Predictive modelling of Loss Of Consciousness under general anaesthesia

Treballs Finals de Grau d'Enginyeria Biomèdica. Facultat de Medicina i Ciències de la Salut. Universitat de Barcelona. Curs: 2021-2022. Director: Pedro L. Gambú

Epigenetic mechanisms involved in neuronal Bdnf gene expression in adult and aged mouse in response to cognitive stimulation

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 12-02-2016Esta tesis tiene embargado el acceso al texto completo hasta el 12-08-2017Transcription of immediate early memory genes is an essential process in brain function, regulating, among other processes, synaptic plasticity. It is well established the necessity of gene transcription in order to maintain the late phases of the long-term potentiation (LTP) and the long-term depression (LTD). Several works performed in animals subjected to different memory paradigms have shown that there are epigenetic mechanisms involved in memory genes regulation. However, little is known about the contribution of these epigenetics mechanisms in response to a single stimulus, in the adult and in the old brain. The aim of this thesis was to characterise such mechanisms in response to LTD, in order to better understand the regulation of Bdnf gene expression, and its possible relation with the aged associated learning and memory deficits. In this thesis we present that LTD stimulation triggered by low NMDA dose in young adult animals, induces the transcription of Bdnf gene from promoters I, II, IV and VI by H3K27Me3 demethylation and H3K27Me3 phosphorylation at Serine 28, leading to displacement of EZH2, the catalytic subunit of Polycomb Repressor Complex 2. LTD not only does induce EZH2 repressor detachment, but also the dissociation of another transcriptionally repressive enzyme such as histone deacetylase 4 (HDAC4). We also show that LTD enhances acetylation of histone H3K27 via pCREB/CBP. Differently from the described situation, typical of the mature brain, we present data showing that the normal singling transduction of the young upon LTD is impaired in the aged hippocampus, leading to a different basal chromatin state at Bdnf promoters in the old. The consequence of this impairment is the loss of Bdnf induction in the old when exposed to LTD, as a result of impaired HDAC4 dissociation, CBP recruitment and Histone H3K27 acetylation at Bdnf promoters. We also have observed that the loss of cholesterol at the neuronal plasma membrane, a physiological feature of the old, plays a role in these epigenetic deficits. In fact, cholesterol addition to old hippocampal slices rescued Bdnf epigenetic regulation and expression in response to LTD. Furthermore, cholesterol reduction in young adult hippocampal slices led to similar deficits to the ones found in the old animals. In further support of the cholesterol loss-epigenetic dysregulation in the old, oral administration of Voriconazole, an inhibitor of the enzyme responsible for cerebral cholesterol loss (Cyp46A1), rescued hippocampal cholesterol loss and enhanced cognitive abilities in the old animals, improving Bdnf epigenetic regulation and expression in response to LTD. These results unveil one of the mechanisms involved in the cognitive decline of the old and propose Cyp46A1 as valuable therapeutic possibility

4-[(5R*,10bR*)-2-Methyl-1,10b-dihydro­pyrazolo[1,5-c][1,3]benzoxazin-5-yl]benzoic acid

In the title compound, C18H16N2O3, a potential inhibitor of the cyclo­oxygenase-2 isoenzyme, the pyrazoline ring exists in a flattened envelope conformation with one C atom deviating by 0.463 Å from the mean plane of the remaining four atoms. The puckering of the central oxazine ring is more severe, with one N atom and one C atom displaced by 0.235 (6) and 0.370 (2) Å, respectively, on opposite sides of the mean plane defined by the other four atoms; the conformation is that of a half-chair. As a result, the mol­ecule as a whole is not planar. The carboxyl group is involved in an inter­molecular O—H⋯N hydrogen bond, which links the mol­ecules into centrosymmetric dimers

Conocimientos y actitudes de los profesionales de los equipos de atención primaria sobre el documento de voluntades anticipadas

ResumenObjetivoDescribir el estado actual de los conocimientos sobre el documento de voluntades anticipadas (DVA) de los profesionales de atención primaria.EmplazamientoSAP Mataró Maresme del Institut Català de la Salut.DiseñoEstudio descriptivo y transversal.ParticipantesProfesionales de los equipos de atención primaria.MedicionesSe diseñó un cuestionario de autorrespuesta individual y anónima. Se definió un patrón de respuesta y un patrón de respuesta mínima correcta para cada bloque. Se realizan 2 pruebas de comprensibilidad y validez de los conceptos, y una prueba piloto de factibilidad.Resultados principalesSobre una población diana de 475 individuos se obtienen 227 respuestas (47%), de las que 219 (46%) fueron válidas. Según los colectivos profesionales, el 59% son médicos, el 28% son pediatras, el 7% son odontólogos, el 59% son diplomados en enfermería, el 12% son auxiliares de enfermería, el 30% son trabajadores sociales y el 25% son de atención al usuario. Solo 4 profesionales tienen redactado su propio DVA. El porcentaje de aciertos por bloques es el siguiente: el 83,8% de definición, el 4,1% de aspectos legales, el 0,5% de procedimiento-registro, el 1,4% de contenidos y el 38,6% de aplicación.ConclusionesLos profesionales tienen un conocimiento general sobre qué son las voluntades anticipadas y el DVA, pero saben poco de la normativa, el contenido y el registro. No hay diferencias significativas entre los colectivos analizados. El cuestionario parece útil para evaluar los conocimientos sobre el DVA.AbstractObjectiveTo assess the current state of knowledge and attitudes on the advance directives (living wills) document of professionals working in primary.DesignDescriptive, cross-sectional study.ParticipantsPrimary care professionals.SettingCatalonia Health Institute, Maresme Province, Barcelona.MethodsAn anonymous self-administered questionnaire was prepared with a correct answer model and a minimum correct level for each block of questions, as well as two comprehensibility and validity tests and a pilot feasibility test.ResultsFrom a target population of 475 individuals, t 227 (47%) responses were received (59% of GPs, 28% of paediatricians, 7% of dentists, 59% of nurses, 12% of assistant clinics, 30% of social workers and 25% of administrative assistants). Four people had written their own advance directive document. The percentage of correct answers was: definition block 83.8%, legal aspects 4.1%, procedure-register 0.5%; content 1.4%, application 38.6%.ConclusionsPrimary care workers have a general knowledge on the advance directives and the advance directive document but not enough about the law, content and registers. There was no significant difference between professional groups. The questionnaire appears useful for assessing knowledge on advance directives document

Inflammation and metabolic dysregulation in diabetic cardiomyopathy

Podeu consultar el llibre complet a: http://hdl.handle.net/2445/67430Diabetic cardiomyopathy is characterized by structural and functional alterations in the heart muscle of people with diabetes that finally lead to heart failure. Metabolic disturbances characterized by increased lipid oxidation, intramyocardial triglyceride accumulation and reduced glucose utilization have all been involved in the pathogenesis of diabetic cardiomyopathy. On the other hand, evidences arisen in the recent years point to a potential link between chronic low-grade inflammation in the heart and metabolic dysregulation. Interestingly, the progression of heart failure and cardiac hypertrophy usually entails the activation of pro-inflammatory pathways. Therefore, in this chapter we summarize novel insights into the crosstalk between inflammatory processes and metabolic dysregulation in the failing heart during diabetes

Electrical Properties of Human Tissues Applied to Wearable Antenna Design

A method for designing wearable antennas at microwave frequencies is presented in this thesis. An antenna placed on the human body is heavily influenced by the electrical properties of tissues. Thus, the proposed method includes of the development of mixtures that mimic the electrical properties of human tissues in order to validate the antenna designs. Simulation of several printed antennas in the presence of tissues are performed and analyzed The work outlines the process of developing phantom tissues and their validation using an open-ended coaxial probe method. A guide-wave permittivity measurement method and a free space measurement method are also discussed. The results show lower values than expected for the complex permittivity compared to those previously published. Some reasons for the discrepancy are suggested. Two prototype antennas are developed: a rectangular patch antenna and a dipole. A layered stack model of tissues is compared to a simpler and computationally more efficient half space model. The effect of the separation between the antenna and the tissues, the bending of tissues and the variation of tissue electrical characteristics are analyzed and quantified. The separation or bending of the tissues greatly influence the performance of the antenna, as expected

Emerging Actors in Diabetic Cardiomyopathy: Heartbreaker Biomarkers or Therapeutic Targets?

The diabetic heart is characterized by metabolic disturbances that are often accompanied by local inflammation, oxidative stress, myocardial fibrosis, and cardiomyocyte apoptosis. Overall changes result in contractile dysfunction, concentric left ventricular (LV) hypertrophy, and dilated cardiomyopathy, that together affect cardiac output and eventually lead to heart failure, the foremost cause of death in diabetic patients. There are currently several validated biomarkers for the diagnosis and risk assessment of cardiac diseases, but none is capable of discriminating patients with diabetic cardiomyopathy (DCM). In this review we point to several novel candidate biomarkers from new activated molecular pathways (including microRNAs) with the potential to detect or prevent DCM in its early stages, or even to treat it once established. The prospective use of selected biomarkers that integrate inflammation, oxidative stress, fibrosis, and metabolic dysregulation is widely discussed

Peroxisome Proliferator-Activated Receptor β/δ (PPAR β/δ) as a Potential Therapeutic Target for Dyslipidemia

Dyslipidemia is a powerful predictor of cardiovascular disease in patients at high risk (Turner et al., 1998), such as type 2 diabetic patients. Lowering of LDL-C is the prime target for treatment (2002), but even with intensification of statin therapy, a substantial residual cardiovascular risk remains (Barter et al., 2007; Miller et al., 2008; Fruchart et al., 2008; Shepherd et al., 2006). This may partly be due to atherogenic dyslipidemia. This term is commonly used to describe a condition of abnormally elevated plasma triglycerides and low high-density lipoprotein cholesterol (HDL-C), irrespective of the levels of LDL-C (Grundy, 1995). In addition to these key components, increased levels of small, dense LDL-C particles are also present, which in conjunction with the former components conform the also called “lipid triad” (Shepherd et al., 2005). Other abnormalities include accumulation in plasma of triglyceride-rich lipoproteins (TLRs), including chylomicron and very-low-density lipoprotein (VLDL) remnants. This is reflected by elevated plasma concentrations of non- HDL-C and apolipoprotein B-100 (apoB). Postprandially, there is also accumulation in plasma of TLRs and their remnants, as well as qualitative alterations in LDL and HDL particles. Thus, hypertriglyceridemia is associated with a wide spectrum of atherogenic lipoproteins not measured routinely (Taskinen, 2003). The presence of this lipid plasma profile with high triglyceride and low HDL-C levels have been shown to increase the risk of cardiovascular events independent of conventional risk factors (Bansal et al., 2007; Barter et al., 2007; deGoma et al., 2008). In fact, guidelines recommend modifying high triglyceride and low HDL-C as secondary therapeutic targets to provide additional vascular protection (2002). The presence of atherogenic dyslipidemia is seen in almost all patients with triglycerides > 2.2 mmol/l and HDL-C < 1.0 mmol/l, virtually all of whom have type 2 diabetes or abdominal obesity and insulin resistance (Taskinen, 2003)..

Caracterització i propietats de dues endo-B-(1,4)-glucanases implicades en l'estovament del fruit de maduixa.

[cat] Un dels enzims que podria tenir una acció important en l'estovament de la maduixa és l'endo-?-(1,4)-glucanasa (EGasa). Donat que aquest estovament produeix pèrdues comercials molt importants, es va plantejar l'objectiu de caracteritzar la funció biològica de dues endo-?-(1,4)-glucanases aïllades prèviament en fruit de maduixa: Cel1 i Cel2. En maduixa, l'activitat EGasa augmenta durant la maduració, i aquest augment coincideix temporalment amb l'increment d'expressió i acumulació proteica de Cel1 i Cel2. L'expressió superposada de Cel1 i Cel2 en maduixa observada per Northern-blot, podria indicar una certa cooperació d'aquests dos enzims en el metabolisme dels polímers de la paret cel·lular que acompanya a la maduració del fruit. Cel1 en maduixera no s'expressa en teixits diferents del fruit, per tant, es pot afirmar que entre totes les EGases descrites fins ara, i que s'expressen en fruits, Cel1 és la que té el patró d'expressió més específic de maduració. L'acumulació de Cel2 durant el procés de maduració suggereix un paper important d'aquesta EGasa en l'estovament dels fruits. A més, l'expressió de Cel2 en teixits en creixement dóna suport a una participació d'aquest gen en les modificacions de la paret cel·lular que acompanyen el creixement i l'expansió cel·lular. El punt isoelèctric trobat per Cel1 és de 8'5, molt proper al valor teòric predit a partir de la seqüència. Cel2 en canvi, presenta un punt isoelèctric de 5'0, molt diferent del valor teòric predit. Ambdues proteïnes presenten un senyal consens per la N-glicosilació, però només Cel1 té afinitat per la concanavalina A. Per tant, o bé només Cel1 està realment glicosilada in vivo, o més probablement, Cel1 i Cel2 es conjuguen amb residus glucosídics diferents. L'eliminació dels aquenis del fruit inicia el procés de maduració de la maduixa, provocant un augment de l'expressió i de l'acumulació proteica de Cel1 i Cel2. Donat que en els aquenis es produeix la síntesi i alliberació d'auxines, es pot afirmar que Cel1 i Cel2 estan sota control negatiu de les auxines. L'aplicació exògena d'etilè en fruits de maduixa no modifica l'expressió de Cel1 i Cel2, indicant que aquesta hormona no intervé en la regulació transcripcional d'aquests gens. S'ha detectat cinc isoformes amb activitat endoglucanasa en extractes proteics totals de maduixa madura; una isoforma bàsica i quatre isoformes àcides. Mitjançant Western-blot del gel nadiu, s'ha vist que la isoforma de pI bàsic (pI 8'5) es correspon a Cel1, mentre una de les isoformes àcides, de pI 5-5'5, es correspon a la proteïna Cel2. La sobreexpressió de Cel1 en el llevat Pichia pastoris produeix una proteïna que es troba glicosilada i probablement unida iònicament a la paret cel·lular del llevat. Aquesta proteïna té un pH òptim d'activitat endoglucanasa de 7'5 i ha mostrat afinitat significativa només per substrats amb enllaços ?-(1,4): CMC, xiloglucans i Cel·lulosa CF-11. Per tant, els substrats potencials in vivo per la proteïna Cel1 podrien ser els xiloglucans i/o la cel·lulosa de la paret cel·lular. La inhibició antisentit de l'expressió de Cel1 en plantes transgèniques de maduixa disminueix clarament l'acumulació de la proteïna i resulta en una reducció parcial de l'activitat endoglucanasa total en fruit madur. Estudis preliminars mostren que això es tradueix només en una lleugera disminució de la textura del fruit. Aquests resultats suggereixen que hi ha altres enzims implicats en l'estovament del fruit que compensen la inhibició de Cel1, o bé que la contribució de Cel1 a l'activitat endoglucanasa total és petita. No s'han pogut obtenir plantes de maduixa transgèniques antisentit amb expressió reduïda per Cel2. Aquest fet es podria explicar perquè Cel2 és un gen imprescindible per la planta, i per tant, sense la seva expressió les plantes no es poden desenvolupar

The PPARβ/δ-AMPK Connection in the Treatment of Insulin Resistance

The current treatment options for type 2 diabetes mellitus do not adequately control the disease in many patients. Consequently, there is a need for new drugs to prevent and treat type 2 diabetes mellitus. Among the new potential pharmacological strategies, activators of peroxisome proliferator-activated receptor (PPAR)β/δ show promise. Remarkably, most of the antidiabetic effects of PPARβ/δ agonists involve AMP-activated protein kinase (AMPK) activation. This review summarizes the recent mechanistic insights into the antidiabetic effects of the PPARβ/δ-AMPK pathway, including the upregulation of glucose uptake, muscle remodeling, enhanced fatty acid oxidation, and autophagy, as well as the inhibition of endoplasmic reticulum stress and inflammation. A better understanding of the mechanisms underlying the effects resulting from the PPARβ/δ-AMPK pathway may provide the basis for the development of new therapies in the prevention and treatment of insulin resistance and type 2 diabetes mellitus