3,111 research outputs found

    Exploring missing heritability in neurodevelopmental disorders:Learning from regulatory elements

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    In this thesis, I aimed to solve part of the missing heritability in neurodevelopmental disorders, using computational approaches. Next to the investigations of a novel epilepsy syndrome and investigations aiming to elucidate the regulation of the gene involved, I investigated and prioritized genomic sequences that have implications in gene regulation during the developmental stages of human brain, with the goal to create an atlas of high confidence non-coding regulatory elements that future studies can assess for genetic variants in genetically unexplained individuals suffering from neurodevelopmental disorders that are of suspected genetic origin

    Systemic function impairment and neurodegeneration in the general population

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    The Structure and Function of the Retina in Multiple Sclerosis

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    Background: Multiple sclerosis (MS) is a complex heterogenous autoimmune inflammatory disease with a prolonged and variable time course. The visual system is frequently implicated, either as the presenting symptom, or, with advancement of the disease. This has been documented in the literature with changes in visual acuity (VA) that are accompanied by functional changes in the optic nerve, measured with the visual evoked potential (VEP) and possible retrograde degeneration involving the retinal ganglion cells in the retina, measured with the pattern reversal electroretinogram (PERG). However, inflammatory episodes may be clinical or subclinical in nature and may go unrecognised. Originating from the same embryological origins, the effect of inflammation in MS on the on the retina is less well known. The research hypothesis was that there is a measurable difference in the function of retinal cells in patients with newly diagnosed multiple sclerosis, suggestive of inflammatory retinopathy compared to healthy controls. The overall aim was to investigate any differences in the electrophysiological function of the visual pathway of patients newly diagnosed with MS compared to healthy controls. Methods: The visual system is explored with clinical (VA), electrophysiology (VEP and electroretinography (ERG – pattern and flash) and structural (OCT) measures, in patients presenting with symptoms suggestive of MS to a specialist service. This prospective case control study investigates the visual pathway at the earliest stage of the disease to look for differences in structure and function between patients and healthy volunteers that might serve as a biomarker in the future. Results: There were a number of variables that were significantly different between the two groups, logistic regression analysis found that VA (p 0.038) and VEP P100 peak-time (p 0.014) from the right eye as significant. Dividing the participants by prolongation of the VEP P100 peak-time as defined in clinical practice, found a number of ERG amplitude variables as well as VA that were consistently different between the groups regardless of symptoms. Conclusion: The study confirms optic nerve involvement in MS with VEP and VA abnormalities consistent with the literature in this cohort. Additionally, VA and some ERG amplitude variables were significantly reduced in participants with MS, when grouped according to VEP P100 peak-time, suggesting inner and outer retinal changes. Further work would be required to confirm these findings. No OCT structural changes were found in any of the analysis that included the macula thickness, ganglion cell layer or retinal nerve fibre layer. Keywords: multiple sclerosis (MS), visual evoked potential (VEP), pattern electroretinogram (PERG), electroretinogram (ERG), optical coherence tomography (OCT

    Effects of municipal smoke-free ordinances on secondhand smoke exposure in the Republic of Korea

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    ObjectiveTo reduce premature deaths due to secondhand smoke (SHS) exposure among non-smokers, the Republic of Korea (ROK) adopted changes to the National Health Promotion Act, which allowed local governments to enact municipal ordinances to strengthen their authority to designate smoke-free areas and levy penalty fines. In this study, we examined national trends in SHS exposure after the introduction of these municipal ordinances at the city level in 2010.MethodsWe used interrupted time series analysis to assess whether the trends of SHS exposure in the workplace and at home, and the primary cigarette smoking rate changed following the policy adjustment in the national legislation in ROK. Population-standardized data for selected variables were retrieved from a nationally representative survey dataset and used to study the policy action’s effectiveness.ResultsFollowing the change in the legislation, SHS exposure in the workplace reversed course from an increasing (18% per year) trend prior to the introduction of these smoke-free ordinances to a decreasing (−10% per year) trend after adoption and enforcement of these laws (β2 = 0.18, p-value = 0.07; β3 = −0.10, p-value = 0.02). SHS exposure at home (β2 = 0.10, p-value = 0.09; β3 = −0.03, p-value = 0.14) and the primary cigarette smoking rate (β2 = 0.03, p-value = 0.10; β3 = 0.008, p-value = 0.15) showed no significant changes in the sampled period. Although analyses stratified by sex showed that the allowance of municipal ordinances resulted in reduced SHS exposure in the workplace for both males and females, they did not affect the primary cigarette smoking rate as much, especially among females.ConclusionStrengthening the role of local governments by giving them the authority to enact and enforce penalties on SHS exposure violation helped ROK to reduce SHS exposure in the workplace. However, smoking behaviors and related activities seemed to shift to less restrictive areas such as on the streets and in apartment hallways, negating some of the effects due to these ordinances. Future studies should investigate how smoke-free policies beyond public places can further reduce the SHS exposure in ROK

    Introduction to Psychology

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    Introduction to Psychology is a modified version of Psychology 2e - OpenStax

    Biological function and clinical implication of coagulation proteins during malignant transformation of pancreatic cells

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    The premalignant pancreatic cellular genotype can remain stable for years before rapid malignant transformation, often associated with inflammation. Tissue factor (TF) is an inflammatory modulator regulated by factor VIIa (fVIIa) for its levels and activity. The presence of TF in PDAC and its role in cell proliferation, angiogenesis, and metastasis suggests that TF may be a marker of the inflammatory microenvironment driving precursor lesions of pancreatic cancer. This study examined the in vitro influence of TF on pancreatic epithelial cells and its clinical value in detecting malignant transformation within pancreatic cyst fluid (PCyF). PCyF from 27 patients with pancreatic cystic lesions was analysed in a blinded fashion. TF and fVIIa levels were measured (ELISA), and the fVIIa:TF ratios were calculated. A cut-off value for TF concentration was determined and compared to the conventional assessment parameters (radiological features, CEA and amylase). Patients were categorised into four groups based on cytopathology and two groups based on indication for resection (‘resective’). Significant histological stage-dependent increases in TF levels were observed. Mean TF concentration was significantly higher (p=0.006) in the resective (high-grade dysplasia & malignant; 1.17 ng/ml, 95% CI 0.68, 1.67) vs non-resective group (benign & low-grade dysplasia; 0.27 ng/ml, 95% CI 0.1, 0.44), with a strong positive correlation (r= 0.746, p <0.001, TF cut-off 0.75 ng/ml, AUC 0.877, p=0.002). The fVIIa:TF ratio did not add further value. Incubation of pancreatic cells with recombinant TF resulted in increased expression of a marker of epithelial to mesenchymal transition (Vimentin). This influence was moderated by supplementation with fVIIa in benign (hTERT-HPNE) but not overtly malignant pancreatic cells (AsPC-1). Cyst-associated TF levels appear to correlate with cytological progression to the malignant phenotype and may allow better discrimination (specificity 94%) of the ‘resective’ lesion, reduce healthcare costs and offer a more nuanced tool for monitoring indeterminate cystic lesions

    Exploration of peripheral electrical stimulation adapted as a modulation tool for reciprocal inhibition through the activation of afferent fibers during gait

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    The most accessible manner to perform physical activity and allow locomotion in human beings is walking. This activity is allowed thanks to reciprocal Ia inhibition mechanism, controlled by the spinal and supraspinal inhibitory circuits. The idea of this mechanism is to deactivate the antagonist muscle while the agonist is being contracted, allowing the proper muscle coordination necessary to walk. The interruption of spinal fibers produced after Spinal Cord Injury, disrupt this control on reciprocal Ia inhibition. The result of this lack of control is a co-activation of antagonist muscles generating spasticity of lower limbs which induce walking impairments. The importance of walking recovery for the independence and society re-integration of patient, raise the quantity of emerging walking rehabilitation therapies. One of these therapies, the application of peripheral nerve stimulation, has demonstrated promising results although more studies are necessary. This theory is the base of this Master Thesis which aim is to develop and validate a gait neuromodu- lation platform that induce neuroplasticity of spinal circuits, improving reciprocal Ia inhibition. The idea of the platform is to deliver afferent stimulation into the Common Peroneal Nerve innervating Tibialis Anterior muscle, to induce reciprocal Ia inhibition onto the antagonist Soleus muscle. This platform has been validated in 20 healthy volunteers in order to assess its effectiveness. The first part of the experimental protocol is an off-line analysis of Gait Cycle to evaluate the activation of mus- cles during the different phases of this cycle. Then, there is an assessment of the activity of antagonist muscle previous to the stimulation intervention by using the analysis of soleus H-reflex. Posteri- orly, the afferent stimulation is applied during a 10 minutes treadmill training using three different strategies depending on patient: In-phase stimulation during swing phase, Out-of-phase stimulation during stance phase, and Control strategy to check if stimulation has a real effect. The final processes of experimental protocol are two different assessments of the soleus activity, one immediately after the intervention and other 30 minutes after to evaluate the duration of effects. The results obtained demonstrate that afferent electrical stimulation has a real effect on modulation of reciprocal Ia inhibition. On the one hand, when electrical stimulation is applied during the swing phase, there is an improvement of reciprocal Ia inhibition. On the other hand, when stimulation is delivered during the stance phase, there is a worsening of reciprocal Ia inhibition. These results conclude that afferent electrical stimulation, applied at the swing phase of gait cycle, is a promising strategy to induce reciprocal Ia inhibition in Spinal Cord Injury patients. The induc- tion of this inhibitory circuit will lead to the proper activation of muscles during walking, recovering impaired walkingLa forma más accesible de locomoción y actividad física en los seres humanos es caminar. Esta activi- dad se realiza gracias al mecanismo de inhibición recíproca, controlado por los circuitos inhibitorios espinales y supraespinales. La idea de este mecanismo es desactivar el músculo antagonista mientras se contrae el agonista, permitiendo la adecuada coordinación muscular durante la marcha. La interrupción de las fibras espinales tras una Lesión de la Médula Espinal desajusta el control de la inhibition reciprocal. El resultado de esta falta de control es una co-activación de los músculos antago- nistas generando espasticidad en las extremidades inferiores, lo que genera alteraciones en la marcha. La importancia de la recuperación de la marcha para lograr la independencia y la reintegración del paciente en la sociedad, ha incrementado el número de terapias emergentes en rehabilitación de la marcha. Una de estas terapias, la estimulación del nervio periférico, ha demostrado resultados prom- etedores. Esta teoría es la base de esta Tesis de Máster cuyo objetivo es desarrollar y validar una plataforma de neuromodulación de la marcha que induzca la neuroplasticidad de los circuitos espinales, mejorando los valores de inhibición recíproca. La idea es aplicar estimulación aferente en el Nervio Peroneo Común que inerva el músculo Tibial Anterior para inducir la inhibición recíproca en su músculo antagonista Soleo. Esta plataforma ha sido validada en 20 voluntarios sanos con el fin de evaluar su eficacia. La primera parte del protocolo experimental es un análisis del ciclo de la marcha para evaluar la activación de cada músculo durante las diferentes fases de este ciclo. Luego, previo a la intervención de estimu- lación, hay una evaluación de la actividad del músculo antagonista analizando el reflejo H del soleo. La intervención de estimulación aferente se aplica durante un entrenamiento de marcha con una du- ración de 10 minutos, utilizando tres estrategias diferentes dependiendo del paciente: estimulación ’In-phase’ durante la fase de oscilación, estimulación ’Out-of-phase’ durante la fase de postura, y ’Control’ para comprobar si la estimulación tiene un efecto real. Los procesos finales del protocolo son dos evaluaciones de la actividad del soleo, una inmediatamente después de la intervención y otra 30 minutos después para evaluar la duración de los efectos. Los resultados obtenidos demuestran que la estimulación eléctrica aferente tiene un efecto real en la modulación de la inhibición recíproca. Por un lado, cuando la estimulación eléctrica se aplica durante la fase de oscilación, hay una mejora de la inhibición recíproca. Por otro lado, cuando la estimulación se administra durante la fase de postura, hay un empeoramiento de la inhibición recíproca. Estos resultados concluyen que la estimulación eléctrica aferente, administrada en la fase de oscilación del ciclo de la marcha, es una estrategia prometedora para inducir la inhibición recíproca en pacientes con Lesión de la Médula Espinal. La inducción de este circuito inhibidor generará la adecuada acti- vación de los músculos durante la marcha, recuperando el ciclo de marcha normalLa manera més accessible de locomoció i activitat física en els éssers humans és caminar. Aquesta ac- tivitat es realitza gràcies al mecanisme d’inhibició recíproca, controlat pels circuits inhibitoris espinals i supraespinals. La idea d’aquest mecanisme és desactivar el múscul antagonista mentre es contrau l’agonista, permetent la coordinació muscular adequada durant la marxa. La interrupció de les fibres espinals després d’una lesió medul·lar desajusta el control de la inhibició reciprocal. El resultat d’aquesta manca de control és una coactivació dels músculs antagonistes gen- erant espasticitat a les extremitats inferiors, cosa que genera alteracions a la marxa. La importància de la recuperació de la marxa per a la independència i la reintegració del pacient a la societat, ha incrementat el nombre de teràpies emergents de rehabilitació de la marxa. Una daquestes teràpies, lestimulació del nervi perifèric, ha demostrat resultats prometedors. Aquesta teoria és la base dáquesta Tesi de Màster que té com a objectiu desenvolupar una plataforma de neuromodulació de la marxa que indueixi la neuroplasticitat dels circuits espinals, millorant els valors de inhibició recíproca. La idea és aplicar una estimulació aferent al Nervi Peroneal Comú que inerva el múscul Tibial Anterior per induir la inhibició recíproca al múscul antagonista Soli. Aquesta plataforma ha estat validada en 20 voluntaris sans per avaluar-ne l’eficàcia. La primera part del protocol experimental és una anàlisi del cicle de marxa per avaluar l’activació de cada múscul durant les diferents fases del cicle de la marxa. Després, amb la intervenció d’estimulació prèvia, hi ha una avaluació de l’activitat del múscul antagonista analitzant el reflex H del soli. La inter- venció d’estimulació aferent s’aplica durant un entrenament de marxa amb una durada de 10 min- uts, utilitzant tres estratègies diferents depenent del pacient: estimulació ’In-phase’ durant la fase d’oscil·lació, estimulació ’Out-of-phase’ durant la fase de postura, i ’Control’ per comprovar si la es- timulació té un efecte real. Els processos finals del protocol són dues avaluacions de l’activitat de soli, una immediatament després de la intervenció i una altra 30 minuts després per avaluar la durada dels efectes. Els resultats obtinguts demostren que l’estimulació elèctrica aferent té un efecte real en la modulació de la inhibició recíproca. D’una banda, quan s’aplica l’estimulació elèctrica durant la fase d’oscil·lació, hi ha una millora de la inhibició recíproca. D’altra banda, quan s’administra l’estimulació durant la fase de postura, hi ha un empitjorament de la inhibició recíproca. Aquests resultats conclouen que l’estimulació elèctrica aferent, a la fase d’oscil·lació del cicle de la marxa, és una estratègia prometedora per induir la inhibició recíproca en pacients amb lesió medul·lar. La inducció d’aquest circuit inhibidor generarà a l’activació adequada dels músculs durant la marxa, recuperant el cicle de marxa norma

    Feasibility of functional MRI on point-of-care MR platforms

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    Magnetic resonance imaging (MRI) has proven to be a clinically valuable tool that can produce anatomical and functional images with improved soft tissue contrast compared to other imaging modalities. There has recently been a surge in low- and mid-field scanners due to hardware developments and innovative acquisition techniques. These compact scanners are accessible, offer reduced siting requirements and can be made operational at a reduced cost. This thesis aims to implement blood-oxygen-level-dependent (BOLD) resting-state functional MRI (fMRI) at such a mid-field point-of-care scanner. The availability of this technique can be beneficial to get neurological information in cases of traumatic brain injury, stroke, epilepsy, and dementia. This technique was previously not implemented at low- and mid-field since signal-to-noise ratio and the contrast scale with field strength. Studies were conducted to gauge the performance of an independent component analysis (ICA) based platform (GraphICA) to analyze artificially added noisy resting state functional data previously collected with a 3T scanner. This platform was used in later chapters to preprocess and perform functional connectivity studies with data from a mid-field scanner. A single echo gradient echo echoplanar imaging (GE-EPI) sequence is typically used for BOLD-based fMRI. Task-based fMRI experiments were performed with this sequence to gauge the feasibility of this technique on a mid-field scanner. Once the feasibility was established, the sequence was further optimized to suit mid-field scanners by considering all the imaging parameters. Resting-state experiments were conducted with an optimized single echo GE-EPI sequence with reduced dead time on a mid-field scanner. Temporal and image signal-to-noise ratio were calculated for different cortical regions. Along with that, functional connectivity studies and identification of resting-state networks were performed with GraphICA which demonstrated the feasibility of this resting-state fMRI at mid-field. The reliability and repeatability of the identified networks were assessed by comparing the networks identified with 3T data. Resting-state experiments were conducted with a multi-echo GE-EPI sequence to use the dead time due to long T2* at mid-field effectively. Temporal signal-to-noise was calculated for different cortical regions. Along with that, functional connectivity studies and identification of resting-state networks were performed with GraphICA which demonstrated the feasibility of this resting-state fMRI at mid-field
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