The EU Clinical Trials Regulation: Key Priorities, Purposes and Aims and the Implications for Public Health

The replacement of the European Union (EU) Clinical Trials Directive by the new Clinical Trials Regulation (CTR), which entered into force on 16 June 2014 but will not apply before 28 May 2016, provides an opportunity to review the legal and political context within which this important aspect of research law and policy sits and to reflect on the implications for public health. My aim in this article is to relate the context to the key purposes and aims of EU law and policy on clinical trials in order to explain and clarify its orientation. On that basis, I argue that the CTR and the changes it introduces to the law on clinical trials are part of the EU's continued focus on market optimisation. It is this focus that orients and directs the wider pharmaceutical development pipeline, but that undermines the achievement of key public health objectives.

Employment regulation, game theory, and the lacuna in employee participation in liberal economies

Employee participation is a vital ingredient of what the International Labour Organization (ILO) calls ‘representation security’. This article provides theoretical and empirical insights relating to social policy impact of worker participation, specifically the European Information and Consultation Directive (ICD) for employee voice rights. While existing research on the ICD offers important empirical insights, there is a need for further theoretical analysis to examine the potential effectiveness of the regulations in liberal market economies (LMEs). Drawing on data from 16 case studies, the article uses game theory and the prisoner's dilemma framework to explain why national implementing legislation is largely ineffective in diffusing mutual gains cooperation in two LMEs: UK and the Republic of Ireland. Three theoretical (metaphorical) propositions advance understanding of the policy impact of national information & consultation regulations in LMEs.

Impaired orthostatic blood pressure recovery and cognitive performance at two-year follow up in older adults: The Irish Longitudinal Study on Ageing

Background: Prospective investigations of the association between impaired orthostatic blood pressure (BP) regulation and cognitive decline in older adults are limited, and findings to-date have been mixed. The aim of this study was to determine whether impaired recovery of orthostatic BP was associated with change in cognitive function over a 2-year period, in a population based sample of community dwelling older adults. 

Methods: Data from the first two waves of the Irish Longitudinal Study on Ageing were analysed. Orthostatic BP was measured during a lying to standing orthostatic stress protocol at wave 1 using beat-to-beat digital plethysmography, and impaired recovery of BP at 40 s post stand was investigated. Cognitive function was assessed at wave 1 and wave 2 (2 years later) using the Mini-Mental State Exam (MMSE), verbal fluency and word recall tasks. 

Results: After adjustment for measured, potential confounders, and multiple imputation for missing data, the change in the number of errors between waves on the MMSE was 10 % higher [IRR (95 % CI) = 1.10 (0.96, 1.26)] in those with impaired recovery at 40 s. However, this was not statistically significant (p = 0.17). Impaired BP recovery was not associated with change in performance on any of the other cognitive measures. 

Conclusions: There was no clear evidence for an association between impaired recovery of orthostatic BP and change in cognition over a 2-year period in this nationally representative cohort of older adults. Longer follow-up and more detailed cognitive testing would be advantageous to further investigate the relationship between orthostatic BP and cognitive decline.

Regulation of single exocytotic events by the cAMP signaling pathway

Permanece por esclarecer como a via de sinalização do cAMP modula a exocitose regulada. Os principais objetivos deste trabalho foram: i) avaliar o efeito do cAMP nos eventos exocitóticos, nas propriedades dos poros de fusão e na secreção hormonal; ii) perceber o impacto da sinalização por cAMP-HCN na exocitose e nas propriedades do poro de fusão; e iii) estudar as propriedades do poro de fusão na presença de um agente neurotóxico comum, como o alumínio. Lactotrofos, isolados a partir da hipófise anterior de ratos Wistar machos, foram usados como modelo celular. Os eventos unitários de fusão exocitótica e a prolactina (PRL) libertada foram avaliados, respetivamente, em ensaios eletrofisiológicos efectuados segundo a técnica de contacto hermético no modo sobre a célula aderida à pipeta porta-elétrodo e com recurso a métodos imunológicos de deteção. Os níveis intracelulares de cAMP foram aumentados por 3-isobutil-1-metilxantina (IMBX), forscolina e N6,2'-O-dibutiril adenosina- 3',5'-monofosfato cíclico (dbcAMP). A expressão dos canais HCN foi determinada por Western-blot, qRT-PCR e imunocitoquímica em combinação com microscopia confocal. Culturas primárias de lactotrofos foram também transfetadas com DNA plasmídico que codifica HCN2 juntamente com a proteína-verde-fluorescente e um agente farmacológico foi usado para avaliar o efeito de cAMP-HCN na exocitose. Observou-se que os lactotrofos responderam à forscolina e ao dbcAMP libertando PRL de um modo bifásico e dependente da concentração, uma vez que a secreção aumentou e diminuiu, respectivamente, na gama de baixas e altas concentrações. Os compostos que elevaram os níveis de cAMP aumentaram os eventos transientes e impediram a fusão completa. Além disso, o dbcAMP promoveu o aparecimento de eventos exocitóticos transientes de elevada periodicidade, cujos poros de fusão, de maior diâmetro, se mativeram abertos durante mais tempo. A expressão das quatro isoformas de HCN foi confirmada nos lactotrofos ao nível do mRNA e, tal como no coração, rim e hipófise, o mais abundante codifica a isoforma HCN2. Nos lactotrofos com sobre-expressão desta isoforma, o dbcAMP não só aumentou a frequência dos eventos transientes e a condutância dos poros, mas também a frequência dos eventos de fusão completa. Enquanto o bloqueador dos canais HCN, ZD7288, reduziu a frequência dos eventos transientes e de fusão completa desencadeados por dbcAMP e diminuiu o diâmetro dos poros de fusão. A simultânea diminuição da libertação de PRL, da frequência dos eventos transientes e do diâmetro dos poros de fusão representaram as principais alterações observados após pré-tratamento dos lactotrofos com concentração micromolar de alumínio. Em conclusão, os resultados demonstram que elevados níveis de cAMP reduzem a secreção de PRL devido à estabilização dos poros de fusão no estado de maior abertura. Além disso, a via de sinalização cAMP-HCN afecta a actividade exocitótica e modifica as propriedades dos poros de fusão, que parecem ser igualmente importantes na citotoxicidade induzida por alumínio.

Molecular regulation of cork development: the QsMYB1 gene

Cork is a natural and renewable material obtained as a sustainable product from cork oak (Quercus suber L.) during the tree’s life. Cork formation is a secondary growth derived process resulting from the activity of cork cambium. However, despite its economic importance, only very limited knowledge is available about the molecular mechanisms underlying the regulation of cork biosynthesis and differentiation. The work of this PhD thesis was focused on the characterization of an R2R3-MYB transcription factor, the QsMYB1, previously identified as being putatively involved in the regulatory network of cork development. The first chapter introduces cork oak and secondary growth, with special emphasis on cork biosynthesis. Some findings concerning transcriptional regulation of secondary growth are also described. The MYB superfamily and the R2R3-MYB family (in particular) of transcription factors are introduced. Chapter II presents the complete QsMYB1 gene structure with the identification of two alternative splicing variants. Moreover, the results of QsMYB1 expression analysis, done by real-time PCR, in several organs and tissues of cork oak are also reported. Chapter III is dedicate to study the influence of abiotic stresses (drought and high temperature) and recovery on QsMYB1 expression levels. The effects of exogenous application of phytohormones on the expression profile of QsMYB1 gene are evaluated on Chapter IV. Chapter V describes the reverse genetic approach to obtain transgenic lines of Populus tremula L. x tremulóides Michx. overexpressing the QsMYB1 gene. Finally, in Chapter VI the final conclusions of this PhD thesis are presented and some future research directions are pointed based on the obtained results.

Communication between nodes for autonomic and distributed management

Over the last decade, the most widespread approaches for traditional management were based on the Simple Network Management Protocol (SNMP) or Common Management Information Protocol (CMIP). However, they both have several problems in terms of scalability, due to their centralization characteristics. Although the distributed management approaches exhibit better performance in terms of scalability, they still underperform regarding communication costs, autonomy, extensibility, exibility, robustness, and cooperation between network nodes. The cooperation between network nodes normally requires excessive overheads for synchronization and dissemination of management information in the network. For emerging dynamic and large-scale networking environments, as envisioned in Next Generation Networks (NGNs), exponential growth in the number of network devices and mobile communications and application demands is expected. Thus, a high degree of management automation is an important requirement, along with new mechanisms that promote it optimally and e ciently, taking into account the need for high cooperation between the nodes. Current approaches for self and autonomic management allow the network administrator to manage large areas, performing fast reaction and e ciently facing unexpected problems. The management functionalities should be delegated to a self-organized plane operating within the network, that decrease the network complexity and the control information ow, as opposed to centralized or external servers. This Thesis aims to propose and develop a communication framework for distributed network management which integrates a set of mechanisms for initial communication, exchange of management information, network (re) organization and data dissemination, attempting to meet the autonomic and distributed management requirements posed by NGNs. The mechanisms are lightweight and portable, and they can operate in di erent hardware architectures and include all the requirements to maintain the basis for an e cient communication between nodes in order to ensure autonomic network management. Moreover, those mechanisms were explored in diverse network conditions and events, such as device and link errors, di erent tra c/network loads and requirements. The results obtained through simulation and real experimentation show that the proposed mechanisms provide a lower convergence time, smaller overhead impact in the network, faster dissemination of management information, increase stability and quality of the nodes associations, and enable the support for e cient data information delivery in comparison to the base mechanisms analyzed. Finally, all mechanisms for communication between nodes proposed in this Thesis, that support and distribute the management information and network control functionalities, were devised and developed to operate in completely decentralized scenarios.

Study of Perkinsus olseni infection mechanisms: identification and regulation of parasite genes differentially expressed in response to host and environmental stress

Tese dout., Biologia, Universidade do Algarve, 2008

Endocrine regulation of extracellular matrix proteins in calcified tissue in teleost fish

Tese dout., Biologia, Universidade do Algarve, 2005