The biochemistry of drug metabolism-an introduction: part 7. Intra-individual factors affecting drug metabolism.

This review on intra-individual factors affecting drug metabolism completes our series on the biochemistry of drug metabolism. The article presents the molecular mechanisms causing intra-individual differences in enzyme expression and activity. They include enzyme induction by transcriptional activation and enzyme inhibition on the protein level. The influencing factors are of physiological, pathological, or external origin. Tissue characteristics and developmental age strongly influence enzyme-expression patterns. Further influencing factors are pregnancy, disease, or biological rhythms. Xenobiotics, drugs, constituents of herbal remedies, food constituents, ethanol, and tobacco can all influence enzyme expression or activity and, hence, affect drug metabolism.

Intra-ovarian roles of activins and inhibins

Granulosa cells are the main ovarian source of inhibins, activins and activin-binding protein (follistatin) while germ (oogonia, oocytes) and somatic (theca, granulosa, luteal) cells express activin receptors, signaling components and inhibin co-receptor (betaglycan). Activins are implicated in various intra-ovarian roles including germ cell survival and primordial follicle assembly; follicle growth from preantral to mid-antral stages; suppression of thecal androgen production; promotion of granulosa cell proliferation, FSHR and CYP19A1 expression; enhancement of oocyte developmental competence; retardation of follicle luteinization and/or atresia and involvement in luteolysis. Inhibins (primarily inhibin A) are produced in greatest amounts by preovulatory follicles (and corpus luteum in primates) and suppress FSH secretion through endocrine negative feedback. Together with follistatin, inhibins act locally to oppose auto-/paracrine activin (and BMP) signaling thus modulating many of the above processes. The balance between activin-inhibin shifts during follicle development with activin signalling prevailing at earlier stages but declining as inhibin and betaglycan expression rise.

Follicular somatic cell factors and follicle development

Considerable attention is currently paid to oocyte-derived secreted factors that act upon cumulus and granulosa cells. Also important for follicle development are somatic cell-derived secreted factors. This is illustrated by the ability of granulosa cell-derived Kit ligand (KITL) to promote primordial follicle activation, and the loss of follicle development that accompanies KITL gene disruption. This review summarises our current understanding of somatic cell factors during both preantral and antral follicle growth, involving not only signalling from granulosa cells to the oocyte, but also signalling between granulosa and theca cells. Principal granulosa cell-derived factors include activin, anti-Mullerian hormone (AMH), bone morphogenetic proteins (BMPs) and fibroblast growth factors (FGFs). Theca cells also secrete BMPs and FGFs. The interplay between these factors is equally important for follicle growth as the activity of oocyte-derived factors.

Ovarian and uterine periovulatory Doppler ultrasonography in bitches

This paper aims to describe the uterine and ovarian ultrasonographic characteristics and Doppler velocimetric features of their arteries in bitches during the periovulatory period. Fifteen estrous cycles in 10 animals were evaluated. The ultrasonographic characteristics, resistance indices (RI) and pulsatility indices (PI) of the uterus and ovaries in each animal were recorded 5 days before and after ovulation (D0). The data were statistically analyzed, and the results were expressed as the mean ± standard error of mean (P<0.05). In results the ultrasonographic features of the uterus were the same on all of the cycles and evaluated days. The uterus had an average diameter of 0.85±0.02cm. An increase in the volume of the ovaries and the diameter of the ovarian follicles were measured. Ovaries had a volume of 0.64±0.06cm³, and the follicles cavities had a diameter of 0.46 ± 0.01 cm on the day of ovulation. After ovulation, it was observed that some follicles not collapse in some cycles. Two days prior to ovulation, the uterine blood perfusion decreased. This decrease remained unchanged until ovulation. Following ovulation, we measured a gradual increase in the uterine perfusion and in the ovarian artery. This artery directed blood flow to the ovaries and increased the intra-ovarian perfusion on the day after ovulation. In conclusion, specific features are observed in the uterus and ovarian ultrasound image and Doppler values of their arteries presented on the periovulatory days and when associated allow to estimate more accurately the date of ovulation.

A functional link between bone morphogenetic proteins and insulin-like peptide 3 signaling in modulating ovarian androgen production

Bone morphogenetic proteins (BMP) are firmly implicated as intra-ovarian regulators of follicle development and steroidogenesis. Here we report a microarray analysis showing that treatment of cultured bovine theca cells (TC) with BMP6 significantly (>2-fold; P<0.01) up- or down-regulated expression of 445 genes. Insulin-like peptide 3 (INSL3) was the most heavily down-regulated gene (-43-fold) with CYP17A1 and other key transcripts involved in TC steroidogenesis including LHCGR, INHA, STAR, CYP11A1 and HSD3B1 also down-regulated. BMP6 also reduced expression of NR5A1 encoding steroidogenic factor-1 known to target the promoter regions of the aforementioned genes. Real-time PCR confirmed these findings and also revealed a marked reduction in expression of INSL3 receptor (RXFP2). Secretion of INSL3 protein and androstenedione were also suppressed suggesting a functional link between BMP and INSL3 pathways in controlling androgen synthesis. RNAi-mediated knockdown of INSL3 reduced INSL3 mRNA and secreted protein level (75 and 94%, respectively) and elicited a 77% reduction in CYP17A1 mRNA level and 83% reduction in androstenedione secretion. Knockdown of RXFP2 also reduced CYP17A1 mRNA level (81%) and androstenedione secretion (88%). Conversely, treatment with exogenous (human) INSL3 increased androstenedione secretion ~2-fold. The CYP17 inhibitor abiraterone abolished androgen secretion and reduced expression of both INSL3 and RXFP2. Collectively, these findings indicate a positive autoregulatory role for INSL3 signaling in maintaining thecal androgen production, and visa versa. Moreover, BMP6-induced suppression of thecal androgen synthesis may be mediated, at least in part, by reduced INSL3-RXFP2 signaling.

Ovarian and uterine periovulatory Doppler ultrasonography in bitches

Este trabalho teve como objetivo descrever as características ultrassonográficas uterinas e ovarianas, e dopplervelocimétricas das suas artérias nos dias periovulatórios em cadelas. Quinze ciclos estrais em 10 animais foram avaliados. As características ultrassonográficas, índices de resistência (IR) e índices de pulsatilidade (IP) do útero e dos ovários em cada animal foram registrados 5 dias antes e depois da ovulação (D0). Os dados foram analisados estatisticamente e os resultados foram expressos em média ± erro padrão da média (P<0,05). Como resultados as características ultrassonográficas uterinas foram semelhantes em todos os ciclos e dias avaliados, tendo o corpo uterino um diâmetro médio de 0,85±0,02cm. Foi observado um aumento no volume dos ovários e nos diâmetros dos folículos, tendo os ovários um volume de 0,64±0,06cm³, e a cavidade dos folículos um diâmetro de 0,46±0,01cm no dia da ovulação. Após a ovulação, foi observado colapso dos folículos somente em alguns ciclos. A perfusão sanguínea uterina diminuiu dois dias antes da ovulação e permaneceu inalterada até a ovulação. Após a ovulação, houve um aumento gradual na perfusão das artérias uterinas e ovarianas, direcionando o fluxo de sangue para os ovários e aumentando a perfusão da artéria intra-ovariana um dia após a ovulação. Conclui-se que características específicas são observadas na imagem ultrassonográfica uterina e ovariana, e dopplervelocimétricas de suas artérias nos dias periovulatórios, e quando associadas permitem estimar com mais precisão o dia da ovulação.

Hormonal and Clinical Predictors for Post-egg Retrieval Pain in Women Undergoing Assisted Reproductive Technology Procedures

OBJECTIVES The intensity of post-egg retrieval pain is underestimated, with few studies examining post-procedural pain and predictors to identify women at risk for severe pain. We evaluated the influence of pre-procedural hormonal levels, ovarian factors, as well as mechanical temporal summation (mTS) as predictors for post-egg retrieval pain in women undergoing in vitro fertilization (IVF). METHODS Eighteen women scheduled for ultrasound-guided egg retrieval under standardized anesthesia and post-procedural analgesia were enrolled. Pre-procedural mTS, questionnaires, clinical data related to anesthesia and the procedure itself, post-procedural pain scores and pain medication for breakthrough pain were recorded. Statistical analysis included Pearson product moment correlations, Mann-Whitney U tests and multiple linear regressions. RESULTS Average peak post-egg retrieval pain during the first 24 hours was 5.0±1.6 on an NRS scale (0=no pain, 10=worst pain imaginable). Peak post-egg retrieval pain was correlated with basal antimullerian hormone (AMH) (r=0.549, P=0.018), pre-procedural peak estradiol (r=0.582, P=0.011), total number of follicles (r=0.517, P=0.028) and number of retrieved eggs (r=0.510, P=0.031). Ovarian hyperstimulation syndrome (OHSS) (n=4) was associated with higher basal AMH (P=0.004), higher peak pain scores (P=0.049), but not with peak estradiol (P=0.13). The mTS did not correlate with peak post-procedural pain (r=0.266, P=0.286), or peak estradiol level (r=0.090, P=0.899). DISCUSSION Peak post-egg retrieval pain intensity was higher than anticipated. Our results suggest that post-egg retrieval pain can be predicted by baseline AMH, high peak estradiol, and OHSS. Further studies to evaluate intra- and post-procedural pain in this population are needed, as well as clinical trials to assess post-procedural analgesia in women presenting with high hormonal levels.

Munkahelyi tanulást befolyásoló tényezők – humán-számítógép együttműködés vizsgálata (Influencing factors of on-the-job learning – Analysis of human-computer collaboration)

A komplex, dinamikus, tudásalapú társadalomban nemcsak a tanulás formái, hanem a tanulás helyszínei is módosulnak, s a munkahely tanulásban betöltött szerepe felértékelődött. A munkahelyi környezet is számos átalakuláson esett át, az információs és kommunikációs technológiák (IKT) fejlődésével egyidejűleg lehetővé vált többek között a távmunka, jelentősen átformálva a munkavégzés és a munkahelyi interakciók módját. A kutatók arra keresték a választ kutatásukban, hogy a szervezeten belül milyen tényezők támogatják vagy gátolják a munkahelyi tanulást. A kutatás fő üzenete, hogy a tanulás keretrendszere, az egyéni képességek és az észlelt tanulási szituáció együttesen határozza meg a munkahelyi tanulást. A kutatók eredményüket kvalitatív kutatással feltárt három esettanulmányon keresztül ismertetik. ____ In a knowledge-based society not only the forms of learning have been changed but also the places of learning. The role of workplace in the learning process is becoming more important. Meantime, there has been a substantial change in the working conditions as the development in information and communication technologies (ICTs) makes it possible to telecommute transforming remarkably the way of working and the interactions at the workplace. The central question of the research is which intra-organizational factors support or hinder onthe- job learning. The main message of the research is that the learning framework, the individual cognitive competences and the perceived learning situation influence collectively on-the-job learning. Authors present the results of the qualitative research though three case studies.

Customer knowledge processing in key account management

The ability of the supplier firm to generate and utilise customer-specific knowledge has attracted increasing attention in the academic literature during the last decade. It has been argued the customer knowledge should treated as a strategic asset the same as any other intangible assets. Yet, at the same time it has been shown that the management of customer-specific knowledge is challenging in practice, and that many firms are better at acquiring customer knowledge than at making use of it. This study examines customer knowledge processing in the context of key account management in large industrial firms. This focus was chosen because key accounts are demanding and complex. It is not unusual for a single key account relationship to constitute a complex web of relationships between the supplier and the key account – thus easily leading to the dispersion of customer-specific knowledge in the supplier firm. Although the importance of customer-specific knowledge generation has been widely acknowledged in the literature, surprisingly little attention has been paid to the processes through which firms generate, disseminate and use such knowledge internally for enhancing the relationships with their major, strategically important key account customers. This thesis consists of two parts. The first part comprises a theoretical overview and draws together the main findings of the study, whereas the second part consists of five complementary empirical research papers based on survey data gathered from large industrial firms in Finland. The findings suggest that the management of customer knowledge generated about and form key accounts is a three-dimensional process consisting of acquisition, dissemination and utilization. It could be concluded from the results that customer-specific knowledge is a strategic asset because the supplier’s customer knowledge processing activities have a positive effect on supplier’s key account performance. Moreover, in examining the determinants of each phase separately the study identifies a number of intra-organisational factors that facilitate the process in supplier firms. The main contribution of the thesis lies in linking the concept of customer knowledge processing to the previous literature on key account management. Moreover, given than this literature is mainly conceptual or case-based, a further contribution is to examine its consequences and determinants based on quantitative empirical data.

Bone morphogenetic protein-6 enhances gonadotrophin-dependent progesterone and inhibin secretion and expression of rnRNA transcripts encoding gonadotrophin receptors and inhibin/activin subunits in chicken granulosa cells

The aims were to examine ovarian expression of bone morphogenetic protein (BMP) ligands/receptor mRNAs in the chicken and to test the hypothesis that theca-derived BMP(s) modulates granulosa cell function in a paracrine manner. RT-PCR revealed expression of multiple BMPs in granulosa and theca cells from prehierarchical and preovulatory follicles with greater expression in theca cells; both cell types expressed BMP receptors-1A, -1B and -II consistent with tissue responsiveness. Preovulatory granulosa cells F1, F2 and F3/4) were cultured with BMP-6 (expressed by theca but not granulosa) in the presence/absence of LH, FSH or 8-Br-cAMP. RMP-6 increased 'basal' and gonadotrophin-induced inhibin-A and progesterone secretion by each cell type but did not enhance the effect of 8-Br-cAMP. This indicates that the observed synergism between BMP-6 and gonadotrophin might involve BMP-induced up-regulation of gonadotrophin receptors. In support of this, BMP-6 alone increased LH-receptor (LHR) mRNA in F1 cells and FSH-receptor (FSHR) mRNA in F1, F2 and F3/4 cells. RMP-6 also enhanced LH/FSH-induced LHR transcript amount in each cell type but did not raise FSHR transcript amounts above those induced by BMP-6 alone. To further explore BMP6 action on inhibin-A secretion, we quantified inhibin/activin subunits (alpha, beta(A), beta(B)) mRNAs. Consistent with its effect on inhibin-A secretion, BMP-6 enhanced 'basal' expression of alpha- and beta(A)-Subunit mRNA in F1, F2 and F3/4 cells, and beta(B)-subunit mRNA in F3/4 cells. BMP-6 markedly enhanced FSH/LH-induced expression of alpha-subunit in all follicles and FSH-induced beta(A)-subunit in F2 and F3/4 follicles but not in F1 follicles. Neither BMP-6 alone, nor FSH/LH alone, affected 'basal' OB mRNA abundance. However, co-treatment with gonadotrophin and BMP-6 greatly increased beta(B)-subunit expression, the response being lowest in F1 follicles and greatest in F3/4 follicles. Collectively, these results support the hypothesis that intra-ovarian OMPs of thecal origin have a paracrine role in modulating granulosa cell function in the chicken in a preovulatory stage-dependent manner.

Managing the duality of IHRM: unravelling the strategy and perceptions of key actors in South Korean MNCs

This research aims to extend our understanding of the duality between global integration and local responsiveness in multinational corporations (MNCs) by exploring the perceptions of corporate HR actors regarding the intra-organisational factors that alter the balance between these pressures. It examines the perceptions and actions of key actors in the context of two Korean MNCs. The study shows the importance attributed to a range of socio-procedural factors by corporate actors and which, therefore, inform the practical management of the dual forces, notably: HR expertise, social ties, trustworthy relationships and co-involvement in decision processes.

Trajetórias De Acumulação De Capacidades Inovadoras, Mecanismos De Aprendizagem E Fatores Organizacionais Relativos A Atividades Em Gestão De Projetos: Estudo De Caso Comparativo Inter-Empresarial Na Indústria De Bens De Capital E De Celulose E Papel No Brasil

Over the last 40 years there has been a profusion of studies about the ccumulation of technological capacities in firms from developing economies. However, there remain few studies that examine, on a combined basis, the relationship among: the trajectories of technological capacities accumulation; the underlying learning mechanisms; and, the implications of organizational factors for these two variables. Still scarcer are the studies that examine the relationship among these variables along time and based on a comparative case study. This dissertation examines the relationship among the trajectory of accumulation of innovative capacities in complex project management, the learning mechanisms underlying these technological capacities and the intra-organizational factors that influence these learning echanisms. That set of relationships is examined through a comparative and a long-term (1988-2008) case study in a capital goods firm (for the pulp and paper industry) and a pulp mill in Brazil. Based on first-hand quantitative and qualitative empiric evidence, gathered through extensive field research, this dissertation found: 1. Both firms accumulated innovative capacity in project management at the international frontier level (Level 6). However, there was variability between the firms in terms of the nature and speed of accumulation of those capacities. It was also observed that, at this level of innovation, the innovative capacities of both firms are not confined to their organizational boundaries, but they are distributed beyond their boundaries. 2. So that these companies could accumulate those levels of innovative capacities it was necessary to manage several learning mechanisms: leveraging of external knowledge and its internalization in terms of internal apacities of the firm. In other words, as the companies accumulated more innovative levels of capacities for project management, it was necessary to manage different cycles of technological learning. 3. Further, the relationship between the ccumulation of technological capacities and learning was affected positively by intra-organizational factors, such as 'authority disposition', 'mutability of work roles' and 'intensity of internal crises', and negatively by the factor 'singularity of goals'. This dissertation revealed divergent results between firms in two of the four factors studied. These results contribute to advance our understanding of the complexity and variability involved in the process of accumulation of innovative capacities in firms from developing economies. This highlights the growing importance of the organizational and the human resource dimensions of innovation and technological capacity as the company approaches the international frontier. The results suggest to managers that: (i) the good performance in project management in the two firms studied did not occur simply as a result of the pulp and paper Brazilian industry growth, rather as a result of the deliberate construction and accumulation of the capacities through an intensive and coordinated cyclical process of technological learning, (ii) to develop innovative capabilities in project management, besides looking for learning mechanisms they should also look at the organizational factors that influence the learning mechanisms directly, (iii) performance of pulp mill¿s projects is better when projects are implemented together with technology suppliers than when performed only by the mill. This dissertation concludes that capital goods firms have been having a fundamental role for the innovative capabilities accumulation in project management of pulp mills in Brazil (and vice-versa) for a long time. This contradicts some authors' propositions that affirm that: a) equipment suppliers for the pulp and paper industry have been creating little, if any, development of processes or engineering projects in Brazil; b) firms in the pulp and paper industry have little capacity for machinery and equipments projects only taking place in few technological activities, being internal or external to the firm. Finally, some studies are proposed for future research.

Respiratory pressures and expiratory peak flow rate of patients undergoing coronary artery bypass graft surgery

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)