Cell disposition of raltegravir and newer antiretrovirals in HIV-infected patients: high inter-individual variability in raltegravir cellular penetration.

Objectives The site of pharmacological activity of raltegravir is intracellular. Our aim was to determine the extent of raltegravir cellular penetration and whether raltegravir total plasma concentration (C(tot)) predicts cellular concentration (C(cell)). Methods Open-label, prospective, pharmacokinetic study on HIV-infected patients on a stable raltegravir-containing regimen. Plasma and peripheral blood mononuclear cells were simultaneously collected during a 12 h dosing interval after drug intake. C(tot) and C(cell) of raltegravir, darunavir, etravirine, maraviroc and ritonavir were measured by liquid chromatography coupled to tandem mass spectrometry after protein precipitation. Longitudinal mixed effects analysis was applied to the C(cell)/C(tot) ratio. Results Ten HIV-infected patients were included. The geometric mean (GM) raltegravir total plasma maximum concentration (C(max)), minimum concentration (C(min)) and area under the time-concentration curve from 0-12 h (AUC(0-12)) were 1068 ng/mL, 51.1 ng/mL and 4171 ng·h/mL, respectively. GM raltegravir cellular C(max), C(min) and AUC(0-12) were 27.5 ng/mL, 2.9 ng/mL and 165 ng·h/mL, respectively. Raltegravir C(cell) corresponded to 5.3% of C(tot) measured simultaneously. Both concentrations fluctuate in parallel, with C(cell)/C(tot) ratios remaining fairly constant for each patient without a significant time-related trend over the dosing interval. The AUC(cell)/AUC(tot) GM ratios for raltegravir, darunavir and etravirine were 0.039, 0.14 and 1.55, respectively. Conclusions Raltegravir C(cell) correlated with C(tot) (r = 0.86). Raltegravir penetration into cells is low overall (∼5% of plasma levels), with distinct raltegravir cellular penetration varying by as much as 15-fold between patients. The importance of this finding in the context of development of resistance to integrase inhibitors needs to be further investigated.

Neocortical maturation during adolescence: change in neuronal soma dimension.

During adolescence, cognitive abilities increase robustly. To search for possible related structural alterations of the cerebral cortex, we measured neuronal soma dimension (NSD = width times height), cortical thickness and neuronal densities in different types of neocortex in post-mortem brains of five 12-16 and five 17-24 year-olds (each 2F, 3M). Using a generalized mixed model analysis, mean normalized NSD comparing the age groups shows layer-specific change for layer 2 (p < .0001) and age-related differences between categorized type of cortex: primary/primary association cortex (BA 1, 3, 4, and 44) shows a generalized increase; higher-order regions (BA 9, 21, 39, and 45) also show increase in layers 2 and 5 but decrease in layers 3, 4, and 6 while limbic/orbital cortex (BA 23, 24, and 47) undergoes minor decrease (BA 1, 3, 4, and 44 vs. BA 9, 21, 39, and 45: p = .036 and BA 1, 3, 4, and 44 vs. BA 23, 24, and 47: p = .004). These data imply the operation of cortical layer- and type-specific processes of growth and regression adding new evidence that the human brain matures during adolescence not only functionally but also structurally.

Investigating university students' adaptation to digital learner course portfolio

Digital learner portfolios are of growing importance in higher education as the sector seeks new teaching-learning-assessment methods which promote students" autonomy as managers of their own virtual learning environment. The purpose of this study was to analyse descriptively the undergraduate students" perceptions, attitudes and behaviour when using an eportfolio to support their learning and assessment in practice based courses at two traditional Spanish universities. The participants were 88 students, who were studying through a blended learning mode. Data were collected through questionnaires: a computer experience survey, another which examined the psychological, pedagogical and technological dimensions of eportfolios use. Further, an individual overall reflection was obtained from each student to help gain an understanding of their experiences of using the eportfolio. A mixed-method analysis was applied in order to study the impact of this technological innovation on students and their satisfaction. The results showed that the students had positive opinions and self-efficiency through the eportfolio as a tool to manage their learning and assessment during a semester, especially from the second month of use. However, the expected impact on their learning was not so significant. Nevertheless, the students emphasised that the eportfolio was valuable as a personal developmental learning tool.

Tuotanto- ja pakkausmateriaalien varastojen nykytila ja kehittäminen lääkeannostelijoita valmistavassa tehtaassa

Diplomityön tarkoituksena oli selvittää lääkeannostelijoita valmistavan tehtaan materiaalivarastojen nykytila. Varaston nykytila-analyysi jaettiin pääoma- ja operatiivisen tehokkuuden arviointiin. Työssä haluttiin kartoittaa toimenpide-ehdotuksia varastonohjauksen tehostamiseksi. Diplomityön tarkoituksena oli myös lisätä avainhenkilöiden ymmärrystä koskien varastojen pidon vaikutuksia yrityksen liiketoimintaan. Varastojen nykytila voitiin kiteyttää suureen pääoman sitoutumiseen, hitaisiin kiertoaikoihin sekä tehokkaan työskentelyn kannalta liian pieniin ja ahtaisiin varastoihin. Kustannuksia ei ole otettu kokonaisuudessaan huomioon tilattaessa ja varastoitaessa materiaalia. Varaston hitaita kiertonopeuksia ei ole tunnistettu vaikuttajina yrityksen tulokseen ja kannattavuuteen. Jotta varastonohjaus- ja hankintaprosesseja voitaisiin tehostaa, pitäisi ostotoimintoihin tehdä muutoksia. Tilausrytmiä ja –määriä täytyisi harkita uudelleen, jotta voitaisiin vähentää varastoihin sitoutuvan pääoman määrää. Informaationvirtaa tehtaalla sekä organisaatiorajojen yli pitäisi parantaa, jotta voitaisiin vähentää kysynnän heilahteluja sekä siihen varautumista. Varmuusvarastojen pidosta saatavien korvausten olisi katettava koko materiaalin kiertoajan aikana syntyvät varastoinnin kustannukset.

Developing short sea shipping transportation chains at Helsinki-Tallinn route

Short sea shipping is an important part of the European economy and an alternative to road transport of goods in Europe. It represents an intermodal transport combination of sea and land on a Door-to-Door basis, and it aims to develop more sustainable transport network with the least negative impacts by the transport modes. This Master’s thesis addresses the development of short sea shipping transportation chains at Helsinki-Tallinn route. The Master´s thesis explores the development of short sea shipping at Helsinki-Tallinn route by analyzing the shipping costs per unit transported by different ship types and sizes between port of Helsinki-Vuosaari harbour and port of Tallinn-Muuga harbour, and examining the possibility of Ro-Ro traffic as well. The study is qualitative-quantitative method and it is based on a case study, data is collected from secondary and primary sources, and mixed methods analysis is used to implement the interviews and observations results with the databases analysis. In the thesis factors affecting on short sea shipping are explored and analyzed, also the possibility of Ro-Ro shipping is examined, by comparing the shipping cost and the environmental impact of different ships like container ships, Ropax, and CONRO ships. The finding of this research shows the importance of time at port and utilization as a shipping cost determinants, the relationship between ship type and costing, and the possibility of Ro-Ro shipping.

Ecological and life-history traits predict bee species responses to environmental disturbances

The ability to predict the responses of ecological communities and individual species to human-induced environmental change remains a key issue for ecologists and conservation managers alike. Responses are often variable among species within groups making general predictions difficult. One option is to include ecological trait information that might help to disentangle patterns of response and also provide greater understanding of how particular traits link whole clades to their environment. Although this ‘‘trait-guild” approach has been used for single disturbances, the importance of particular traits on general responses to multiple disturbances has not been explored. We used a mixed model analysis of 19 data sets from throughout the world to test the effect of ecological and life-history traits on the responses of bee species to different types of anthropogenic environmental change. These changes included habitat loss, fragmentation, agricultural intensification, pesticides and fire. Individual traits significantly affected bee species responses to different disturbances and several traits were broadly predictive among multiple disturbances. The location of nests – above vs. below ground – significantly affected response to habitat loss, agricultural intensification, tillage regime (within agriculture) and fire. Species that nested above ground were on average more negatively affected by isolation from natural habitat and intensive agricultural land use than were species nesting below ground. In contrast below-ground-nesting species were more negatively affected by tilling than were above-ground nesters. The response of different nesting guilds to fire depended on the time since the burn. Social bee species were more strongly affected by isolation from natural habitat and pesticides than were solitary bee species. Surprisingly, body size did not consistently affect species responses, despite its importance in determining many aspects of individuals’ interaction with their environment. Although synergistic interactions among traits remain to be explored, individual traits can be useful in predicting and understanding responses of related species to global change.

Discrete time representation of continuous time ARMA processes

This paper derives exact discrete time representations for data generated by a continuous time autoregressive moving average (ARMA) system with mixed stock and flow data. The representations for systems comprised entirely of stocks or of flows are also given. In each case the discrete time representations are shown to be of ARMA form, the orders depending on those of the continuous time system. Three examples and applications are also provided, two of which concern the stationary ARMA(2, 1) model with stock variables (with applications to sunspot data and a short-term interest rate) and one concerning the nonstationary ARMA(2, 1) model with a flow variable (with an application to U.S. nondurable consumers’ expenditure). In all three examples the presence of an MA(1) component in the continuous time system has a dramatic impact on eradicating unaccounted-for serial correlation that is present in the discrete time version of the ARMA(2, 0) specification, even though the form of the discrete time model is ARMA(2, 1) for both models.

Implications of innovation for inclusive growth: a study of Medellín, Colombia's metro system and integral urban projects

Medellín, Colombia continues to attract global recognition for its evolution from a crimesaturated and desegregated city to an award-winning paragon of innovation. Two innovations in particular, the Metro System & the Integral Urban Projects, have fostered and contributed to Medellín’s inclusive growth, as indicated by a corresponding increase in both social and economic capital. Through a mixed methodology analysis of these two experiences, including participant observation, in-depth interviews with different industry leaders, and household surveys, this thesis explores the extent to which inclusive innovation has contributed to inclusive growth in Medellín. The surveys were distributed to three sensitive neighborhoods of Medellín and apply a Synthesized Framework for measuring inclusive growth, one that includes five indicators for social capital and five indicators for economic capital, emphasizing the importance of progression in both dimensions. By drawing on concepts of inclusivity surfacing more frequently in business lexicon and the emergence of a newly branded Medellín, the findings of this thesis indicates that the implementation of innovations in association with a unified city vision practiced by the local government, corporate and non-profit sector has contributed to achieving inclusive growth, and has left civilians hungry for more.

Comparação entre alguns critérios de seleção para crescimento na raça Nelore

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Transcriptome architecture across tissues in the pig

Background: Artificial selection has resulted in animal breeds with extreme phenotypes. As an organism is made up of many different tissues and organs, each with its own genetic programme, it is pertinent to ask: How relevant is tissue in terms of total transcriptome variability? Which are the genes most distinctly expressed between tissues? Does breed or sex equally affect the transcriptome across tissues?Results: In order to gain insight on these issues, we conducted microarray expression profiling of 16 different tissues from four animals of two extreme pig breeds, Large White and Iberian, two males and two females. Mixed model analysis and neighbor - joining trees showed that tissues with similar developmental origin clustered closer than those with different embryonic origins. Often a sound biological interpretation was possible for overrepresented gene ontology categories within differentially expressed genes between groups of tissues. For instance, an excess of nervous system or muscle development genes were found among tissues of ectoderm or mesoderm origins, respectively. Tissue accounted for similar to 11 times more variability than sex or breed. Nevertheless, we were able to confidently identify genes with differential expression across tissues between breeds (33 genes) and between sexes (19 genes). The genes primarily affected by sex were overall different than those affected by breed or tissue. Interaction with tissue can be important for differentially expressed genes between breeds but not so much for genes whose expression differ between sexes.Conclusion: Embryonic development leaves an enduring footprint on the transcriptome. The interaction in gene x tissue for differentially expressed genes between breeds suggests that animal breeding has targeted differentially each tissue's transcriptome.

Modelos mistos na avaliação e ordenação de genótipos de cana-de-açúcar, com e sem efeitos de competição com parcelas vizinhas

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Análise exploratória de experimentos com bovinos terminados em confinamento

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Emissão de dióxido de carbono e estoque de carbono em sistemas convencionais e alternativo de produção agropecuária no Nordeste paraense

A aplicação de técnicas menos agressivas ao meio ambiente, como o uso de sistemas alternativos (corte e trituração), no lugar dos sistemas convencionais (corte-e-queima), além de favorecer o equilíbrio dos ciclos biogeoquímicos em áreas florestais, contribui para a mitigação das mudanças climáticas. O objetivo deste estudo foi estimar a emissão e o estoque de carbono do solo em sistemas de produção agropecuária em unidades rurais familiares do Nordeste paraense. Os estudos foram conduzidos em área de agricultor familiar no Município de Mãe do Rio, com temperatura média anual de 25 a 28°C, precipitação pluviométrica acimade 2500 mm e com solo predominante do tipo Latossolo Amarelo distrófico de textura média a argilosa. Foram selecionados 3 sistemas de uso da terra (cultivo com Schizolobium amazonicum, roça e silvipastoril) e mais uma área de referencia (floresta secundária), com 4 parcelas, medindo 20 m x 20 m cada. Foram avaliados a emissão de CO2 do solo, estoque de carbono no solo, estoque da liteira no solo e estoque de carbono na liteira. Os dados foram submetidos à Análise de Variância (ANOVA) e à comparação das médias pelo teste de Tukey, ao nível de 5%. Em todos os sistemas avaliados, as maiores emissões de CO2 do solo, observadas no período chuvoso, foram no sistema silvipastoril (5,02 Wmol CO2 m^-2 s^-1), em comparação à área da floresta secundária (3,56 Wmol CO2 m^-2 s^-1). De todas as áreas estudadas a maior emissão anual foi encontrada no sistema silvipastoril. O estoque de carbono no solo foi maior na área da floresta secundária, com total de 157± 31,10 Mg ha^-1 (0-100 cm). O maior estoque de liteira no solo encontrado foi para a fração da liteira não-lenhosa, em todos os sistemas agropecuários e floresta secundária. O maior estoque de carbono na liteira não-lenhosa total foi observada no mês de janeiro/2010, com média geral de 4,31± 3,0 Mg ha^-1, em todos os sistemas avaliados. Os sistemas de uso da terra que não utilizam o fogo no preparo da área, como os sistemas alternativos de corte-e-trituração, além de contribuirem para a mitigação das mudanças climáticas, ajudam na manutenção do funcionamento adequado dos ciclos biogeoquímicos nos ecossistemas terrestres.

Effect of partially demineralized dentin beneath the hybrid layer on dentin-adhesive interface micromechanics

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Diminished Mycophenolic Acid Exposure Caused by Omeprazole May Be Clinically Relevant in the First Week Posttransplantation

Background: Some studies have reported a decreased absorption of mycophenolic acid (MPA) from mycophenolate mofetil (MMF) in renal transplanted (RTx) patients under proton-pump inhibitors (PPIs). There is still a lack of information regarding (1) whether this effect occurs when MMF is administered with either tacrolimus or cyclosporine A [calcineurin inhibitors (CNIs)], (2) whether the effect has the same amplitude during the first year after RTx, and finally (3) whether this decrease in exposure is clinically relevant. Methods: We retrospectively analyzed the omeprazole effect in 348 12-hour pharmacokinetic samplings [area under the curve (AUC) 0-12h] performed on days 7, 14, 30, 60, 180, and 360 after RTx in 77 patients who participated in previous trials. Results: For all periods, the groups with and without PPI did not differ in all variables. By mixed-model analysis of variance, PPI reduced the MPA AUC(0-12h) (P < 0.0008) in the patients under both CNIs mainly due to decreased absorption (P = 0.049). In the tacrolimus group, a lower exposure seemed also due to a decreased MPA reabsorption at 10-12 hours. The PPI effect remains throughout the first year but was clinically more important on day 7. By Cox analysis, the use of PPI was associated with a 25% less chance of being adequately exposed to MPA (95% confidence interval 0.58-0.99, P = 0.04). Similarly, the number of patients underexposed to MPA (AUC < 30 ng.h/mL) was higher at most periods in the PPI group but again not statistically significant. Conclusions: These data indicate that PPI decreases the MPA exposure when associated with both CNIs but particularly in the first week after RTx. In this period, the MMF dose should be increased. This effect lasts throughout the first year but does not seem to be clinically relevant after the first week.