Evolution and treatment of vitamin B12 deficiency as a risk factor for (cognitive and functional) neurodegenerative diseases in institutionalized elderly = Evolución y tratamiento de la deficiencia de vitamina B12 como factor de riesgo de enfermedades neurodegenerativas (cognitivas y funcionales) en las personas mayores institucionalizadas.

Prevalence of vitamin B12 deficiency is very common in elderly people and can reach values as high as 40.5% of the population. It can be the result of the interaction among several factors. Vitamin B12 deficiencies have been associated with neurological, cognitive deterioration, haematological abnormalities and cardiovascular diseases that have an important influence on the health of the elderly and their quality of life. It is necessary to approach the problems arisen from the lack of data relative to them. The main objective of this thesis was to analyse the evolution of vitamin B12 status and related parameters, lipid and haematological profiles and their relationship to health risk factors, and to functional and cognitive status over one year and to determine the effect of an oral supplementation of 500 μg of cyanocobalamin for a short period of 28 days. An additional objective was to analyze the possible effects of medicine intakes on vitamin B status. Three studies were performed: a) a one year longitudinal follow-up with four measure points; b) an intervention study providing an oral liquid supplement of 500 μg of cyanocobalamin for a 28 days period; and c) analysis of the possible effect of medication intake on vitamin B status using the ATC classification of medicines. The participants for these studies were recruited from nursing homes for the elderly in the Region of Madrid. Sixty elders (mean age 84 _ 7y, 19 men and 41 women) were recruited for Study I and 64 elders (mean age 82 _ 7y, 24 men and 40 women) for Study II. For Study III, baseline data from the initially recruited participants of the first two studies were used. An informed consent was obtained from all participants or their mentors. The studies were approved by the Ethical Committee of the University of Granada. Blood samples were obtained at each examination date and were analyzed for serum cobalamin, holoTC, serum and RBC folate and total homocysteine according to laboratory standard procedures. The haematological parameters analyzed were haematocrit, haemoglobin and MCV. For the lipid profile TG, total cholesterol, LDL- and HDLcholesterol were analyzed. Anthropometric measures (BMI, skinfolds [triceps and subscapular], waist girth and waist to hip ratio), functional tests (hand grip, arm and leg strength tests, static balance) and MMSE were obtained or administered by trained personal. The vitamin B12 supplement of Study II was administered with breakfast and the medication intake was taken from the residents’ anamnesis. Data were analyzed by parametric and non-parametric statistics depending on the obtained data. Comparisons were done using the appropriate ANOVAs or non-parametric tests. Pearsons’ partial correlations with the variable “time” as control were used to define the association of the analyzed parameters. XIII The results showed that: A) Over one year, in relationship to vitamin B status, serum cobalamin decreased, serum folate and mean corpuscular volumen increased significantly and total homocysteine concentrations were stable. Regarding blood lipid profile, triglycerides increased and HDL-cholesterol decreased significantly. Regarding selected anthropometric measurements, waist circumference increased significantly. No significant changes were observed for the rest of parameters. B) Prevalence of hyperhomocysteinemia was high in the elderly studied, ranging from 60% to 90 % over the year depending on the cut-off used for the classification. LDL-cholesterol values were high, especially among women, and showed a tendency to increase over the year. Results of the balance test showed a deficiency and a tendency to decrease; this indicates that the population studied is at high risk for falls. Lower extremity muscular function was deficient and showed a tendency to decrease. A highly significant relationship was observed between the skinfold of the triceps and blood lipid profile. C) Low cobalamin concentrations correlated significantly with low MMSE scores in the elderly studied. No correlations were observed between vitamin B12 status and functional parameters. D) Regarding vitamin B12 status, holo-transcobalamin seems to be more sensitive for diagnosis; 5-10% of the elderly had a deficiency using serum cobalamin as a criterion, and 45-52% had a deficiency when using serum holotranscobalamin as a criterion. E) 500 μg of cyanocobalamin administered orally during 28 days significantly improved vitamin B12 status and significantly decreased total homocysteine concentrations in institutionalized elderly. No effect of the intervention was observed on functional and cognitive parameters. F) The relative change (%) of improvement of vitamin B12 status was higher when using serum holo-transcobalamin as a criterion than serum cobalamin. G) Antiaenemic drug intake normalized cobalamin, urologic drugs and corticosteroids serum folate, and psychoanaleptics holo-transcobalamin levels. Drugs treating pulmonary obstruction increased total homocysteine concentration significantly. H) The daily mean drug intake was 5.1. Fiftynine percent of the elderly took medication belonging to 5 or more different ATC groups. The most prevalent were psycholeptic (53%), antiacid (53%) and antithrombotic (47%) drugs.

Early dysfunction of functional connectivity in healthy elderly with subjective memory complaints

It is still an open question whether subjective memory complaints (SMC) can actually be considered to be clinically relevant predictors for the development of an objective memory impairment and even dementia. There is growing evidence that suggests that SMC are associated with an increased risk of dementia and with the presence of biological correlates of early Alzheimer's disease. In this paper, in order to shed some light on this issue, we try to discern whether subjects with SMC showed a different profile of functional connectivity compared with subjects with mild cognitive impairment (MCI) and healthy elderly subjects. In the present study, we compare the degree of synchronization of brain signals recorded with magnetoencephalography between three groups of subjects (56 in total): 19 with MCI, 12 with SMC and 25 healthy controls during a memory task. Synchronization likelihood, an index based on the theory of nonlinear dynamical systems, was used to measure functional connectivity. Briefly, results show that subjects with SMC have a very similar pattern of connectivity to control group, but on average, they present a lower synchronization value. These results could indicate that SMC are representing an initial stage with a hypo-synchronization (in comparison with the control group) where the brain system is still not compensating for the failing memory networks, but behaving as controls when compared with the MCI subjects.

Functional and effective connectivity in MEG. Application to the study of epilepsy

Nuestro cerebro contiene cerca de 1014 sinapsis neuronales. Esta enorme cantidad de conexiones proporciona un entorno ideal donde distintos grupos de neuronas se sincronizan transitoriamente para provocar la aparición de funciones cognitivas, como la percepción, el aprendizaje o el pensamiento. Comprender la organización de esta compleja red cerebral en base a datos neurofisiológicos, representa uno de los desafíos más importantes y emocionantes en el campo de la neurociencia. Se han propuesto recientemente varias medidas para evaluar cómo se comunican las diferentes partes del cerebro a diversas escalas (células individuales, columnas corticales, o áreas cerebrales). Podemos clasificarlos, según su simetría, en dos grupos: por una parte, la medidas simétricas, como la correlación, la coherencia o la sincronización de fase, que evalúan la conectividad funcional (FC); mientras que las medidas asimétricas, como la causalidad de Granger o transferencia de entropía, son capaces de detectar la dirección de la interacción, lo que denominamos conectividad efectiva (EC). En la neurociencia moderna ha aumentado el interés por el estudio de las redes funcionales cerebrales, en gran medida debido a la aparición de estos nuevos algoritmos que permiten analizar la interdependencia entre señales temporales, además de la emergente teoría de redes complejas y la introducción de técnicas novedosas, como la magnetoencefalografía (MEG), para registrar datos neurofisiológicos con gran resolución. Sin embargo, nos hallamos ante un campo novedoso que presenta aun varias cuestiones metodológicas sin resolver, algunas de las cuales trataran de abordarse en esta tesis. En primer lugar, el creciente número de aproximaciones para determinar la existencia de FC/EC entre dos o más señales temporales, junto con la complejidad matemática de las herramientas de análisis, hacen deseable organizarlas todas en un paquete software intuitivo y fácil de usar. Aquí presento HERMES (http://hermes.ctb.upm.es), una toolbox en MatlabR, diseñada precisamente con este fin. Creo que esta herramienta será de gran ayuda para todos aquellos investigadores que trabajen en el campo emergente del análisis de conectividad cerebral y supondrá un gran valor para la comunidad científica. La segunda cuestión practica que se aborda es el estudio de la sensibilidad a las fuentes cerebrales profundas a través de dos tipos de sensores MEG: gradiómetros planares y magnetómetros, esta aproximación además se combina con un enfoque metodológico, utilizando dos índices de sincronización de fase: phase locking value (PLV) y phase lag index (PLI), este ultimo menos sensible a efecto la conducción volumen. Por lo tanto, se compara su comportamiento al estudiar las redes cerebrales, obteniendo que magnetómetros y PLV presentan, respectivamente, redes más densamente conectadas que gradiómetros planares y PLI, por los valores artificiales que crea el problema de la conducción de volumen. Sin embargo, cuando se trata de caracterizar redes epilépticas, el PLV ofrece mejores resultados, debido a la gran dispersión de las redes obtenidas con PLI. El análisis de redes complejas ha proporcionado nuevos conceptos que mejoran caracterización de la interacción de sistemas dinámicos. Se considera que una red está compuesta por nodos, que simbolizan sistemas, cuyas interacciones se representan por enlaces, y su comportamiento y topología puede caracterizarse por un elevado número de medidas. Existe evidencia teórica y empírica de que muchas de ellas están fuertemente correlacionadas entre sí. Por lo tanto, se ha conseguido seleccionar un pequeño grupo que caracteriza eficazmente estas redes, y condensa la información redundante. Para el análisis de redes funcionales, la selección de un umbral adecuado para decidir si un determinado valor de conectividad de la matriz de FC es significativo y debe ser incluido para un análisis posterior, se convierte en un paso crucial. En esta tesis, se han obtenido resultados más precisos al utilizar un test de subrogadas, basado en los datos, para evaluar individualmente cada uno de los enlaces, que al establecer a priori un umbral fijo para la densidad de conexiones. Finalmente, todas estas cuestiones se han aplicado al estudio de la epilepsia, caso práctico en el que se analizan las redes funcionales MEG, en estado de reposo, de dos grupos de pacientes epilépticos (generalizada idiopática y focal frontal) en comparación con sujetos control sanos. La epilepsia es uno de los trastornos neurológicos más comunes, con más de 55 millones de afectados en el mundo. Esta enfermedad se caracteriza por la predisposición a generar ataques epilépticos de actividad neuronal anormal y excesiva o bien síncrona, y por tanto, es el escenario perfecto para este tipo de análisis al tiempo que presenta un gran interés tanto desde el punto de vista clínico como de investigación. Los resultados manifiestan alteraciones especificas en la conectividad y un cambio en la topología de las redes en cerebros epilépticos, desplazando la importancia del ‘foco’ a la ‘red’, enfoque que va adquiriendo relevancia en las investigaciones recientes sobre epilepsia. ABSTRACT There are about 1014 neuronal synapses in the human brain. This huge number of connections provides the substrate for neuronal ensembles to become transiently synchronized, producing the emergence of cognitive functions such as perception, learning or thinking. Understanding the complex brain network organization on the basis of neuroimaging data represents one of the most important and exciting challenges for systems neuroscience. Several measures have been recently proposed to evaluate at various scales (single cells, cortical columns, or brain areas) how the different parts of the brain communicate. We can classify them, according to their symmetry, into two groups: symmetric measures, such as correlation, coherence or phase synchronization indexes, evaluate functional connectivity (FC); and on the other hand, the asymmetric ones, such as Granger causality or transfer entropy, are able to detect effective connectivity (EC) revealing the direction of the interaction. In modern neurosciences, the interest in functional brain networks has increased strongly with the onset of new algorithms to study interdependence between time series, the advent of modern complex network theory and the introduction of powerful techniques to record neurophysiological data, such as magnetoencephalography (MEG). However, when analyzing neurophysiological data with this approach several questions arise. In this thesis, I intend to tackle some of the practical open problems in the field. First of all, the increase in the number of time series analysis algorithms to study brain FC/EC, along with their mathematical complexity, creates the necessity of arranging them into a single, unified toolbox that allow neuroscientists, neurophysiologists and researchers from related fields to easily access and make use of them. I developed such a toolbox for this aim, it is named HERMES (http://hermes.ctb.upm.es), and encompasses several of the most common indexes for the assessment of FC and EC running for MatlabR environment. I believe that this toolbox will be very helpful to all the researchers working in the emerging field of brain connectivity analysis and will entail a great value for the scientific community. The second important practical issue tackled in this thesis is the evaluation of the sensitivity to deep brain sources of two different MEG sensors: planar gradiometers and magnetometers, in combination with the related methodological approach, using two phase synchronization indexes: phase locking value (PLV) y phase lag index (PLI), the latter one being less sensitive to volume conduction effect. Thus, I compared their performance when studying brain networks, obtaining that magnetometer sensors and PLV presented higher artificial values as compared with planar gradiometers and PLI respectively. However, when it came to characterize epileptic networks it was the PLV which gives better results, as PLI FC networks where very sparse. Complex network analysis has provided new concepts which improved characterization of interacting dynamical systems. With this background, networks could be considered composed of nodes, symbolizing systems, whose interactions with each other are represented by edges. A growing number of network measures is been applied in network analysis. However, there is theoretical and empirical evidence that many of these indexes are strongly correlated with each other. Therefore, in this thesis I reduced them to a small set, which could more efficiently characterize networks. Within this framework, selecting an appropriate threshold to decide whether a certain connectivity value of the FC matrix is significant and should be included in the network analysis becomes a crucial step, in this thesis, I used the surrogate data tests to make an individual data-driven evaluation of each of the edges significance and confirmed more accurate results than when just setting to a fixed value the density of connections. All these methodologies were applied to the study of epilepsy, analysing resting state MEG functional networks, in two groups of epileptic patients (generalized and focal epilepsy) that were compared to matching control subjects. Epilepsy is one of the most common neurological disorders, with more than 55 million people affected worldwide, characterized by its predisposition to generate epileptic seizures of abnormal excessive or synchronous neuronal activity, and thus, this scenario and analysis, present a great interest from both the clinical and the research perspective. Results revealed specific disruptions in connectivity and network topology and evidenced that networks’ topology is changed in epileptic brains, supporting the shift from ‘focus’ to ‘networks’ which is gaining importance in modern epilepsy research.

Electronic structure of copper nitrides as a function of nitrogen content

he nitrogen content dependence of the electronic properties for copper nitride thin films with an atomic percentage of nitrogen ranging from 26 ± 2 to 33 ± 2 have been studied by means of optical (spectroscopic ellipsometry), thermoelectric (Seebeck), and electrical resistivity measurements. The optical spectra are consistent with direct optical transitions corresponding to the stoichiometric semiconductor Cu3N plus a free-carrier contribution, essentially independent of temperature, which can be tuned in accordance with the N-excess. Deviation of the N content from stoichiometry drives to significant decreases from − 5 to − 50 μV/K in the Seebeck coefficient and to large enhancements, from 10− 3 up to 10 Ω cm, in the electrical resistivity. Band structure and density of states calculations have been carried out on the basis of the density functional theory to account for the experimental results.

Functional characterization of Rhizobium leguminosarum bv. viciae DmeRF, a cation diffusion facilitator system involved in nickel and cobalt resistance

In prokaryotes, nickel is an essential element participating in the structure of enzymes involved in multiple cellular processes. Nickel transport is a challenge for microorganisms since, although essential, high levels of this metal inside the cell are toxic. For this reason, bacteria have developed high-affinity nickel transporters as well as nickel-specific detoxification systems. Ultramafic soils, and soils contaminated with heavy metals are excellent sources of nickel resistant bacteria. Molecular analysis of strains isolated in the habitats has revealed novel genetic systems involved in adaptation to such hostile conditions.

Identification and functional characterization of Rhizobium leguminosarum bv. viciae genetic systems involved in nickel homeostasis.

A collection of Rhizobium leguminosarum bv. viciae strains isolated from ultramafic and contaminated soils in Italy and Germany, respectively, was analyzed for resistance to nickel and cobalt ions. These assays led to the identification of strain UPM1137, which is able to grow at high concentrations of nickel and cobalt. In order to identify genetic systems involved in the homeostasis to these metals, a random mutagenesis was carried out in UPM1137 by inserting a Tn5-derivative minitransposon. As a result 4313 transconjugants were obtained, being 39 of them (0.90%) unable to grow at 1.5 mM NiCl2. The identification of the transposon insertion site in these mutants showed that the disrupted genes encode proteins belonging to different functional categories, where the secreted and membrane proteins were the most numerous. The analysis of heavy metal resistance and phenotypes in symbiotic and free –living cells will define the contribution of these genes to metal homeostasis.

Improving the management of water and nitrogen resources in cropping systems by using simulation models

Los modelos de simulación de cultivos permiten analizar varias combinaciones de laboreo-rotación y explorar escenarios de manejo. El modelo DSSAT fue evaluado bajo condiciones de secano en un experimento de campo de 16 años en la semiárida España central. Se evaluó el efecto del sistema de laboreo y las rotaciones basadas en cereales de invierno, en el rendimiento del cultivo y la calidad del suelo. Los modelos CERES y CROPGRO se utilizaron para simular el crecimiento y rendimiento del cultivo, mientras que el modelo DSSAT CENTURY se utilizó en las simulaciones de SOC y SN. Tanto las observaciones de campo como las simulaciones con CERES-Barley, mostraron que el rendimiento en grano de la cebada era mas bajo para el cereal continuo (BB) que para las rotaciones de veza (VB) y barbecho (FB) en ambos sistemas de laboreo. El modelo predijo más nitrógeno disponible en el laboreo convencional (CT) que en el no laboreo (NT) conduciendo a un mayor rendimiento en el CT. El SOC y el SN en la capa superficial del suelo, fueron mayores en NT que en CT, y disminuyeron con la profundidad en los valores tanto observados como simulados. Las mejores combinaciones para las condiciones de secano estudiadas fueron CT-VB y CT-FB, pero CT presentó menor contenido en SN y SOC que NT. El efecto beneficioso del NT en SOC y SN bajo condiciones Mediterráneas semiáridas puede ser identificado por observaciones de campo y por simulaciones de modelos de cultivos. La simulación del balance de agua en sistemas de cultivo es una herramienta útil para estudiar como el agua puede ser utilizado eficientemente. La comparación del balance de agua de DSSAT , con una simple aproximación “tipping bucket”, con el modelo WAVE más mecanicista, el cual integra la ecuación de Richard , es un potente método para valorar el funcionamiento del modelo. Los parámetros de suelo fueron calibrados usando el método de optimización global Simulated Annealing (SA). Un lisímetro continuo de pesada en suelo desnudo suministró los valores observados de drenaje y evapotranspiración (ET) mientras que el contenido de agua en el suelo (SW) fue suministrado por sensores de capacitancia. Ambos modelos funcionaron bien después de la optimización de los parámetros de suelo con SA, simulando el balance de agua en el suelo para el período de calibración. Para el período de validación, los modelos optimizados predijeron bien el contenido de agua en el suelo y la evaporación del suelo a lo largo del tiempo. Sin embargo, el drenaje fue predicho mejor con WAVE que con DSSAT, el cual presentó mayores errores en los valores acumulados. Esto podría ser debido a la naturaleza mecanicista de WAVE frente a la naturaleza más funcional de DSSAT. Los buenos resultados de WAVE indican que, después de la calibración, este puede ser utilizado como "benchmark" para otros modelos para periodos en los que no haya medidas de campo del drenaje. El funcionamiento de DSSAT-CENTURY en la simulación de SOC y N depende fuertemente del proceso de inicialización. Se propuso como método alternativo (Met.2) la inicialización de las fracciones de SOC a partir de medidas de mineralización aparente del suelo (Napmin). El Met.2 se comparó con el método de inicialización de Basso et al. (2011) (Met.1), aplicando ambos métodos a un experimento de campo de 4 años en un área en regadío de España central. Nmin y Napmin fueron sobreestimados con el Met.1, ya que la fracción estable obtenida (SOC3) en las capas superficiales del suelo fue más baja que con Met.2. El N lixiviado simulado fue similar en los dos métodos, con buenos resultados en los tratamientos de barbecho y cebada. El Met.1 subestimó el SOC en la capa superficial del suelo cuando se comparó con una serie observada de 12 años. El crecimiento y rendimiento del cultivo fueron adecuadamente simulados con ambos métodos, pero el N en la parte aérea de la planta y en el grano fueron sobreestimados con el Met.1. Los resultados variaron significativamente con las fracciones iniciales de SOC, resaltando la importancia del método de inicialización. El Met.2 ofrece una alternativa para la inicialización del modelo CENTURY, mejorando la simulación de procesos de N en el suelo. La continua emergencia de nuevas variedades de híbridos modernos de maíz limita la aplicación de modelos de simulación de cultivos, ya que estos nuevos híbridos necesitan ser calibrados en el campo para ser adecuados para su uso en los modelos. El desarrollo de relaciones basadas en la duración del ciclo, simplificaría los requerimientos de calibración facilitando la rápida incorporación de nuevos cultivares en DSSAT. Seis híbridos de maiz (FAO 300 hasta FAO 700) fueron cultivados en un experimento de campo de dos años en un área semiárida de regadío en España central. Los coeficientes genéticos fueron obtenidos secuencialmente, comenzando con los parámetros de desarrollo fenológico (P1, P2, P5 and PHINT), seguido de los parámetros de crecimiento del cultivo (G2 and G3). Se continuó el procedimiento hasta que la salida de las simulaciones estuvo en concordancia con las observaciones fenológicas de campo. Después de la calibración, los parámetros simulados se ajustaron bien a los parámetros observados, con bajos RMSE en todos los casos. Los P1 y P5 calibrados, incrementaron con la duración del ciclo. P1 fue una función lineal del tiempo térmico (TT) desde emergencia hasta floración y P5 estuvo linealmente relacionada con el TT desde floración a madurez. No hubo diferencias significativas en PHINT entre híbridos de FAO-500 a 700 , ya que tuvieron un número de hojas similar. Como los coeficientes fenológicos estuvieron directamente relacionados con la duración del ciclo, sería posible desarrollar rangos y correlaciones que permitan estimar dichos coeficientes a partir de la clasificación del ciclo. ABSTRACT Crop simulation models allow analyzing various tillage-rotation combinations and exploring management scenarios. DSSAT model was tested under rainfed conditions in a 16-year field experiment in semiarid central Spain. The effect of tillage system and winter cereal-based rotations on the crop yield and soil quality was evaluated. The CERES and CROPGRO models were used to simulate crop growth and yield, while the DSSAT CENTURY was used in the SOC and SN simulations. Both field observations and CERES-Barley simulations, showed that barley grain yield was lower for continuous cereal (BB) than for vetch (VB) and fallow (FB) rotations for both tillage systems. The model predicted higher nitrogen availability in the conventional tillage (CT) than in the no tillage (NT) leading to a higher yield in the CT. The SOC and SN in the top layer, were higher in NT than in CT, and decreased with depth in both simulated and observed values. The best combinations for the dry land conditions studied were CT-VB and CT-FB, but CT presented lower SN and SOC content than NT. The beneficial effect of NT on SOC and SN under semiarid Mediterranean conditions can be identified by field observations and by crop model simulations. The simulation of the water balance in cropping systems is a useful tool to study how water can be used efficiently. The comparison of DSSAT soil water balance, with a simpler “tipping bucket” approach, with the more mechanistic WAVE model, which integrates Richard’s equation, is a powerful method to assess model performance. The soil parameters were calibrated by using the Simulated Annealing (SA) global optimizing method. A continuous weighing lysimeter in a bare fallow provided the observed values of drainage and evapotranspiration (ET) while soil water content (SW) was supplied by capacitance sensors. Both models performed well after optimizing soil parameters with SA, simulating the soil water balance components for the calibrated period. For the validation period, the optimized models predicted well soil water content and soil evaporation over time. However, drainage was predicted better by WAVE than by DSSAT, which presented larger errors in the cumulative values. That could be due to the mechanistic nature of WAVE against the more functional nature of DSSAT. The good results from WAVE indicate that, after calibration, it could be used as benchmark for other models for periods when no drainage field measurements are available. The performance of DSSAT-CENTURY when simulating SOC and N strongly depends on the initialization process. Initialization of the SOC pools from apparent soil N mineralization (Napmin) measurements was proposed as alternative method (Met.2). Method 2 was compared to the Basso et al. (2011) initialization method (Met.1), by applying both methods to a 4-year field experiment in a irrigated area of central Spain. Nmin and Napmin were overestimated by Met.1, since the obtained stable pool (SOC3) in the upper layers was lower than from Met.2. Simulated N leaching was similar for both methods, with good results in fallow and barley treatments. Method 1 underestimated topsoil SOC when compared with a 12-year observed serial. Crop growth and yield were properly simulated by both methods, but N in shoots and grain were overestimated by Met.1. Results varied significantly with the initial SOC pools, highlighting the importance of the initialization procedure. Method 2 offers an alternative to initialize the CENTURY model, enhancing the simulation of soil N processes. The continuous emergence of new varieties of modern maize hybrids limits the application of crop simulation models, since these new hybrids should be calibrated in the field to be suitable for model use. The development of relationships based on the cycle duration, would simplify the calibration requirements facilitating the rapid incorporation of new cultivars into DSSAT. Six maize hybrids (FAO 300 through FAO 700) were grown in a 2-year field experiment in a semiarid irrigated area of central Spain. Genetic coefficients were obtained sequentially, starting with the phenological development parameters (P1, P2, P5 and PHINT), followed by the crop growth parameters (G2 and G3). The procedure was continued until the simulated outputs were in good agreement with the field phenological observations. After calibration, simulated parameters matched observed parameters well, with low RMSE in most cases. The calibrated P1 and P5 increased with the duration of the cycle. P1 was a linear function of the thermal time (TT) from emergence to silking and P5 was linearly related with the TT from silking to maturity . There were no significant differences in PHINT between hybrids from FAO-500 to 700 , as they had similar leaf number. Since phenological coefficients were directly related with the cycle duration, it would be possible to develop ranges and correlations which allow to estimate such coefficients from the cycle classification.

Adaptaciones cardiacas hemodinámicas, estructurales y funcionales a un programa de ejercicio físico supervisado durante el embarazo: ensayo clínico aleatorizado = Hemodynamic, structural and functional cardiac adaptations in a supervised physical exercise program during pregnancy: a randomized controlled trial

Introducción: Diversos cambios ocurren en el sistema cardiovascular materno durante el embarazo, lo que genera un gran estrés sobre este sistema especialmente durante el tercer trimestre, pudiendo acentuarse en presencia de determinados factores de riesgo. Los objetivos de este estudio fueron, valorar las adaptaciones cardiovasculares producidas por un programa específico de ejercicio físico; su seguridad sobre el sistema cardiovascular materno y los resultados del embarazo; y su eficacia en el control de los factores de riesgo cardiovascular. Material y métodos: El diseño del estudio fue un ensayo clínico aleatorizado. 151 gestantes sanas fueron evaluadas mediante un ecocardiograma y un electrocardiograma en la semana 20 y 34 de gestación. Un total de 89 gestantes participaron en un programa de ejercicio físico (GE) desde el primer hasta el tercer trimestre de embarazo, constituido principalmente por 25-30 minutos de trabajo aeróbico (55-60% de la frecuencia cardiaca de reserva), trabajo de fortalecimiento general y específico, y un trabajo de tonificación del suelo pélvico; desarrollado 3 días a la semana con una duración de 55-60 minutos cada sesión. Las gestantes aleatoriamente asignadas al grupo de control (GC; n=62) permanecieron sedentarias durante el embarazo. El estudio fue aprobado por el Comité Ético de investigación clínica del Hospital Universitario de Fuenlabrada. Resultados: Las características basales fueron similares entre ambos grupos. A diferencia del GC, las gestantes del GE evitaron el descenso significativo del gasto cardiaco indexado, entre el 2º y 3ºT de embarazo, y conservaron el patrón geométrico normal del ventrículo izquierdo; mientras que en el GC cambió hacia un patrón de remodelado concéntrico. En la semana 20, las gestantes del GE presentaron valores significativamente menores de frecuencia cardiaca (GC: 79,56±10,76 vs. GE: 76,05±9,34; p=0,04), tensión arterial sistólica (GC: 110,19±10,23 vs. GE: 106,04±12,06; p=0,03); tensión arterial diastólica (GC: 64,56±7,88 vs. GE: 61,81±7,15; p=0,03); tiempo de relajación isovolumétrica (GC: 72,94±14,71 vs. GE: 67,05±16,48; p=0,04); y un mayor tiempo de deceleración de la onda E (GC: 142,09±39,11 vs. GE: 162,10±48,59; p=0,01). En la semana 34, el GE presentó valores significativamente superiores de volumen sistólico (GC: 51,13±11,85 vs. GE: 56,21±12,79 p=0,04), de llenado temprano del ventrículo izquierdo (E) (GC: 78,38±14,07 vs. GE: 85,30±16,62; p=0,02) y de tiempo de deceleración de la onda E (GC: 130,35±37,11 vs. GE: 146,61±43,40; p=0,04). Conclusión: La práctica regular de ejercicio físico durante el embarazo puede producir adaptaciones positivas sobre el sistema cardiovascular materno durante el tercer trimestre de embarazo, además de ayudar en el control de sus factores de riesgo, sin alterar la salud materno-fetal. ABSTRACT Background: Several changes occur in the maternal cardiovascular system during pregnancy. These changes produce a considerable stress in this system, especially during the third trimester, which can be increased in presence of some risk factors. The aims of this study were, to assess the maternal cardiac adaptations in a specific exercise program; its safety on the maternal cardiovascular system and pregnancy outcomes; and its effectiveness in the control of cardiovascular risk factors. Material and methods: A randomized controlled trial was designed. 151 healthy pregnant women were assessed by an echocardiography and electrocardiography at 20 and 34 weeks of gestation. A total of 89 pregnant women participated in a physical exercise program (EG) from the first to the third trimester of pregnancy. It consisted of 25-30 minutes of aerobic conditioning (55-60% of their heart rate reserve), general and specific strength exercises, and a pelvic floor muscles training; 3 times per weeks during 55-60 minutes per session. Pregnant women randomized allocated to the control group (CG) remained sedentary during pregnancy. The study was approved by the Research Ethics Committee of Hospital Universitario de Fuenlabrada. Results: Baseline characteristics were similar between groups. Difference from the CG, pregnant women from the EG prevented the significant decrease of the cardiac output index, between the 2nd and 3rd trimester of pregnancy, and preserved the normal left ventricular pattern; whereas in the CG shifted to concentric remodeling pattern. At 20 weeks, women in the EG had significant lower heart rate (CG: 79,56±10,76 vs. EG: 76,05±9,34; p=0,04), systolic blood pressure (CG: 110,19±10,23 vs. EG: 106,04±12,06; p=0,03); diastolic blood pressure (CG: 64,56±7,88 vs. EG: 61,81±7,15; p=0,03); isovolumetric relaxation time (GC: 72,94±14,71 vs. GE: 67,05±16,48; p=0,04); and a higher deceleration time of E Wave (GC: 142,09±39,11 vs. GE: 162,10±48,59; p=0,01). At 34 weeks, the EG had a significant higher stroke volume (CG: 51,13±11,85 vs. EG: 56,21±12,79 p=0,04), early filling of left ventricular (E) (CG: 78,38±14,07 vs. EG: 85,30±16,62; p=0,02) and deceleration time of E wave (CG: 130,35±37,11 vs. EG:146,61±43,40; p=0,04). Conclusion: Physical regular exercise program during pregnancy may produce positive maternal cardiovascular adaptations during the third trimester of pregnancy. In addition, it helps to control the cardiovascular risk factors without altering maternal and fetus health.

Guiding functional connectivity estimation by structural connectivity in MEG: an application to discrimination of mild cognitive impaired conditions

Whole brain resting state connectivity is a promising biomarker that might help to obtain an early diagnosis in many neurological diseases, such as dementia. Inferring resting-state connectivity is often based on correlations, which are sensitive to indirect connections, leading to an inaccurate representation of the real backbone of the network. The precision matrix is a better representation for whole brain connectivity, as it considers only direct connections. The network structure can be estimated using the graphical lasso (GL), which achieves sparsity through l1-regularization on the precision matrix. In this paper, we propose a structural connectivity adaptive version of the GL, where weaker anatomical connections are represented as stronger penalties on the corre- sponding functional connections. We applied beamformer source reconstruction to the resting state MEG record- ings of 81 subjects, where 29 were healthy controls, 22 were single-domain amnestic Mild Cognitive Impaired (MCI), and 30 were multiple-domain amnestic MCI. An atlas-based anatomical parcellation of 66 regions was ob- tained for each subject, and time series were assigned to each of the regions. The fiber densities between the re- gions, obtained with deterministic tractography from diffusion-weighted MRI, were used to define the anatomical connectivity. Precision matrices were obtained with the region specific time series in five different frequency bands. We compared our method with the traditional GL and a functional adaptive version of the GL, in terms of log-likelihood and classification accuracies between the three groups. We conclude that introduc- ing an anatomical prior improves the expressivity of the model and, in most cases, leads to a better classification between groups.

Objective metrics for functional evaluation of upper limb during the ADL of drinking: application in SCI

Three-dimensional kinematic analysis provides quantitative assessment of upper limb motion and is used as an outcome measure to evaluate movement disorders. The aim of the present study is to present a set of kinematic metrics for quantifying characteristics of movement performance and the functional status of the subject during the execution of the activity of daily living (ADL) of drinking from a glass. Then, the objective is to apply these metrics in healthy people and a population with cervical spinal cord injury (SCI), and to analyze the metrics ability to discriminate between healthy and pathologic people. 19 people participated in the study: 7 subjects with metameric level C6 tetraplegia, 4 subjects with metameric level C7 tetraplegia and 8 healthy subjects. The movement was recorded with a photogrammetry system. The ADL of drinking was divided into a series of clearly identifiable phases to facilitate analysis. Metrics describing the time of the reaching phase, the range of motion of the joints analyzed, and characteristics of movement performance such as the efficiency, accuracy and smoothness of the distal segment and inter-joint coordination were obtained. The performance of the drinking task was more variable in people with SCI compared to the control group in relation to the metrics measured. Reaching time was longer in SCI groups. The proposed metrics showed capability to discriminate between healthy and pathologic people. Relative deficits in efficiency were larger in SCI people than in controls. These metrics can provide useful information in a clinical setting about the quality of the movement performed by healthy and SCI people during functional activities.

Cognitive reserve is associated with the functional organization of brain networks in healthy aging: a MEG study

The proportion of elderly people in the population has increased rapidly in the last century and consequently "healthy aging" is expected to become a critical area of research in neuroscience. Evidence reveals how healthy aging depends on three main behavioral factors: social lifestyle, cognitive activity and physical activity. In this study, we focused on the role of cognitive activity, concentrating specifically on educational and occupational attainment factors, which were considered two of the main pillars of cognitive reserve. 21 subjects with similar rates of social lifestyle, physical and cognitive activity were selected from a sample of 55 healthy adults. These subjects were divided into two groups according to their level of cognitive reserve; one group comprised subjects with high cognitive reserve (9 members) and the other contained those with low cognitive reserve (12 members). To evaluate the cortical brain connectivity network, all participants were recorded by Magnetoencephalography (MEG) while they performed a memory task (modified version of the Sternberg¿s Task). We then applied two algorithms (Phase Locking Value & Phase-Lag Index) to study the dynamics of functional connectivity. In response to the same task, the subjects with lower cognitive reserve presented higher functional connectivity than those with higher cognitive reserve. These results may indicate that participants with low cognitive reserve needed a greater 'effort' than those with high cognitive reserve to achieve the same level of cognitive performance. Therefore, we conclude that cognitive reserve contributes to the modulation of the functional connectivity patterns of the aging brain.

Optical imaging of functional domains in the cortex of the awake and behaving monkey

As demonstrated by anatomical and physiological studies, the cerebral cortex consists of groups of cortical modules, each comprising populations of neurons with similar functional properties. This functional modularity exists in both sensory and association neocortices. However, the role of such cortical modules in perceptual and cognitive behavior is unknown. To aid in the examination of this issue we have applied the high spatial resolution optical imaging methodology to the study of awake, behaving animals. In this paper, we report the optical imaging of orientation domains and blob structures, approximately 100–200 μm in size, in visual cortex of the awake and behaving monkey. By overcoming the spatial limitations of other existing imaging methods, optical imaging will permit the study of a wide variety of cortical functions at the columnar level, including motor and cognitive functions traditionally studied with positron-emission tomography or functional MRI techniques.

Human PEX1 cloned by functional complementation on a CHO cell mutant is responsible for peroxisome-deficient Zellweger syndrome of complementation group I

The peroxisome biogenesis disorders (PBDs), including Zellweger syndrome (ZS) and neonatal adrenoleukodystrophy (NALD), are autosomal recessive diseases caused by defects in peroxisome assembly, for which at least 10 complementation groups have been reported. We have isolated a human PEX1 cDNA (HsPEX1) by functional complementation of peroxisome deficiency of a mutant Chinese hamster ovary (CHO) cell line, ZP107, transformed with peroxisome targeting signal type 1-tagged “enhanced” green fluorescent protein. This cDNA encodes a hydrophilic protein (Pex1p) comprising 1,283 amino acids, with high homology to the AAA-type ATPase family. A stable transformant of ZP107 with HsPEX1 was morphologically and biochemically restored for peroxisome biogenesis. HsPEX1 expression restored peroxisomal protein import in fibroblasts from three patients with ZS and NALD of complementation group I (CG-I), which is the highest-incidence PBD. A CG-I ZS patient (PBDE-04) possessed compound heterozygous, inactivating mutations: a missense point mutation resulting in Leu-664 → Pro and a deletion of the sequence from Gly-634 to His-690 presumably caused by missplicing (splice site mutation). Both PBDE-04 PEX1 cDNAs were defective in peroxisome-restoring activity when expressed in the patient fibroblasts as well as in ZP107 cells. These results demonstrate that PEX1 is the causative gene for CG-I peroxisomal disorders.

Dynamic mapping at the laminar level of odor-elicited responses in rat olfactory bulb by functional MRI

We have applied functional MRI (fMRI) based on blood oxygenation level-dependent (BOLD) image-contrast to map odor-elicited olfactory responses at the laminar level in the rat olfactory bulb (OB) elicited by iso-amyl acetate (10−2 dilution of saturated vapor) with spatial and temporal resolutions of 220×220×1,000 μm and 36 s. The laminar structure of the OB was clearly depicted by high-resolution in vivo anatomical MRI with spatial resolution of 110×110×1,000 μm. In repeated BOLD fMRI measurements, highly significant (P < 0.001) foci were located in the outer layers of both OBs. The occurrence of focal OB activity within a domain at the level of individual glomeruli or groups of glomeruli was corroborated on an intra- and inter-animal basis under anesthetized conditions with this noninvasive method. The dynamic studies demonstrated that the odor-elicited BOLD activations were highly reproducible on a time scale of minutes, whereas over tens of minutes the activations sometimes varied slowly. We found large BOLD signal (ΔS/S = 10–30%) arising from the olfactory nerve layer, which is devoid of synapses and composed of unmyelinated fibers and glial cells. Our results support previous studies with other methods showing that odors elicit activity within glomerular layer domains in the mammalian OB, and extend the analysis to shorter time periods at the level of individual glomeruli or groups of glomeruli. With further improvement, BOLD fMRI should be ideal for systematic analysis of the functional significance of individual glomeruli in olfactory information encoding and of spatiotemporal processing within the olfactory system.