Cellular reprogramming strategies for degenerative disorders involving the retinal pigment epithelium

RESUMO: A reprogramação celular permite que uma célula somática seja reprogramada para outra célula diferente através da expressão forçada de factores de transcrição (FTs) específicos de determinada linhagem celular, e constitui uma área de investigação emergente nos últimos anos. As células somáticas podem ser experimentalmente manipuladas de modo a obter células estaminais pluripotentes induzidas (CEPi), ou convertidas directamente noutro tipo de célula somática. Estas descobertas inovadoras oferecem oportunidades promissoras para o desenvolvimento de novas terapias de substituição celular e modelos de doença, funcionando também como ferramentas valiosas para o estudo dos mecanismos moleculares que estabelecem a identidade celular e regulam os processos de desenvolvimento. Existem várias doenças degenerativas hereditárias e adquiridas da retina que causam deficiência visual devido a uma disfunção no tecido de suporte da retina, o epitélio pigmentar da retina (EPR). Uma destas doenças é a Coroideremia (CHM), uma doença hereditária monogénica ligada ao cromossoma X causada por mutações que implicam a perda de função duma proteína com funções importantes na regulação do tráfico intracelular. A CHM é caracterizada pela degenerescência progressiva do EPR, assim como dos foto-receptores e da coróide. Resultados experimentais sugerem que o EPR desempenha um papel importante na patogénese da CHM, o que parece indicar uma possível vantagem terapêutica na substituição do EPR nos doentes com CHM. Por outro lado, existe uma lacuna em termos de modelos in vitro de EPR para estudar a CHM, o que pode explicar o ainda desconhecimento dos mecanismos moleculares que explicam a patogénese desta doença. Assim, este trabalho focou-se principalmente na exploração das potencialidades das técnicas de reprogramação celular no contexto das doenças de degenerescência da retina, em particular no caso da CHM. Células de murganho de estirpe selvagem, bem como células derivadas de um ratinho modelo de knockout condicional de Chm, foram convertidos com sucesso em CEPi recorrendo a um sistema lentiviral induzido que permite a expressão forçada dos 4 factores clássicos de reprogramação, a saber Oct4, Sox2, Klf4 e c-Myc. Estas células mostraram ter equivalência morfológica, molecular e funcional a células estaminais embrionárias (CES). As CEPi obtidas foram seguidamente submetidas a protocolos de diferenciação com o objectivo final de obter células do EPR. Os resultados promissores obtidos revelam a possibilidade de gerar um valioso modelo de EPR-CHM para estudos in vitro. Em alternativa, a conversão directa de linhagens partindo de fibroblastos para obter células do EPR foi também abordada. Uma vasta gama de ferramentas moleculares foi gerada de modo a implementar uma estratégia mediada por FTs-chave, seleccionados devido ao seu papel fundamental no desenvolvimento embrionário e especificação do EPR. Conjuntos de 10 ou menos FTs foram usados para transduzir fibroblastos, que adquiriram morfologia pigmentada e expressão de alguns marcadores específicos do EPR. Adicionalmente, observou-se a activação de regiões promotoras de genes específicos de EPR, indicando que a identidade transcricional das células foi alterada no sentido pretendido. Em conclusão, avanços significativos foram atingidos no sentido da implementação de tecnologias de reprogramação celular já estabelecidas, bem como na concepção de novas estratégias inovadoras. Metodologias de reprogramação, quer para pluripotência, quer via conversão directa, foram aplicadas com o objectivo final de gerar células do EPR. O trabalho aqui descrito abre novos caminhos para o estabelecimento de terapias de substituição celular e, de uma maneira mais directa, levanta a possibilidade de modelar doenças degenerativas da retina com disfunção do EPR numa placa de petri, em particular no caso da CHM.---------------ABSTRACT: Cellular reprogramming is an emerging research field in which a somatic cell is reprogrammed into a different cell type by forcing the expression of lineage-specific transcription factors (TFs). Cellular identities can be manipulated using experimental techniques with the attainment of pluripotency properties and the generation of induced Pluripotent Stem (iPS) cells, or the direct conversion of one somatic cell into another somatic cell type. These pioneering discoveries offer new unprecedented opportunities for the establishment of novel cell-based therapies and disease models, as well as serving as valuable tools for the study of molecular mechanisms governing cell fate establishment and developmental processes. Several retinal degenerative disorders, inherited and acquired, lead to visual impairment due to an underlying dysfunction of the support cells of the retina, the retinal pigment epithelium (RPE). Choroideremia (CHM), an X-linked monogenic disease caused by a loss of function mutation in a key regulator of intracellular trafficking, is characterized by a progressive degeneration of the RPE and other components of the retina, such as the photoreceptors and the choroid. Evidence suggest that RPE plays an important role in CHM pathogenesis, thus implying that regenerative approaches aiming at rescuing RPE function may be of great benefit for CHM patients. Additionally, lack of appropriate in vitro models has contributed to the still poorly-characterized molecular events in the base of CHM degenerative process. Therefore, the main focus of this work was to explore the potential applications of cellular reprogramming technology in the context of RPE-related retinal degenerations. The generation of mouse iPS cells was established and optimized using an inducible lentiviral system to force the expression of the classic set of TFs, namely Oct4, Sox2, Klf4 and c-Myc. Wild-type cells, as well as cells derived from a conditional knockout (KO) mouse model of Chm, were successfully converted into a pluripotent state, that displayed morphology, molecular and functional equivalence to Embryonic Stem (ES) cells. Generated iPS cells were then subjected to differentiation protocols towards the attainment of a RPE cell fate, with promising results highlighting the possibility of generating a valuable Chm-RPE in vitro model. In alternative, direct lineage conversion of fibroblasts into RPE-like cells was also tackled. A TF-mediated approach was implemented after the generation of a panoply of molecular tools needed for such studies. After transduction with pools of 10 or less TFs, selected for their key role on RPE developmental process and specification, fibroblasts acquired a pigmented morphology and expression of some RPE-specific markers. Additionally, promoter regions of RPE-specific genes were activated indicating that the transcriptional identity of the cells was being altered into the pursued cell fate. In conclusion, highly significant progress was made towards the implementation of already established cellular reprogramming technologies, as well as the designing of new innovative ones. Reprogramming into pluripotency and lineage conversion methodologies were applied to ultimately generate RPE cells. These studies open new avenues for the establishment of cell replacement therapies and, more straightforwardly,raise the possibility of modelling retinal degenerations with underlying RPE defects in apetri dish, particularly CHM.

Banco BPI and the reimbursement of contingent convertible subordinated bonds (CoCos)

This case study focuses on the BPI’s recapitalization plan, its causes and the reasons for the early reimbursement of CoCos in June 2014. The need for a capital intervention and the subsequent subscription agreement with the Portuguese Government of €1 500 million Core Tier 1 instruments were the result of a temporary capital buffer for sovereign debt exposures imposed by the European Banking Authority. The capital increase, the positive earnings in 2012 and 2013, the improvements in the sovereign debt crisis, the implementation of Basel III, in addition to the public exchange offer and the conversion of deferred tax assets into tax credits are the main factors for concluding the entire recapitalization operation three years before the deadline.

Cabelte restructuring by OxyCapital

This case study describes OxyCapital’s intervention in Cabelte’s operational and financial restructuring. Despite Cabelte’s strong debt burden, OxyCapital believed that the Group’s financial difficulties were temporary and that it had growth potential if the said restructuring would be implemented. Hence, while striving for an operational turnaround, OxyCapital managed to reach an agreement among not only the several banks but also the Group’s shareholder for the financial restructuring. The transaction included the acquisition of a majority stake on the Group’s share capital and of a significant part of Cabelte’s bank debt by OxyCapital’s Corporate Restructuring Fund.

Relatório de estágio no departamento central de investigação e acção penal

The means of obtaining evidence, the amount of evidence obtained, the number of defendants related to each criminal case and the gravity of the crimes for which the magistrates of the Department are holders of penal action, define its real importance to the Rule of Law. I have deeply studied the subject of the institution of hierarchical intervention required by the assistant and the application of an opening statement by the defendant, starting from a hypothetical case, provided when the query of an investigation with the subject of the crime of active corruption, where this institution was called as a reaction to the archiving dispatch delivered by the Public Ministry. I have study about the implementation of the institution of provisional suspension of the process, specifically in the scope of fiscal criminality, analyzing the effective satisfaction of the purposes of the sentences in two slopes: general prevention and special prevention. I went for my first time to a Central Court of Criminal Instruction, where I attended the measures of inquiry and instructive debate of a process that culminated with the prosecution and pronunciation of the defendants. In addition to this criminal experience, I have deepened and consolidated the academic knowledge with the study of various criminal cases from various fields in the scope of criminality investigated by the Department. I could therefore check the basis of procedural delays, regarding to our legal system, especially in this type of crime, raising issues that I analyzed and discussed, always in a critical and academic way. I had the opportunity to attend and witness a seminar in the Lisbon Directorate of Finance as well of entering the Centre for Judicial Studies to attend a conference on the International Anti-Corruption Day. Focus on the investigatory importance of the international judicial cooperation, through the various organs, with special interest to EUROJUST. I comprehended the organization and functioning of these communitarian organs and means of communication of procedural acts, in particular, the rogatory letters and european arrest warrants. This involvement is motivated by the moratorium factor of the investigations where rogatory letters are necessary for the acquisition of evidence or information relevant to the good continuation of the process. For this reason the judicial cooperation through the relevant communitarian organs, translates a streamlined response between the competent judicial authorities of the Member States, through the National Member that integrates EUROJUST. This report aims to highlight some of the difficulties and procedural issues that Public Prosecutors of DCIAP and criminal police bodies that assist them, face in combating violent and organized crime, of national and transnational nature, of particular complexity, according to the specifics of criminal types.

A internet e o sistema de justiça

The subject of study of this Thesis aims to highlight and recognize as an object of reflection the undoubted relationship between the Internet and the Justice System, based on the issue of digital evidence. The simultaneously crossing of the juridical-legal implications and the more technical computer issues is the actual trigger for the discussion of the issues established. The Convention on Cybercrime of the Council of Europe of 23rd November 2001 and the Council Framework Decision n.° 2005/222/JHA of 24th February 2005 were avant-garde in terms of the international work about the crimes in the digital environment. In addition they enabled the harmonization of national legislations on the matter and, consequently, a greater flexibility in international judicial cooperation. Portugal, in compliance with these international studies, ratified, implemented and approved Law n. º 109/2009 of 15th September concerning the Cybercrime Act, establishing a more specific investigation and collection of evidence in electronic support when it comes to combating this type of crime, as it reinforced the Substantive Criminal Law and Procedural Nature. Nevertheless, the constant debates about the New Technologies of Information and Communication have not neglected the positive role of these tools for the user. However, they express a particular concern for their counterproductive effects; a special caution prevails on the part of the judge in assessing the digital evidence, especially circumstantial evidence, due to the its fragility. Indisputably, the practice of crimes through the computer universe, given its inexorable technical complexity, entails many difficulties for the forensic investigation, since the proofs hold temporary, changeable, volatile, and dispersed features. In this pillar, after the consummation of iter criminis, the Fundamental Rights of the suspects may be debated in the course of the investigation and the construction of iter probatorium. The intent of this Thesis is to contribute in a reflective way on the issues presented in order to achieve a bigger technical and legal awareness regarding the collection of digital proof, looking for a much lighter approach to its suitability in terms of evidentiary value.

An analysis of associations between human resources practices, affective commitment, exhaustion and cynicism of temportary workers

This research examines the relationships between Human Resources Practices (HRP) and affective commitment, exhaustion, and cynicism of temporary workers. Furthermore, voluntariness and tenure with the client organization are assumed in the analysis as moderators. A sample of Temporary Agency workers was surveyed. It was assumed that HRP positively relates with affective commitment, while negatively with exhaustion and cynicism. Results confirmed the proposed relationships. Regarding the moderators, it has been proved that voluntariness partially weakens the relationships between HRP and temporary workers’ outcomes. However, contrary to the hypothesis, this effect cannot be affirmed also for the tenure with the client organization. Previous literature as well as implications of the findings are discussed.

Proteomic and Metabolomic Analyses of Mitochondrial Complex I-deficient Mouse Model Generated by Spontaneous B2 Short Interspersed Nuclear Element (SINE) Insertion into NADH Dehydrogenase (Ubiquinone) Fe-S Protein 4 (Ndufs4) Gene.

Eukaryotic cells generate energy in the form of ATP, through a network of mitochondrial complexes and electron carriers known as the oxidative phosphorylation system. In mammals, mitochondrial complex I (CI) is the largest component of this system, comprising 45 different subunits encoded by mitochondrial and nuclear DNA. Humans diagnosed with mutations in the gene NDUFS4, encoding a nuclear DNA-encoded subunit of CI (NADH dehydrogenase ubiquinone Fe-S protein 4), typically suffer from Leigh syndrome, a neurodegenerative disease with onset in infancy or early childhood. Mitochondria from NDUFS4 patients usually lack detectable NDUFS4 protein and show a CI stability/assembly defect. Here, we describe a recessive mouse phenotype caused by the insertion of a transposable element into Ndufs4, identified by a novel combined linkage and expression analysis. Designated Ndufs4(fky), the mutation leads to aberrant transcript splicing and absence of NDUFS4 protein in all tissues tested of homozygous mice. Physical and behavioral symptoms displayed by Ndufs4(fky/fky) mice include temporary fur loss, growth retardation, unsteady gait, and abnormal body posture when suspended by the tail. Analysis of CI in Ndufs4(fky/fky) mice using blue native PAGE revealed the presence of a faster migrating crippled complex. This crippled CI was shown to lack subunits of the "N assembly module", which contains the NADH binding site, but contained two assembly factors not present in intact CI. Metabolomic analysis of the blood by tandem mass spectrometry showed increased hydroxyacylcarnitine species, implying that the CI defect leads to an imbalanced NADH/NAD(+) ratio that inhibits mitochondrial fatty acid β-oxidation.

Etude des propriétés dynamiques de la sécrétion régulée des vésicules glutamatergiques des astrocytes

RESUME GRAND PUBLICLe cerveau est composé de différents types cellulaires, dont les neurones et les astrocytes. Faute de moyens pour les observer, les astrocytes sont très longtemps restés dans l'ombre alors que les neurones, bénéficiant des outils ad hoc pour être stimulés et étudiés, ont fait l'objet de toutes les attentions. Le développement de l'imagerie cellulaire et des outils fluorescents ont permis d'observer ces cellules non électriquement excitables et d'obtenir des informations qui laissent penser que ces cellules sont loin d'être passives et participent activement au fonctionnement cérébral. Cette participation au fonctionnement cérébral se fait en partie par le biais de la libération de substances neuro-actives (appellées gliotransmetteurs) que les astrocytes libèrent à proximité des synapses permettant ainsi de moduler le fonctionnement neuronal. Cette libération de gliotransmetteurs est principalement causée par l'activité neuronale que les astrocytes sont capables de sentir. Néanmoins, nous savons encore peu de chose sur les propriétés précises de la libération des gliotransmetteurs. Comprendre les propriétés spatio-temporelles de cette libération est essentiel pour comprendre le mode de communication de ces cellules et leur implication dans la transmission de l'information cérébrale. En utilisant des outils fluorescents récemment développés et en combinant différentes techniques d'imagerie cellulaire, nous avons pu obtenir des informations très précises sur la libération de ces gliotransmetteurs par les astrocytes. Nous avons ainsi confirmé que cette libération était un processus très rapide et qu'elle était contrôlée par des augmentations de calcium locales et rapides. Nous avons également décrit une organisation complexe de la machinerie supportant la libération des gliotransmetteurs. Cette organisation complexe semble être à la base de la libération extrêmement rapide des gliotransmetteurs. Cette rapidité de libération et cette complexité structurelle semblent indiquer que les astrocytes sont des cellules particulièrement adaptées à une communication rapide et qu'elles peuvent, au même titre que les neurones dont elles seraient les partenaires légitimes, participer à la transmission et à l'intégration de l'information cérébrale.RESUMEDe petites vésicules, les « SLMVs » ou « Synaptic Like MicroVesicles », exprimant des transporteurs vésiculaires du glutamate (VGluTs) et libérant du glutamate par exocytose régulée, ont récemment été décrites dans les astrocytes en culture et in situ. Néanmoins, nous savons peu de chose sur les propriétés précises de la sécrétion de ces SLMVs. Contrairement aux neurones, le couplage stimulussécrétion des astrocytes n'est pas basé sur l'ouverture des canaux calciques membranaires mais nécessite l'intervention de seconds messagers et la libération du calcium par le reticulum endoplasmique (RE). Comprendre les propriétés spatio-temporelles de la sécrétion astrocytaire est essentiel pour comprendre le mode de communication de ces cellules et leur implication dans la transmission de l'information cérébrale. Nous avons utilisé des outils fluorescents récemment développés pour étudier le recyclage des vésicules synaptiques glutamatergiques comme les colorants styryles et la pHluorin afin de pouvoir suivre la sécrétion des SLMVs à l'échelle de la cellule mais également à l'échelle des évènements. L'utilisation combinée de l'épifluorescence et de la fluorescence à onde évanescente nous a permis d'obtenir une résolution temporelle et spatiale sans précédent. Ainsi avons-nous confirmé que la sécrétion régulée des astrocytes était un processus très rapide (de l'ordre de quelques centaines de millisecondes). Nous avons découvert que cette sécrétion est contrôlée par des augmentations de calcium locales et rapides. Nous avons également décrit des compartiments cytosoliques délimités par le RE à proximité de la membrane plasmique et contenant les SLMVs. Cette organisation semble être à la base du couplage rapide entre l'activation des GPCRs et la sécrétion. L'existence de compartiments subcellulaires indépendants permettant de contenir les messagers intracellulaires et de limiter leur diffusion semble compenser de manière efficace la nonexcitabilité électrique des astrocytes. Par ailleurs, l'existence des différents pools de vésicules recrutés séquentiellement et fusionnant selon des modalités distinctes ainsi que l'existence de mécanismes permettant le renouvellement de ces pools lors de la stimulation suggèrent que les astrocytes peuvent faire face à une stimulation soutenue de leur sécrétion. Ces données suggèrent que la libération de gliotransmetteurs par exocytose régulée n'est pas seulement une propriété des astrocytes en culture mais bien le résultat d'une forte spécialisation de ces cellules pour la sécrétion. La rapidité de cette sécrétion donne aux astrocytes toutes les compétences pour pouvoir intervenir de manière active dans la transmission et l'intégration de l'information.ABSTRACTRecently, astrocytic synaptic like microvesicles (SLMVs), that express vesicular glutamate transporters (VGluTs) and are able to release glutamate by Ca2+-dependent regulated exocytosis, have been described both in tissue and in cultured astrocytes. Nevertheless, little is known about the specific properties of regulated secretion in astrocytes. Important differences may exist between astrocytic and neuronal exocytosis, starting from the fact that stimulus-secretion coupling in astrocytes is voltage independent, mediated by G-protein-coupled receptors and the release of Ca2+ from internal stores. Elucidating the spatiotemporal properties of astrocytic exo-endocytosis is, therefore, of primary importance for understanding the mode of communication of these cells and their role in brain signaling. We took advantage of fluorescent tools recently developed for studying recycling of glutamatergic vesicles at synapses like styryl dyes and pHluorin in order to follow exocytosis and endocytosis of SLMVs at the level of the entire cell or at the level of single event. We combined epifluorescence and total internal reflection fluorescence imaging to investigate, with unprecedented temporal and spatial resolution, the events underlying the stimulus-secretion in astrocytes. We confirmed that exo-endocytosis process in astrocytes proceeds with a time course on the millisecond time scale. We discovered that SLMVs exocytosis is controlled by local and fast Ca2+ elevations; indeed submicrometer cytosolic compartments delimited by endoplasmic reticulum (ER) tubuli reaching beneath the plasma membrane and containing SLMVs. Such complex organization seems to support the fast stimulus-secretion coupling reported here. Independent subcellular compartments formed by ER, SLMVs and plasma membrane containing intracellular messengers and limiting their diffusion seem to compensate efficiently the non-electrical excitability of astrocytes. Moreover, the existence of two pools of SLMVs which are sequentially recruited suggests a compensatory mechanisms allowing the refill of SLMVs and supporting exocytosis process over a wide range of multiple stimuli. These data suggest that regulated secretion is not only a feature of cultured astrocytes but results from a strong specialization of these cells. The rapidity of secretion demonstrates that astrocytes are able to actively participate in brain information transmission and processing.

Late removal of retrievable caval filters.

The advent of retrievable caval filters was a game changer in the sense, that the previously irreversible act of implanting a medical device into the main venous blood stream of the body requiring careful evaluation of the pros and cons prior to execution suddenly became a "reversible" procedure where potential hazards in the late future of the patient lost most of their weight at the time of decision making. This review was designed to assess the rate of success with late retrieval of so called retrievable caval filters in order to get some indication about reasonable implant duration with respect to relatively "easy" implant removal with conventional means, i.e., catheters, hooks and lassos. A PubMed search (www.pubmed.gov) was performed with the search term "cava filter retrieval after 30 days clinical", and 20 reports between 1994 and 2013 dealing with late retrieval of caval filters were identified, covering approximately 7,000 devices with 600 removed filters. The maximal duration of implant reported is 2,599 days and the maximal implant duration of removed filters is also 2,599 days. The maximal duration reported with standard retrieval techniques, i.e., catheter, hook and/or lasso, is 475 days, whereas for the retrievals after this period more sophisticated techniques including lasers, etc. were required. The maximal implant duration for series with 100% retrieval accounts for 84 days, which is equivalent to 12 weeks or almost 3 months. We conclude that retrievable caval filters often become permanent despite the initial decision of temporary use. However, such "forgotten" retrievable devices can still be removed with a great chance of success up to three months after implantation. Conventional percutaneous removal techniques may be sufficient up to sixteen months after implantation whereas more sophisticated catheter techniques have been shown to be successful up to 83 months or more than seven years of implant duration. Tilting, migrating, or misplaced devices should be removed early on, and replaced if indicated with a device which is both, efficient and retrievable.

Pescadores y aves marinas compitiendo por el mismo recurso: estrategias de forrajeo, interacciones y consecuencias

Con el examen conjunto de datos de seguimiento satelital de la flota pesquera y de marcaje electrónico de aves marinas, se analizan las interacciones entre la actividad pesquera y el forrajeo de las aves en periodo de reproducción. Se evidencia que las aves pueden mitigar la competencia con la pesca hasta cierto punto, forrajeando más lejos o quedándose más tiempo en el mar. Sin embargo, las aves en reproducción enfrentan a la vez un alto requerimiento energético para alimentar los pichones, y viajes de forrajeo limitados en distancia y tiempo por la necesidad de atender el nido. Para optimizar el éxito reproductivo de las aves marinas se recomienda: (1) Estimar, con la ayuda de modelos ecotróficos, qué cantidad de anchoveta sería conveniente ‘reservar’ para la alimentación de las aves; (2) Establecer zonas temporalmente cerradas a la pesca, alrededor de las principales colonias en los meses de reproducción de las aves. Los rangos máximos de forrajeo observados en guanayes y piqueros sugieren un radio de 50 a 100 km alrededor de las colonias, lo cual permitiría asegurar el forrajeo de estas especies en periodo de reproducción y así favorecer la sostenibilidad de sus poblaciones.

Impact of enhanced compliance initiatives on the efficacy of rosuvastatin in reducing low density lipoprotein cholesterol levels in patients with primary hypercholesterolaemia.

The effectiveness of lipid-lowering medication critically depends on the patients' compliance and the efficacy of the prescribed drug. The primary objective of this multicentre study was to compare the efficacy of rosuvastatin with or without access to compliance initiatives, in bringing patients to the Joint European Task Force's (1998) recommended low-density lipoprotein cholesterol (LDL-C) level goal (LDL-C, <3.0 mmol/L) at week 24. Secondary objectives were comparison of the number and percentage of patients achieving European goals (1998, 2003) for LDL-C and other lipid parameters. Patients with primary hypercholesterolaemia and a 10-year coronary heart disease risk of >20% received open label rosuvastatin treatment for 24 weeks with or without access to compliance enhancement tools. The initial daily dosage of 10 mg could be doubled at week 12. Compliance tools included: a) a starter pack for subjects containing a videotape, an educational leaflet, a passport/goal diary and details of the helpline and/or website; b) regular personalised letters to provide message reinforcement; c) a toll-free helpline and a website. The majority of patients (67%) achieved the 1998 European goal for LDL-C at week 24. 31% required an increase in dosage of rosuvastatin to 20 mg at week 12. Compliance enhancement tools did not increase the number of patients achieving either the 1998 or the 2003 European target for plasma lipids. Rosuvastatin was well tolerated during this study. The safety profile was comparable with other drugs of the same class. 63 patients in the 10 mg group and 58 in the 10 mg Plus group discontinued treatment. The main reasons for discontinuation were adverse events (39 patients in the 10 mg group; 35 patients in the 10 mg Plus group) and loss to follow-up (13 patients in the 10 mg group; 9 patients in the 10 mg Plus group). The two most frequently reported adverse events were myalgia (34 patients, 3% respectively) and back pain (23 patients, 2% respectively). The overall rate of temporary or permanent study discontinuation due to adverse events was 9% (n = 101) in patients receiving 10 mg rosuvastatin and 3% (n = 9) in patients titrated up to 20 mg rosuvastatin. Rosuvastatin was effective in lowering LDL-C values in patients with hypercholesterolaemia to the 1998 European target at week 24. However, compliance enhancement tools did not increase the number of patients achieving any European targets for plasma lipids.

A Legislator under Surveillance: The Creation and Implementation of Swiss Banking Legislation 1910-1934

This paper analyses how banking regulation was introduced in Switzerland - one of the world's most prominent financial centres - which remained in place until the beginning of the twenty-first century. It shows that the law adopted on 8 November 1934 is a perfect example of capture of the regulator by the regulated. Essentially a political response in the context of the economic crisis of the 1930s, it largely reflected the interests of banking circles by limiting the intervention of the State as much as possible. The introduction of the new legislation was facilitated by the temporary weakness of Swiss banking circles, as they depended on the State to delay or prevent the collapse of many major credit institutions. They did not manage to derail the law as they had two decades earlier when they scuppered the federal bill on banks drawn up between 1914 and 1916. But this time they were better organized and more united, and intervened all the more effectively in the legislative process itself. The 1934 law is thus distinctive in that it made no structural changes to the architecture of the financial centre but merely codified its practices through flexible legislation meant to reassure the public. The law was aimed less at controlling banking activity than at keeping - thanks to skilfully calibrated political concessions - the State from having to intervene more directly in the internal management of banks or in the fixing of interest rates and the export of capital.

Glenridge Residences

In 1968 Brock University purchased 5 quadruplexes on Glenridge Avenue to serve as Brock's first student residences. Three additional units were later purchased and in total these first residences could accommodate around 150 students. They were used as temporary residences until the Decew Residence was completed.

Decew Residence Construction

The Decew Residence was the first on-campus residence constructed and replaced the temporary student residences on Glenridge Avenue at the base of the escarpment. The Decew residence accommodated 400 students, and included a 300 seat dining hall, 10 activity rooms and 5 student lounges. Construction completed in 1970.

Capacity and transformational development within the 2005 Canada Summer Games host society

Although capacity has been used in recent federal government accords and policies related to the voluntary and amateur sport sectors, there is little consensus over the meaning of the term. Consequently, the purpose of this qualitative case study was to explore the concept of organizational capacity within a temporary voluntary sport organization. Specifically, the nature of organizational capacity was examined within the case of the Volunteers Division of the 2005 Canada Summer Games (CSG) Host Society. Data were collected from executive planning and middle management CSG volunteers through the use of a variety of methods: verbal journals, interviews, observations, documents and a focus group. Findings indicated several challenges associated with the volunteer management model utilized by the host society, varying levels of importance among six elements of capacity, and key aspects of the relationship between organizational capacity and transformational development. Implications focused upon the importance of highlighting individuals rather than the organizational as a whole in order to build capacity, and utilizing a brain or hybrid brain-machine organizational form to enhance capacity. Recommendations are provided for both the Canada Games Council and Canada Games host societies.