Rifampicina y biodisponibilidad en productos combinados

The drug rifampicin (R) is used as a first line antibiotic treatment for tuberculosis (TB), together withIsoniazide (H), Pyrazinamide (Z) and Ethambutol (E). According to recent statistics, there has been anincrease in TB on a worldwide scale, with the main causes being: monotherapies, the appearance ofresistant microorganisms, the lack of effective preventative programs, non-compliance to treatment andmistaken dosage schedules. The world health organisation (WHO) and the International Union AgainstTuberculosis and Lung Diseases(IUTALD) declared a state of emergency with respect to the disease andestablished programs to increase compliance to therapy and to reduce the incidence of problems arisingfrom such. Along these lines, a list of first line drug therapy treatments were established, whichincluded R, Z, H & E combinations at fixed dosage combinations (FDC), permitting safe combinedadministrations of the drugs at correct dosage levels. These fixed dose combinations have been officiallyrecommended by the WHO in the treatment of TB. However, as has been widely recognised in numerousscientific publications, in such formulations, there are factors that alter the bioavailability of R. Theobjective of this work has been to study the most relevant aspects concerning R bioavailability alterationsand to consider possible solutions to the problem.La rifampicina (R) es un antibiótico de primera elección en el tratamiento de la tuberculosis (TB) juntoa la Isoniazida (H), Pirazinamida (Z) y Etambutol (E). De acuerdo a las últimas estadísticas, la TBaumentó a nivel mundial y entre las causas más citadas figuran: las monoterapias, la aparición demicroorganismos resistentes, la carencia de programas efectivos, el incumplimiento en el tratamiento ylas dosis erróneas. La Organización Mundial de la Salud (OMS) y la Unión Internacional Contra laTuberculosis y Enfermedades de Pulmón (IUATLD) declararon a la enfermedad en emergencia mundialy establecieron programas terapéuticos para asegurar el cumplimiento y disminuir los problemas relacionadosa la terapia. Sobre esta base, figura en la lista oficial la asociación de los cuatro fármacos deprimera línea R, Z, H y E combinados en dosis fijas (FDC) que permiten la administración conjunta delos mismos y, en las dosis correctas. Los productos FDC son recomendados oficialmente por la OMSpara el tratamiento de la TB. No obstante existen factores que alteran la biodisponibilidad de la R enestas formulaciones, hecho ampliamente reconocido en publicaciones científicas. El objetivo de estetrabajo es estudiar los aspectos más relevantes que alteran la biodisponibilidad de la R en los productosFDC y plantear posibles soluciones al problema

Rifampicina y biodisponibilidad en productos combinados

The drug rifampicin (R) is used as a first line antibiotic treatment for tuberculosis (TB), together withIsoniazide (H), Pyrazinamide (Z) and Ethambutol (E). According to recent statistics, there has been anincrease in TB on a worldwide scale, with the main causes being: monotherapies, the appearance ofresistant microorganisms, the lack of effective preventative programs, non-compliance to treatment andmistaken dosage schedules. The world health organisation (WHO) and the International Union AgainstTuberculosis and Lung Diseases(IUTALD) declared a state of emergency with respect to the disease andestablished programs to increase compliance to therapy and to reduce the incidence of problems arisingfrom such. Along these lines, a list of first line drug therapy treatments were established, whichincluded R, Z, H & E combinations at fixed dosage combinations (FDC), permitting safe combinedadministrations of the drugs at correct dosage levels. These fixed dose combinations have been officiallyrecommended by the WHO in the treatment of TB. However, as has been widely recognised in numerousscientific publications, in such formulations, there are factors that alter the bioavailability of R. Theobjective of this work has been to study the most relevant aspects concerning R bioavailability alterationsand to consider possible solutions to the problem.La rifampicina (R) es un antibiótico de primera elección en el tratamiento de la tuberculosis (TB) juntoa la Isoniazida (H), Pirazinamida (Z) y Etambutol (E). De acuerdo a las últimas estadísticas, la TBaumentó a nivel mundial y entre las causas más citadas figuran: las monoterapias, la aparición demicroorganismos resistentes, la carencia de programas efectivos, el incumplimiento en el tratamiento ylas dosis erróneas. La Organización Mundial de la Salud (OMS) y la Unión Internacional Contra laTuberculosis y Enfermedades de Pulmón (IUATLD) declararon a la enfermedad en emergencia mundialy establecieron programas terapéuticos para asegurar el cumplimiento y disminuir los problemas relacionadosa la terapia. Sobre esta base, figura en la lista oficial la asociación de los cuatro fármacos deprimera línea R, Z, H y E combinados en dosis fijas (FDC) que permiten la administración conjunta delos mismos y, en las dosis correctas. Los productos FDC son recomendados oficialmente por la OMSpara el tratamiento de la TB. No obstante existen factores que alteran la biodisponibilidad de la R enestas formulaciones, hecho ampliamente reconocido en publicaciones científicas. El objetivo de estetrabajo es estudiar los aspectos más relevantes que alteran la biodisponibilidad de la R en los productosFDC y plantear posibles soluciones al problema

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Published evidence suggests a strong association between nutrition and the development and maintenance of tumoral processes. In Córdoba, a greater adherence to dietary patterns (DP) provided by carbohydrates- and saturated fatty acids-rich food, represented mainly by fructose (F) and palmitic acid (PA), is positively associated with the risk of colorectal and breast cancer. However, the cellular mechanisms by which these components promote tumor aggressiveness are not fully understood. Our objective was to evaluate in vitro the role of tumor-associated fibroblasts (CAFs) as mediators of the proliferative effects of F and PA. F88 cell line, corresponding to human breast cancer CAFs, was grown in DMEM with 10% FBS and stimulated with F 40 mM, AP 250 uM, combinations of both (F+PA) or their respective vehicles, for 24 hours (characteristic concentrations of DP in Cordoba). Subsequently, supernatants were removed, total proteins were quantified and stored at -80 °C for assays. Breast epithelial tumor cells of the MCF7 line were cultured in DMEM medium with 10% FBS and then stimulated with conditioned media (from F88 cells) for 24 hours. As controls, conditioned media from vehicle-treated cells were used. Any of the stimuli did not cause statistically significant changes in F88 cell proliferation. F + AP combination did induce a strong phenotypic change, with greater development of proteinopoietic and secretory organelles when observed by transmission electron microscopy. In addition, stimuli with PA and F + PA produced a decrease in the expression of Fibroblast Activation Protein (FAP) by western blot. On the other hand, MCF7 cells when stimulated with conditioned media from F88 treated with F + PA showed an increase in cell proliferation (ANOVA, p <0.05), determined by incorporation of bromodeoxyuridine and cell count. However, there were no significant differences between F and PA individually. These results suggest a pathogenic effect of food rich in F and PA on tumor proliferation in breast cancer, which would be mediated by CAFs. Numerosas evidencias señalan una fuerte asociación entre componentes nutricionales y el desarrollo y mantenimiento de procesos tumorales. En Córdoba, se describió que la mayor adherencia a patrones dietarios (PD) provistos por alimentos ricos en carbohidratos y ácidos grasos saturados, representados principalmente por fructosa (F) y ácido palmítico (AP) respectivamente, se asocia positivamente al riesgo de cáncer colorrectal y de mama. Sin embargo, no se conocen completamente los mecanismos celulares por los cuales estos componentes promoverían mayor agresividad tumoral. Nuestro objetivo fue evaluar in vitro el rol de los fibroblastos asociados a tumores (CAFs) como mediadores de posibles efectos proliferativos de F y AP. Para ello, células de la línea F88, correspondientes a CAFs de cáncer mamario humano fueron crecidas en medio DMEM con 10% SFB y estimuladas con F 40 mM, AP 250 uM, combinaciones de ambos (F+AP) o sus respectivos vehículos, por 24 horas (concentraciones características de PD cordobeses). Posteriormente, se retiraron sobrenadantes, se cuantificaron proteínas totales y se guardaron a -80 °C para los ensayos posteriores. Células tumorales epiteliales de mama de la línea MCF7 fueron cultivadas en medio DMEM con 10% SFB y posteriormente estimuladas con los medios condicionados (provenientes de las células F88) por 24 horas. Como controles, se utilizaron los medios condicionados de células tratadas con vehículo. Los estímulos no provocaron cambios estadísticamente significativos en la proliferación celular de las F88, aunque la combinación F+AP sí indujo un fuerte cambio fenotípico, con mayor desarrollo de organelas proteinopoiéticas y secretorias al ser observadas por microscopía electrónica de transmisión. Además, los estímulos con AP y F+AP produjeron una disminución en la expresión de Fibroblast Activation Protein (FAP) por western blot.  Por otro lado, las células MCF7 al ser estimuladas con medios condicionados provenientes de F88 tratadas con F+AP mostraron un incremento en la proliferación celular (ANOVA, p<0,05), determinada mediante incorporación de bromodeoxiuridina y conteo celular. No obstante, no hubo diferencias significativas entre F y AP en forma individual. Estos resultados sugieren un efecto patogénico de alimentos ricos en F y AP sobre la proliferación tumoral en el cáncer de mama, que sería mediado por CAFs.

Mexico City and the biogeochemistry of global urbanization

Mexico City is far advanced in its urban evolution, and cities in currently developing nations may soon follow a similar course. This paper investigates the strengths and weaknesses of infrastructures for the emerging megacities. The major driving force for infrastructure change in Mexico City is concern over air quality. Air chemistry data from recent field campaigns have been used to calculate fluxes in the atmosphere of the Valley of Mexico, for compounds that are important to biogeochemistry including methane (CH4), carbon monoxide (CO), nonmethane hydrocarbons (NMHCs), ammonia (NH3), sulfur dioxide (SO2), nitrogen oxides (NOx and NOy), soot, and dust. Leakage of liquified petroleum gas approached 10% during sampling periods, and automotive pollutant sources in Mexico City were found to match those in developed cities, despite a lower vehicle-to-person ratio of 0.1. Ammonia is released primarily from residential areas, at levels sufficient to titrate pollutant acids into particles across the entire basin. Enhancements of reduced nitrogen and hydrocarbons in the vapor phase skew the distribution of NOy species towards lower average deposition velocities. Partly as a result, downwind nutrient deposition occurs on a similar scale as nitrogen fixation across Central America, and augments marine nitrate upwelling. Dust suspension from unpaved roads and from the bed of Lake Texcoco was found to be comparable to that occurring on the periphery of the Sahara, Arabian, and Gobi deserts. In addition, sodium chloride (NaCl) in the dust may support heterogeneous chlorine oxide (ClOx) chemistry. The insights from our Mexico City analysis have been tentatively applied to the upcoming urbanization of Asia

Complete re-utilization of waste concretes–Valorisation pathways and research needs

Global demand for buildings and infrastructure is extremely high as provision of shelter, sanitation and healthcare are paramount to safeguard the world's growing population. Concrete is a preferred construction material to meet this demand, but its production is leading to overexploitation of natural gravel and sand, causing an environmental crisis in regions where these materials are extracted unsustainably. Waste concrete is available globally, particularly in regions with fast growth of the built environment, and those struck by coordinated attacks, earthquakes or severe weather events. Waste concrete has mainly been used for producing recycled aggregates; however, its full recycling is still not practiced. Alternative uses include applications as fine recycled aggregates, supplementary cementitious materials, filler, and feedstocks for clinker production. These technologies still face challenges concerning their adoption and eco-efficiency. Restricted knowledge and operational barriers have also prevented implementation of beneficiation technologies for complete re-recycling of waste concretes, particularly the fine fractions produced during crushing. Despite these issues, it is recognised that the complete utilization of waste concrete offers unique opportunities for supply chain security, reducing natural resources consumption and enabling to move towards a Circular Economy. Harmonizing current practices for the treatment of waste concrete and the by-products generated during their processing, is a first step toward policy and standards development to enable their widespread use. This critical discussion addresses challenges and opportunities, as well as facilitation strategies needed to progress the complete re-utilization of waste concrete as a valuable resource for creating sustainable future infrastructure

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Abstract:  The estrogenic action on pituitary cell growth is widely known. We have previously demonstrated the activation of the antioxidant pathway of phosphorylated erythroid 2-derived nuclear factor 2 (p-Nrf2) in response to DNA damage by 17β-estradiol (E2). In this study we analyzed the impact of E2 on the tumoral suppressor p53 and cell cycle regulator p21 activation, as well as the damage response in pituitary cells in vitro. Pituitary tumour development was induced in adult male Wistar rats by subcutaneous implantation of silastic capsules containing estradiol benzoate (30mg) for 10 days (E10; n = 5). The control group was implanted with empty capsules (n=5). Subsequently, pituitary glands were collected, with cells being cultured and exposed to E2 (1-10-100nM) for 15, 30 and 60 min. The p53 and p21 protein levels were determined by western blot. By immunofluorescence, the co-expression of prolactin (PRL)/p-Nrf2 and growth hormone (GH)/p-Nrf2 was evaluated to determinate the cell type involved in the activation of the oxidative damage response. Statistical analysis: ANOVA-Fischer (p <0.05). Under tumoral contexts, a significant increase in p53 protein at the cytoplasmic level was detected after 15 and 30 min of treatment with E2 (1nM). After supraphysiological concentrations (10-100nM), this response was observed after 30 and 60 min. At nuclear level, we only detected an increase in p53 at 15 min, regardless of the dose. The p2 expression showed a similar profile in both subcellular compartments, with significant increases after 15 and 30 min of exposure with 1nM E2 and 30 and 60 min with supraphysiological doses. In normal cells cultures we did not observe significant changes in the expression of both markers. The number of lactotroph tumoral cells co-expressing PRL/p-Nrf2 increased significantly at 30 min compared to supraphysiological doses of E2. No changes were detected in the expression of GH/p-Nrf2 in GH cells. In tumoral pituitary cells, the pro-oxidant action induced by E2 triggers the activation of p53 and p21 in order to repair DNA damage, through the stabilization of Nrf2. This response would mainly have an impact on PRL tumoral cells. These mechanisms could guarantee the cell viability, thus regulating pituitary tumor development.Resumen:  Es ampliamente conocida la acción estrogénica sobre el crecimiento celular hipofisario. Previamente demostramos la activación de la vía antioxidante del factor nuclear 2 derivado del eritroide 2 fosforilado (Nrf2-p) en respuesta al daño del ADN por 17β-estradiol (E2). Analizamos entonces, el impacto del E2 sobre la activación del supresor tumoral p53 y el regulador del ciclo celular p21, y la respuesta al daño en células hipofisarias in vitro. Indujimos el desarrollo tumoral hipofisario en ratas Wistar macho adultas mediante la implantación subcutánea de cápsulas de silástico conteniendo benzoato de estradiol (30 mg) durante 10 días (E10; n=5). El grupo control fue implantado con cápsulas vacía (n=5). Posteriormente, extrajimos las adenohipófisis, cultivamos sus células y fueron expuestas a E2 (1-10-100nM) por 15, 30 y 60min. Determinamos los niveles proteicos de p53 y p21 por western blot. Por inmunofluorescencia, evaluamos la co-expresión de Prolactina (PRL)/Nrf2-p y hormona de crecimiento (GH)/Nrf2-p para determinar el tipo celular involucrado con activación de respuesta al daño oxidativo. Análisis estadístico: ANOVA-Fischer (p <0,05). En contextos tumorales, detectamos un aumento significativo de la proteína p53 a nivel citoplasmático luego de 15 y 30 min de tratamiento con E2 (1nM); frente a concentraciones suprafisiológicas (10-100nM) esta respuesta se observó luego de 30 y 60 min. A nivel nuclear, detectamos un aumento de p53 solo a los 15 min, de manera independiente de la dosis. La expresión de p21 mostró un perfil similar en ambos compartimientos subcelulares con incrementos significativos luego de 15 y 30 min de exposición con E2 1nM y 30 y 60 min con dosis suprafisiológicas. En cultivos normales no observamos cambios significativos en la expresión de ambos marcadores. El número de células lactotropas tumorales que co-expresaron PRL/Nrf2-p aumentó significativamente a los 30 min frente a dosis suprafisiológicas de E2; sin detectarse modificaciones en la expresión de GH/Nrf2-p en células somatotropas. En células hipofisarias tumorales, la acción pro-oxidante inducida por E2 desencadena la activación de p53 y de p21 a fin de reparar el daño del ADN, vía estabilización de Nrf2. Esta respuesta impactaría principalmente sobre células lactotropas tumorales. Mediante estos mecanismos se garantizaría la viabilidad celular, regulando el desarrollo tumoral hipofisario.

Leg length, skull circumference, and the incidence of dementia in Latin America and China: A 10/66 population-based cohort study

\ua9 2018 Prince et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background Adult leg length is influenced by nutrition in the first few years of life. Adult head circumference is an indicator of brain growth. Cross-sectional studies indicate inverse associations with dementia risk, but there have been few prospective studies. Methods Population-based cohort studies in urban sites in Cuba, Dominican Republic Puerto Rico and Venezuela, and rural and urban sites in Peru, Mexico and China. Sociodemographic and risk factor questionnaires were administered to all participants, and anthropometric measures taken, with ascertainment of incident dementia, and mortality, three to five years later. Results Of the original at risk cohort of 13,587 persons aged 65 years and over, 2,443 (18.0%) were lost to follow-up; 10,540 persons with skull circumference assessments were followed up for 40,466 person years, and 10,400 with leg length assessments were followed up for 39,954 person years. There were 1,009 cases of incident dementia, and 1,605 dementia free deaths. The fixed effect pooled meta-analysed adjusted subhazard ratio (ASHR) for leg length (highest vs. lowest quarter) was 0.80 (95% CI, 0.66–0.97) and for skull circumference was 1.02 (95% CI, 0.84–1.25), with no heterogeneity of effect between sites (I2 = 0%). Leg length measurements tended to be shorter at follow-up, particularly for those with baseline cognitive impairment and dementia. However, leg length change was not associated with dementia incidence (ASHR, per cm 1.006, 95% CI 0.992–1.020), and the effect of leg length was little altered after adjusting for baseline frailty (ASHR 0.82, 95% CI 0.67–0.99). A priori hypotheses regarding effect modification by gender or educational level were not supported. However, the effect of skull circumference was modified by gender (M vs F ASHR 0.86, 95% CI 0.75–0.98), but in the opposite direction to that hypothesized with a greater protective effect of larger skull dimensions in men. Conclusions Consistent findings across settings provide quite strong support for an association between adult leg length and dementia incidence in late-life. Leg length is a relatively stable marker of early life nutritional programming, which may confer brain reserve and protect against neu-rodegeneration in later life through mitigation of cardiometabolic risk. Further clarification of these associations could inform predictive models for future dementia incidence in the context of secular trends in adult height, and invigorate global efforts to improve childhood nutrition, growth and development

Successful new product development by optimizing development process effectiveness in highly regulated sectors: the case of the Spanish medical devices sector

Rapid development and commercialization of new products is of vital importance for small and medium sized enterprises (SME) in regulated sectors. Due to strict regulations, competitive advantage can hardly be achieved through the effectiveness of product concepts only. If an SME in a highly regulated sector wants to excell in new product development (NPD) performance, the company should focus on the flexibility, speed, and productivity of its NPD function: i.e. the development process effectiveness. Our main research goals are first to explore if SMEs should focus on their their development process effectiveness rather than on their product concept effectiveness to achieve high NPD performance; and second, to explore whether a shared pattern in the organization of the NPD function can be recognized to affect NPD performance positively. The medical devices sector in Spain is used as an example of a\ud highly regulated sector. A structured survey among 11 SMEs, of which 2 were studied also as in in-depth case studies, led to the following results. First of all, indeed the companies in the dataset which focused on the effectiveness of their development process, stood out in NPD performance. Further, the higher performing companies did have a number of commonalities in the organisation of their NPD function: 1) The majority of the higher performing firms had an NPD strategy characterized by a predominantly incremental project portfolio.\ud 2) a) Successful firms with an incremental project portfolio combined this with a functional team structure b) Successful firms with a radical project portfolio combined this with a heavyweight or autonomous team structure.\ud 3) A negative reciprocal relationship exists between formalization of the NPD processes and the climate of the NPD function, in that a formalized NPD process and an innovative climate do not seem to reinforce each other. Innovative climate combined with an informal NPD process does however contribute positively to NPD performance. This effect was stronger in combination with a radical project portfolio. The highest NPD performance was measured for companies focusing mainly on incremental innovation. It is argued that in highly regulated sectors, companies with an incremental product portfolio would benefit from employing a functional structure. Those companies who choose for a more radical project portfolio in highly regulated sectors should be aware\ud that they are likely to excell only in the longer term by focusing on strategic flexibility. In their NPD organization, they might be well advised to combine informal innovation processes with an innovative climate

Testing in the incremental design and development of complex products

Testing is an important aspect of design and development which consumes significant time and resource in many companies. However, it has received less research attention than many other activities in product development, and especially, very few publications report empirical studies of engineering testing. Such studies are needed to establish the importance of testing and inform the development of pragmatic support methods. This paper combines insights from literature study with findings from three empirical studies of testing. The case studies concern incrementally developed complex products in the automotive domain. A description of testing practice as observed in these studies is provided, confirming that testing activities are used for multiple purposes depending on the context, and are intertwined with design from start to finish of the development process, not done after it as many models depict. Descriptive process models are developed to indicate some of the key insights, and opportunities for further research are suggested