Reproducció digital de l'exemplar mecanografiat dipositat a la Biblioteca de Medicina / Al cumplirse en 1960 el segundo centenario de la fundación del Real Colegio de Cirugía de Barcelona, tuvimos oportunidad de estudiar detenidamente su evolución hasta que desaparece en 1843 al reorganizarse la enseñanza de la Medicina y volver a Barcelona su Universidad exiliada en Cervera desde el reinado de Felipe V, y como consecuencia de la Guerra de Sucesión. Ello fue posible gracias a la consulta de la documentación completa del Colegio guardada en diferentes Archivos y Bibliotecas. Este Real Colegio fue edificado sobre terrenos propiedad del Hospital General de Santa Cruz de la ciudad y expropiados al mismo; a partir de ese momento el Hospital vio truncada su independencia e incluso podríamos decir que perdió su primacía en cuanto a asistencia médica en Barcelona, que había mantenido desde su fundación en 1401. El Colegio necesitaba del Hospital y de sus enfermos para cumplir su función docente; esta convivencia forzada y el entrometimiento en la vida cotidiana del segundo provocó toda una serie de incidentes, pleitos, reclamaciones, etc., que aumentaron cuando en 1760 sus cirujanos mayores pasaron a ser nombrados por el Poder Central y pasaron a depender del Colegio, compartiendo con éste sus servicios de Cirugía. Todos estos incidentes quedaron reflejados fielmente en la documentación del Real Colegio, pero según su punto de vista. Eso motivó que nos quedásemos con la curiosidad de conocer el reverso de la cuestión, es decir, la interpretación de tales problemas desde la visión de la Administración del Hospital. Sin embargo, no pudimos localizar en ningún lugar nada referente a ellos. La bibliografía sobre el Hospital es escasa, y las personalidades consultadas sobre la historiografía de Barcelona tampoco nos pudieron ofrecer pista alguna. Todas estas dificultades no hicieron más que aumentar nuestro interés. Fue entonces cuando recibimos información sobre la posibilidad de que quizás en el propio Hospital (hoy de la Santa Cruz y San Pablo), pudiera haber quedado parte de su documentación antigua. Tras diversas consultas infructuosas, localizamos en la antigua Administración del Hospital, un impresionante archivo perfectamente conservado, aunque sin catalogación ni registro. En él se encontraban un gran número de protocolos, encuadernados y en perfecto estado de conservación, entre los que se hallaban los Manuales de los Notarios del Hospital, los libros de Censos, Censales y Capbreus; libros del Patrimonio, de cuentas, etc. Posteriormente, en la Biblioteca Central de la Diputación pudimos consultar un importante fondo adquirido por el “Institut d’Estudis Catalans” en 1921 al Hospital, y que contiene entre otros los libros de Entrada de Enfermos, libros de Compras o los Libros del Racional y del Subprior, algunos de los cuales ha permitido realizar estudios sobre la economía de la Cataluña del siglo XVI. Este acopio documental, desconocido hasta ahora, nos ha permitido estudiar de manera exhaustiva el centro hospitalario más importante que ha existido en Cataluña, reconstruyendo de modo ininterrumpido su historia desde el siglo XV. En el presente trabajo, intentaremos dar a conocer la organización de este importante Centro Asistencial, en especial durante los años en que el Hospital era el único centro asistencial de la ciudad, o al menos el más importante, administrado de una manera autónoma, hasta la entrada en escena primero del Colegio de Cirugía y luego de la Facultad de Medicina, hasta la construcción del Hospital Clínico. En el primer capítulo, tras una somera recapitulación de los antecedentes hospitalarios de Barcelona pasamos a analizar la creación del Hospital de la Santa Cruz. En el segundo, trataremos sobre la construcción del edificio, y más adelante describiremos la Administración del Hospital y su régimen interior y exterior, la asistencia a los enfermos, la plantilla de médicos y cirujanos… Unos apéndices con la transcripción de las actas más interesantes y demostrativas, junto a la cita de todas las fuentes documentales consultadas, completan la obra.

El trabajo de investigación se ha desarrollado conjuntamente en el Instituto de Ciencia de Materiales de Barcelona (ICMAB-CSIC) y en el Instituto de Investigación del Hospital Universitario Vall d’Hebron (VHIR) en Barcelona. El trabajo se enmarca dentro del contexto tanto de nanomateriales como de nanomedicina. El objetivo principal de la tesis doctoral es desarrollar materiales para terapias no invasivas encaminadas a potenciar la regeneración de vasos sanguinos después de un evento isquémico. Para ello se han utilizado nanopartículas magnéticas de oxido de hierro como instrumentos de visualización (“imaging” por resonancia magnética) y de acumulación de proteínas/células en tejidos específicos bajo la influencia de un campo magnético externo. Se han desarrollado dos estrategias: la primera introduciendo las nanopartículas magnéticas en células endoteliales progenitora y la segunda en nanocápsulas poliméricas junto a un factor de crecimiento vascular. La tesis está estructurada en seis capítulos: CAPÍTULO 1 Las nanopartículas superparamagnéticas de óxido de hierro (SPIONs) son conocidas en diagnosis clínico por utilizarse como agentes de contraste que permiten la visualización de los tejidos a través de resonancia magnética (MRI). El capítulo contiene una breve introducción a la nanotecnología y una presentación de las características magnéticas de los materiales. Además contiene una revisión de los métodos de síntesis de las nanopartículas superparamagnéticas de oxido de hierro. CAPÍTULO 2 Describe la síntesis de nanopartículas superparamagnéticas de oxido de hierro mediante dos técnicas: descomposición térmica y microonda. Ambos métodos nos permiten de obtener partículas monodispersas con tamaño inferior a 20 nm y con excelentes propiedades magnéticas. Se ha logrado estabilizar las partículas en agua y en distintos medios celulares mediante estabilizantes iónicos (hidróxido de tetrametilamonio y sodio citrato). CAPÍTULO 3 La isquemia cerebral se define como la obstrucción de arterias intracraneales, debida a trombos o émbolos, que producen una lesión en los tejidos no perfundidos por la sangre. La regeneración y reparación del tejido cerebral basadas en la mejora de la angiogénesis endógena podría convertirse en realidad en un futuro próximo, al haberse identificado células progenitoras endoteliales (EPCs) en individuos adultos. Las EPCs son células que pueden inducir neo-vascularización y/o remodelación de vasos mediante liberación de factores angiogénicos. Nuestro objetivo es potenciar la acción terapéutica de las EPCs guiándolas a áreas específicas del cerebro con un campo magnético externo para potenciar la regeneración cerebral después de un ictus. En este capítulo se describen los experimentos in vitro de marcaje celular, toxicidad y funcionalidad de células. Además se describe un experimento in vivo con modelos animales demostrando la acumulación de EPCs magnetizadas en la zona del cerebro en la que se aplicó un campo magnético externo. CAPÍTULO 4 Otra estrategia que se ha investigado consiste en encapsular factores de crecimientos junto con las nanopartículas magnéticas (SPIONs) en nanocápsulas biodegradables de polímero de ácido poli(D,L-láctico-co-glicólico) (PLGA), para que éstas puedan guiarse a la lesión cerebral mediante la aplicación de un campo magnético externo. Durante los meses de estancia en el grupo de la Ecole de Pharmacie Genève-Lausanne (EPGL) se empezó la síntesis de nanocápsulas poliméricas con SPIONs y proteínas modelos. Este capítulo describe la síntesis y las caracterizaciones de las nanocápsulas obtenidas. CAPÍTULO 5 Conclusiones: se detallan los resultados más importantes obtenidos en esta tesis. En la primera parte se evidencian los siguientes resultados: 1. Se han sintetizado nanopartículas de óxido de hierro biocompatibiles y con las características adecuadas para la terapia celular; 2. Se ha realizado un marcaje no tóxico de células endoteliales progenitoras con SPIONs. Además se han reportado diferentes eficiencias de marcaje celular dependiendo del tipo de EPCs (early- y outgrowth). También se ha evidenciado que la eficiencia del marcaje celular puede variar utilizando diferentes condiciones de tiempo de incubación, de concentración de SPIONs y de agregación de partículas en los medios cultivos. Aún así, no se ha reportado ningún cambio significativo en la capacidad de tubulogénesis (formación de conexiones inter-celulares) ni de migración en población outgrowth de células endoteliales progenitoras marcadas con SPIONs; 3. Se ha detectado un aumento en la liberación de factores de crecimiento angiogénicos en células outgrowth marcadas con SPIONs respecto a células outgrowth no marcadas; 4. En un estudio preliminar in vivo en ratones, se ha demostrado con éxito la migración y acumulación de células endoteliales progenitoras (poblaciones early), marcadas con SPIONs, en la zona del celebro próxima a la aplicación del campo magnético externo. En la segunda parte del trabajo de tesis se ha conseguido: 1. La síntesis de nanocápsulas de polímero biodegradable de ácido poli(D,L-láctico-co-glicólico), mediante un proceso de doble emulsión, con tamaños de partícula de 200 nm adecuadas para la administración sistémica; 2. Co-encapsulación de SPIONs y factor de crecimiento vascular endotelial (proteína comercial, recombinant human VEGF165) con buena eficiencia. 3. La proliferación de células endoteliales potenciada por la actividad biológica de VEGF165 encapsulado. CAPÍTULO 6 Contiene el curriculum del autor y los trabajos publicados durante el periodo de doctorado. / The research was developed at the Institute of Materials Science of Barcelona (ICMAB-CSIC) and the Research Institute at Hospital Vall d'Hebron (VHIR) in Barcelona. The main objective of the thesis is to develop materials for non-invasive therapies to promote blood vessel regeneration after an ischemic event. For that we used iron oxide magnetic nanoparticles for imaging (through Magnetic Resonance Imaging) and accumulation of proteins / cells into specific tissues under the influence of an external magnetic field. Two strategies have been developed: the first one by introducing magnetic nanoparticles in endothelial progenitor cells (EPCs) and the second one into polymeric nanocapsules together with a vascular growth factor. The thesis is organized in six chapters: CHAPTER 1 Superparamagnetic iron oxide nanoparticles (SPIONs) are known for their use in clinical diagnosis as contrast agents allowing the visualization of tissues through magnetic resonance imaging (MRI). The chapter contains a brief introduction to nanotechnology and a presentation of the magnetic properties of the materials. It also contains a review of the most common synthetic methods used to obtain superparamagnetic iron oxide nanoparticles. CHAPTER 2 In this chapter is described the synthesis of superparamagnetic iron oxide nanoparticles using two techniques: thermal decomposition and microwave assisted sol-gel route. Both methods allow to obtain monodisperse particles with size less than 20 nm and excellent magnetic properties. Particles have been successfully stabilized in water and different cell media by ionic stabilizers (tetramethylammonium hydroxide and sodium citrate). CHAPTER 3 Cerebral ischaemia is defined as the blockage of cerebral arteries, due to a thrombus or embolus, which produce tissue damage in the zone not perfused with blood. Brain tissue regeneration and repair, based on the improvement of endogenous angiogenesis, could become reality in the near future having identified endothelial progenitors (EPCs) cells in adults. The EPCs are cells that can induce revascularization and / or remodeling of blood vessels by release of angiogenic factors. Our goal is to enhance the therapeutic action of EPCs guiding them toward specific areas of the brain with an external magnetic field to enhance regeneration after cerebral stroke. Experiments of in vitro cell labeling, cell toxicity and functionality are described in this chapter. In addition we showed an in vivo experiment using animal models to demonstrate the accumulation of magnetized EPCs in the brain under a magnetic field due to an external magnet implantation. CHAPTER 4 Another strategy is to encapsulate growth factors together with magnetic nanoparticles (SPIONs) into biodegradable nanocapsules of poly (D,l-lactic-co-glycolic acid) (PLGA), so that these can be guided toward the brain injury by applying an external magnetic field. During the training period in the group of the Ecole de Pharmacie Genève-Lausanne (EPGL) I started the synthesis of polymeric nanocapsules with SPIONs and model proteins. This chapter describes the synthesis and characterization of the nanocapsules. CHAPTER 5 In this chapter are described the most important results obtained during the thesis. The first part regards the following results: 1. The attainment of biocompatible iron oxide nanoparticles suitable for cell therapy; 2. Non toxic labeling of endothelial progenitor cells with SPIONs. Furthermore different efficiencies in cell labeling have been reported depending on the type of EPC cell population (early - and outgrowth). It has also been shown that cell labeling efficiency may vary using different conditions of incubation time, concentration of SPIONs and particle aggregation in the culture media. Still, it has been reported no significant change in tubulogenesis (formation of inter- cellular connections) or migration ability in outgrowth EPC cell population labeled with SPIONs; 3. An increase in the release of angiogenic growth factors in outgrowth EPCs labeled with SPIONs compared to unlabeled cells; 4. A preliminary in vivo study in mice has demonstrated the migration and accumulation of endothelial progenitor cells (early populations) labeled with SPIONs in the area next to the application of the external magnetic field. In the second part of the thesis work have been achieved: 1. The synthesis of biodegradable poly (D,L-lactic - co- glycolic acid) nanocapsules by a double emulsion process, with particle sizes of 200 nm suitable for systemic administration; 2. Co- encapsulation of SPIONs and vascular endothelial growth factor (commercial protein, recombinant human VEGF165) with good efficiency. 3. Endothelial cell proliferation enhanced by the biological activity of VEGF165 encapsulated. CHAPTER 6 It contains the curriculum vitae of the author and the publications obtained during the PhD period.

Introduzione: l’epatite cronica C è la più comune infezione virale trasmessa per via ematica e la principale causa di mortalità tra le epatopatie. La terapia antivirale può prevenire la progressione della malattia nei pazienti HCV. Telaprevir e simeprevir sono Direct Acting Antivirals e due inibitori delle proteasi, utili nell’eradicazione del virus. Scopo: stabilire l’efficacia e sicurezza di un regime di terapia antivirale con telaprevir, pegIFN/ribavirin e di uno con simeprevir-sofosbuvir+/- ribavirina. Metodi: 35 pazienti venivano consecutivamente arruolati nel gruppo telaprevir (54.3% maschi, età mediana 61, 43-71) e confrontati con 70 controlli, selezionati random da una popolazione di pazienti trattati con simeprevir-sofosbuvir e appaiati per età, sesso e fibrosi. Erano valutati l’efficacia misurata attraverso la risposta virologica sostenuta (SVR) e il miglioramento dei parametri biochimici, e la sicurezza. Risultati: i pazienti trattati con telaprevir presentavano eventi avversi nel 94.2% dei casi contro il 28.6% del gruppo simeprevir (p.000). Gli eventi avversi di grado severo si concentravano poi tutti nel gruppo telaprevir (20% vs 0%, p.000). Il più comune evento avverso in entrambi i gruppi era rappresentato dall’anemia (77.1% nel gruppo telaprevir va 14.3% nel gruppo simeprevir, p 0.000). L’SVR era del 91.4% nei casi e del 71.4% nei controlli (p 0.01). L’utilizzo di ribavirina, il tipo di genotipo 1 e lo stadio di fibrosi, non influenzavano i tassi di SVR. Conclusioni: il nostro studio ha mostrato che il telaprevir è meno efficace e sicuro del simeprevir nei pazienti con fibrosi avanzata o cirrosi epatica. I dati confermano l’indicazione a preferire i regimi liberi da interferone a quelli che lo contengono ancora. / Introduction: Chronic hepatitis C (CHC) is the most common viral infection blood-transmitted and it is the leading cause of death from liver disease. Antiviral therapy can prevent disease progression in patients with CHC. Telaprevir and Simeprevir are Direct Acting Antivirals and two protease inhibitor, useful in the eradication of the virus. Aim: to assess the safety and efficacy of telaprevir-based antiviral therapy with pegIFN/ribavirin or simeprevir-based antiviral therapy with sofosbuvir ± ribavirin. Methods: consecutive 35 CHC patients (54.3% males, median age 61, range 43-71) were enrolled in telaprevir group and compared with 70 controls, randomly selected from the population of patients treated with simeprevir-sofosbuvir and matched by age ± 5 years, sex and degree of fibrosis. Efficacy by sustained virological response (SVR) and improvement of laboratory tests and safety were evaluated. Results: patients treated with telaprevir had adverse events in 94.2% of cases while occurred in 28.6% of patients treated with simeprevir (p.000). Severe adverse events occurred all in telaprevir group (20% vs 0%, p 0.000). The most common adverse event in both groups was anemia (77.1% in telaprevir treatment vs 14.3% in simeprevir treatment, p 0.000). SVR was 91.4% in cases and 71.4% in controls (p 0.01). Use of ribavirin, type of genotype 1 and stage of fibrosis did not affect SVR rates. Conclusion: our study showed the telaprevir is less effective and safe compared to simeprevir in patients with advanced fibrosis or cirrhosis. The data confirm the indication to prefer interferon free regimens to those still based on interferon in this setting.

Oggetto: Ruolo dell’ ecoendoscopia (EUS) nello studio dei tumori neuroendocrini del tratto digestivo è la stadiazione locoregionale basata sulla valutazione dell’ estensione di profondità di parete (T) e l’ interessamento dei linfonodi loco-regionali (N) con un’accuratezza diagnostica del 94-100%. La resezione endoscopica è un’ opzione di trattamento. Scopo dello studio è stato valutare l’ accuratezza diagnostica dell’ EUS nella stadiazione locale dei tumori neuroendocrini gastrici, duodenali e rettali macroscopicamente suscettibili di resezione endoscopica e valutare l’efficacia della resezione endoscopica. Materiali e metodi: Studio retrospettivo condotto su una coorte consecutiva di pazienti con diagnosi di neoplasia neuroendocrina del tratto gastroenterico afferenti all’ Istituto Europeo di Oncologia di Milano. Risultati: Sono stati sottoposti ad EUS 21 pazienti per un totale di 22 lesioni da Settembre 2001 a Gennaio 2016. 21 lesioni erano confinate alla sottomucosa, soltanto in una lesione gastrica è stato posto il dubbio di infiltrazione superficiale della tonaca muscolare propria e in una lesione del retto riscontro di una linfoadenopatia di aspetto secondario. 11 lesioni erano nello stomaco (NET gastrico di tipo 1), 5 nel duodeno e 5 nel retto. Le lesioni sono state asportate per via endoscopica in pezzo unico intero. All’ analisi istopatologica 21 lesioni erano limitate alla sottomucosa, tranne il caso con dubbia infiltrazione della tonaca muscolare che presentava interessamento dello strato muscolare superficiale. In 2 dei 21 è stato valutato l’ interessamento linfonodale dopo resezione chirurgica. In 10 di 22 lesioni con infiltrazione dei margini di resezione non si è riscontrata recidiva di malattia durante il follow-up (media 34 mesi, 3-126 mesi). Conclusioni: L’ EUS è una metodica valida nella valutazione della resecabilità endoscopica dei NETs gastrici di tipo 1, del bulbo e del retto. La resezione endoscopica è risultata efficace nel trattamento di queste neoplasie anche in presenza di infiltrazione dei margini di resezione. / Background and aim: Diagnostic role of endoscopic ultrasound (EUS) in gastrointestinal neuroendocrine tumors (GE-NETs) is the local staging based on the assessment of wall depth (T) and of lymph nodes metastasis (N). Diagnostic accuracy of EUS in T-staging is 94-100%. Endoscopic resection is a treatment option in selected cases. Aim of the current study was to evaluate diagnostic accuracy of EUS in the local staging of GE-NETs candidates to endosciopic resection and the efficacy of endoscopic resection in gastrointestinal neuroendocrine NETs’ treatment. Methods: This is a retrospective analysis of a prospectively collected database. Patients with GE-NETs that underwent EUS and endoscopic resection at Istituto Oncologico Europeo (IEO) were included. Results: From September 2001 to January 2016, 21 patients for a total of 22 GE-NETs underwent EUS: 21 GE-NETs were confined to the submucosa layer; 1 case presented a doubtful involvement of the proper muscolaris layer. 11 NETs were in the stomach, 5 NETs in the duodenum and 5 NETs in the rectum. All but one rectal NET case were negative for metastatic lymph nodes. All the 22 lesions were endoscopically resected in one piece by endoscopic resection. The histological analysis confirmed that twenty-one lesions were confined to the submucosa layer and that one case was involved the proper muscolaris layer. The involvement of lymph nodes was evaluated in only the two cases who underwent surgical resection. Ten out of 22 lesions had positive margins at the histological analysis but no recurrence were observed during follow-up (mean 34 months; range 3-126). Conclusions: EUS is useful for estimating the depth of invasion of type 1 gastric neuroendocrine tumor, duodenal and rectal neuroendocrine tumors and for determining whether endoscopic resection is indicated. Endoscopic resection is effective in gastrointestinal neuroendocrine NETs’ treatment.

La trombosi portale non neoplastica (PVT) è una complicanza frequente della cirrosi epatica. Attualmente, gli unici fattori di rischio associati, ripetutamente confermati in letteratura, sono il precedente sanguinamento da varici esofagee e la piastrinopenia che sbilancia il precario equilibrio coagulativo tipico della cirrosi. Tra Gennaio 2013 e Ottobre 2015, sono stati arruolati prospetticamente 253 pazienti cirrotici (età media 58,8 ± 10,3 (23 – 75) anni) senza neoplasie anamnestiche e/o malattia ematologica e liberi da terapia anticoagulante/antiaggregante assunta er altre cause. Nel campione raccolto sono stati studiati: lo stadio di malattia secondo il Child-Pugh (CP) e il Model for end-stage liver disease (MELD) scores, eziologia, età ed esami laboratoristici. I pazienti con PVT sono stati il 13%, di cui il 63,3% maschi, significativamente più giovani dei controllonegativi (51,9 ± 13,2 (23 – 75) anni; P=0,004), con una maggior piastrinopenia (73,1 ± 48,1 (25 – 174); P = 0,001), INR > 1.25 in 54,5% dei casi (P=0,024) e MELD >10 in 86,2% (P=0,001). INR e MELD sono state considerate anche come valore continuo senza raggiungere la significatività come eziologia, ematocrito, Bilirubina ttale, AST, ALT, Albumina, Creatinina e CP score e classe. All'analisi multivariata solo la conta piastrinica è risultata indipendentemente associata alla presenza di PVT (OR = 0.97, 95% CI: 0.96-0.99; P <0.001) come da letteratura. Le trombocitopenie ereditarie (ITs) sono un gruppo eterogeneo di disordini genetici con diversi gradi di severità e cmplessità caratterizzate da piastrinopenia associata o meno a sanguinamento di variabile entità. Tali disordini, in un substrato così favorevole come la cirrosi epatica, potrebbe spiegare l'eterogeneità dei quadri clinici e la risposta apparentemente casuale alla terapia anticoagulante. Non abbiamo ancora dati che confermino questa ipotesi alternativa, ma se così fosse, probabilmente l'approccio clinico a questa problematica cambierebbe significativamente. / Non-neoplastic porta vein thrombosis (PVT) in cirrhotic patients is a frequent complication of liver cirrhosis. Yet, only confirmed data about its natural history are the association with variceal bleeding and low platelet count which influences this precarious coagulation balance. In our prospective study, from January 2013 to October 2015, we enrolled 253 cirrhotic patients (mean age 58,8 ± 10,3 (23 – 75) years) without a history of malignancy and/or hematological disease and who aren’t on oral anticoagulants or antiplatelet therapy taken for other reasons. Overall were subsequently studied according to the degree of liver disease using the Child-Pugh (CP) and Model for end-stage liver disease (MELD) scores, etiology, age and blood tests. Patient with PVT, of which 63,3% males, was significantly younger (51,9 ± 13,2 (23 – 75) yrs; P=0,004), with lesser platelet count (73,1 ± 48,1 (25 – 174); P = 0,001), INR > 1.25 in 54,5% of cases (P=0,024) and MELD >10 in 86,2% (P=0,001). INR and MELD considered as continuous variables were not significant as well as etiology, hematocrit, total Bilirubin, AST, ALT, Albumine, Creatinine and CP score and class. In multivariate analysis, only the platelet count was independently associated with the occurance of PVT (OR = 0.97, 95% CI: 0.96-0.99; P <0.001) confirming the literature. The inheritated thrombocytopenias (ITs) are a heterogeneous group of genetic disorders with different degrees of complexity and severity, characterized by a low platelets count associated or not with a bleeding tendency which varies from absent to very strict. This group of diseases, in the context of an extremely favorable substrate such as cirrhotic degeneration, would explain the heterogeneity of the cadres and random responses to anticoagulation. We have no data yet certain about this, but if this hypothesis be confirmed, the clinical approach to the disease might change dramatically.

Cardiovascular diseases (CVD) comprise the most common chronic disease worldwide. High lipid levels are a strong risk factor, making lipid-lowering statin therapy an important preventive measure. Here we explore the effects of common variants at the KIF6 and HMGCR loci on a range of cardio-metabolic traits and on response to statin therapy. While HMGCR is a well-established lipid-related locus, the role of KIF6 in response to statin therapy is controversial, and its contribution to related phenotype variability has not been clarified. We genotyped a coding KIF6 variant (p.W719R, rs20455) and two intronic ones in high LD to the former (rs9462535,rs9471077), as well as two non-coding variants in HMGCR (rs3761740 and rs3846662). Effects on 14 quantitative and 5 categorical cardiometabolic phenotypes including lipid-lowering therapy response were tested in a sample of 1,645 individuals from the Genetics in Brisighella Health Study (GBHS) from Italy and replicated in 10,662 individuals from the Estonian Genome Center (EGCUT). In GBHS the established HMGCR variant rs3846662 affects LDL cholesterol levels (P=8.5x10-4) while the intronic KIF6 variant rs9471077 modifies APOB levels (P=8.2x10-4). The latter association was confirmed in EGCUT. No significant association between KIF6 variants and response to statin therapy was observed. In the first genetic study involving GBHS we confirm the HMGCR effect on LDL-Cholesterol and demonstrate a novel KIF6 effect on APOB. The latter association needs to be evaluated for its predictive value for overall CVD risk and its potential contribution to stratified patient care.

Introduzione: la trombosi del sistema venoso portale (PVT) rappresenta una complicanza frequente nel paziente con cirrosi epatica. La gestione terapeutica del paziente cirrotico con PVT non è chiara. Obiettivi: analizzare retrospettivamente la storia naturale della trombosi portale e gli eventi emorragici in un gruppo di pazienti cirrotici trattati e non trattati con terapia anticoagulante. Metodi: Da Gennaio 2008 a Dicembre 2015 abbiamo retrospettivamente individuato una coorte di 182 pazienti affetti da PVT. 81 pazienti sono stati trattati con terapia anticoagulante e 101 non hanno ricevuto terapia. Abbiamo valutato le caratteristiche demografiche, l’estensione della trombosi, l’eventuale trattamento anticoagulante, l’evoluzione della patologia e gli eventi emorragici. Risultati: La trombosi è andata incontro a ricanalizzazione in 46 (56,8%) pazienti trattati e in 26 (25,7%) pazienti non trattati (p<0,001). La durata del trattamento (p=0,005) e la doppia somministrazione giornaliera (p=0,003) sono risultati essere gli unici fattori predittivi di ricanalizzazione nei pazienti trattati. Dopo la sospensione della terapia, dei 46 pazienti che hanno ottenuto la ricanalizzazione, 17(36%) hanno presentato una recidiva della trombosi. L’analisi di Kaplan-Meier ha mostrato un tasso di sopravvivenza maggiore nel gruppo dei pazienti trattati (p=0,010) e il trattamento anticoagulante è risultato essere l’unico fattore indipendente correlato alla sopravvivenza all’analisi multivariata (p=0,014). Complicanze emorragiche si sono verificate in 22(21,8%) pazienti non trattati e in 16 (19,7%) pazienti trattati, solo in 4 casi dovute al trattamento anticoagulante. Conclusioni: il trattamento anticoagulante è sicuro ed efficace nei pazienti cirrotici con PVT, raggiungendo dei tassi di ricanalizzazione completa e parziale del 56,8%. La durata del trattamento di almeno 12 mesi e la doppia somministrazione giornaliera sembrano associati a più alti tassi di ricanalizzazione. Nei pazienti che hanno raggiunto la ricanalizzazione, l’interruzione della terapia è associata ad un alto rischio di recidiva. Il trattamento anticoagulante sembra migliorare la sopravvivenza dei pazienti cirrotici con PVT. / Introduction: Portal vein thrombosis (PVT) is a frequent event in patients with cirrhosis. It can be treated with anticoagulants, but the optimal management is still unclear. Aim: The aim of this study was to retrospectively analyze the natural history of portal thrombosis in cirrhotic patients and bleeding events in a large cohort of patients with or without anticoagulation therapy. Methods: We analyzed data from 182 patients with cirrhosis and PVT, diagnosed from January 2008 to December 2015. 81 patients were anticoagulated and 101 were untreated. Demographic characteristics, extension of portal vein thrombosis, anticoagulant treatment and hemorrhagic events were evaluated. Results: thrombosis had improved in 46 (56.8%) treated patients and in 26 (25.7%) untreated patients. The anticoagulation group had significantly better recanalization rate than the untreated group (p <0.001). The duration of treatment (p = 0.005) and twice-daily dosing (p = 0.003) were the only predictors of recanalization in treated patients. Of 46 patients who achieved recanalization, 17 (36%) had recurrent thrombosis after stopping anticoagulation therapy. Kaplan–Meier curve analysis revealed a higher survival rate in the treated group than in controls (p=0,010). Anticoagulant treatment was the only independent factor related to survival in multivariate analysis (p=0,014, HR:0,303, CI: 0.101-0.907). Bleeding complications occurred in 22 (21.8%) untreated patients and in 16 (19.7%) treated patients, only in 4 cases related to the anticoagulant treatment. Conclusions: Anticoagulant is a safe and effective treatment that leads to partial or complete recanalization of the portal venous axis in 56% of patients with cirrhosis and PVT. Duration of treatment of at least 12 months and twice-daily dosing seem associated with higher recanalization rates. Discontinuation of therapy is associated with high risk of recurrence of PVT. The anticoagulant treatment seems to improve survival in cirrhotic patients with PVT.

En condicions d’estrès pot existir un dèficit relatiu de glutamina (Gln). Aquesta actua com a font energètica i en la protecció cel·lular, activant l’expressió de les “Heat Shock Proteins” (HSP). Disminucions en la seva concentració mitja provoquen una alteració en la regulació inflamatòria. La seva suplementació estimula mecanismes de mort bacteriana i disminueix l’explosió citotòxica. OBJECTIUS: Determinar la resposta inflamatòria en els pacients pediàtrics suplementats amb Gln parenteral respecte els que reben nutrició estàndard. Valorar la morbi-mortalitat. METODOLOGIA: Estudi prospectiu, a doble cec i aleatoritzat amb blocs balancejats. Es van recollir mostres analítiques i dades de la història clínica dels pacients ingressats en la Unitat de Cures Intensives Pediàtriques (UCIP) de l’Hospital Sant Joan de Déu de Barcelona. Criteris d’inclusió: pacients (1 mes – 14 anys), que van requerir nutrició parenteral (NPT), afectes d’infeccions sistèmiques o focals greus, i post operats cirurgia major abdominal. Criteris d’exclusió: pacients amb patologia prèvia de base i derivats d’altres centres amb evolució clínica de més de 48 h. Aleatorització en dos grups: Grup 1 o grup experimental al que es va administrar una solució d’aminoàcids (Aminopaed® o Vamin®) i es va suplementar amb Gln (Dipeptiven®), anomenat NPS + Gln. Grup 2 o grup control al que es va administrar una solució d’aminoàcids(Aminopaed® o Vamin®) no suplementada, anomenat NPS. Es van recollir 73 pacients en cada grup. Les variables a estudi van ser: edat; sexe; Pediatric Risk Score of Mortality II (PRISM-II) a l’ingrés; malaltia actual; nivells de limfòcits CD4, CD8 i CD4/CD8; valors d’interleuquines (IL) IL-6, IL-10 i de HSP-70 a les 0 hores (h) a les 48h al cinquè dia; i presència de sobre infecció, fallida multi orgànica i mortalitat. RESULTATS: Els nivells de Gln no van mostrar diferències entre els grups. El dia 5, els pacients del grup experimental presentaren nivells d’HSP-70 significativament superiors que el grup control (68,6 vs 5,4, p = 0,014). En tots dos grups, els nivells d’IL-6 van tenir un descens significatiu des de el dia 0 al dia (NPS: 42,24 vs 9,39, p < 0,001; NPS + Gln: 35,20 vs 13,80, p<0,001), però tan sols en el grup experimental va existir un descens significatiu entre el dia 2 i el dia 5 (13,80 vs 10,55, p = 0,013). Els nivells d’IL-10 no van variar durant les visites excepte en el grup control entre el dia 0 i el dia 2 (9,55 vs 5,356, p < 0,001). Al final de l’estudi no s’observaren diferències significatives entre els grups referent a l’estància en UCIP o a l’estància hospitalària, tot i que va haver una menor estada a intensius en els pacients suplementats amb Gln. No es van detectar efectes adversos en cap grup. CONCLUSIONS: La suplementació amb Gln en pacients crítics contribueix al manteniment de majors nivells d’HSP-70, durant més temps. Aquesta suplementació no influeix en els nivells d’IL-10 i no mostra disminució significativa dels nivells d’IL-6. La Gln podria disminuir la estada en la UCIP. / In a stress situation, there is a Glutamine (Gln) deficit owing to an increase in its consumption as much as a decrease of its availability. This amino acid acts as a source of energy and also intervenes in the cellular and tissue protection activating the Heat Shock Proteins (HSP) expression. The Gln average concentration value is associated with a fall in immune response. It has been also proved that, if a supplement of Gln is added, it stimulates the mechanisms of bacteria death and diminishes the cytotoxic response. OBJECTIVES: To determine if there exist differences in the inflammatory response in seriously ill patients who received Gln supplemented nutrition with regard to those who received standard nutrition. To evaluate the patient clinical response and mortality. METHODOLOGY: It was a prospective, interventional, double blind, randomized and stratified clinical trial. Collection of samples and data for patients admitted at the Pediatric Intensive Care Unit (PICU) of the “Sant Joan de Déu” Hospital in Barcelona. Inclusion criteria: Patients (1 month to 14 years) who require parenteral nutrition, with one of the following diagnosis: Systemic or local infection and Major abdominal surgery. Exclusion criteria: patient with prior illnesses and patients coming from other centers with more than 48 hours clinical evolution. Sample selection: Group 1: Standard total parenteral nutrition (NPS) (Aminopaed® o Vamin®) and Gln perfusion (Dipeptiven®), denominated NPS + Gln. Group 2: Standard total parenteral nutrition (Aminopaed® o Vamin®) without Gln, denominated NPS. It will be necessary to include 73 experimental units in the reference group and 73 units in the experimental group. Variables: Age; sex; Pediatric Risk Score of Mortality (PRISM-II) score at admission; illness cause for the admission; CD4, CD8 i CD4/CD8 lymphocyte levels; determination at 0 hours (h), 48 h and 5th day of Interleukins(IL), IL-6, IL-10 and HSP-70; and infection complication, multiorganic failure and death. RESULTS: Gln levels failed to show statistical differences between groups. At day 5, patients in the experimental group had significantly higher levels of HSP-70 as compared with the control group (68.6 vs 5.4, p = 0.014). In both groups, IL-6 levels showed a remarkable descent from baseline and day 2 (SPN: 42.24 vs 9.39, p < 0.001; SPN + Gln: 35.20 vs 13.80, p<0.001) but only the treatment group showed a statistically significant decrease between day 2 and day 5 (13.80 vs 10.55, p = 0.013). Levels of IL-10 did not vary among visits except in the SPN between baseline and day 2 (9.55 vs 5.356, p < 0.001). At the end of the study, no significant differences between groups for PICU and hospital stay were observed. Although there was a shorter stay in the supplemented patients. No adverse events were detected in any group. CONCLUSIONS: Gln supplementation in critically-ill children contributed to maintain high HSP-70 levels for longer. Glutamine supplementation had no influence on IL-10 and failed to show a significant reduction of IL-6 levels. The Gln could reduce PICU stay.

Objectiu: L’objectiu principal d’aquest estudi és descriure les troballes a nivell clínic, neuropsicològic i de neuroimatge derivats de l’estudi d’una mostra de subjectes empresonats avaluats amb la PCL-R. Metodologia: Aquesta tesi està formada per quatre estudis on s’investiga la comorbiditat dels diferents trastorns de la personalitat amb la psicopatia, així com les funcions executives, la impulsivitat, el reconeixement de les emocions i la correlació entre el reconeixement emocional i l’estructura regional cerebral en una mostra intrapenitenciaria de subjectes antisocials i psicòpates. Resultats: A la nostra mostra trobem un percentatge del 100% de trastorn antisocial de la personalitat en subjectes psicòpates. Els subjectes antisocials amb trastorn psicopàtic presenten una millor funció executiva que els subjectes antisocials sense psicopatia, i similars als controls. Els subjectes antisocials van ser més impulsius, mentre que els psicòpates van mostrar dèficits en el reconeixement d’algunes emocions i alteracions volumètriques cerebrals en àrees de reconeixement de les emocions. / Objetivo: El objetivo principal del presente trabajo es describir los hallazgos clínicos, neuropsicológicos y de neuroimagen derivados del estudio de una muestra de sujetos intrapenitenciarios evaluados con la PCL-R. Metodología: Esta tesis está formada por cuatro estudios dónde se investiga la comorbilidad de los diferentes trastornos de la personalidad con la psicopatía, así como las funciones ejecutivas, la impulsividad, el reconocimiento de las emociones y la correlación entre el reconocimiento emocional y la estructura regional cerebral en una muestra intrapenitenciaria de sujetos antisociales y psicópatas. Resultados: En nuestra muestra encontramos un porcentaje del 100% de trastorno antisocial de la personalidad en sujetos psicópatas. Los sujetos antisociales con trastorno psicopático presentan una mejor función ejecutiva que los sujetos antisociales sin psicopatía, y similares a los controles. Los sujetos antisociales fueron más impulsivos, mientras que los psicópatas mostraron déficits en el reconocimiento de algunas emociones y alteraciones volumétricas cerebrales en áreas de reconocimiento de las emociones. / Objective: The main purpose of the study is to describe clinical, neuropsychological and neuroimaging findings derived from a sample of incarcerated subjects evaluated with the PCL-R. Methodology: This thesis consists of four studies which investigate the comorbidity of different personality disorders with psychopathy, as well as executive functions, impulsivity, recognizing emotions and the correlation between emotion recognition and regional brain structure in a imprisoned sample of antisocial and psychopath subjects. Results: In our sample, 100% of the psychopaths obtained an antisocial personality disorder diagnosis. Antisocial offenders with psychopathy had better executive functions compared to antisocial offenders without psychopathy, and similar to controls. The antisocial subjects were more impulsive, whereas psychopaths showed some deficits in emotion recognition and volumetric brain abnormalities in relation to areas involved in recognizing emotions.

INTRODUCCIÓ: La infecció nosocomial (IN) a les Unitats de Cures Intensives Pediàtriques (UCIP) incrementa la morbimortalitat dels nens. En aquesta memòria de tesi doctoral es presenten dos estudis relacionats. El primer valora l’impacte d’ una campanya de prevenció d’IN a la UCIP, i el segon presenta un registre multicèntric d’IN a UCIP a Espanya. HIPÒTESIS: La campanya de prevenció d’IN a la UCIP podria disminuir les taxes d’IN i comportaria un descens de la morbimortalitat dels pacients. La creació d’un registre nacional multicèntric d’IN a les UCIPs permetria tenir informació sobre l’epidemiología de la infecció i el perfil de resistències. METODOLOGIA: El primer treball és un estudi prospectiu amb intervenció múltiple per reduir IN a la UCIP de l’hospital Sant Joan de Déu. Es dividí en tres períodes: Pre-intervenció (2006), intervenció (2007) en el que simplementaren els mesures i el període de seguiment a llarg plaç (2008). La intervenció radicava en tres accions principals: Crear un grup de Control d’ infecció, un programa educatiu d’higiene de mans i aplicar un paquet de mesures per reduir la IN. S’inclogueren nens ingressats a la UCIP t més de 24 hores. Es calcularen taxes de Bacterièmia relacionada con catèter (BRC), pneumònia associada a ventilació mecànica (NAVM) i infecció urinària associada a sondatge uretral (ITU-SU). El segon estudi és un estudi multicèntric prospectiu, observacional i descriptiu. El 2007 es creà el registre VINCIP (Vigilancia de Infección Nosocomial en Cuidados Intensivos Pediátricos). Es recolliren dades durant un mes (1-31 de març) per cada any d’estudi (2008-2012). No es van fer intervencions específiques durant aquest període com grup, però la majoria de les UCIPs implementen mesures per reduir la IN. Es recolliren taxes de BRC, NAVM i ITU-SU, microorganismes causants i patrons de resistències. RESULTATS: Primer estudi: S’inclogueren 851, 822 y 940 pacients, respectivament. Milloraren la taxa de BRC (8.1 a 6/1000-dies de catèter venós central CVC, p = 0.640), la de NAVM (28.3 a 10.6/1000 dies de ventilació mecànica, p = 0.005) i ITU-SU (23.3 a 5.8/1000 dies de sonda urinària, p < 0.001). Es va reduir l’estada hospitalària (18.56 vs 14,57 dies, p = 0,035) i la mortalitat (5,1% a 3,3%, p = 0.056). El model de regressió logística multivariable mostrà que la presència d’IN era factor independent de risc de mortalitat (OR 2.35 [95% IC, 1.02-5.55]; p = 0.046). Durant el seguiment a llarg plaç (en comparació amb el període pre-intervenció), les taxes van seguir millorant, BRC 4,6/1000 dies de CVC; NAVM, 9,1/1000 dies de ventilació mecànica i ITU-SU 5,2/1000 dies de sonda urinària (p = 0,205, p = 0.001 i p < 0.001 respectivament). Segon estudi. Ingressaren 3667 pacients. El nombre de pacients amb infecció nosocomial fou 90 (2.45%). La mitja de taxes dels 5 anys foren: BRC 3.8/1000 dies de CVC, NAVM 7.5/1000 dies de ventilació mecànica i ITU-SU 4.1/1000 dies de sonda urinària. Les taxes es reduiren homogèniament des de 2009 a 2012: BRC de 5.83 (95% CI 2.67- 11.07) a 0.49 (95% CI 0.0125- 2.76), p =0.0029; NAVM de 10.44 (95% CI 5.21-18.67) a 4.04 (95% CI 1.48-8.80), p= 0.0525; ITU-SU 7.10 (95% CI 3.067-13.999) a2.56 (95% CI 0.697-6.553), p= 0.0817; respectivament. Microorganismes: 63 de 99 (83.6%) bacteris gram-negatius (36.5% resistents), 19 (19.2%) bacteris gram-positius i 17 (17.2%) infeccions per Candida spp. CONCLUSIONS: Respecte al primer estudi, la campanya de prevenció d’IN va baixar globalment les taxes d’IN, l’estada hospitalària i la mortalitat. Els resultats es mantingueren en el període de seguimient a llarg plaç. Respecte al segon estudi presentat, els sistemes de vigilància local aporten informació per millorar les taxes d’infecció nosocomial, així com el patró de resistències. / INTRODUCTION: Nosomial infections (NI) in the Pediatric Intensive care Unit (PICU) increases morbidity and mortality of patients. In this thesis we include two related articles. OBJECTIVES: - First study: To evaluate whether a quality improvement intervention could reduce NI in a PICU. - Second study: To report 5-years of NI surveillance data, as well as trends in infections by multidrug resistant organisms in Spanish PICU. METODOLOGY: - First article: Prospective interventional cohort study conducted during three periods: preintervention period, intervention period, and long-term follow-up. The quality improvement intervention consisted of the creation of an infection control team, a program targeting hand hygiene, and quality practices focused on preventing NI. - Second article: multicentre, prospective, descriptive and observational study was conducted using the data from surveillance system for NI created in 2007 for Spanish PICU. Data were collected for one month, between 01 and 31 March, for every study year (2008–2012). RESULTS: - First study: We included 851, 822 and 940 patients. Compared with the preintervention period, in the intervention period, the rates of central line–associated bloodstream infection (CLABSI) decreased from 8.1to 6/1,000 central venous catheter-days (p = 0.640), ventilator associated pneumonia (VAP) decreased from 28.3 to 10.6/1,000 days of ventilation (p = 0.005), and catheter-associated urinary tract infection (CAUTI) decreased from 23.3 to 5.8/1,000 urinary catheter-days (p < 0.001). Furthermore, hospital length of stay decreased from 18.56 to 14.57 days (p = 0.035) and mortality decreased from 5.1% to 3.3% (p = 0.056). - Second study: A total of 3667 patients were admitted to the units during the study period. There were 90 (2.45%) patients with NI. The mean rates during the 5 years study were:CLABSI, 3.8/1000 central venous catheter-days, VAP 7.5/1000 endotracheal tube-days, and cathet CAUTI 4.1/1000 urinary catheter-days. All rates homogeneously decreased from 2009 to 2012. The microorganism analysis: 63 of the 99 isolated bacteria (63.6%) were Gramnegative bacteria (36.5% were resistant), 19 (19.2%) Gram-positive bacteria, and 17 (17.2%) were Candida spp. CONCLUSIONS: A multifaceted quality improvement intervention reduced nosocomial infections rates, hospital length of stay, and mortality in our PICU. The local surveillance systems provide information for dealing with nosocomial infections