Comparative analysis of the US and the EU Regulatory Models for Money Market Funds

This chapter sets out a comprehensive analysis of the regulation of money market funds in the EU and US. The theoretical framework has unique cases and examples and includes checklists to assist with the practice of fund management and legal risk analysis.

Efficacy, safety, quality control, marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents)

This review highlights the current advances in knowledge about the safety, efficacy, quality control, marketing and regulatory aspects of botanical medicines. Phytotherapeutic agents are standardized herbal preparations consisting of complex mixtures of one or more plants which contain as active ingredients plant parts or plant material in the crude or processed state. A marked growth in the worldwide phytotherapeutic market has occurred over the last 15 years. For the European and USA markets alone, this will reach about $7 billion and $5 billion per annum, respectively, in 1999, and has thus attracted the interest of most large pharmaceutical companies. Insufficient data exist for most plants to guarantee their quality, efficacy and safety. The idea that herbal drugs are safe and free from side effects is false. Plants contain hundreds of constituents and some of them are very toxic, such as the most cytotoxic anti-cancer plant-derived drugs, digitalis and the pyrrolizidine alkaloids, etc. However, the adverse effects of phytotherapeutic agents are less frequent compared with synthetic drugs, but well-controlled clinical trials have now confirmed that such effects really exist. Several regulatory models for herbal medicines are currently available including prescription drugs, over-the-counter substances, traditional medicines and dietary supplements. Harmonization and improvement in the processes of regulation is needed, and the general tendency is to perpetuate the German Commission E experience, which combines scientific studies and traditional knowledge (monographs). Finally, the trend in the domestication, production and biotechnological studies and genetic improvement of medicinal plants, instead of the use of plants harvested in the wild, will offer great advantages, since it will be possible to obtain uniform and high quality raw materials which are fundamental to the efficacy and safety of herbal drugs.

Modelagem da dispersão de odores em ambientes urbanos

O presente trabalho investigou o problema da modelagem da dispersão de compostos odorantes em presença de obstáculos (cúbicos e com forma complexa) sob condição de estabilidade atmosférica neutra. Foi empregada modelagem numérica baseada nas equações de transporte (CFD1) bem como em modelos algébricos baseados na pluma Gausseana (AERMOD2, CALPUFF3 e FPM4). Para a validação dos resultados dos modelos e a avaliação do seu desempenho foram empregados dados de experimentos em túnel de vento e em campo. A fim de incluir os efeitos da turbulência atmosférica na dispersão, dois diferentes modelos de sub-malha associados à Simulação das Grandes Escalas (LES5) foram investigados (Smagorinsky dinâmico e WALE6) e, para a inclusão dos efeitos de obstáculos na dispersão nos modelos Gausseanos, foi empregado o modelo PRIME7. O uso do PRIME também foi proposto para o FPM como uma inovação. De forma geral, os resultados indicam que o uso de CFD/LES é uma ferramenta útil para a investigação da dispersão e o impacto de compostos odorantes em presença de obstáculos e também para desenvolvimento dos modelos Gausseanos. Os resultados também indicam que o modelo FPM proposto, com a inclusão dos efeitos do obstáculo baseado no PRIME também é uma ferramenta muito útil em modelagem da dispersão de odores devido à sua simplicidade e fácil configuração quando comparado a modelos mais complexos como CFD e mesmo os modelos regulatórios AERMOD e CALPUFF. A grande vantagem do FPM é a possibilidade de estimar-se o fator de intermitência e a relação pico-média (P/M), parâmetros úteis para a avaliação do impacto de odores. Os resultados obtidos no presente trabalho indicam que a determinação dos parâmetros de dispersão para os segmentos de pluma, bem como os parâmetros de tempo longo nas proximidades da fonte e do obstáculo no modelo FPM pode ser melhorada e simulações CFD podem ser usadas como uma ferramenta de desenvolvimento para este propósito. Palavras chave: controle de odor, dispersão, fluidodinâmica computacional, modelagem matemática, modelagem gaussiana de pluma flutuante, simulação de grandes vórtices (LES).

Drogas, sujeito e proibicionismo: uma discussão sobre os modelos de atenção aos usuários de drogas

Pós-graduação em Psicologia - FCLAS

Pharmacy Review Group Report

Pharmacy Review Group Report (PDF, 420KB) Indecon Assessment of the 1996 Pharmacy Regulations (PDF, 430KB) Indecon Review of Proposed Regulatory Models for the Pharmacy Sector (PDF, 400KB)  

Implication of DNA methylation and PAX5 factor in the transcriptional regulation of hTERT, the human telomerase reverse transcriptase gene

RESUME La télomérase est une enzyme dite "d'immortalité" qui permet aux cellules de maintenir la longueur de leurs télomères, ce qui confère une capacité de réplication illimitée aux cellules reproductrices et cancéreuses. A l'inverse, les cellules somatiques normales, qui n'expriment pas la télomérase, ont une capacité de réplication limitée. La sous-unité catalytique de la télomérase, hTERT, est définie comme le facteur limitant l'activité télomérasique. Entre activateurs et répresseurs, le rôle de la méthylation de l'ADN et de l'acétylation des histones, de nombreux modèles ont été suggérés. La découverte de l'implication de CTCF dans la régulation transcriptionnelle de hTERT explique en partie le mécanisme de répression de la télomérase dans la plupart des cellules somatiques et sa réactivation dans les cellules tumorales. Dans les cellules télomérase-positives, l'activité inhibitrice de CTCF est bloquée par un mécanisme dépendent ou non de la méthylation. Dans la plupart des carcinomes, une hyperméthylation de la région 5' de hTERT bloque l'effet inhibiteur de CTCF, alors qu'une petite région hypométhylée permet un faible niveau de transcription du gène. Nous avons démontré que la protéine MBD2 se lie spécifiquement sur la région 5' méthylée de hTERT dans différentes lignées cellulaires et qu'elle est impliquée dans la répression partielle de la transcription de hTERT dans les cellules tumorales méthylées. Par contre, nous avons montré que dans les lymphocytes B normaux et néoplasiques, la régulation de hTERT est indépendante de la méthylation. Dans ces cellules, le facteur PAX5 se lie sur la région 5' de hTERT en aval du site d'initiation de la traduction (ATG). L'expression exogène de PAX5 dans les cellules télomérase-négatives active la transcription de hTERT, alors que la répression de PAX5 dans les cellules lymphomateuses inhibe la transcription du gène. PAX5 est donc directement impliqué dans l'activation de l'expression de hTERT dans les lymphocytes B exprimant la télomérase. Ces résultats révèlent des différences entre les niveaux de méthylation de hTERT dans les cellules de carcinomes et les lymphocytes B exprimant la télomérase. La méthylation de hTERT en tant que biomarqueur de cancer a été évaluée, puis appliquée à la détection de métastases. Nous avons ainsi montré que la méthylation de hTERT est positivement corrélée au diagnostic cytologique dans les liquides céphalorachidiens. Nos résultats conduisent à un modèle de régulation de hTERT, qui aide à comprendre comment la transcription de ce gène est régulée par CTCF, avec un mécanisme lié ou non à la méthylation du gène hTERT. La méthylation de hTERT s'est aussi révélée être un nouveau et prometteur biomarqueur de cancer. SUMMARY Human telomerase is an "immortalizing" enzyme that enables cells to maintain telomere length, allowing unlimited replicative capacity to reproductive and cancer cells. Conversely, normal somatic cells that do not express telomerase have a finite replicative capacity. The catalytic subunit of telomerase, hTERT, is defined as the limiting factor for telomerase activity. Between activators and repressors, and the role of DNA methylation and histone acetylation, an abundance of hTERT regulatory models have been suggested. The discovery of the implication of CTCF in the transcriptional regulation of hTERT in part explained the mechanism of silencing of telomerase in most somatic cells and its reactivation in neoplastic cells. In telomerase-positive cells, the inhibitory activity of CTCF is blocked by methylation-dependent and -independent mechanisms. In most carcinoma cells, hypermethylation of the hTERT 5' region has been shown to block the inhibitory effect of CTCF, while a short hypomethylated region allows a low transcription level of the gene. We have demonstrated that MBD2 protein specifically binds the methylated 5' region of hTERT in different cell lines and is therefore involved in the partial repression of hTERT transcription in methylated tumor cells. In contrast, we have shown that in normal and neoplastic B cells, hTERT regulation is methylation-independent. The PAX5 factor has been shown to bind to the hTERT 5'region downstream of the ATG translational start site. Ectopic expression of PAX5 in telomerase-negative cells or repression of PAX5 expression in B lymphoma cells respectively activated and repressed hTERT transcription. Thus, PAX5 is strongly implicated in hTERT expression activation in telomerase-positive B cells. These results reveal differences between the hTERT methylation patterns in telomerase-positive carcinoma cells and telomerase-positive normal B cells. The potential of hTERT methylation as a cancer biomarker was evaluated and applied to the detection of metastasis. We have shown that hTERT methylation correlates with the cytological diagnosis in cerebrospinal fluids. Our results suggest a model of hTERT gene regulation, which helps us to better understand how hTERT transcription is regulated by CTCF in methylation-dependant and independent mechanisms. Our data also indicate that hTERT methylation is a promising new cancer biomarker.

Implication of DNA methylation, CTCF and BORIS factors in the transcriptional regulation of the human telomerase catalytic subunit hTERT

RESUME La télomérase confère une durée de vie illimitée et est réactivée dans la plupart des cellules tumorales. Sa sous-unité catalytique hTERT est définie comme le facteur limitant pour son activation. De l'identification de facteurs liant la région régulatrice d'hTERT, au rôle de la méthylation de l'ADN et de la modification des histones, de nombreux modèles de régulation ont été suggérés. Cependant, aucun de ces modèles n'a pu expliquer l'inactivation de la télomérase dans la plupart des cellules somatiques et sa réactivation dans la majorité des cellules tumorales. De plus, les observations contradictoires entre le faible niveau d'expression d'ARN messager d'hTERT dans les cellules télomérase-positives et la très forte activité transcriptionnelle du promoteur d'hTERT en transfection restent incomprises. Dans cette étude, nous avons montré que la région proximale du gène hTERT (exon 1 et 2) était impliquée dans la répression de l'activité de son promoteur. Nous avons identifié le facteur CTCF comme étant un inhibiteur du promoteur d'hTERT, en se liant au niveau de son premier exon. La méthylation de l'exon 1 du gène hTERT, couramment observée dans les tumeurs mais pas dans les cellules normales, empêcherait la liaison de CTCF. L'étude du profil de méthylation du promoteur d'hTERT indique qu'une partie du promoteur reste déméthylée et qu'elle semble suffisante pour permettre une faible activité transcriptionnelle du gène hTERT. Ainsi, la méthylation particulière des régions régulatrices d'hTERT inhibe la liaison de CTCF tout en permettant une faible transcription du gène. Cependant, dans certaines cellules tumorales, le promoteur et la région proximale du gène hTERT ne sont pas méthylés. Dans les lignées cellulaires tumorales de tesitcules et d'ovaires, l'inhibition de CTCF est contrée par son paralogue BORIS, qui se lie aussi au niveau de l'exon 1 d'hTERT, mais permet ainsi l'activation du promoteur. L'étude de l'expression du gène BORIS montre qu'il est exclusivement exprimé dans les tissus normaux de testicules et d'ovaires jeunes, ainsi qu'à différents niveaux dans la plupart des tumeurs. Sa transcription est sous le contrôle de deux promoteurs. Le promoteur proximal est régulé par méthylation et un transcrit alternatif majoritaire, délété de l'exon 6, est trouvé lorsque ce promoteur est actif. Tous ces résultats conduisent à un modèle de régulation du gène hTERT qui tient compte du profil épigénétique du gène et qui permet d'expliquer le faible taux de transcription observé in vivo. De plus, l'expression de BORIS dans les cancers et son implication dans l'activation du gène hTERT pourrait permettre de comprendre les phénomènes de dérégulation épigénétique et d'immortalisation qui ont lieu durant la tumorigenèse. SUMMARY Telomerase confers an unlimited lifespan, and is reactivated in most tumor cells. The catalytic subunit of telomerase, hTERT, is defined as the limiting factor for telomerase activity. Between activators and repressors that bind to the hTERT 5' regulatory region, and the role of CpG methylation and histone acetylation, an abundance of regulatory models have been suggested. None of these models can explain the silence of telomerase in most somatic cells and its reactivation in tumor cells. Moreover, the contradictory observations of the low level of hTERT mRNA in telomerase-positive cells and the high transcriptional activity of the hTERT promoter in transfection experiments remain unresolved. In this study, we demonstrated that the proximal exonic region of the hTERT gene (exon 1 and 2) is involved in the inhibition of its promoter. We identified the protein CTCF as the inhibitor of the hTERT promoter, through its binding to the first exon. The methylation of the first exon region, which is often observed in cancer cells but not in noimal cells, represses CTCF binding. Study of hTERT promoter methylation shows a partial demethylation sufficient to activate the transcription of the hTERT gene. Therefore, we demonstrated that the particular methylation profile of the hTERT regulatory sequences inhibits the binding of CTCF, while it allows a low transcription of the gene. Nevertheless, in some tumor cells, the promoter and the proximal exonic region of hTERT are unmethylated. In testicular and ovarian cancer cell lines, CTCF inhibition is counteracted by its BORIS paralogue that also binds the hTERT first exon but allows the promoter activation. The study of BORIS gene regulation showed that this factor is exclusively expressed in normal tissue of testis and ovary of young woman, as well as in almost all tumors with different levels. Two promoters were found to induce its transcription. The proximal promoter was regulated by methylation. Moreover, a major alternative transcript, deleted of the exon 6, is detected when this promoter is active. All these results lead to a model for hTERT regulation that takes into account the epigenetic profile of the gene and provides an explanation for the low transcriptional level observed in vivo. BORIS expression in cancers and its implication in hTERT activation might also permit the understanding of epigenetic deregulation and immortalization phenomena that occur during tumorigenesis.

Avaliação do impacto da utilização de parceria público-privada para construção e operação de unidades municipais de educação infantil em Belo Horizonte

As Parcerias Público-Privadas (PPP) de infraestrutura escolar são cada vez mais utilizadas no mundo, entretanto as avaliações de impacto desse modelo ainda são escassas. O presente estudo contribui para essa área do conhecimento ao avaliar o impacto da utilização de PPP tanto na construção como na operação das Unidades Municipais de Educação Infantil (UMEIs) de Belo Horizonte (BH). A metodologia de pesquisa foi baseada na comparação de 46 UMEIs, sendo 27 unidades de PPP e 19 unidades construídas e operadas no modelo tradicional de contratação pública. Em relação ao impacto na construção, os principais resultados são que o tempo de obra das unidades de PPP foi 45% menor e que 79% das unidades tradicionais foram entregues fora do prazo contratado de 13 meses, enquanto que nenhuma PPP foi entregue acima deste prazo. Além disso, a PPP permitiu aumentar a escala na construção das UMEIs, superando as limitações do modelo tradicional. Dentre as principais evidências encontradas quanto ao impacto na operação, pode-se citar que os diretores de unidades de PPP afirmam ter 25% mais tempo para focar nas atividades pedagógicas, pois gastam menos tempo na gestão dos serviços não pedagógicos, e que o grau de satisfação com os serviços de manutenção das instalações físicas é substancialmente maior nessas unidades. Os resultados positivos para PPP só não apareceram em relação aos serviços de manutenção de TI. Uma limitação deste trabalho foi não conseguir realizar a comparação de custos das duas modalidades. O estudo pretende contribuir para o aprimoramento dos modelos regulatórios de PPPs em educação e para a discussão sobre o papel que pode ser desempenhado pelas PPPs na redução do déficit de infraestrutura escolar.

A transição para a assimetria regulatória e os mecanismos de sustentabilidade deste modelo: uma análise dos aeroportos concedidos e dos aeroportos autorizados

O presente estudo destina-se à análise do modelo de assimetria regulatória, a partir de dois problemas pontuais, quais sejam: os mecanismos necessários para se obter um ambiente assimétrico, bem como a maneira pela qual se deve orquestrar tal modelo, de forma a compatibilizar uma convivência sustentável em uma estrutura híbrida de competição. Observar-se-á a maneira pela qual pode ser promovida a alteração de um ambiente de simetria regulatória para um ambiente de assimetria, resguardando os direitos e obrigações dos prestadores de determinada atividade, inseridos naquela seara. Ademais, buscar-se-á sugerir instrumentos legais para se permitir a composição de dois meios de exploração de determinada atividade econômica, um que se dê segundo o direito público (publicatio); e outro, que se relacione com o direito privado (ordenatio); compreendendo assim, a dita assimetria regulatória. A título ilustrativo, adentrar-se-á na verificação da medida provisória (MP) 656/14 - a qual previa um possível modelo em que se teria duas ofertas de infraestrutura aeroportuária - para melhor exemplificar como, juridicamente, pode-se viabilizar esta disposição de prestação dual, via poder público (ou delegatários), segundo a forma de concessão; e iniciativa privada, segundo a forma de autorização.

Drogas, sujeito e proibicionismo: uma discussão sobre os modelos de atenção aos usuários de drogas

Pós-graduação em Psicologia - FCLAS

Re-conceptualizing the Global Digital Divide

The article seeks a re-conceptualization of the global digital divide debate. It critically explores the predominant notion, its evolution and measurement, as well as the policies that have been advanced to bridge the digital divide. Acknowledging the complexity of this inequality, the article aims at analyzing the disparities beyond the connectivity and skills barriers. Without understating the first two digital divides, it is argued that as the Internet becomes more sophisticated and more integrated into economic, social, and cultural processes, a “third” generation of divides becomes critical. These divides are drawn not at the entry to the net but within the net itself, and limit access to content. The increasing barriers to content, though of a diverse nature, all relate to some governance characteristics inherent in cyberspace, such as global spillover of local decisions, regulation through code, and proliferation of self- and co-regulatory models. It is maintained that as the practice of intervention intensifies in cyberspace, multiple and far-reaching points of control outside formal legal institutions are created, threatening the availabil- ity of public goods and making the pursuit of public objectives difficult. This is an aspect that is rarely ad- dressed in the global digital divide discussions, even in comprehensive analyses and political initiatives such as the World Summit on the Information Society. Yet, the conceptualization of the digital divide as impeded access to content may be key in terms of ensuring real participation and catering for the longterm implications of digital technologies.

The Changing Environment of Audiovisual Media. New Technologies, New Patterns of Consumer/Business Behaviour and Their Implications for Audiovisual Media Regulation

Digital TV offers of 200 channels and 500 video-on-demand films, podcasting, mobile television, a new web blog being created every two seconds - these are some of the factual elements depicting contemporary audiovisual media in the digital environment. The present article looks into some of these technological advances and sketches their implications for the markets of media content, in particular as newly emerging patterns of consumer and business behaviour are concerned. Ultimately, it puts forward the question of whether the existing audiovisual media regulatory models, which are still predominantly analogue-based, have been rendered obsolete by the transformed (and continually transforming) digital environment.

The Global Digital Divide as Impeded Access to Content

The paper seeks a re-conceptualization of the global digital divide debate. It critically explores the predominant notion, its evolution and measurement, as well as the policies that have been advanced to bridge the digital divide. Acknowledging the complexity of this inequality, the paper aims at analyzing the disparities beyond the connectivity and the skills barriers. Without understating the first two digital divides, it is argued that as the Internet becomes more sophisticated and more integrated into economic, social and cultural processes, a ‘third’ generation of divides becomes critical. These divides are drawn not at the entry to the net but within the net itself, and limit access to content. The increasing barriers to content, although of diverse nature, all relate to some governance characteristics inherent in cyberspace, such as global spillover of local decisions, regulation through code or proliferation of self- and co-regulatory models. It is maintained that as the practice of intervention intensifies in cyberspace, multiple and far-reaching points of control outside formal legal institutions are created, which threaten the availability of public goods and make the pursuit of public objectives difficult. This is an aspect that is rarely addressed in the global digital divide discussions, even in comprehensive analysis and political initiatives such as the World Summit on the Information Society. Yet, the conceptualization of the digital divide as impeded access to content may be key in terms of ensuring real participation and catering for the long-term implications of digital technologies.

Rezension zu: Irini Katsirea, Public Broadcasting and European Law

Public broadcasting has always been a regulatory field somewhat zealously guarded within the nation states' sphere and kept willingly untouched by regional or international rules. Values inherent to the role of public broadcasting, such as cultural and national identity, social cohesion, pluralism and a sustained public sphere, were thought too critical and too historically connected with the particular society to allow any "outside" influence. Different regulatory models have emerged to reflect these specificities within the national boundaries of European countries. Yet, as media evolved technologically and economically, the constraints of state borders were rendered obsolete and the inner tension between culture and commerce of the television medium became more pronounced. This tension was only intensified with the formulation of a European Community (EC) layer of regulation, which had as its primary objective the creation of a single market for audiovisual services (or as the EC Directive beautifully put it, a "Television without Frontiers"), while also including some provisions catering for cultural concerns, such as the infamous quota system for European and independent productions. Against this backdrop, public broadcasting makes a particularly intriguing subject for a study of regulatory dilemmas of national versus supranational, integration versus intergovernmentalism, culture versus commerce, intervention versus liberalisation, and all this in the dynamic setting of contemporary media. The present paper reviews Irini Katsirea's book PUBLIC BROADCASTING AND EUROPEAN LAW and seeks to identify whether all elements of the complex governance puzzle of European public service broadcasting rules are analytically well fitted together.

Re-Conceptualizing the Global Digital Divide

The article seeks a re-conceptualization of the global digital divide debate. It critically explores the predominant notion, its evolution and measurement, as well as the policies that have been advanced to bridge the digital divide. Acknowledging the complexity of this inequality, the article aims at analyzing the disparities beyond the connectivity and skills barriers. Without understating the first two digital divides, it is argued that as the Internet becomes more sophisticated and more integrated into economic, social, and cultural processes, a “third” generation of divides becomes critical. These divides are drawn not at the entry to the net but within the net itself, and limit access to content. The increasing barriers to content, though of a diverse nature, all relate to some governance characteristics inherent in cyberspace, such as global spillover of local decisions, regulation through code, and proliferation of self- and co-regulatory models. It is maintained that as the practice of intervention intensifies in cyberspace, multiple and far-reaching points of control outside formal legal institutions are created, threatening the availability of public goods and making the pursuit of public objectives difficult. This is an aspect that is rarely addressed in the global digital divide discussions, even in comprehensive analyses and political initiatives such as the World Summit on the Information Society. Yet, the conceptualization of the digital divide as impeded access to content may be key in terms of ensuring real participation and catering for the long-term implications of digital technologies.