Modelos de resposta à interação entre fármacos anestésicos : análise de regressão e análise de Clusters

Os avanços tecnológicos e científicos, na área da saúde, têm vindo a aliar áreas como a Medicina e a Matemática, cabendo à ciência adequar de forma mais eficaz os meios de investigação, diagnóstico, monitorização e terapêutica. Os métodos desenvolvidos e os estudos apresentados nesta dissertação resultam da necessidade de encontrar respostas e soluções para os diferentes desafios identificados na área da anestesia. A índole destes problemas conduz, necessariamente, à aplicação, adaptação e conjugação de diferentes métodos e modelos das diversas áreas da matemática. A capacidade para induzir a anestesia em pacientes, de forma segura e confiável, conduz a uma enorme variedade de situações que devem ser levadas em conta, exigindo, por isso, intensivos estudos. Assim, métodos e modelos de previsão, que permitam uma melhor personalização da dosagem a administrar ao paciente e por monitorizar, o efeito induzido pela administração de cada fármaco, com sinais mais fiáveis, são fundamentais para a investigação e progresso neste campo. Neste contexto, com o objetivo de clarificar a utilização em estudos na área da anestesia de um ajustado tratamento estatístico, proponho-me abordar diferentes análises estatísticas para desenvolver um modelo de previsão sobre a resposta cerebral a dois fármacos durante sedação. Dados obtidos de voluntários serão utilizados para estudar a interação farmacodinâmica entre dois fármacos anestésicos. Numa primeira fase são explorados modelos de regressão lineares que permitam modelar o efeito dos fármacos no sinal cerebral BIS (índice bispectral do EEG – indicador da profundidade de anestesia); ou seja estimar o efeito que as concentrações de fármacos têm na depressão do eletroencefalograma (avaliada pelo BIS). Na segunda fase deste trabalho, pretende-se a identificação de diferentes interações com Análise de Clusters bem como a validação do respetivo modelo com Análise Discriminante, identificando grupos homogéneos na amostra obtida através das técnicas de agrupamento. O número de grupos existentes na amostra foi, numa fase exploratória, obtido pelas técnicas de agrupamento hierárquicas, e a caracterização dos grupos identificados foi obtida pelas técnicas de agrupamento k-means. A reprodutibilidade dos modelos de agrupamento obtidos foi testada através da análise discriminante. As principais conclusões apontam que o teste de significância da equação de Regressão Linear indicou que o modelo é altamente significativo. As variáveis propofol e remifentanil influenciam significativamente o BIS e o modelo melhora com a inclusão do remifentanil. Este trabalho demonstra ainda ser possível construir um modelo que permite agrupar as concentrações dos fármacos, com base no efeito no sinal cerebral BIS, com o apoio de técnicas de agrupamento e discriminantes. Os resultados desmontram claramente a interacção farmacodinâmica dos dois fármacos, quando analisamos o Cluster 1 e o Cluster 3. Para concentrações semelhantes de propofol o efeito no BIS é claramente diferente dependendo da grandeza da concentração de remifentanil. Em suma, o estudo demostra claramente, que quando o remifentanil é administrado com o propofol (um hipnótico) o efeito deste último é potenciado, levando o sinal BIS a valores bastante baixos.

Cerebral perfusion and automated individual analysis using SPECT among an obsessive-compulsive population

OBJECTIVE: To make individual assessments using automated quantification methodology in order to screen for perfusion abnormalities in cerebral SPECT examinations among a sample of subjects with OCD. METHODS: Statistical parametric mapping (SPM) was used to compare 26 brain SPECT images from patients with OCD individually with an image bank of 32 normal subjects, using the statistical threshold of p < 0.05 (corrected for multiple comparisons at the level of individual voxels or clusters). The maps were analyzed, and regions presenting voxels that remained above this threshold were sought. RESULTS: Six patients from a sample of 26 OCD images showed abnormalities at cluster or voxel level, considering the criteria described above, which represented 23.07%. However, seven images from the normal group of 32 were also indicated as cases of perfusional abnormality, representing 21.8% of the sample. CONCLUSION: The automated quantification method was not considered to be a useful tool for clinical practice, for analyses complementary to visual inspection.

Detecting the number of clusters of individuals using the software STRUCTURE: a simulation study.

The identification of genetically homogeneous groups of individuals is a long standing issue in population genetics. A recent Bayesian algorithm implemented in the software STRUCTURE allows the identification of such groups. However, the ability of this algorithm to detect the true number of clusters (K) in a sample of individuals when patterns of dispersal among populations are not homogeneous has not been tested. The goal of this study is to carry out such tests, using various dispersal scenarios from data generated with an individual-based model. We found that in most cases the estimated 'log probability of data' does not provide a correct estimation of the number of clusters, K. However, using an ad hoc statistic DeltaK based on the rate of change in the log probability of data between successive K values, we found that STRUCTURE accurately detects the uppermost hierarchical level of structure for the scenarios we tested. As might be expected, the results are sensitive to the type of genetic marker used (AFLP vs. microsatellite), the number of loci scored, the number of populations sampled, and the number of individuals typed in each sample.

Comparative genomics of ParaHox clusters of teleost fishes: gene cluster breakup and the retention of gene sets following whole genome duplications.

BACKGROUND: The evolutionary lineage leading to the teleost fish underwent a whole genome duplication termed FSGD or 3R in addition to two prior genome duplications that took place earlier during vertebrate evolution (termed 1R and 2R). Resulting from the FSGD, additional copies of genes are present in fish, compared to tetrapods whose lineage did not experience the 3R genome duplication. Interestingly, we find that ParaHox genes do not differ in number in extant teleost fishes despite their additional genome duplication from the genomic situation in mammals, but they are distributed over twice as many paralogous regions in fish genomes. RESULTS: We determined the DNA sequence of the entire ParaHox C1 paralogon in the East African cichlid fish Astatotilapia burtoni, and compared it to orthologous regions in other vertebrate genomes as well as to the paralogous vertebrate ParaHox D paralogons. Evolutionary relationships among genes from these four chromosomal regions were studied with several phylogenetic algorithms. We provide evidence that the genes of the ParaHox C paralogous cluster are duplicated in teleosts, just as it had been shown previously for the D paralogon genes. Overall, however, synteny and cluster integrity seems to be less conserved in ParaHox gene clusters than in Hox gene clusters. Comparative analyses of non-coding sequences uncovered conserved, possibly co-regulatory elements, which are likely to contain promoter motives of the genes belonging to the ParaHox paralogons. CONCLUSION: There seems to be strong stabilizing selection for gene order as well as gene orientation in the ParaHox C paralogon, since with a few exceptions, only the lengths of the introns and intergenic regions differ between the distantly related species examined. The high degree of evolutionary conservation of this gene cluster's architecture in particular - but possibly clusters of genes more generally - might be linked to the presence of promoter, enhancer or inhibitor motifs that serve to regulate more than just one gene. Therefore, deletions, inversions or relocations of individual genes could destroy the regulation of the clustered genes in this region. The existence of such a regulation network might explain the evolutionary conservation of gene order and orientation over the course of hundreds of millions of years of vertebrate evolution. Another possible explanation for the highly conserved gene order might be the existence of a regulator not located immediately next to its corresponding gene but further away since a relocation or inversion would possibly interrupt this interaction. Different ParaHox clusters were found to have experienced differential gene loss in teleosts. Yet the complete set of these homeobox genes was maintained, albeit distributed over almost twice the number of chromosomes. Selection due to dosage effects and/or stoichiometric disturbance might act more strongly to maintain a modal number of homeobox genes (and possibly transcription factors more generally) per genome, yet permit the accumulation of other (non regulatory) genes associated with these homeobox gene clusters.

An analysis of the currently available calibrations inStromgren photometry by using open clusters

In recent years, several authors have revised the calibrations used to compute physical parameters (tex2html_wrap_inline498, tex2html_wrap_inline500, log g, [Fe/H]) from intrinsic colours in the tex2html_wrap_inline504 photometric system. For reddened stars, these intrinsic colours can be computed through the standard relations among colour indices for each of the regions defined by Strömgren (1966) on the HR diagram. We present a discussion of the coherence of these calibrations for main-sequence stars. Stars from open clusters are used to carry out this analysis. Assuming that individual reddening values and distances should be similar for all the members of a given open cluster, systematic differences among the calibrations used in each of the photometric regions might arise when comparing mean reddening values and distances for the members of each region. To classify the stars into Strömgren's regions we extended the algorithm presented by Figueras et al. (1991) to a wider range of spectral types and luminosity classes. The observational ZAMS are compared with the theoretical ZAMS from stellar evolutionary models, in the range tex2html_wrap_inline506 K. The discrepancies are also discussed.

Persistent spatial clusters of high body mass index in a Swiss urban population as revealed by the 5-year GeoCoLaus longitudinal study.

OBJECTIVE: Body mass index (BMI) may cluster in space among adults and be spatially dependent. Whether and how BMI clusters evolve over time in a population is currently unknown. We aimed to determine the spatial dependence of BMI and its 5-year evolution in a Swiss general adult urban population, taking into account the neighbourhood-level and individual-level characteristics. DESIGN: Cohort study. SETTING: Swiss general urban population. PARTICIPANTS: 6481 georeferenced individuals from the CoLaus cohort at baseline (age range 35-74 years, period=2003-2006) and 4460 at follow-up (period=2009-2012). OUTCOME MEASURES: Body weight and height were measured by trained healthcare professionals with participants standing without shoes in light indoor clothing. BMI was calculated as weight (kg) divided by height squared (m(2)). Participants were geocoded using their postal address (geographic coordinates of the place of residence). Getis-Ord Gi statistic was used to measure the spatial dependence of BMI values at baseline and its evolution at follow-up. RESULTS: BMI was not randomly distributed across the city. At baseline and at follow-up, significant clusters of high versus low BMIs were identified and remained stable during the two periods. These clusters were meaningfully attenuated after adjustment for neighbourhood-level income but not individual-level characteristics. Similar results were observed among participants who showed a significant weight gain. CONCLUSIONS: To the best of our knowledge, this is the first study to report longitudinal changes in BMI clusters in adults from a general population. Spatial clusters of high BMI persisted over a 5-year period and were mainly influenced by neighbourhood-level income.

Environments of Acitive Galaxies

This dissertation presents studies on the environments of active galaxies. Paper I is a case study of a cluster of galaxies containing BL Lac object RGB 1745+398. We measured the velocity dispersion, mass, and richness of the cluster. This was one of the most thorough studies of the environments of a BL Lac object. Methods used in the paper could be used in the future for studying other clusters as well. In Paper II we studied the environments of nearby quasars in the Sloan Digital Sky Survey (SDSS). We found that quasars have less neighboring galaxies than luminous inactive galaxies. In the large-scale structure, quasars are usually located at the edges of superclusters or even in void regions. We concluded that these low-redshift quasars may have become active only recently because the galaxies in low-density environments evolve later to the phase where quasar activity can be triggered. In Paper III we extended the analysis of Paper II to other types of AGN besides quasars. We found that different types of AGN have different large-scale environments. Radio galaxies are more concentrated in superclusters, while quasars and Seyfert galaxies prefer low-density environments. Different environments indicate that AGN have different roles in galaxy evolution. Our results suggest that activity of galaxies may depend on their environment on the large scale. Our results in Paper III raised questions of the cause of the environment-dependency in the evolution of galaxies. Because high-density large-scale environments contain richer groups and clusters than the underdense environments, our results could reflect smaller-scale effects. In Paper IV we addressed this problem by studying the group and supercluster scale environments of galaxies together. We compared the galaxy populations in groups of different richnesses in different large-scale environments. We found that the large-scale environment affects the galaxies independently of the group richness. Galaxies in low-density environments on the large scale are more likely to be star-forming than those in superclusters even if they are in groups with the same richness. Based on these studies, the conclusion of this dissertation is that the large-scale environment affects the evolution of galaxies. This may be caused by different “speed” of galaxy evolution in low and high-density environments: galaxies in dense environments reach certain phases of evolution earlier than galaxies in underdense environments. As a result, the low-density regions at low redshifts are populated by galaxies in earlier phases of evolution than galaxies in high-density regions.

Respuesta educativa al alumnado con sobredotación intelectual : guía para elaborar el documento individual de adaptaciones curriculares de ampliación o enriquecimiento.

La atención a la diversidad es un requisito para que los alumnos reciban una educación de calidad. En este sentido, los alumnos con sobredotación presentan unas características especiales, por lo que hay que considerar que el trabajo didáctico con ellos debe abarcar un amplio abanico de posibilidades. El objetivo de esta guía es orientar a profesores y educadores en su tarea educativa. Este recurso se divide en cuatro capítulos. El primero se refiere al alumnado con necesidades educativas especiales asociadas a condiciones personales de sobredotación intelectual. Se analizan aspectos que identifican a este tipo de alumnos y sus necesidades específicas a través de una evaluación psicopedagógica; El segundo trata de la respuesta educativa al alumnado con estas características y se explican las medidas educativas que la Comunidad de Madrid desarrolla. Estas medidas son ordinarias, extraordinarias y complementarias a la educación reglada. El tercero presenta las orientaciones para la elaboración de la adaptación curricular individual. Se expone el modelo orientativo y una serie de orientaciones para la elaboración de adaptaciones curriculares de ampliación o enriquecimiento. El cuarto es una ejemplificación práctica de adaptación curricular. Contiene dos anexos, el primero desarrolla normativa específica y el segundo un glosario de términos.

Estudio de perfiles evolutivos en la lectura : validación y revisión del test individual de diagnóstico de errores en lectura (TIDEL).

Llegar al proceso evolutivo del aprendizaje de la lectura sirviéndose de un instrumento diagnóstico que permitiera realizar un análisis de errores que parecía aislar con suficiente nitidez su naturaleza evolutiva con relación a este proceso de aprendizaje. Como objetivos más específicos se pretendía: extraer de la lectura oral errores de diferente calidad y cantidad en distintas etapas del desarrollo de la lectura, sistematizar un registro de errores objetivo y contextualizar al máximo la observación de la lectura oral, acercándola a la realidad del aula. Se han tenido en cuenta dos criterios en la selección: los sujetos y las conductas. En la selección de sujetos se centró en niños con problemas de aprendizaje de la lectura. Partiendo de un total de 41612 sujetos de primer curso y 43036 de segundo curso de Educación Primaria para el curso académico 1995-96, con una ratio alumnos/unidad (aula) respectivamente de 22.12 y 21.33. Se trata de un muestreo no probabilístico del tipo 'muestras de juicio, de casos típicos' con 1102 casos. En la selección de conductas el criterio de muestreo inicial fue libre dado que utiliza como unidades de muestra de conductas, todas las ocurrencias o gama de ellas a lo largo de la grabación. En primer lugar se concretó el problema y se elaboró en reactivo, atendiendo a tres criterios contextuales, metodológicos y para el muestreo observacional. Las fases de investigación fueron tres: recogida inicial de la información, con registro de grabaciones y observación cualitativa, categorización de errores y elaboración del primer cuestionario de errores; después se hizo una aplicación piloto del cuestionario, con registro de grabaciones, análisis cuantitativo y formulación del test individual de diagnóstico de errores en lectura (TIDEL) ; y la tercera fue la aplicación del TIDEL. Después hubo un análisis de datos, mediante un análisis descriptivo, seguido de un análisis y validación teniendo en cuenta las evidencias. Sigue la fase de análisis e interpretación de resultados de los perfiles de errores. Finalmente se exponen las conclusiones. Textos de lectura, hojas de observación para registrar los resultados y datos identificativos, encuestas para diferenciar entre los textos que los sujetos conocían realmente, de los que les sonaban, discusiones en grupo para determinar la categorización de los errores. El instrumento más importante fue el TIDEL (Test Individual de Diagnóstico de Errores en Lectura), que permite detectar errores en la lectura. Se recogieron diversos tipos de errores: falta de integración de las palabras, confusión de letras por la forma, deformación y cambio de elementos, doble/triple consonante e inversiones, en las reglas convencionales, reiteración-relectura-inhibición proactiva, variantes y anticipación con sentido, inmadurez en la pronunciación, y cadencia-entonación-gestos marginales, entre otros. Se infiere un proceso determinado en el desarrollo lector, en el sentido de que un descenso progresivo de los errores elementales del perfil urgente pude facilitar, en un segundo perfil atendible, las primeras tentativas de búsqueda del significado, que se hacen más patentes en el perfil aceptable, con la mayor probabilidad de aparición de los errores de 'anticipación del significado' y 'variantes con sentido'. Se produce una preponderancia de los errores elementales y otros producidos por convenciones idiomáticas. En una segunda etapa será vital la transición y salto al sentido, donde se cometen errores anticipatorios relacionados con el contenido del texto. Así pues, la evolución de la habilidad lectora escalaría dos niveles de la inteligencia que irían de la combinatoria -forma de las letras y su sonido-, al sentido (semántico). Una fase posterior de la lectura encajaría con el razonamiento.

Individual differences in the effects of perceived controllability on pain perception: critical role of the prefrontal cortex

The degree to which perceived controllability alters the way a stressor is experienced varies greatly among individuals. We used functional magnetic resonance imaging to examine the neural activation associated with individual differences in the impact of perceived controllability on self-reported pain perception. Subjects with greater activation in response to uncontrollable (UC) rather than controllable (C) pain in the pregenual anterior cingulate cortex (pACC), periaqueductal gray (PAG), and posterior insula/SII reported higher levels of pain during the UC versus C conditions. Conversely, subjects with greater activation in the ventral lateral prefrontal cortex (VLPFC) in anticipation of pain in the UC versus C conditions reported less pain in response to UC versus C pain. Activation in the VLPFC was significantly correlated with the acceptance and denial subscales of the COPE inventory [Carver, C. S., Scheier, M. F., & Weintraub, J. K. Assessing coping strategies: A theoretically based approach. Journal of Personality and Social Psychology, 56, 267–283, 1989], supporting the interpretation that this anticipatory activation was associated with an attempt to cope with the emotional impact of uncontrollable pain. A regression model containing the two prefrontal clusters (VLPFC and pACC) predicted 64% of the variance in pain rating difference, with activation in the two additional regions (PAG and insula/SII) predicting almost no additional variance. In addition to supporting the conclusion that the impact of perceived controllability on pain perception varies highly between individuals, these findings suggest that these effects are primarily top-down, driven by processes in regions of the prefrontal cortex previously associated with cognitive modulation of pain and emotion regulation.

Evolutionary genomics of the Fox genes: origin of gene families and the ancestry of gene clusters

Over the past decade genomic approaches have begun to revolutionise the study of animal diversity. In particular, genome sequencing programmes have spread beyond the traditional model species to encompass an increasing diversity of animals from many different phyla, as well as unicellular eukaryotes that are closely related to the animals. Whole genome sequences allow researchers to establish, with reasonable confidence, the full complement of any particular family of genes in a genome. Comparison of gene complements from appropriate genomes can reveal the evolutionary history of gene families, indicating when both gene diversification and gene loss have occurred. More than that, however, assembled genomes allow the genomic environment in which individual genes are found to be analysed and compared between species. This can reveal how gene diversification occurred. Here, we focus on the Fox genes, drawing from multiple animal genomes to develop an evolutionary framework explaining the timing and mechanism of origin of the diversity of animal Fox genes. Ancient linkages between genes are a prominent feature of the Fox genes, depicting a history of gene clusters, some of which may be relevant to understanding Fox gene function.

The old metal-poor open cluster ESO 92-SC05: accreted from a dwarf galaxy ?

The study of old open clusters outside the solar circle can bring constraints on formation scenarios of the outer disc. In particular, accretion of dwarf galaxies has been proposed as a likely mechanism in the area. We use BVI photometry for determining fundamental parameters of the faint open cluster ESO 92-SC05. Colour-magnitude diagrams are compared with Padova isochrones, in order to derive age, reddening and distance. We derive a reddening E(B - V) = 0.17, and an old age of similar to 6.0 Gyr. It is one of the rare open clusters known to be older than 5 Gyr. A metallicity of Z similar to 0.004 or [M/H] similar to -0.7 is found. The rather low metallicity suggests that this cluster might be the result of an accretion episode of a dwarf galaxy.

Metallicity gradients at large galactocentric radii using the near-infrared Calcium triplet

We describe a new spectroscopic technique for measuring radial metallicity gradients out to large galactocentric radii. We use the DEep Imaging Multi-Object Spectrograph (DEIMOS) on the Keck telescope and the galaxy spectrum extraction technique of Proctor et al. We also make use of the metallicity sensitive near-infrared Calcium ii triplet (CaT) features together with single stellar population models to obtain metallicities. Our technique is applied as a pilot study to a sample of three relatively nearby (< 30 Mpc) intermediate-mass to massive early-type galaxies. Results are compared with previous literature inner region values and generally show good agreement. We also include a comparison with profiles from dissipational disc-disc major merger simulations. Based on our new extended metallicity gradients combined with other observational evidence and theoretical predictions, we discuss possible formation scenarios for the galaxies in our sample. The limitations of our new technique are also discussed.

Signature of the interaction between dark energy and dark matter in galaxy clusters

We investigate the influence of ail interaction between dark energy and dark matter upon the dynamics of galaxy clusters. We obtain file general Layser-Irvine equation in the presence of interactions, and find how, in that case. the virial theorem stands corrected. Using optical, X-ray and weak lensing data from 33 relaxed galaxy clusters, we put constraints on the strength of the coupling between the dark sectors. Available data Suggests that this coupling is small but positive, indicating that dark energy might be decaying into dark matter. Systematic effects between the several mass estimates, however, should be better known, before definitive conclusions oil the magnitude and significance of this coupling could be established. (C) 2009 Published by Elsevier B.V.