Autonomic Regulation during Quiet and Active Sleep States in Very Preterm Neonates

The immature autonomic nervous system (ANS) in premature infants regulates heart rate (HR) and respiration different during quiet sleep (QS) and active sleep (AS). Little information is available about ANS regulation in these subjects. The aim of this study was to investigate changes in autonomic regulation and cardiorespiratory coupling during AS and QS in five very preterm neonates with gestational age (GA) 26–31 weeks, applying univariate and bivariate linear and non-linear dynamics methods to the recorded cardiorespiratory signals. During QS univariate linear indices revealed lower standard deviations and entropies, indicating decreased heart rate (HR) variability. More balanced sympatho-vagal behavior of the ANS was revealed by decreased low frequency (LF), increased high frequency (HF), and a trend toward lower ratio LF/HF in QS. Applied non-linear indices (probabilities, entropies, and fractal measures) quantifying the complexity and scaling behavior of HR regulation processes were significantly altered in QS in comparison to AS. This reflects a lower short-term variability, less complexity, and a loss of fractal-like correlation properties of HR dynamics in QS. One major finding is that cardiorespiratory coupling is not yet completely developed in very preterm neonates with 26–31 weeks GA. Significantly different regulation patterns in bivariate oscillations of HR and respiration during AS and QS could be recognized. These patterns were characterized on the one hand by predominant monotonous regulating sequences originating from respiration independently from HR time series in AS, and to a minor degree in QS, and on the other hand by some prominent HR regulation sequences in QS independent of respiratory regulation. We speculate that these findings might be suitable for monitoring preterm neonates and for detecting disorders in the developing cardiorespiratory system

Análisis lineal y no lineal de la dinámica de la regulación autonómica de los sistemas cardiovascular y respiratorio durante la prueba ortostática

En la presente tesis doctoral en Ciencias en Ingeniería Biomédica se investigó la regulación autonómica durante el reto ortostático con un enfoque en el análisis de su dinámica temporal utilizando segmentos de corto plazo de las series de tiempo cardiovasculares y respiratorias. Los sujetos enrolados en el estudio incluyeron 12 hombres y 12 mujeres sanos jóvenes, así como 16 mujeres con diagnóstico de síncope vasovagal, con edad similar. La investigación tuvo un doble objetivo: primero, estudiar el efecto de género en personas sanas y segundo, evaluar en mujeres el efecto del síncope vasovagal, sobre la regulación autonómica de los sistemas cardiovascular y respiratorio utilizando un reto ortostático. Además de incluir el análisis de variables hemodinámicas, se analizaron la variabilidad de los intervalos entre latido y latido, de las señales respiratorias, así como de la presión arterial sistólica y diastólica. Las series de tiempo se adquirieron durante la prueba de inclinación a 70°. Las series de tiempo se analizaron mediante técnicas de procesamiento univariadas y bivariadas que proporcionaron información de la variabilidad, la complejidad, el acoplamiento y las interacciones presentes durante la progresión del reto ortostático. La extracción de características se llevó a cabo usando diversos métodos lineales y no lineales en los dominios del tiempo, frecuencia e información. Las técnicas lineales incluyen las recomendadas por Task Force como la función de correlación, el método de doble secuencia y la función de coherencia dirigida parcial. Los métodos no lineales involucraron la dinámica simbólica, la compresión por entropía, análisis de fluctuación sin tendencia, análisis de la irreversibilidad con respecto al tiempo, información mutua, así como diferentes enfoques basados en la entropía en múltiples escalas de tiempo, análisis de la representación de Poincaré y la dinámica simbólica conjunta. En cuanto a los resultados, los valores medios de las variables hemodinámicas no arrojaron diferencias estadísticas entre grupos. Con respecto al efecto del género en los controles, en hombres se obtuvieron diferencias estadísticas durante la línea de base (posición supina) incluyendo una mayor presión arterial sistólica, una menor variabilidad y complejidad de la frecuencia cardíaca, así como un acoplamiento cardiorrespiratorio reducido. Durante la progresión de la fase ortostática, las diferencias de género siguieron o fueron más pronunciadas, especialmente con relación a la variabilidad de la frecuencia cardíaca. Además, la frecuencia respiratoria también aumentó significativamente durante la fase ortostática. Del mismo modo, en hombres el acoplamiento cardiovascular y cardiorrespiratorio disminuyó durante la fase ortostática.En general, los resultados indicaron que en los controles masculinos existió un incremento de la actividad simpática, inmediatamente después de la inclinación, y que se mantuvo durante la fase ortostática. Por el contrario en las mujeres sanas, la regulación autonómica se caracterizó por un equilibrio simpático-vagal pronunciado durante el reto ortostático seguido por un ligero aumento, pero retrasado, de la actividad simpática al final de la fase ortostática. En consecuencia, los análisis mostraron que en estudios de reto ortostático los hombres y las mujeres deben investigarse por separado debido a las diferentes respuestas temporales autonómicas. Con respecto al efecto de síncope vasovagal en las mujeres, casi todas las técnicas aplicadas demostraron diversas diferencias estadísticamente significativas, durante varios minutos e incluso en toda la fase ortostática. Varios de los métodos mostraron diferencias considerables dentro de los primeros minutos después de inclinar al sujeto, donde aún no existían síntomas de presíncope. Las diferencias distintivas durante la fase ortostática incluyeron un aumento de la frecuencia respiratoria, una disminución de la variabilidad y complejidad de la frecuencia cardiaca, un aumento de la variabilidad y complejidad respiratoria, un aumento de la variabilidad y complejidad de la presión arterial sistólica así como una disminución y/o alteración de los acoplamientos e interacciones cardiovasculares y cardiorrespiratorias en pacientes femeninas. Los resultados claramente señalaron un aumento sostenido de la actividad simpática que afectó la regulación autonómica del sistema cardiovascular y respiratorio debido al reto ortostático en pacientes femeninas jóvenes y susceptibles al síncope vasovagal. Los resultados mostraron la ventaja de realizar una descripción temporal detallada de la regulación autonómica durante el reto ortostático que depende del género y de la susceptibilidad al síncope vasovagal. Además, durante la investigación doctoral se formularon y evaluaron procedimientos alternativos para analizar la dinámica temporal de las series de tiempo cardiovasculares y respiratorias. Se propusieron nuevos procedimientos que combinan la entropía multiescala y la dinámica simbólica, y se establecieron sugerencias para el análisis segmentado de Poincaré. Asimismo, se propusieron nuevos parámetros para la dinámica simbólica a corto plazo y la entropía multiescala. Adicionalmente, se introdujo un nuevo método no lineal para estudiar acoplamientos e interacciones, llamado el análisis gráfico en el espacio delta. Estos índices y métodos revelaron resultados prometedores que deben de investigarse en mayor medida en futuros estudios

Fast automated placement of polar hydrogen atoms in protein-ligand complexes

<p>Abstract</p> <p>Background</p> <p>Hydrogen bonds play a major role in the stabilization of protein-ligand complexes. The ability of a functional group to form them depends on the position of its hydrogen atoms. An accurate knowledge of the positions of hydrogen atoms in proteins is therefore important to correctly identify hydrogen bonds and their properties. The high mobility of hydrogen atoms introduces several degrees of freedom: Tautomeric states, where a hydrogen atom alters its binding partner, torsional changes where the position of the hydrogen atom is rotated around the last heavy-atom bond in a residue, and protonation states, where the number of hydrogen atoms at a functional group may change. Also, side-chain flips in glutamine and asparagine and histidine residues, which are common crystallographic ambiguities must be identified before structure-based calculations can be conducted.</p> <p>Results</p> <p>We have implemented a method to determine the most probable hydrogen atom positions in a given protein-ligand complex. Optimality of hydrogen bond geometries is determined by an empirical scoring function which is used in molecular docking. This allows to evaluate protein-ligand interactions with an established model. Also, our method allows to resolve common crystallographic ambiguities such as as flipped amide groups and histidine residues. To ensure high speed, we make use of a dynamic programming approach.</p> <p>Conclusion</p> <p>Our results were checked against selected high-resolution structures from an external dataset, for which the positions of the hydrogen atoms have been validated manually. The quality of our results is comparable to that of other programs, with the advantage of being fast enough to be applied on-the-fly for interactive usage or during score evaluation.</p

Long Time to Diagnosis of Medulloblastoma in Children Is Not Associated with Decreased Survival or with Worse Neurological Outcome

International audienceBACKGROUND: The long time to diagnosis of medulloblastoma, one of the most frequent brain tumors in children, is the source of painful remorse and sometimes lawsuits. We analyzed its consequences for tumor stage, survival, and sequelae. PATIENTS AND METHODS: This retrospective population-based cohort study included all cases of pediatric medulloblastoma from a region of France between 1990 and 2005. We collected the demographic, clinical, and tumor data and analyzed the relations between the interval from symptom onset until diagnosis, initial disease stage, survival, and neuropsychological and neurological outcome. RESULTS: The median interval from symptom onset until diagnosis for the 166 cases was 65 days (interquartile range 31-121, range 3-457). A long interval (defined as longer than the median) was associated with a lower frequency of metastasis in the univariate and multivariate analyses and with a larger tumor volume, desmoplastic histology, and longer survival in the univariate analysis, but not after adjustment for confounding factors. The time to diagnosis was significantly associated with IQ score among survivors. No significant relation was found between the time to diagnosis and neurological disability. In the 62 patients with metastases, a long prediagnosis interval was associated with a higher T stage, infiltration of the fourth ventricle floor, and incomplete surgical resection; it nonetheless did not influence survival significantly in this subgroup. CONCLUSIONS: We found complex and often inverse relations between time to diagnosis of medulloblastoma in children and initial severity factors, survival, and neuropsychological and neurological outcome. This interval appears due more to the nature of the tumor and its progression than to parental or medical factors. These conclusions should be taken into account in the information provided to parents and in expert assessments produced for malpractice claims

Application of the PM6 semi-empirical method to modeling proteins enhances docking accuracy of AutoDock

<p>Abstract</p> <p>Background</p> <p>Molecular docking methods are commonly used for predicting binding modes and energies of ligands to proteins. For accurate complex geometry and binding energy estimation, an appropriate method for calculating partial charges is essential. AutoDockTools software, the interface for preparing input files for one of the most widely used docking programs AutoDock 4, utilizes the Gasteiger partial charge calculation method for both protein and ligand charge calculation. However, it has already been shown that more accurate partial charge calculation - and as a consequence, more accurate docking- can be achieved by using quantum chemical methods. For docking calculations quantum chemical partial charge calculation as a routine was only used for ligands so far. The newly developed Mozyme function of MOPAC2009 allows fast partial charge calculation of proteins by quantum mechanical semi-empirical methods. Thus, in the current study, the effect of semi-empirical quantum-mechanical partial charge calculation on docking accuracy could be investigated.</p> <p>Results</p> <p>The docking accuracy of AutoDock 4 using the original AutoDock scoring function was investigated on a set of 53 protein ligand complexes using Gasteiger and PM6 partial charge calculation methods. This has enabled us to compare the effect of the partial charge calculation method on docking accuracy utilizing AutoDock 4 software. Our results showed that the docking accuracy in regard to complex geometry (docking result defined as accurate when the RMSD of the first rank docking result complex is within 2 Å of the experimentally determined X-ray structure) significantly increased when partial charges of the ligands and proteins were calculated with the semi-empirical PM6 method.</p> <p>Out of the 53 complexes analyzed in the course of our study, the geometry of 42 complexes were accurately calculated using PM6 partial charges, while the use of Gasteiger charges resulted in only 28 accurate geometries. The binding affinity estimation was not influenced by the partial charge calculation method - for more accurate binding affinity prediction development of a new scoring function for AutoDock is needed.</p> <p>Conclusion</p> <p>Our results demonstrate that the accuracy of determination of complex geometry using AutoDock 4 for docking calculation greatly increases with the use of quantum chemical partial charge calculation on both the ligands and proteins.</p

A Formação na Maturidade como Apropriação da Própria História de Vida

No presente artigo, a disposi&#231;&#227;o e a compet&#234;ncia para a apropria&#231;&#227;o da pr&#243;pria hist&#243;ria de vida s&#227;o consideradas como modos de forma&#231;&#227;o1 na maturidade. Estas se relacionam com fatores hist&#243;ricos e s&#243;cio-pol&#237;ticos e est&#227;o inscritas em contextos multigeracionais de forma&#231;&#227;o e processos de desenvolvimento ao longo da vida. Nesta perspectiva, conceitos como gera&#231;&#227;o, geracionalidade, geratividade e transmiss&#227;o transgeracional ganham destaque e ser&#227;o aprofundados no texto. A linha argumentativa que sustenta este ponto de vista baseia-se em estudos de pa&#237;ses de l&#237;ngua alem&#227; sobre crian&#231;as da Segunda Guerra Mundial que envelheceram. Apesar de se tratar de uma situa&#231;&#227;o espec&#237;fica, nos parece poss&#237;vel a extens&#227;o das reflex&#245;es tamb&#233;m para o contexto brasileiro