45,259 research outputs found

    Exploring the effects of spinal cord stimulation for freezing of gait in parkinsonian patients

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    Dopaminergic replacement therapies (e.g. levodopa) provide limited to no response for axial motor symptoms including gait dysfunction and freezing of gait (FOG) in Parkinson’s disease (PD) and Richardson’s syndrome progressive supranuclear palsy (PSP-RS) patients. Dopaminergic-resistant FOG may be a sensorimotor processing issue that does not involve basal ganglia (nigrostriatal) impairment. Recent studies suggest that spinal cord stimulation (SCS) has positive yet variable effects for dopaminergic-resistant gait and FOG in parkinsonian patients. Further studies investigating the mechanism of SCS, optimal stimulation parameters, and longevity of effects for alleviating FOG are warranted. The hypothesis of the research described in this thesis is that mid-thoracic, dorsal SCS effectively reduces FOG by modulating the sensory processing system in gait and may have a dopaminergic effect in individuals with FOG. The primary objective was to understand the relationship between FOG reduction, improvements in upper limb visual-motor performance, modulation of cortical activity and striatal dopaminergic innervation in 7 PD participants. FOG reduction was associated with changes in upper limb reaction time, speed and accuracy measured using robotic target reaching choice tasks. Modulation of resting-state, sensorimotor cortical activity, recorded using electroencephalography, was significantly associated with FOG reduction while participants were OFF-levodopa. Thus, SCS may alleviate FOG by modulating cortical activity associated with motor planning and sensory perception. Changes to striatal dopaminergic innervation, measured using a dopamine transporter marker, were associated with visual-motor performance improvements. Axial and appendicular motor features may be mediated by non-dopaminergic and dopaminergic pathways, respectively. The secondary objective was to demonstrate the short- and long-term effects of SCS for alleviating dopaminergic-resistant FOG and gait dysfunction in 5 PD and 3 PSP-RS participants without back/leg pain. SCS programming was individualized based on which setting best improved gait and/or FOG responses per participant using objective gait analysis. Significant improvements in stride velocity, step length and reduced FOG frequency were observed in all PD participants with up to 3-years of SCS. Similar gait and FOG improvements were observed in all PSP-RS participants up to 6-months. SCS is a promising therapeutic option for parkinsonian patients with FOG by possibly influencing cortical and subcortical structures involved in locomotion physiology

    Identification of Hindbrain Neural Substrates for Motor Initiation in the hatchling Xenopus laevis Tadpole

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    Animal survival profoundly depends on the ability to detect stimuli in the environment, process them and respond accordingly. In this respect, motor responses to a sensory stimulation evolved into a variety of coordinated movements, which involve the control of brain centres over spinal locomotor circuits. The hatchling Xenopus tadpole, even in its embryonic stage, is able to detect external sensory information and to swim away if the stimulus is considered noxious. To do so, the tadpole relies on well-known ascending sensory pathway, which carries the sensory information to the brain. When the stimulus is strong enough, descending interneurons are activated, leading to the excitation of spinal CPG neurons, which causes the undulatory movement of swimming. However, the activation of descending interneurons that marks the initiation of motor response appears after a long delay from the sensory stimulation. Furthermore, the long-latency response is variable in time, as observed in the slow-summating excitation measured in descending interneurons. These two features, i.e. long-latency and variability, cannot be explained by the firing time and pattern of the ascending sensory pathway of the Xenopus tadpole. Therefore, a novel neuronal population has been proposed to lie in the hindbrain of the tadpole, and being able to 'hold' the sensory information, thus accounting for the long and variable delay of swim initiation. In this work, the role of the hindbrain in the maintenance of the long and variable response to trunk skin stimulation is investigated in the Xenopustadpole at developmental stage 37/38. A multifaceted approach has been used to unravel the neuronal mechanisms underlying the delayed motor response, including behavioural experiments, electrophysiology analysis of fictive swimming, hindbrain extracellular recordings and imaging experiments. Two novel neuronal populations have been identified in the tadpole's hindbrain, which exhibit activation patterns compatible with the role of delaying the excitation of the spinal locomotor circuit. Future work on cellular properties and synaptic connections of these newly discovered populations might shed light on the mechanism of descending control active at embryonic stage. Identifying supraspinal neuronal populations in an embryonic organism could aid in understanding mechanisms of descending motor control in more complex vertebrates

    Bioinformatic characterization of a triacylglycerol lipase produced by Aspergillus flavus isolated from the decaying seed of Cucumeropsis mannii

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    Lipases are enzymes of industrial importance responsible for the hydrolysis of ester bonds of triglycerides. A lipolytic fungus was isolated and subsequently identified based on the ITS sequence analysis as putative Aspergillus flavus with accession number LC424503. The gene coding for extracellular triacylglycerol lipase was isolated from Aspergillus flavus species, sequenced, and characterised using bioinformatics tools. An open reading frame of 420 amino acid sequence was obtained and designated as Aspergillus flavus lipase (AFL) sequence. Alignment of the amino acid sequence with other lipases revealed the presence GHSLG sequence which is the lipase consensus sequence Gly-X1-Ser-X2-Gly indicating that it a classical lipase. A catalytic active site lid domain composed of TYITDTIIDLS amino acids sequence was also revealed. This lid protects the active site, control the catalytic activity and substrate selectivity in lipases. The 3-Dimensional structural model shared 34.08% sequence identity with a lipase from Yarrowia lipolytica covering 272 amino acid residues of the template model. A search of the lipase engineering database using AFL sequence revealed that it belongs to the class GX-lipase, superfamily abH23 and homologous family abH23.02, molecular weight and isoelectric point values of 46.95 KDa and 5.7, respectively. N-glycosylation sites were predicted at residues 164, 236 and 333, with potentials of 0.7250, 0.7037 and 0.7048, respectively. O-glycosylation sites were predicted at residues 355, 358, 360 and 366. A signal sequence of 37 amino acids was revealed at the N-terminal of the polypeptide. This is a short peptide sequence that marks a protein for transport across the cell membrane and indicates that AFL is an extracellular lipase. The findings on the structural and molecular properties of Aspergillus flavus lipase in this work will be crucial in future studies aiming at engineering the enzyme for biotechnology applications

    Medicina personalizada en lactantes con cáncer: Estudio farmacogenético de polimorfismos relacionados con toxicidad y respuesta a la quimioterapia

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    Introducción La farmacogenética es una herramienta de la “Medicina personalizada” que contribuye a optimizar los tratamientos antineoplásicos, adaptándolos a las características genéticas particulares de cada individuo, maximizando su eficacia y minimizando su toxicidad. El lactante con cáncer es un paciente de particular vulnerabilidad y sus comorbilidades tiene una especial repercusión vital. El estudio farmacogenético en esta población resulta pionero y novedoso en nuestro medio. La identificación de marcadores predictivos específicos permitirá individualizar más la terapéutica en esta población tan frágil y mejorar en consecuencia su calidad de vida y su pronóstico vital. Material y métodos Estudio de cohortes ambispectivo de pacientes oncológicos entre 1 y 18 meses de edad, receptores de quimioterapia en el Hospital La Fe de Valencia, en el periodo comprendido entre enero 2007 y agosto 2019. La parte retrospectiva comprende hasta diciembre 2015, el estudio prospectivo desde enero 2016 hasta agosto 2019. En primer lugar, se realiza un análisis descriptivo de variables epidemiológicas, clínico/biológicas, terapéuticas y pronósticas de 72 pacientes con dichas características. Se describe la toxicidad derivada de sus 578 ciclos de quimioterapia (37 variables clínicas), el tiempo de seguimiento y su supervivencia (meses). En segundo lugar, se realiza un estudio analítico cuyo objetivo es correlacionar los polimorfismos genéticos relacionados con la quimioterapia de 64 de los pacientes, la toxicidad grave secundaria al tratamiento (≥ grado 3 según CTAE 4.0) y su supervivencia. El genotipado se realiza en el Centro Nacional de Genotipado (CEGEN) mediante la tecnología MassArray (AgenaBioscience), previa configuración de un panel farmacogenético pediátrico en base a las evidencias recogidas en la base de datos PharmGKB, fichas técnicas de los medicamentos y consorcios internacionales expertos. El análisis estadístico descriptivo se realiza con los programas Excel 2016 y R: las variables cualitativas con el recuento numérico (porcentaje) y las variables cuantitativas como mediana +/- rango intercuartílico ante ausencia de normalidad en la distribución de los datos (p <0,05, prueba de Kolmogorov-Smirnov). En el análisis de supervivencia se utiliza el estimador Kaplan-Meier. El análisis estadístico analítico de correlación entre polimorfismos y toxicidad se realiza mediante regresión logística penalizada por Elastic Net empleando R. El análisis estadístico analítico de correlación entre polimorfismos y recaída/muerte se realiza mediante regresión de Cox penalizada por Elastic Net. Resultados Las variables epidemiológicas, clínico/biológicas y terapéuticas de los pacientes de la muestra son consecuentes con las descritas en la literatura del lactante con cáncer. Las neoplasias con mayor impacto negativo en la supervivencia son la leucemia mieloblástica aguda y los tumores del sistema nervioso central. La toxicidad más prevalente es hematológica, digestiva e infecciosa. Existe correlación entre la toxicidad grave secundaria a los quimioterápicos en forma de anemia, neutropenia y/o trombopenia y 46 polimorfismos genéticos diferentes. Así mismo se encuentra asociación estadísticamente significativa entre la supervivencia global y la supervivencia libre de enfermedad y ciertos polimorfismos genéticos (26 y 13 respectivamente). Los polimorfismos obtenidos pertenecen a genes encargados del transporte (6 genes) y metabolismo (17 genes) de los fármacos, de la reparación del material genético y la supresión tumoral (5 genes) y de otras funciones biológicas (4 genes). Conclusión Los resultados del presente estudio muestran correlación estadística entre 46 polimorfismos de genes implicados en la cinética farmacológica y la reparación del material genético y la variabilidad en la toxicidad quimioterápica y supervivencia de pacientes lactantes con cáncer. En definitiva, aportaciones de la farmacogenética que pueden contribuir a la optimización del tratamiento antineoplásico en esta población particular y a la predicción de sus riesgos, de especial impacto en los supervivientes del cáncer infantil

    Uso de las histonas circulantes y sus modificaciones post-traduccionales como biomarcadores en sepsis y shock séptico

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    La sepsis es una afección potencialmente mortal causada por una respuesta anormal del huésped a una infección, produciendo respuestas fisiológicas alteradas que dañan los propios tejidos del paciente y pueden provocar disfunción orgánica e incluso la muerte. Asimismo, algunos pacientes sépticos progresan a shock séptico, caracterizado por alteraciones circulatorias, celulares y metabólicas sustanciales que aumentan el riesgo de mortalidad. A pesar de que la sepsis se caracteriza por un mal funcionamiento del sistema inmunológico, lo que a su vez conduce a una respuesta inmune alterada e inmunosupresión, la alta complejidad de la fisiopatología de la sepsis requiere una mayor investigación para comprender las respuestas inmunes que ocurren durante la sepsis. Asimismo, las histonas extracelulares circulantes han ganado relevancia como mediadores citotóxicos en la sepsis, ya que actúan como patrones moleculares asociados a daño, que inducen estrés oxidativo y activan el inflamasoma NLRP3. Estos mecanismos median la activación de la piroptosis, un mecanismo de muerte celular programada que produce inflamación mediante la expresión de IL-18, IL-1β and IL-1α. Sin embargo, a pesar de la evidencia de activación del inflamasoma en las células inmunes durante la sepsis, se desconoce si las histonas extracelulares son capaces de activar los inflamasomas endoteliales y sus consecuencias. En este trabajo destacamos el papel previamente desconocido de las histonas extracelulares, mediando la activación del inflamasoma NLRP3 y la piroptosis en las células endoteliales, contribuyendo a la disfunción endotelial y la desregulación de la respuesta inmune mediada por el endotelio. Asimismo, también demostramos cómo la acetilación de histonas disminuye la activación de la piroptosis. Además, demostramos que la piroptosis se produce en pacientes con shock séptico y los niveles de histonas circulantes se correlacionan con la expresión de citoquinas proinflamatorias y citoquinas piroptóticas, la liberación de factores de adhesión endotelial y la gravedad de la enfermedad. Proponemos la piroptosis mediada por histonas como un nuevo objetivo para desarrollar intervenciones clínicas. De manera similar, hemos analizado las respuestas inmunorelacionadas que ocurren durante las primeras etapas de la sepsis con el objetivo de proporcionar nuevos datos comparando las cantidades de citoquinas, inmunomoduladores y otros mediadores endoteliales en pacientes críticamente enfermos no sépticos, sépticos y de shock séptico. Nuestro enfoque ayudará a caracterizar rápidamente las respuestas inmunes alteradas en pacientes sépticos y de shock séptico ingresados en la Unidad de Cuidados Intensivos. Finalmente analizamos el papel de la metilación del ADN en el control del sistema inmune séptico. Nuestros resultados demostraron el papel central de la metilación del ADN modulando la respuesta molecular en los pacientes de shock séptico y contribuyendo a la inmunosupresión, a través de la alteración de los patrones de metilación de los promotores de IL-10 y TREM-2.Sepsis is a life-threatening condition caused by an abnormal host response to an infection that produce altered physiological responses which damages own tissues of the patient and can result in organ dysfunction and in some cases death. Likewise, a subset of septic patients progresses to septic shock, characterized by substantial circulatory, cellular and metabolic abnormalities, which substantially increase the risk of mortality. Sepsis is characterized by a malfunction of the immune system and it can lead to an altered immune response and immunosuppression. Moreover, the high complexity of the pathophysiology of sepsis requires of further investigation to characterize the immune responses in sepsis and septic shock. Likewise, circulating extracellular histones have gained relevance as cytotoxic mediators in sepsis pathophysiology, since they act as damage-associated molecular patterns, which induce oxidative stress and activate NLRP3 inflammasome. Subsequently, inflammasome mediates pyroptosis activation, a programmed cell death mechanism that produces inflammation through the release of IL-18, IL-1β and IL-1α. However, despite inflammasome activation may occur in immune cells during sepsis, it is unknown if this process also takes place in endothelial cells and particularly whether extracellular histones are capable of activating endothelial inflammasomes and their consequences. In this work we highlight a previously unknown role for extracellular histones, that mediates the activation of NLRP3 inflammasome and pyroptosis in endothelial cells by contributing to endothelial dysfunction and the dysregulation of the immune response mediated by endothelium. Likewise, we demonstrated how histone acetylation decreases pyroptosis activation. Furthermore, we show how pyroptosis occurs in septic shock patients and how circulating histone levels correlate with the expression of pro-inflammatory and pyroptotic cytokines, the release of endothelial adhesion factors and septic shock severity. We propose histone-mediated pyroptosis as a new target to develop clinical interventions. Similarly, we have analyzed the immune-related responses occurring during the early stages of sepsis with the aim of providing new data by comparing the amounts of cytokines, immune modulators and other endothelial mediators in critically-ill non-septic patients, septic and septic shock patients. Our approach will help to rapidly characterize the altered immune responses in septic and septic shock patients admitted in the Intensive Care Unit. Finally, we also analyzed the role of DNA methylation in the control of septic immune system. Our results demonstrated the central role of DNA methylation modulating the molecular response in septic shock patients and contributing to immunosuppression, through the alteration of DNA methylation patterns of IL-10 and TREM2 promoters

    Rainfall Prediction: A Comparative Analysis of Modern Machine Learning Algorithms for Time-Series Forecasting

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    Rainfall forecasting has gained utmost research relevance in recent times due to its complexities and persistent applications such as flood forecasting and monitoring of pollutant concentration levels, among others. Existing models use complex statistical models that are often too costly, both computationally and budgetary, or are not applied to downstream applications. Therefore, approaches that use Machine Learning algorithms in conjunction with time-series data are being explored as an alternative to overcome these drawbacks. To this end, this study presents a comparative analysis using simplified rainfall estimation models based on conventional Machine Learning algorithms and Deep Learning architectures that are efficient for these downstream applications. Models based on LSTM, Stacked-LSTM, Bidirectional-LSTM Networks, XGBoost, and an ensemble of Gradient Boosting Regressor, Linear Support Vector Regression, and an Extra-trees Regressor were compared in the task of forecasting hourly rainfall volumes using time-series data. Climate data from 2000 to 2020 from five major cities in the United Kingdom were used. The evaluation metrics of Loss, Root Mean Squared Error, Mean Absolute Error, and Root Mean Squared Logarithmic Error were used to evaluate the models' performance. Results show that a Bidirectional-LSTM Network can be used as a rainfall forecast model with comparable performance to Stacked-LSTM Networks. Among all the models tested, the Stacked-LSTM Network with two hidden layers and the Bidirectional-LSTM Network performed best. This suggests that models based on LSTM-Networks with fewer hidden layers perform better for this approach; denoting its ability to be applied as an approach for budget-wise rainfall forecast applications

    Dynamic and Static Cognitive Deficits in Schizophrenia and Bipolar Disorder After the First Episode

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    Abstract Few studies have comprehensively examined the profile of cognitive functioning in first episode psychosis patients throughout the lifespan, and from first episode to chronic stage. We assessed functioning in general and specific cognitive functions, comparing both schizophrenia (N = 64) and bipolar I (N = 19) patients to controls (N = 103). Participants were from a population-based, case-control study of first episode psychosis patients, who were followed prospectively up to 10 years post first admission. A cognitive battery was administered at baseline and follow-up. By combining longitudinal and cross-sectional data, we were able to examine the cognitive profile of patients and controls throughout the entire age range of our sample (16–65). Schizophrenia patients exhibited widespread declines in IQ, executive function, visual memory, language ability, and verbal knowledge. However, the ages at which these declines occurred differed between functions. Deficits in verbal memory, working memory, processing speed, and visuospatial ability, on the other hand, were present at the first episode, and remained relatively static thereafter. Bipolar I patients also showed declines in IQ, verbal knowledge, and language ability, albeit at different ages to schizophrenia patients and only in verbal functions. Deficits on measures of verbal memory, processing speed, and executive function remained relatively static. Thus, both schizophrenia and bipolar I patients experienced cognitive decline in general and specific functions after the first episode, but the age at which these declines occurred differed between disorder and function. Cognitive remediation efforts may be most fruitful when targeting individual functions during specific time periods throughout adulthood

    The applied psychology of addictive orientations : studies in a 12-step treatment context.

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    The clinical data for the studies was collected at The PROMIS Recovery Centre, a Minnesota Model treatmentc entre for addictions,w hich encouragesth e membership and use of the 12 step Anonymous Fellowships, and is abstinence based. The area of addiction is contextualised in a review chapter which focuses on research relating to the phenomenon of cross addiction. A study examining the concept of "addictive orientations" in male and female addicts is described, which develops a study conductedb y StephensonM, aggi, Lefever, & Morojele (1995). This presents study found a four factor solution which appeared to be subdivisions of the previously found Hedonism and Nurturance factors. Self orientated nurturance (both food dimensions, shopping and caffeine), Other orientated nurturance (both compulsive helping dimensions and work), Sensation seeking hedonism (Drugs, prescription drugs, nicotine and marginally alcohol), and Power related hedonism (Both relationship dimensions, sex and gambling. This concept of "addictive orientations" is further explored in a non-clinical population, where again a four factor solution was found, very similar to that in the clinical population. This was thought to indicate that in terms of addictive orientation a pattern already exists in this non-clinical population and that consideration should be given to why this is the case. These orientations are examined in terms of gender differences. It is suggested that the differences between genders reflect power-related role relationships between the sexes. In order to further elaborate the significance and meaning behind these orientations, the next two chapters look at the contribution of personality variables and how addictive orientations relate to psychiatric symptomatology. Personality variables were differentially, and to a considerable extent predictably involved with the four factors for both males and females.Conscientiousness as positively associated with "Other orientated Nurturance" and negatively associated with "Sensation seeking hedonism" (particularly for men). Neuroticism had a particularly strong association with the "Self orientated Nurturance" factor in the female population. More than twice the symptomatology variance was explained by the factor scores for females than it was for males. The most important factorial predictors for psychiatric symptomatology were the "Power related hedonism" factor for males, and "Self oriented nurturance" for females. The results are discussed from theoretical and treatment perspectives

    Self-help/mutual aid groups in mental health : ideology, helping mechanisms and empowerment

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    In the last quarter of the twentieth century, self-help/mutual aid groups for mental health issues started to emerge in growing numbers, mainly in Western societies, offering and/or advocating for alternative non-traditional forms of support, and attracted the attention of many researchers and clinicians for their unique characteristics. Among the subjects of interest are typologies of groups, helping mechanisms and benefits from participation. However, there is lack of systematic research in the area and existing studies have been largely confined to the therapeutic value of these groups instead of acknowledging their socio-political meaning and subsequent psychosocial benefits for their members like personal empowerment. The present study was conducted during the transitional years from a Conservative to a newly elected Labour Government (1996 -1998), with subsequent policy shifts taking place in the welfare sector. The purpose of the study was to explore the potential of self-help groups as part of a broader new social movement, the service user movement, focussing on the English scene. It addressed this issue examining the relevance of a group typology based on political ideology and focus of change. To test the validity of this classification for members, a set of individual characteristics and group mechanisms as well as their change through time were examined. The sample consisted of fourteen mental health selfhelp/mutual aid groups from London and South East England, with a variety of structural and organisational features. The methodology used was a combination of both quantitative (self-completion questionnaires) and qualitative techniques (analysis of written material, participant observation and interviews). Measurements were repeated after a one-year interval (Time 1N=67, Time 2 N=56). Findings showed that, indeed, political ideology of self-help/mutual aid groups provided the basis of a meaningful typology and constitutes a comprehensive way of categorising them. Group ideology was related to specific helping mechanisms and aspects of personal empowerment. Specifically, conservative and combined group members reported more expressive group processes like sharing of feelings and self-disclosure, while radical group members were more empowered and optimistic. Group identification was also associated with specific helping activities and aspects of empowerment in the three group categories. The psychosocial character of group types and the beneficial outcomes for members remained stable through time. In general, prolonged participation was reflected in greater member identification with the group and resulted in improved mental wellbeing, increased social support, companionship and optimism for the future

    Studies of strategic performance management for classical organizations theory & practice

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    Nowadays, the activities of "Performance Management" have spread very broadly in actually every part of business and management. There are numerous practitioners and researchers from very different disciplines, who are involved in exploring the different contents of performance management. In this thesis, some relevant historic developments in performance management are first reviewed. This includes various theories and frameworks of performance management. Then several management science techniques are developed for assessing performance management, including new methods in Data Envelopment Analysis (DEA) and Soft System Methodology (SSM). A theoretical framework for performance management and its practical procedures (five phases) are developed for "classic" organizations using soft system thinking, and the relationship with the existing theories are explored. Eventually these results are applied in three case studies to verify our theoretical development. One of the main contributions of this work is to point out, and to systematically explore the basic idea that the effective forms and structures of performance management for an organization are likely to depend greatly on the organizational configuration, in order to coordinate well with other management activities in the organization, which has seemingly been neglected in the existing literature of performance management research in the sense that there exists little known research that associated particular forms of performance management with the explicit assumptions of organizational configuration. By applying SSM, this thesis logically derives some main functional blocks of performance management in 'classic' organizations and clarifies the relationships between performance management and other management activities. Furthermore, it develops some new tools and procedures, which can hierarchically decompose organizational strategies and produce a practical model of specific implementation steps for "classic" organizations. Our approach integrates popular types of performance management models. Last but not least, this thesis presents findings from three major cases, which are quite different organizations in terms of management styles, ownership, and operating environment, to illustrate the fliexbility of the developed theoretical framework
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