Role of the human concentrative nucleoside transporter (hCNT1) in the cytotoxic action of 5[Prime]-deoxy-5-fluorouridine, an active intermediate metabolite of capecitabine, a novel oral anticancer drug.

We attempt to identify the plasma membrane transporter involved in the uptake of 5'-deoxy-5-fluorouridine (5'-DFUR), an intermediate metabolite of capecitabine. This novel oral fluoropyrimidine is used in cancer treatments and is a direct precursor of the cytostatic agent 5'-fluorouracil. We also examine the role of the transporter in 5'-DFUR cytotoxicity. The human concentrative nucleoside transporter (hCNT1) was cloned from human fetal liver and expressed in Xenopus laevis oocytes. The two-electrode voltage-clamp technique was used to demonstrate that 5'-DFUR, but not capecitabine or 5'-FU, is an hCNT1 substrate. Then, hCNT1 was heterologously expressed in the mammalian cell line Chinese hamster ovary-K1. Functional expression was demonstrated by monitoring transport of radiolabeled substrates and by using a monospecific polyclonal antibody generated against the transporter. hCNT1-expressing cells were more sensitive to 5'-DFUR than vector-transfected or wild-type cells. The sensitivity of the three cell types to other agents such as cisplatin or 5'-FU was identical. In conclusion, this study shows that 1) the pharmacological profile of a nucleoside transporter can be determined by an electrophysiological approach; 2) the hCNT1 transporter is involved in 5'-DFUR uptake; and 3) hCNT1 expression may increase cell sensitivity to 5'-DFUR treatment. This study also reports for the first time the generation of an antibody against hCNT1, which may be useful in the elucidation of the relationship between hCNT1 expression and tumor response to capecitabine treatmen

Use it or lose it! Cognitive activity as a protec-tive factor for cognitive decline associated with Alzheimer's disease.

Because of the worldwide aging of populations, Alzheimer's disease and other dementias constitute a devastating experience for patients and families as well as a major social and economic burden for both healthcare systems and society. Multiple potentially modifiable cardiovascular and lifestyle risk factors have been associated with this disease. Thus, modifying these risk factors and identifying protective factors represent important strategies to prevent and delay disease onset and to decrease the social burden. Based on the cognitive reserve hypothesis, evidence from epidemiological studies shows that low education and cognitive inactivity constitute major risk factors for dementia. This indicates that a cognitively active lifestyle may protect against cognitive decline or delay the onset of dementia. We describe a newly developed preventive programme, based on this evidence, to stimulate and increase cognitive activity in older adults at risk for cognitive decline. This programme, called "BrainCoach", includes the technique of "motivational interviewing" to foster behaviour change. If the planned feasibility study is successful, we propose to add BrainCoach as a module to the already existing "Health Coaching" programme, a Swiss preventive programme to address multiple risk factors in primary care

Long-term effect of 2 intensive statin regimens on treatment and incidence of cardiovascular events in familial hypercholesterolemia : The SAFEHEART study

Funding: This study was supported by Fundación Hipercolesterolemia Familiar; Grant G03/181 Grant 08-2008 Centro Nacional de Investigaci?n Cardiovascular (CNIC).Background: Maximal doses of potent statins are the basement of treatment of familial hypercholesterolemia (FH). Little is known about the use of different statin regimens in FH. Objectives: The objectives of the study were to describe the treatment changes and low-density lipoprotein cholesterol (LDL-C) goal achievement with atorvastatin (ATV) and rosuvastatin (RV) in the SAFEHEART cohort, as well as to analyze the incidence of atherosclerotic cardiovascular events (ACVEs) and changes in the cardiovascular risk. Methods: SAFEHEART is a prospective follow-up nationwide cohort study in a molecularly defined FH population. The patients were contacted on a yearly basis to obtain relevant changes in life habits, medication, and ACVEs. Results: A total of 1939 patients were analyzed. Median follow-up was 6.6 years (5-10). The estimated 10-year risk according the SAFEHEART risk equation was 1.61 (0.67-3.39) and 1.22 (0.54-2.93) at enrollment for ATV and RV, respectively (P <.001). There were no significant differences at the follow-up: 1.29 (0.54-2.82) and 1.22 (0.54-2.76) in the ATV and RV groups, respectively (P =.51). Sixteen percent of patients in primary prevention with ATV and 18% with RV achieved an LDL-C <100 mg/dL and 4% in secondary prevention with ATV and 5% with RV achieved an LDL-C <70 mg/dL. The use of ezetimibe was marginally greater in the RV group. One hundred sixty ACVEs occurred during follow-up, being its incidence rate 1.1 events/100 patient-years in the ATV group and 1.2 in the RV group (P =.58). Conclusion: ATV and RV are 2 high-potency statins widely used in FH. Although the reduction in LDL-C levels was greater with RV than with ATV, the superiority of RV for reducing ACVEs was not demonstrated

The comparative responsiveness of Hospital Universitario Princesa Index and other composite indices for assessing rheumatoid arthritis activity

Objective To evaluate the responsiveness in terms of correlation of the Hospital Universitario La Princesa Index (HUPI) comparatively to the traditional composite indices used to assess disease activity in rheumatoid arthritis (RA), and to compare the performance of HUPI-based response criteria with that of the EULAR response criteria. Methods Secondary data analysis from the following studies: ACT-RAY (clinical trial), PROAR (early RA cohort) and EMECAR (pre-biologic era long term RA cohort). Responsiveness was evaluated by: 1) comparing change from baseline (Delta) of HUPI with Delta in other scores by calculating correlation coefficients; 2) calculating standardised effect sizes. The accuracy of response by HUPI and by EULAR criteria was analyzed using linear regressions in which the dependent variable was change in global assessment by physician (Delta GDA-Phy). Results Delta HUPI correlation with change in all other indices ranged from 0.387 to 0.791); HUPI's standardized effect size was larger than those from the other indices in each database used. In ACT-RAY, depending on visit, between 65 and 80% of patients were equally classified by HUPI and EULAR response criteria. However, HUPI criteria were slightly more stringent, with higher percentage of patients classified as non-responder, especially at early visits. HUPI response criteria showed a slightly higher accuracy than EULAR response criteria when using Delta GDA-Phy as gold standard. Conclusion HUPI shows good responsiveness in terms of correlation in each studied scenario (clinical trial, early RA cohort, and established RA cohort). Response criteria by HUPI seem more stringent than EULAR''s

Estudio comparativo de los macrohongos presentes en troncos de roble en dos bosques montanos neotropicales de Costa Rica

Abstract: The presence of macrofungi on dead oak wood was studied in two neotropical montane forests in Costa Rica during 2008-2012. The two sites chosen for the study were a mature forest (approx. 200 yr. old) and a secondary forest (32 yr. old). One hundred and eighty-one taxa (80 species and 101 morpho species) were identified. A similar number of species was present in both forests, but there were some differences in the species composition of each forest. According to the results, it is suggested that the percentage of different and shared species could each represent a third of the diversity present in these forests. Xylobolus subpileatus and Hymenochaete rubiginosa were the most common species in both forests. Several ectomycorrhizal species were found growing on logs, and the genera most commonly found were: Inocybe, Cortinarius, Laccaria, Leccinum and Russula. The relationship between fungal fructifications and the environmental conditions present during the study period is discussed, as well as the importance of conserving fragments of secondary forest.Resumen: Se estudió la presencia de macrohongos en troncos caídos de roble en dos bosques montanos neotropicales en Costa Rica durante los años 2008-2012. Se seleccionó un bosque maduro (aprox. de 200 años) y uno en proceso de regeneración (32 años). Se identificaron 181 taxones (80 especies y 101 morfoespecies). Un número similar de especies se presentó en ambos bosques, aunque la composición de éstas fue diferente en cada uno. De acuerdo a los resultados obtenidos, se sugiere que los porcentajes de especies diferentes y compartidas para cada bosque, pueden representar cada uno un tercio de la diversidad presente en estos bosques. Xylobolus subpileatus e Hymenochaete rubiginosa fueron las especies más comunes. Varias especies de hongos ectomicorrízicos se encontraron sobre los troncos caídos, pertenecientes principalmente a los géneros Inocybe, Cortinarius, Laccaria, Leccinum y Russula. Se discute la relación entre la aparición de los cuerpos fructíferos y las condiciones ambientales presentes durante el periodo de estudio; así como la importancia de la conservación de estos bosques en procesos de regeneración

Descomposición de la madera de roble (Quercus spp.) in vivo e in vitro

ABSTRACT Wood decomposition produces a considerable flow of carbon in the ecosystem, but decomposition rates have been observed to change in tropical areas compared with temperate ones, and are affected by the type of wood and the fungal community involved in the process. Several studies have been carried out with oak wood decomposition in temperate zones but they are scarce or lacking in highland tropical areas. The aim of this study was to determine the degree of decay (1-4) of logs and stumps in two neotropical montane forests in Costa Rica, and to observe the decomposition of oak wood samples exposed to selected fungi under laboratory conditions. The most common decay category in the logs and stumps was 1, and it remained that way during the whole study. Xylobolus subpileatus, Hymenochaete rubiginosa, and Trametes versicolor were selected for the decay studies. Twenty-five decay chambers with oak wood samples were inoculated with each fungus. After 4 or 8 months of exposure, wood samples were removed to determine weight loss. Considerable variation was observed in weight loss (2.08-51.06%), depending on the fungi selected. In light of our results, the duration of the oak decay process in these neotropical montane forests is discussed, as well as its carbon contribution to the ecosystem.RESUMEN La descomposición de los restos de madera en los bosques ocasiona un flujo considerable de carbono. Las tasas de descomposición varían en zonas templadas y tropicales y de acuerdo al tipo de madera y a los hongos que están involucrados en este proceso. Varios estudios relacionados con la descomposición de la madera de roble han sido llevados a cabo en zonas templadas, pero éstos son escasos o inexistentes en bosques neotropicales de altura. Esta investigación se llevó a cabo para determinar el avance en los niveles de podredumbre (1-4) de troncos y tocones de roble en un bosque primario y en uno secundario en Costa Rica, en diferentes estaciones a lo largo de cinco años, así como para observar el proceso de descomposición en muestras de madera de roble, expuestas a hongos seleccionados en condiciones de laboratorio. Los niveles de podredumbre de los troncos y tocones en los bosques se mantuvieron ˗en su mayoría˗ en el nivel 1 durante todo el estudio. Para las pruebas de podredumbre se seleccionaron tres hongos comunes en los troncos de roble: Xylobolus subpileatus, Hymenochaete rubiginosa y Trametes versicolor, y se utilizaron bloques de madera provenientes de ramas de árboles de la zona de estudio. Se montaron 25 cámaras de podredumbre para cada hongo, y los bloques de madera se removieron a los cuatro u ocho meses para determinar las pérdidas de peso. Se obtuvo una gran variación en los porcentajes de pérdidas de peso (2.08-51.06%), en todos los tratamientos. Con base en los resultados obtenidos, se discute la posible duración de la descomposición total de la madera de roble en estos bosques neotropicales y su aporte de carbono al ecosistema