentina, conducen a desarrollar un rico conglomerado de particularidades culturales con un denominador común, en todas ellas, se han desarrollado distintas experiencias basadas en el modelo cooperativista como opción para su desarrollo. El estudio de caso permitió evaluar la aplicabilidad del modelo cooperativo como estrategia de etnodesarrollo para las comunidades indígenas en América. La investigación que aquí se presenta abre nuevas líneas de debate en torno al tema, pues como un modelo integrado e integrante, devela el potencial de una filosofía que, a través de la educación se abre a las culturas promoviéndolas. La transformación que subyace en las experiencias estudiadas posee el potencial de ser la respuesta a los embates de la globalización que excluye a las minorías indígenas provocando la desaparición de sus culturas.The present work is the result of the investigation of the Academic Committee “Comunidades indígenas y cooperativismo” (Indigenous Communities and Economical Cooperative system), in which we find the study of five indigenous realities from the north to the south of America. From the Quebec Innus’ ethnic group to the Mexican Otomi community, from the Colombian Páez ethnic group to, at the other end of the continent, the Chilean Aymarás and the Argentinian Kollas, The encounter of diverse realities allowed us to acknowledge a rich group of cultural features with a common denominator: the cooperative model as an option for their development. The method of case study allowed us to assess the applicability of the cooperative model as a strategy for the ethno‐development of indigenous communities in America. The work which we now present, result in new lines of debate around a model integrated and integrating to the particular philosophical functionalities which, through education, opens up to cultures and in fact even promotes them. The transformation that underlies the experiences that have been studied could reveal itself to be a valuable response to the forces of globalization that exclude the indigenous minority and cause the disappearance of their cultures.Facultad de Ciencias Económica

Integración económica en el mundo globalizado de las comunidades indígenas a través del modelo cooperativo

El presente trabajo es resultado de la investigación del Comité Académico “Comunidades indígenas y cooperativismo”, en el que se conjuntan el estudio de cinco realidades autóctonas de América. El encuentro de diversas realidades, desde la etnia Innu de Québec, pasando por la comunidad Otomí de México, la etnia Páez de Colombia, hasta el otro extremo del continente con los Aymarás en Chile y los Kollas en Argentina, conducen a desarrollar un rico conglomerado de particularidades culturales con un denominador común, en todas ellas, se han desarrollado distintas experiencias basadas en el modelo cooperativista como opción para su desarrollo. El estudio de caso permitió evaluar la aplicabilidad del modelo cooperativo como estrategia de etnodesarrollo para las comunidades indígenas en América. La investigación que aquí se presenta abre nuevas líneas de debate en torno al tema, pues como un modelo integrado e integrante, devela el potencial de una filosofía que, a través de la educación se abre a las culturas promoviéndolas. La transformación que subyace en las experiencias estudiadas posee el potencial de ser la respuesta a los embates de la globalización que excluye a las minorías indígenas provocando la desaparición de sus culturas.The present work is the result of the investigation of the Academic Committee “Comunidades indígenas y cooperativismo” (Indigenous Communities and Economical Cooperative system), in which we find the study of five indigenous realities from the north to the south of America. From the Quebec Innus’ ethnic group to the Mexican Otomi community, from the Colombian Páez ethnic group to, at the other end of the continent, the Chilean Aymarás and the Argentinian Kollas, The encounter of diverse realities allowed us to acknowledge a rich group of cultural features with a common denominator: the cooperative model as an option for their development. The method of case study allowed us to assess the applicability of the cooperative model as a strategy for the ethno‐development of indigenous communities in America. The work which we now present, result in new lines of debate around a model integrated and integrating to the particular philosophical functionalities which, through education, opens up to cultures and in fact even promotes them. The transformation that underlies the experiences that have been studied could reveal itself to be a valuable response to the forces of globalization that exclude the indigenous minority and cause the disappearance of their cultures.Facultad de Ciencias Económica

Assessment of exposure to Plasmodium falciparum transmission in a low endemicity area by using multiplex fluorescent microsphere-based serological assays

Background: The evaluation of malaria transmission intensity is a crucial indicator for estimating the burden of malarial disease. In this respect, entomological and parasitological methods present limitations, especially in low transmission areas. The present study used a sensitive multiplex assay to assess the exposure to Plasmodium falciparum infection in children living in an area of low endemicity. In three Senegalese villages, specific antibody (IgG) responses to 13 pre-erythrocytic P. falciparum peptides derived from Lsa1, Lsa3, Glurp, Salsa, Trap, Starp, Csp and Pf11.1 proteins were simultaneously evaluated before (June), at the peak (September) and after (December) the period of malaria transmission, in children aged from 1 to 8 years. Results: Compared to other antigens, a high percentage of seropositivity and specific antibody levels were detected with Glurp, Salsa1, Lsa3NR2, and Lsa1J antigens. The seropositivity increased with age for all tested antigens. Specific IgG levels to Glurp, Salsa1, Lsa3NR2, and Lsa1J were significantly higher in P. falciparum infected children compared to non-infected and this increase is significantly correlated with parasite density. Conclusion: The multiplex assay represents a useful technology for a serological assessment of rapid variations in malaria transmission intensity, especially in a context of low parasite rates. The use of such combined serological markers (i.e. Glurp, Lsa1, Lsa3, and Salsa) could offer the opportunity to examine these variations over time, and to evaluate the efficacy of integrated malaria control strategies

Micronutrient Deficits Are Still Public Health Issues among Women and Young Children in Vietnam

Background: The 2000 Vietnamese National Nutrition Survey showed that the population’s dietary intake had improved since 1987. However, inequalities were found in food consumption between socioeconomic groups. As no national data exist on the prevalence of micronutrient deficiencies, a survey was conducted in 2010 to assess the micronutrient status of randomly selected 1526 women of reproductive age and 586 children aged 6–75 mo. Principal Findings: In women, according to international thresholds, prevalence of zinc deficiency (ZnD, 67.262.6%) and vitamin B12 deficiency (11.761.7%) represented public health problems, whereas prevalence of anemia (11.661.0%) and iron deficiency (ID, 13.761.1%) were considered low, and folate (,3%) and vitamin A (VAD,,2%) deficiencies were considered negligible. However, many women had marginal folate (25.1%) and vitamin A status (13.6%). Moreover, overweight (BMI$23 kg/m 2 for Asian population) or underweight occurred in 20 % of women respectively highlighting the double burden of malnutrition. In children, a similar pattern was observed for ZnD (51.963.5%), anemia (9.161.4%) and ID (12.961.5%) whereas prevalence of marginal vitamin A status was also high (47.362.2%). There was a significant effect of age on anemia and ID prevalence, with the youngest age group (6–17 mo) having the highest risk for anemia, ID, ZnD and marginal vitamin A status as compared to other groups. Moreover, the poorest groups of population had a higher risk for zinc, anemia and ID