Development and implementation of the population Fisher information matrix for the evaluation of population pharmacokinetic designs.

In population pharmacokinetic studies, the precision of parameter estimates is dependent on the population design. Methods based on the Fisher information matrix have been developed and extended to population studies to evaluate and optimize designs. In this paper we propose simple programming tools to evaluate population pharmacokinetic designs. This involved the development of an expression for the Fisher information matrix for nonlinear mixed-effects models, including estimation of the variance of the residual error. We implemented this expression as a generic function for two software applications: S-PLUS and MATLAB. The evaluation of population designs based on two pharmacokinetic examples from the literature is shown to illustrate the efficiency and the simplicity of this theoretic approach. Although no optimization method of the design is provided, these functions can be used to select and compare population designs among a large set of possible designs, avoiding a lot of simulations.

Getting the adrenaline going: Crystal structure of the adrenaline-synthesizing enzyme PNMT

Background: Adrenaline is localized to specific regions of the central nervous system (CNS), but its role therein is unclear because of a lack of suitable pharmacologic agents. Ideally, a chemical is required that crosses the blood-brain barrier, potently inhibits the adrenaline-synthesizing enzyme PNMT, and does not affect other catecholamine processes. Currently available PNMT inhibitors do not meet these criteria. We aim to produce potent, selective, and CNS-active PNMT inhibitors by structure-based design methods. The first step is the structure determination of PNMT. Results: We have solved the crystal structure of human PNMT complexed with a cofactor product and a submicromolar inhibitor at a resolution of 2.4 Angstrom. The structure reveals a highly decorated methyltransferase fold, with an active site protected from solvent by an extensive cover formed from several discrete structural motifs. The structure of PNMT shows that the inhibitor interacts with the enzyme in a different mode from the (modeled) substrate noradrenaline. Specifically, the position and orientation of the amines is not equivalent. Conclusions: An unexpected finding is that the structure of PNMT provides independent evidence of both backward evolution and fold recruitment in the evolution of a complex enzyme from a simple fold. The proposed evolutionary pathway implies that adrenaline, the product of PNMT catalysis, is a relative newcomer in the catecholamine family. The PNMT structure reported here enables the design of potent and selective inhibitors with which to characterize the role of adrenaline in the CNS. Such chemical probes could potentially be useful as novel therapeutics.

A genetic algorithm/method of moments approach to the optimization of an RF coil for MRI applications - Theoretical considerations - Abstract

A Combined Genetic Algorithm and Method of Moments design methods is presented for the design of unusual near-field antennas for use in Magnetic Resonance Imaging systems. The method is successfully applied to the design of an asymmetric coil structure for use at 190MHz and demonstrates excellent radiofrequency field homogeneity.

Projecto de funda����es e estrutura de um edif��cio destinado a pavilh��o gimnodesportivo

Este trabalho tem como objectivo a elabora����o do projecto de estruturas de um edif��cio destinado a pavilh��o gimnodesportivo, caracterizando as suas diferentes fases de execu����o, desde a etapa inicial de concep����o at�� �� fase final de dimensionamento. Trata-se de um projecto complexo de uma estrutura com elementos estruturais em bet��o armado e pr��-esfor��ado, e com muros de conten����o. Na concep����o do edif��cio foram utilizados os crit��rios gerais de dimensionamento presentes na regulamenta����o Europeia (Euroc��digos), uma vez que estes elementos representam o futuro da regulamenta����o de estruturas em termos Europeus, vindo substituir a n��vel nacional o ���Regulamento de Seguran��a e Ac����es para Estruturas de Bet��o Armado (RSA)��� e o ���Regulamento para Estruturas de Bet��o Armado e Pr��- Esfor��ado (REBAP)���. A adop����o das normas europeias representam assim um elevado desafio devido ao aumento da complexidade na concep����o e dimensionamento de estruturas que estes regulamentos traduzem, principalmente o Euroc��digo 8, que define de um modo mais detalhado e complexo a an��lise s��smica, relativamente �� regulamenta����o actual em vigor. Devido �� elevada complexidade que os projectos de estruturas apresentam, utilizam-se actualmente ferramentas de c��lculo autom��tico. No dimensionamento deste edif��cio foi utilizado um programa tridimensional de elementos finitos para a modela����o da estrutura. Pretende-se com a escolha deste projecto e dos m��todos de dimensionamento presentes nos Euroc��digos, o desenvolvimento de um trabalho detalhado e correcto, permitindo assim adquirir conhecimentos importantes relativamente ��s futuras normas, e p��r em pr��tica as compet��ncias e os conhecimentos obtidos ao longo curso.

Foresight methodologies to understand changes in the labour process. Experience from Portugal

The foresight and scenario building methods can be an interesting reference for social sciences, especially in terms of innovative methods for labour process analysis. A scenario ��� as a central concept for the prospective analysis ��� can be considered as a rich and detailed portrait of a plausible future world. It can be a useful tool for policy-makers to grasp problems clearly and comprehensively, and to better pinpoint challenges as well as opportunities in an overall framework. The features of the foresight methods are being used in some labour policy making experiences. Case studies developed in Portugal will be presented, and some conclusions will be drawn in order to organise a set of principles for foresight analysis applied to the European project WORKS on the work organisation re-structuring in the knowledge society, and on the work design methods for new management structures of virtual organisations.

Dimensionamento de um pavilh��o industrial met��lico com funda����es indirectas

Trabalho de projecto para obten����o do grau de Mestre em Engenharia Civil na ��rea de Especializa����o em Estruturas

Desenvolvimento de modelo de primeiros princ��pios para simula����o din��mica de uma coluna de destila����o cont��nua

Trabalho Final de Mestrado para obten����o do grau de Mestre em Engenharia Qu��mica e Biol��gica

Aperfei��oamento dos M��todos Utilizados, para a Or��amenta����o e Planeamento de Obras Rodovi��rias

Este relat��rio foi realizado no ��mbito da unidade curricular de DIPRE (Disserta����o/Projecto/Est��gio) lecionada no Mestrado em Engenharia Civil ��� Infraestruturas, no Instituto Superior de Engenharia do Porto. O est��gio foi realizado na Divis��o Municipal de Obras e Ilumina����o P��blica, na C��mara Municipal do Porto. Neste relat��rio procurou-se descrever e caracterizar todos os tipos de pavimentos, desenvolver e estudar novas t��cnicas de or��amenta����o e planeamento, e ainda analisar v��rios casos para mostrar a validade do que se realizou. Este relat��rio inicia-se com uma primeira parte de ��mbito te��rico, em que se faz refer��ncia aos diferentes tipos de pavimentos, analisando-se o seu comportamento, execu����o, patologias e m��todos de dimensionamento. Para al��m disso faz-se a interpreta����o do Decreto-Lei n�� 163/2006 e das quest��es de mobilidade urbana. Para o est��gio foram necess��rias diversas ferramentas de trabalho, n��o s�� fornecidas pela Divis��o Municipal de Obras e Ilumina����o P��blica, mas tamb��m propostas e exploradas pelo aluno. Com estas ferramentas conseguiu-se desenvolver um novo m��todo de or��amenta����o, estudando os Rendimentos dos oper��rios para um maior rigor nas estimativas de custo efetuadas. As solu����es que se apresentam para mostrar o trabalho desenvolvido foram escolhidas de acordo com a sua import��ncia e abrang��ncia para demonstrar tudo o que foi acompanhado e realizado durante o est��gio. Come��ando pela Rua do Dr. Magalh��es Lemos, que foi selecionada porque houve a oportunidade de acompanhar e fiscalizar uma obra que contempla a execu����o de dois pavimentos distintos, o pavimento flex��vel e o r��gido, em Bet��o Armado Cont��nuo. Optou-se tamb��m por selecionar dois casos de melhoria da acessibilidade no centro da cidade, porque foram dois projetos desenvolvidos pelo aluno em que se conseguiu explorar as diferentes decis��es que teve de se tomar. Por fim, apresenta-se o estudo do dimensionamento da Rua de Santo Ildefonso de acordo com as diretrizes da C��mara Municipal do Porto no percurso acad��mico.

High strain rate constitutive modeling forhistorical structures subjected to blast loading

Doctoral Thesis Civil Engineering

Vestu��rio interactivo para desporto e reabilita����o

Disserta����o de mestrado em Design e Marketing

RT-PCR diagnosis of patients with acute nonlymphocytic leukemia and inv(16)(p13q22) and identification of new alternative splicing in CBFB-MYH11 transcripts.

As acute nonlymphocytic leukemia (ANLL) with inv(16) (p13q22) or t(16;16)(p13;q22) has been shown to result from the fusion of transcription factor subunit core binding factor (CBFB) to a myosin heavy chain (MYH11), we sought to design methods to detect this rearrangement using reverse transcriptase-polymerase chain reaction (RT-PCR). In all of 27 inv(16)(p13q22) and four t(16;16)(p13;q22) cases tested, a chimeric CBFB-MYH11 transcript coding for an in-frame fusion protein was detected. In a more extensive RT-PCR analysis with different primer pairs, we detected a second new chimeric CBFB-MYH11 transcript in 10 of 11 patients tested. The CBFB-MYH11 reading frame of the second transcript was maintained in one patient but not in the others. We show that the different CBFB-MYH11 transcripts in one patient arise from alternative splicing. Translation of the transcript in which the CBFB-MYH11 reading frame is not maintained leads to a slightly truncated CBFB protein.

Relay card for capacitance measurements

In this bachelor's thesis a relay card for capacitance measurements was designed, built and tested. The study was made for the research and development laboratory of VTI Technologies, which manufactures capacitive silicon micro electro mechanical accelerometers and pressure sensors. As the size of the sensors is decreasing the capacitance value of the sensors also decreases. The decreased capacitance causes a need for new and more accurate measurement systems. The technology used in the instrument measuring the capacitance dictates a framework how the relay card should be designed, thus the operating principle of the instrument must be known. To achieve accurate results the measurement instrument and its functions needed to be used correctly. The relay card was designed using printed circuit board design methods that minimize interference coupling to the measurement. The relay card that was designed in this study is modular. It consists of a separate CPU card, which was used to control the add-on cards connected to it. The CPU card was controlled from a computer through a serial bus. Two add-on cards for the CPU card were designed in this study. The first one was the measurement card, which could be used to measure 32 capacitive sensors. The second add-on card was the MUX card, which could be used to switch between two measurement cards. The capacitance measurements carried out through the MUX card and the measurement cards were characterized with a series of test measurements. The test measurement data was then analysed. The relay card design was confirmed to work and offer accurate measurement results up to a measurement frequency of 10 MHz. The length of the measurement cables limited the measurement frequency.

Quantitative Assessment of T1 Relaxation and Diffusion as a Prognostic Tool for Brain Development: A Longitudinal Preliminary Study on Preterm Babies

BACKGROUND: Despite major advances in care of premature infants, survivors exhibit mild cognitive deficits in around 40%. Beside severe intraventricular haemorrhages (IVH) and cystic periventricular leucomalacia (PVL), more subtle patterns such as grade I and II IVH, punctuate WM lesions and diffuse PVL might be linked to the cognitive deficits. Grey matter disease is also recognized to contribute to long-term cognitive impairment.��OBJECTIVE: We intend to use novel MR techniques to study more precisely the different injury patterns. In particular MP2RAGE (magnetization prepared dual rapid echo gradient) produces high-resolution quantitative T1 relaxation maps. This contrast is known to reflect tissue anomalies such as white matter injury in general and dysmyelination in particular. We also used diffusion tensor imaging, a quantitative technique known to reflect white matter maturation and disease.��DESIGN/METHODS: All preterm infants born under 30 weeks of GA were included. Serial 3T MR-imaging using a neonatal head-coil at DOL 3, 10 and at term equivalent age (TEA), using DTI and MP2RAGE sequences was performed. MP2RAGE generates a T1 map and allows calculating the relaxation time T1. Multiple measurements were performed for each exam in 12 defined white and grey matter ROIs.��RESULTS: 16 patients were recruited: mean GA 27 2/7 w (191,2d SD��10,8), mean BW 999g (SD��265). 39 MRIs were realized (12 early: mean 4,83d��1,75, 13 late: mean 18,77d��8,05 and 14 at TEA: 88,91d��8,96). Measures of relaxation time T1 show a gradual and significant decrease over time (for ROI PLIC mean��SD in ms: 2100.53��102,75, 2116,5��41,55 and 1726,42��51,31 and for ROI central WM: 2302,25��79,02, 2315,02��115,02 and 1992,7��96,37 for early, late and TEA MR respectively). These trends are also observed in grey matter area, especially in thalamus. Measurements of ADC values show similar monotonous decrease over time.��CONCLUSIONS: From these preliminary results, we conclude that quantitative MR imaging in very preterm infants is feasible. On the successive MP2RAGE and DTI sequences, we observe a gradual decrease over time in the described ROIs, representing the progressive maturation of the WM micro-structure and interestingly the same evolution is observed in the grey matter. We speculate that our study will provide normative values for T1map and ADC and might be a predictive factor for favourable or less favourable outcome.

Subconjunctival Injection of XG-102, a c-Jun N-Terminal Kinase Inhibitor Peptide, in the Treatment of Endotoxin-Induced Uveitis in Rats.

Abstract Purpose: XG-102, a TAT-coupled dextrogyre peptide inhibiting the c-Jun N-terminal kinase, was shown efficient in the treatment of experimental uveitis. Preclinical studies are now performed to determine optimal XG-102 dose and route of administration in endotoxin-induced uveitis (EIU) in rats with the purpose of clinical study design. METHODS: EIU was induced in Lewis rats by lipopolysaccharides (LPS) injection. XG-102 was administered at the time of LPS challenge by intravenous (IV; 3.2, 35 or 355 μg/injection), intravitreal (IVT; 0.08, 0.2 or 2.2 μg/eye), or subconjunctival (SCJ; 0.2, 1.8 or 22 μg/eye) routes. Controls received either the vehicle (saline) or dexamethasone phosphate injections. Efficacy was assessed by clinical scoring, infiltrating cells count, and expression of inflammatory mediators [inducible nitric oxide synthase (iNOS), cytokine-induced neutrophil chemoattractant-1 (CINC-1)]. The effect of XG-102 on phosphorylation of c-Jun was evaluated by Western blot. RESULTS: XG-102 demonstrated a dose-dependent anti-inflammatory effect in EIU after IV and SCJ administrations. Respective doses of 35 and 1.8 μg were efficient as compared with the vehicle-injected controls, but only the highest doses, respectively 355 and 22 μg, were as efficient as dexamethasone phosphate. After IVT injections, the anti-inflammatory effect of XG-102 was clinically evaluated similar to the corticoid's effect with all the tested doses. Regardless of the administration route, the lowest efficient doses of XG-102 significantly decreased the ration of phospho c-Jun/total c-Jun, reduced cells infiltration in the treated eyes, and significantly downregulated iNOS and CINC-1 expression in the retina. CONCLUSION: These results confirm that XG-102 peptide has potential for treating intraocular inflammation. SCJ injection appears as a good compromise to provide a therapeutic effect while limiting side effects.

Centres di��rns d'atenci�� a la gent gran: grau de satisfacci�� dels usuaris i familiars

Estudi descriptiu sobre els centres de dia i centres de serveis per a la gent gran, dos recursos que ofereixen atenci�� di��rna, i sobre la satisfacci�� que comporta assistir a un o a l���altre. OBJECTIUS. Descriure i comparar dos models d���atenci�� di��rna per a la gent gran, i els graus de satisfacci�� d���aquells que els utilitzen. M��TODES. Estudi multic��ntric descriptiu, de disseny ��s transversal. Portat a terme entre els mesos d���abril i juny de 2011, en set centres de serveis i un centre de dia, ha incl��s un total de 296 persones. S���ha fet una valoraci�� del grau de satisfacci�� d���usuaris i familiars mitjan��ant una enquesta de disseny propi. RESULTATS. Els centres de dia, que es troben situats en zones urbanes, ofereixen un ��nic servei (servei d���estada), on el 41,94% de les persones tenen una elevada depend��ncia. Els centres de serveis, que estan situats en zones rurals, ofereixen serveis d���estada, ambulatoris, tallers i atenci�� a domicili, i el 25,58% de les persones mostra una depend��ncia elevada. El grau de satisfacci�� en els dos tipus de centres ��s elevada tant en fam��lies 87,63%, com en usuaris 96.5% . CONCLUSI��. S��n dos models que tenen similituds, per�� ofereixen diferents tipus de serveis. Creats amb m��s de 15 anys de difer��ncia, ��s possible que el centre de serveis acabi sent l���evoluci�� natural del centre de dia.