Background Parkinson’s disease (PD) is one of the most common neurodegenerative diseases in Europe. Besides motor dysfunction, PD is characterized by several non-motor and secondary motor features, such as weight change, sialorrhea, constipation and swallowing problems. Of these, swallowing is one of the most critical, as it is associated with aspiration pneumonia and consequently is the comorbidity with the highest mortality rate. Swallowing problems affect four of every five patients with PD, and even mild swallowing problems have notable psychosocial effects for patients and their caregivers. Consequently, it is essential to find treatment strategies for PD that may alleviate symptoms for patients with swallowing problems and their potential consequences. Deep Brain Stimulation (DBS) is a surgical treatment option for PD, which improves overall motor function and quality of life, but its effect on swallowing function is not clear. The purpose of this thesis was to contribute to the understanding of the effect of deep brain stimulation in the subthalamic nucleus (STN DBS) and the caudal zona incerta (cZI DBS) on pharyngeal swallowing function and on swallow-specific quality of life in patients with PD. The specific aims were to assess longitudinally the effect of STN DBS and cZI DBS on swallowing at 6 and 12 months postoperatively, in order to identify possible effects of the DBS on swallowing function. In addition, the effects of cZI DBS on ratings of swallowing-related non-motor and secondary motor features such as body weight changes, sialorrhea and speech problems were to be assessed. Methods Eleven PD patients with STN DBS (Paper I) and seventeen patients with cZI DBS (Paper II-IV) were included in this thesis. All patients were evaluated preoperatively and 6 and 12 months postoperatively. The effect of STN DBS and cZI DBS on swallowing was assessed with Fibreoptic-Endoscopic Evaluation of Swallowing (FEES) according to a predefined protocol including Penetration-Aspiration scale, Secretion Severity scale, preswallow spillage, pharyngeal residue, and pharyngeal clearance. Self-assessments were addressed using a visual analogue scale. The cZI DBS patients also completed the Swallowing Quality of Life (SWAL-QOL) questionnaire. Weight changes measured by Body Mass Index, and specific items from the Unified Parkinson’s Disease Rating Scale were also examined. Nine controls without PD were included in Paper IV, by answering the SWAL-QOL questionnaire. Results No clear effect of DBS on swallowing function or swallow-specific quality of life could be observed. There was no effect of DBS on the occurrence of aspiration, secretion, pharyngeal residue or clearance in the study groups with STN DBS or cZI DBS. Patients with STN DBS reported a subjective improvement in swallowing function with DBS stimulation turned on at 6 and 12 months after surgery. In patients with cZI DBS, the median body mass index was postoperatively increased with 1.1kg/m2 and the median increase in weight were +3.0 kg after 12 months with cZI DBS. The scores from the SWAL-QOL questionnaire were high overall in the group with cZI DBS, and the scores were unaffected by the cZI DBS surgery and stimulation. The SWAL-QOL total score was not significantly different between the PD patients and the controls, but the scores from the ‘burden’ and the ‘symptom’ subscales were worse in PD patients. Conclusions STN DBS or cZI DBS did not have a negative effect on swallowing function or ratings of swallow-specific ‘quality of life’ aspects in this cohort. Patients with STN DBS reported a self-perceived improvement in swallowing function when DBS was turned on. With regard to swallowing, patients with cZI DBS had an overall good quality of life throughout the conduct of the study and their swallow-specific quality of life was not negatively affected by cZI DBS. There seems to be no increased risk for aspiration or penetration due to surgery or stimulation for either the STN DBS or the cZI DBS groups. cZI DBS caused weight gain postoperatively. Since the sample sizes in these cohorts are small, the findings need to be confirmed in larger studies.

This thesis deals with the chemical communication of wood mouse of genus Apodemus with a focus on the special sebaceous gland on the ventral side of the tail - the caudal organ. Role of the caudal organ in chemical communication is unclear. To illustrate the function of the sebaceous glands, I decided to use metods of 454 pyrosequencing, proteomic analysis and qPCR. I created a database of transcriptionally active genes of caudal organ using 454 pyrosequencing. In proteomic analysis, I focused on proteins with a molecular weight 14-18kDa to verify the presence of the lipocalins, proteins involved in chemical communication. I compared the relative mRNA abundance of selected genes between individuals of the opposite sex using qPCR. In my research, I found that the caudal organ is active organ and caudal organ could participate in chemical communication. I detected a different relative mRNA abundance of genes in males and females at the mRNA level, which could play a role in differences in development of caudal organ between individuals of the opposite sex. Finally, I suggested possible ways of using the caudal organ in the chemical communication in wood mouse genus Apodemus from the obtained results. Key words: caudal organ, Apodemus, chemical communication, FABP5, Scd1

Neuromesodermal progenitors (NMPs) are bipotent progenitors, located at the caudal end of the embryo and are essential for axis formation. These stem cell-like progenitors possess the ability to self-renew and differentiate to both mesodermal and neural lineages, such as skeletal muscle and spinal cord derivatives. These progenitors arise at E8.5 and are localised in the caudal lateral epiblast (CLE), a posterior region of the embryo near the primitive streak. Later in development, they reside in the tail bud until cessation of axial elongation at E13.5. Throughout these stages NMPs are characteristically marked by co-expression of T(Bra) (Brachyury) and Sox2. This characteristic is also present in in vitro NMPs, which can be derived from Epiblast Stem Cells (EpiSCs) through treatment with Wnt/β-catenin signalling agonists and Fgf2, which simulates their in vivo environment. Protein and mRNA profiling of NMPs and mutant phenotypes in vivo supports the hypothesis that a non-canonical Wnt pathway, the Wnt/Planar Cell Polarity pathway (PCP) could be involved in NMP fate decision and/or maintenance. This thesis focuses on understanding more about the role of PCP by aiming to identify the spatio-temporal profile of Wnt/PCP pathway components in NMP regions during axial elongation, as well as determining its role in NMP behaviour through manipulation of this pathway via in vivo and in vitro assays Employing in situ hybridisation and immunohistochemistry techniques, key Wnt/PCP components, including Pk1, Vangl2 and Ptk7, were confirmed to be present in in vivo and in vitro NMPs, thus, providing strong evidence that Wnt/PCP may be involved regulating NMP behaviour. Disruption of Wnt/PCP signalling through overexpression of Wnt/PCP components was tested in refined in vivo and in vitro assays. Overexpression of Vangl2 and Ptk7, but not Pk1 in NMPs regions in vivo resulted in loss of contribution to neural lineages, as well as lower contribution to NMP regions themselves. Similarly, Wnt/PCP components were disrupted in vitro through generation of dox-inducible overexpression cells lines for Wnt/PCP components. These lines were used to generate NMPs from an optimised novel alternative source Epiblast-Like Cells (EpiLCs), however no clear affect to lineage was observed. Overall this work has successfully advanced our knowledge of Wnt/PCP mediated control of NMP differentiation and maintenance, and provided a finer grained description of the relationships between them.

Desarrolla una nueva metodología para el estudio de peligros ambientales, basándonos en las inundaciones fluviales como factor desencadenante de los peligros en la desembocadura de los valles fluviales. A partir del análisis bibliográfico y metodológico de los diferentes antecedentes internacionales y nacionales de modelos de peligros, la metodología propuesta considera el análisis geográfico del territorio como base de un modelo de peligros, considerando como variables ambientales la geomorfología, geología y la vegetación para lograr un primer escenario de zonas susceptibles a las dinámicas del territorio. Asimismo, utiliza una simulación numérica para determinar zonas posibles de inundación en función al caudal máximo del río. La combinación de estos dos escenarios mediante un análisis ponderado dio como resultado zonas de peligro en las categorías alto, moderado y bajo para toda la zona de estudio. Las zonas críticas fueron consideradas los niveles de peligro Alto y moderado en conjunto, dando un total de 546.40 ha, siendo un aproximado de 44% del total del área investigada que podría sufrir los efectos de una posible inundación luego de registrarse un caudal extremo en la cuenca baja del río Tambo. Finalmente, se hace una breve comparación de las ventajas y desventajas con las metodologías estudiadas y se hace una propuesta para los próximos modelos que tengan escenarios territoriales similares a las descritas en la investigación. / Tesis

No presente estudo abordamos as diferentes noções de risco, os diversos tipos de riscos, dando especial atenção aos riscos climáticos. Constatamos que o consenso em torno da noção de risco e na classificação dos riscos ainda não foi alcançado. Procuramos conhecer um pouco melhor os riscos associados ao elemento climático precipitação. nesse sentido, estudamos o regime pluviométrico da estação do Port-Serra do Pilar (1930/31-2002/03) e de Sobrado (2003/04/). Constatamos que em ambos os locais a variabilidade pluviométrica é significativa. Ao longo do anos hidrológico 20003/04 a precipitação foi mais frequente no Porto-Serra do Pilar, mas registou quantitativos mais elevados em Sobrado. Apesar das diferenças quantitativas e de frequência a precipitação mensal tendeu a ter o mesmo ritmo. A variabilidade pluviométrica parece ter influenciado o caudal (instantâneo) da Ribeira da Ermida (2003/045). A correcta definição e gestão da REN poderá contribuir para prevenir as consequências gravosas dos episódios de precipitações intensas e para a correcta gestão da Bacia Hidrográfica da Ermida.

El presente trabajo consiste en el modelamiento hidrológico e hidráulico de la quebrada Cashahuacra ubicada en el distrito de Santa Eulalia con el fin de proponer la estructura de un sistema de alerta temprana que integre estos modelos para evitar la pérdida, primordialmente, de vidas humanas. Se presenta una síntesis de los principales eventos de flujo de detritos ocurridos en dicho lugar así como un marco teórico que aborda conceptos básicos relacionados al estudio de la hidrología e hidráulica. Para el modelo hidrológico, se llevó a cabo la caracterización de la quebrada Cashahuacra y se obtuvo sus parámetros principales, así también, fue necesario la adquisición de los datos históricos de precipitación. De esta manera, el modelo hidrológico fue realizado con el software HEC-HMS versión 4.2 en colaboración con ArcGIS versión 10.2.1. y su extensión HEC-GeoHMS. Así, se pudo determinar los caudales máximos bajo los periodos de retorno de 5, 10, 20, 50, 100, 200 y 500 años. El modelo hidráulico fue desarrollado con el software FLO-2D versión PRO. Tuvo como parámetros de entrada al hidrograma calculado por el modelo hidrológico, a la topografía digital del terreno, y a parámetros reológicos como la viscosidad y el esfuerzo de cedencia. Luego, fueron obtenidas las velocidades y profundidades máximas de los periodos de retorno mencionados líneas arriba. Finalmente, se ha integrado estas dos modelaciones en la estructura de un sistema de alerta temprana frente a huaycos y se ha sugerido la implementación de un radar meteorológico para la quebrada en estudio. / The present work consists of hydrological and hydraulic modeling of the Cashahuacra stream located in the Santa Eulalia district in order to propose the structure of an early warning system that integrates these models to avoid the loss, primarily of human lives. A synthesis of the main debris flow events occurring in that place is presented as well as a theoretical framework that addresses basic concepts related to the study of hydrology and hydraulics. For the hydrological model, the characterization of the Cashahuacra stream was carried out and its main parameters were obtained, as well as the acquisition of the historical precipitation data. In this way, the hydrological model was made with the HEC-HMS software version 4.2 in collaboration with ArcGIS version 10.2.1. and its HEC-GeoHMS extension. Thus, it was possible to determine the maximum flow rates under the return periods of 5, 10, 20, 50, 100, 200 and 500 years. The hydraulic model was developed with the FLO-2D PRO version software. It had as input parameters to the hydrograph calculated by the hydrological model, to the digital topography of the land, and to rheological parameters such as viscosity and yield strength. Then, the maximum speeds and depths of the return periods mentioned above were obtained. Finally, these two models have been integrated into the structure of an early warning system against hurricanes and the implementation of a meteorological radar for the stream under study has been suggested. / Tesis

The development of the nervous system is a complex process. Cell divisions, cell differentiation and signalling interactions must be tightly regulated. To comprehend the mature nervous system, we have to understand its assembly during development. Two main questions were addressed in this thesis: (1) how is the caudal part of the central nervous system specified and (2) how is the early development of the olfactory placode regulated? By using tissue and whole embryo assays in the chick, we identified signalling molecules involved in these processes and propose possible mechanisms for their function. The central nervous system is regionalized along its rostrocaudal axis during development. However, the mechanisms by which cells in the caudal part of the neuraxis acquire rostrocaudal regional identity have been unresolved. We provide evidence that at gastrula stages cells in the caudal neural plate are specified as cells of caudal spinal cord character in response to Wnt and FGF signals and that cells of rostral spinal cord and caudal hindbrain character only emerge later at neurulation stages in response to retinoic acid signalling acting on previously caudalized cells. In the hindbrain and spinal cord distinct motor neuron subtypes differentiate at precise rostrocaudal positions from progenitor cells. We provide evidence that cells in the caudal neural plate have acquired sufficient positional information to differentiate into motor neurons of the correct rostrocaudal subtype. The olfactory placode gives rise to all the structures of the peripheral olfactory system, which, in the chick consists of the olfactory nerve, the sensory epithelium, where the olfactory sensory neurons (OSN) are located and the respiratory epithelium, that produces the mucus. Several studies have addressed the role of signalling cues in the specification of OSNs but much less is known about the regulation of sensory versus respiratory patterning and the events controlling early neurogenesis in the developing olfactory placode. We show that by stage 14 the olfactory placode is specified to give rise to both cells of sensory and respiratory epithelial character. Moreover, cells of respiratory epithelial character require BMP signalling, whereas cells of sensory epithelial character require FGF signalling. We suggest a mechanism in which FGF and BMP signals act in an opposing manner to regulate olfactory versus respiratory epithelial cell fate decision. BMP signalling has also been implicated in the regulation of neurogenesis in the sensory epithelium, and we show that BMP signals are required for the generation of OSNs, because in the absence of BMP signalling cells in the sensory epithelium do not mature. Independently, we also analyzed the role of Notch signalling during early olfactory development both in vitro and in vivo and provide evidence that active Notch signalling is required to prevent cells in the olfactory placode from premature differentiation.

Background In advanced Parkinson’s disease (PD) the motor symptoms can be treated with deep brain stimulation (DBS). Subthalamic nucleus (STN) has been the most common target and caudal zona incerta (cZi) is a more recent target for stimulation. Stimulation in both of these targets has proved to be positive for the motor symptoms but there is no consensus about how DBS affects the speech and the articulation. Aim The aim of this study was to investigate how fricatives are realized within patients suffering from PD treated with DBS in STN or cZi. Method 9 patients stimulated in STN and 10 patients stimulated in cZi were recorded reading a shorter text.  The recordings were made preoperatively (Pre) and 12 months after surgery with the stimulation switched off (sOff) and on (sOn). From the recordings the fricatives were extracted and assessed in a blinded and randomized procedure. Results For the patients stimulated in cZi the target fricative /s/ had significant lower correct realizations in the sOn condition compared to the other two conditions. The other target fricatives in cZi showed the same pattern as well. For the STN group no unequivocal pattern could be seen. Conclusions The results suggest that stimulation in cZi may affect the patients’ articulation of fricatives and thereby their extended articulatory movements more negative than stimulation in STN.

El presente estudio se centra en la interpretación del fenómeno de dispersión geoquímica a través del agua, tratando de comprender y a la vez explicar las asociaciones existentes entre cada uno de los elementos metálicos y no metálicos analizados. Los trabajos de campo fueron desarrollados en el río Mishca y sus principales afluentes, este río se ubica en el sector central de la Provincia Víctor Fajardo, en el Departamento de Ayacucho y constituye un afluente importante del río Sondondo, a su vez participante en la formación de la cuenca del río Pampas, atravesando unidades litológicas distintas, como la Formación Chunumayo, los grupos Pucará y Mitu, y en su tramo final la unidad granítica correspondiente al Batolito Querobamba. Para ello se siguieron procesos de toma de muestras en aguas, en puntos estratégicos del cauce del río Mishca así como también en zonas de confluencia con otras quebradas importantes y con afluentes provenientes del subsuelo, habiendo hecho una clasificación tipo para las aguas superficiales y las aguas con recorrido subterráneo. El análisis hidrogeoquímico mediante la técnica de espectrometría de emisión óptica por (ICP-OES) para aguas brindó resultados importantes, siendo que se encontraron proporciones altas de ciertos elementos como el arsénico, el plomo, los sulfatos, carbonatos y manganeso, así como también la correlación existente entre la carga metálica (conductividad eléctrica) y los valores de acidez o basicidad; todo esto teniendo en cuenta la litoestratigrafía y los aspectos geológicos estructurales, con influencia directa sobre los valores fisicoquímicos existentes en las aguas analizadas. Finalmente, se logra entender y explicar la presencia y movilidad de dichos elementos químicos provenientes; a partir de los afloramientos en los que estos se han emplazado naturalmente, así como también por el desarrollo de los procesos de erosión, transporte y depositación (dispersión secundaria) por parte de los drenajes superficiales y subterráneos, que también han adquirido las características fisicoquímicas que nos permiten clasificarlos dentro del tipo de aguas sulfatadas y carbonatadas; además de la existencia de puntos de muestreo en los que se ha detectado valores que superan los límites para la evaluación de calidad de aguas, fácilmente asociable a los procesos de dispersión hidrogeoquímica natural.

Publicación a texto completo no autorizada por el autor / El documento digital no refiere asesor / Plantea como alternativa de solución una de las tantas medidas de mitigación ante los eventos de la naturaleza que afectan a las estructuras y servicios principales en las comunidades aledañas a zonas ribereñas, tales como son las defensas ribereñas, las cuales ayudan en la mitigación de los fenómenos naturales que incrementan el caudal de los ríos, en este caso se analiza los que conllevan el aumento del caudal del Rio Rímac en el A.A.HH. Huampani Distrito de Lurigancho el cual puede deteriorar o inhabilitar los servicios principales afectando así las estructuras y calidad de vida de la población. Se analizara el diseño hidráulico de la defensa ribereña a implementarse como medida de seguridad y protección al momento de la instalación del sistema de agua potable y alcantarillado en el AA.HH. Huampani Distrito de Lurigancho, con lo cual se busca que este no sea afectado y funcione de forma adecuada en los escenarios planteados. / Trabajo de suficiencia profesional