Developments in renal pharmacogenomics and applications in chronic kidney disease

Chronic kidney disease (CKD) has shown an increasing prevalence in the last century. CKD encompasses a poor prognosis related to a remarkable number of comorbidities, and many patients suffer from this disease progression. Once the factors linked with CKD evolution are distinguished, it will be possible to provide and enhance a more intensive treatment to high-risk patients. In this review, we focus on the emerging markers that might be predictive or related to CKD progression physiopathology as well as those related to a different pattern of response to treatment, such as inhibitors of the renin–angiotensin system (including angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers; the vitamin D receptor agonist; salt sensitivity hypertension; and progressive kidney-disease markers with identified genetic polymorphisms). Candidate-gene association studies and genome-wide association studies have analyzed the genetic basis for common renal diseases, including CKD and related factors such as diabetes and hypertension. This review will, in brief, consider genotype-based pharmacotherapy, risk prediction, drug target recognition, and personalized treatments, and will mainly focus on findings in CKD patients. An improved understanding will smooth the progress of switching from classical clinical medicine to gene-based medicine

Left Frontal Hub Connectivity during Memory Performance Supports Reserve in Aging and Mild Cognitive Impairment

Reserve in aging and Alzheimer's disease (AD) is defined as maintaining cognition at a relatively high level in the presence of neurodegeneration, an ability often associated with higher education among other life factors. Recent evidence suggests that higher resting-state functional connectivity within the frontoparietal control network, specifically the left frontal cortex (LFC) hub, contributes to higher reserve. Following up these previous resting-state fMRI findings, we probed memory-task related functional connectivity of the LFC hub as a neural substrate of reserve. In elderly controls (CN, n = 37) and patients with mild cognitive impairment (MCI, n = 17), we assessed global connectivity of the LFC hub during successful face-name association learning, using generalized psychophysiological interaction analyses. Reserve was quantified as residualized memory performance, accounted for gender and proxies of neurodegeneration (age, hippocampus atrophy, and APOE genotype). We found that greater education was associated with higher LFC-connectivity in both CN and MCI during successful memory. Furthermore, higher LFC-connectivity predicted higher residualized memory (i.e., reserve). These results suggest that higher LFC-connectivity contributes to reserve in both healthy and pathological aging

The bounds of education in the human brain connectome

Inter-individual heterogeneity is evident in aging; education level is known to contribute for this heterogeneity. Using a cross-sectional study design and network inference applied to resting-state fMRI data, we show that aging was associated with decreased functional connectivity in a large cortical network. On the other hand, education level, as measured by years of formal education, produced an opposite effect on the long-term. These results demonstrate the increased brain efficiency in individuals with higher education level that may mitigate the impact of age on brain functional connectivity.This work was funded by the European Commission (FP7): “SwitchBox” (Contract HEALTH-F2-2010-259772) and co-financed by the Portuguese North Regional Operational Program (ON.2 – O Novo Norte) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER). José M. Soares, Paulo Marques, and Nadine C. Santos are supported by fellowships of the project “SwitchBox”; Ricardo Magalhães is supported by a fellowship from the project FCT ANR/NEU-OSD/0258/2012 funded by FCT/MEC (www.fct.pt) and by ON.2 – ONOVONORTE – North Portugal Regional Operational Programme 2007/2013, of the National Strategic Reference Framework (NSRF) 2007/2013, through FEDER

The BDNF Val66Met polymorphism moderates the relationship between cognitive reserve and executive function

The concept of cognitive reserve (CR) has been proposed to account for observed discrepancies between pathology and its clinical manifestation due to underlying differences in brain structure and function. In 433 healthy older adults participating in the Tasmanian Healthy Brain Project, we investigated whether common polymorphic variations in apolipoprotein E (APOE) or brain-derived neurotrophic factor (BDNF) influenced the association between CR contributors and cognitive function in older adults. We show that BDNF Val66Met moderates the association between CR and executive function. CR accounted for 8.5% of the variance in executive function in BDNF Val homozygotes, but CR was a nonsignificant predictor in BDNF Met carriers. APOE polymorphisms were not linked to the influence of CR on cognitive function. This result implicates BDNF in having an important role in capacity for building or accessing CR

STRIDE LENGTH REGULATION AT THE APPROACH PHASE OF LONG JUMP IN VISUALLY IMPAIRED (F12 CLASS) ATHLETES

The present study examined whether long jumpers with visual impairment (class F12) demonstrate at the approach run the same pattern of footfall variability across trials as athletes without visual impairment. Five male and five female elite F12 class long jumpers were recorded during a competition. The athletes demonstrated an initial ascending footfall variability followed by a descending one, suggesting the existence of stride length regulation. This regulation emerged on the fourth and the third stride prior to take-off area and at a mean distance of 9.09 ± 0.26 m and 6.28 ± 0.26 m for the males and the females respectively from the take-off line. Results indicated that the stride pattern of F12 class long jumpers was similar to that reported in the literature for athletes without visual impairment, with stride regulation commencing one stride closer to the take-off board

Organic pollution impact on the phytoplankton of a stream of the Pampas plains

Este trabajo analiza la influencia de la calidad del agua sobre el fitoplancton y, en particular, sobre el ensamble de euglenofitas de un arroyo periurbano de la provincia de Buenos Aires (Argentina), muy afectado por la recepción de aguas residuales urbanas e industriales. Los índices de calidad de agua ICA (Berón 1984) calculados sobre el cauce principal y sus afluentes mostraron un deterioro marcado de las aguas y evidenciaron un claro patrón espacial. Además, en más de un sitio muestreado, muchos de los valores de los parámetros indicadores de la calidad del agua para la preservación de la vida acuática excedieron los rangos establecidos por las normas nacionales. El fitoplancton estuvo dominado por clorofitas, con codominancia de cianobacterias y euglenofitas. Se identificaron las especies de euglenofitas y se evaluó la presencia de deformaciones morfológicas, que fueron asociadas a la contaminación orgánica. Dada la importancia de las comunidades autotróficas en arroyos de llanura, se sugiere implementar el uso de los ensambles de euglenofitas como centinelas de los cambios producidos por el exceso de materia orgánica característico de los cursos urbanizados.This paper analyzes the influence of water quality on phytoplankton, focusing on the euglenoid assemblages of a periurban stream in the province of Buenos Aires (Argentina), strongly impacted by urban and industrial wastewater. The ICA water quality index (Berón 1984) calculated for the main channel and its tributaries showed a marked deterioration of the waters and evidenced a clear spatial pattern. In addition, in some of the sampled sites, water quality indicators exceeded the ranges established by national standards. The phytoplankton was dominated by chlorophytes, with codominance of cyanobacteria and euglenophytes. Euglenophyta species were identified and the occurrence of morphological anomalies was associated and evaluated in relation with organic pollution. Given the importance of autotrophic communities in lowland streams, we suggest the use of euglenophyte assemblages as sentinels of changes produced by the excess of organic matter, which is characteristic of urban watercourses

The leaf economic and plant size spectra of European forest understory vegetation

Forest understories play a vital role in ecosystem functioning and the provision of ecosystem services. However, the extent to which environmental conditions drive dominant ecological strategies in forest understories at the continental scale remains understudied. Here, we used similar to 29 500 forest vegetation plots sampled across Europe and classified into 25 forest types to explore the relative role of macroclimate, soil pH and tree canopy cover in driving abundance-weighted patterns in the leaf economic spectrum (LES) and plant size spectrum (PSS) of forest understories (shrub and herb layers). We calculated LES using specific leaf area (SLA) and leaf dry matter content (LDMC) and PSS using plant height and seed mass of vascular plant species found in the understories. We found that forest understories had more conservative leaf economics in areas with more extreme mean annual temperatures (mainly Fennoscandia and the Mediterranean Basin), more extreme soil pH and under more open canopies. Warm and summer-dry regions around the Mediterranean Basin and areas of Atlantic Europe also had taller understories with heavier seeds than continental temperate or boreal areas. Understories of broadleaved deciduous forests, such as Fagus forests on non-acid soils, or ravine forests, more commonly hosted species with acquisitive leaf economics. In contrast, some coniferous forests, such as Pinus, Larbc and Picea mire forests, or Pinus sylvestris light taiga and sclerophyllous forests, more commonly hosted species with conservative leaf economics. Our findings highlight the importance of macroclimate and soil factors in driving trait variation of understory communities at the continental scale and the mediator effect of canopy cover on these relationships. We also provide the first maps and analyses of LES and PSS of forest understories across Europe and give evidence that the understories of European forest types are differently positioned along major axes of trait variation

Risk Factors of Daptomycin-Induced Eosinophilic Pneumonia in a Population with Osteoarticular Infection

Background: Daptomycin-induced eosinophilic pneumonia (DEP) is a rare but severe adverse effect and the risk factors are unknown. The aim of this study was to determine risk factors for DEP. Methods: A retrospective cohort study was performed at the Bone and Joint Infection Unit of the Hospital Universitari Bellvitge (January 2014-December 2018). To identify risk factors for DEP, cases were divided into two groups: those who developed DEP and those without DEP. Results: Among the whole cohort (n = 229) we identified 11 DEP cases (4.8%) and this percentage almost doubled in the subgroup of patients ≥70 years (8.1%). The risk factors for DEP were age ≥70 years (HR 10.19, 95%CI 1.28-80.93), therapy >14 days (7.71, 1.98-30.09) and total cumulative dose of daptomycin ≥10 g (5.30, 1.14-24.66). Conclusions: Clinicians should monitor cumulative daptomycin dosage to minimize DEP risk, and be cautious particularly in older patients when the total dose of daptomycin exceeds 10 g

Environmental factors conditioning the metabolism of a Pampean shallow lake

Las concentraciones naturales de fósforo y nitrógeno en las lagunas pampeanas permiten el desarrollo de densas praderas de vegetación acuática sumergida, el dominio de fitoplancton o plantas acuáticas flotantes. En las últimas décadas, la eutrofización de las lagunas aumentó con el avance de labores agrícolas, fertilización de campos y el stock ganadero. La turbidez que producen las floraciones fitoplanctónicas inhibe el crecimiento de macrófitas sumergidas y el fitoplancton domina. Este es el caso de la laguna de Lobos, que por más de 20 años se mantuvo como una laguna turbia orgánica con predominio de cianobacterias. Estudiar el metabolismo ecosistémico aporta gran información sobre el modo en que el estado trófico de la laguna contribuye a la producción, respiración y metabolismo neto, con posibles consecuencias para la biota acuática. Aquí presentamos una evaluación del metabolismo en esta laguna a partir de los cambios en la concentración de oxígeno disuelto, estimado para otoño y primavera. La producción bruta de la laguna fue menor y menos variable en otoño (1.57±1.33 g O2 .m-2.día-1) que en primavera (20.45±18.00 g O2 .m-2.día-1). Si bien la producción fue alta durante el día, la respiración también fue elevada —incluso, la superó— sobre todo en primavera, cuando fue mayor la densidad de organismos planctónicos, principalmente cianobacterias. Por ello, el metabolismo neto tuvo valores bajos o negativos. Esta situación de gran consumo de oxígeno se acentuó en el período de mayor temperatura y de menor profundidad de la laguna, que coincide con la mayor concentración de clorofila-a y de material particulado, y la menor transparencia del agua. Concluimos que la laguna fue predominantemente heterotrófica durante el período que duró el estudio. De mantenerse las altas concentraciones de nutrientes es probable que aumenten los factores que producen estrés y sus consecuencias negativas para la fauna acuática.Pampean shallow lakes naturally have water nitrogen and phosphorous concentrations that allow the development of dense beds of submerged aquatic vegetation, phytoplankton, or free-floating aquatic plants. In recent years, the eutrophication of these shallow lakes has increased due to the intensification of agriculture, use of fertilization and livestock. Phytoplankton- induced turbidity inhibits the growth of the submerged aquatic vegetation leading to phytoplankton dominance. This is the case of the Lobos shallow lake, which in a period greater than 20 years has remained as an organic turbid shallow lake, with cyanobacteria dominance. The study of the ecosystem metabolism can give relevant information about how the trophic state of a shallow lake drives production, respiration and net metabolism, and the potential consequences for aquatic biota. We evaluated the Lobos shallow lake metabolism using diel changes in dissolved oxygen concentrations during autumn and spring. Gross primary production showed lower values and variability in Autumn (1.57±1.33 g O2 .m-2.day-1) than in Spring (20.45±18.00 g O2 .m-2.day-1). Although there was high production during the day, respiration was also high, especially in Spring, where there was higher density of planktonic organisms principally cyanobacteria, exceeding net production in both seasons. Thus, we found mainly low or negative values for the net metabolism in Lobos shallow lake. A high oxygen consumption occurred during spring and at the lowest depth, coinciding with the highest chlorophyll-a concentrations, particulate matter, and lowest water transparency. We conclude that Lobos shallow lake was predominantly heterotrophic during study period. High nutrient concentrations will likely increase the factors that produce stress and negative impacts on aquatic fauna.Fil: Padulles, María Luz. Universidad Nacional de Luján - CONICET. Instituto de Ecología y Desarrollo Sustentable (INEDES)Fil: Torremorell, Ana María. Universidad Nacional de Luján - CONICET. Instituto de Ecología y Desarrollo Sustentable (INEDES)Fil: Pozzobon, María Virginia. Universidad Nacional de Luján - CONICET. Instituto de Ecología y Desarrollo Sustentable (INEDES)Fil: Diaz, María Belén. Argentina. Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT)Fil: Giorgi, Adonis. Universidad Nacional de Luján - CONICET. Instituto de Ecología y Desarrollo Sustentable (INEDES

Individualización posológica de natalizumab en la esclerosis múltiple remitente recurrente

La esclerosis multiple (EM) es la enfermedad autoinmune, inflamatoria, cronica y degenerativa mas prevalente a nivel mundial, cuya forma mas frecuente es la EM remitente recurrente (EMRR). Para el manejo de la EMRR grave se aprobo natalizumab, un anticuerpo monoclonal IgG4 que se une a la integrina 41 de la superficie de los leucocitos, impidiendo que migren al sistema nervioso central. Con la dosis fija intravenosa aprobada, de 300 mg cada 4 semanas, se ha comprobado que mas del 90% de los pacientes alcanzan concentraciones sericas preinfusion de NTZ >10 μg/mL, cuando la eficacia se ha demostrado con unos niveles de 2,5-10 μg/mL. Una concentracion plasmatica de NTZ de 2,5 μg/mL asegura una ocupacion del 50% de la biofase y demuestra una eficacia terapeutica, mientras que tasas de ocupacion del 20-40% se han relacionado con un aumento de la actividad de la enfermedad. Palabras clave: Esclerosis multiple, natalizumab, farmacocinétic