The Role of Cytochrome P450 3A Inducers and Inhibitors in the Metabolism and the Effects of Oxycodone

Oxycodone is an opioid used in the treatment of moderate or severe pain. It is principally metabolized in the liver by cytochrome P450 3A (CYP3A) enzymes whereas approximately 10% is metabolized by CYP2D6. Little is known about the interactions between oxycodone and other drugs, herbals and nutritional substances. In this work the effects of CYP3A inducers rifampicin and St. John’s wort and CYP3A inhibitors voriconazole, grapefruit juice, ritonavir and lopinavir/ritonavir were investigated on the pharmacokinetics and pharmacodynamics of oxycodone. All studies were randomized, balanced, placebo-controlled crossover clinical studies in healthy volunteers. The plasma concentrations of oxycodone and its metabolites were determined for 48 hours and pharmacodynamic parameters were recorded for 12 hours in each study. Pharmacokinetic parameters were calculated by noncompartmental methods. Rifampicin decreased the plasma concentrations, analgesic effects, and oral bioavailability of oral oxycodone. St. John’s wort reduced the concentrations of oxycodone and diminished the self-reported drug effect. Voriconazole increased the exposure to oral oxycodone by 3.6-fold whereas grapefruit juice, which inhibits predominantly the intestinal CYP3A, elevated the mean concentrations of oxycodone by 1.7-fold. Ritonavir and lopinavir/ritonavir increased the mean AUC of oxycodone by 3.0- and 2.6-fold, respectively, and prolonged its elimination half-life. In spite of increased oxycodone plasma concentrations during concomitant administration of CYP3A inhibitors, the analgesic effects were not increased. These studies show that the induction or inhibition of CYP3A alters the pharmacokinetics and pharmacologic effects of oxycodone. The exposure to oxycodone decreased after induction and increased after inhibition of CYP3A. As a conclusion, the clinicians should avoid concomitant administration of CYP3A inducers or inhibitors and oral oxycodone. If this is not possible, they should be prepared to interactions leading to impaired analgesia after CYP3A inducers or increased adverse effects after CYP3A inhibitors and oral oxycodone.

Soldiering and the making of Finnish manhood : conscription and masculinity in interwar Finland, 1918–1939

Military conscription and peacetime military service were the subjects of heated political, social and cultural controversies during the early years of national independence in Finland. Both the critics and the supporters of the existing military system described it as strongly formative of young men’s physical and moral development into adult men and male citizens. The conflicts over conscription prompted the contemporaries to express their notions about what Finnish men were like, at their best and at their worst, and what should and could be done about it. This thesis studies military conscription as an arena for the “making of manhood” in peacetime Finnish society, 1918–1939. It examines a range of public images of conscripted soldiering, asking how soldiering was depicted and given gendered meanings in parliamentary debates, war hero myths, texts concerned with the military and civic education of conscripts, as well as in works of fiction and reminiscences about military training as a personal experience. Studying conscription with a focus on masculinity, the thesis explores the different cultural images of manliness, soldiering and male citizenship on offer in Finnish society. It investigates how political parties, officers, educators, journalists, writers and “ordinary” conscripts used and developed, embraced or rejected these notions, according to their political purposes or personal needs. The period between the two world wars can be described as a fast-forward into military modernity in Finland. In the process, European middle class gender ideologies clashed with Finnish agrarian masculinities. Nationalistic agendas for the militarisation of Finnish manhood stumbled against intense class conflicts and ideological resistance. Military propaganda used images of military heroism, civic virtue and individual success to persuade the conscripts into ways of thinking and acting that were shaped by bourgeois mentality, nationalistic ideology and religious morality. These images are further analysed as expressive of the personal experiences and emotions of their middle-aged, male authors. The efforts of these military educators were, however, actively resisted on many fronts, ranging from rural working class masculinities among the conscripted young men to ideological critiques of the standing army system in parliament. In narratives about military training, masculinity was depicted as both strengthened and contradicted by the harsh and even brutal practices of interwar Finnish military training. The study represents a combination of new military history and the historical study of men and masculinities. It approaches masculinity as a contested and highly political form of social and cultural knowledge that is actively and selectively used by historic actors. Instead of trying to identify a dominant or “hegemonic” form of masculinity within a pre-determined theoretical structure, this study examines how the meanings ascribed to manhood varied according to class, age, political ideology and social situation. The interwar period in Finland can be understood as a period of contest between different notions of militarised masculinity, yet to judge by the materials studied, there was no clear winning party in that contest. A gradual movement from an atmosphere of conflict surrounding conscription towards political and cultural compromises can be discerned, yet this convergence was incomplete and many division lines remained.

Web Archiving in Finland. Memorandum for the members of the CDNL

This report describes web archiving in the National Library of Finland. The National Library of Finland has been archiving Finnish web on a regular basis since 2006. Web archiving is an important part of the Library'ʹs endeavours to collect and preserve Finnish published cultural heritage. In 2010, the amount of harvested data was 200 million files, or 25 Terabytes. The report takes the reader through the relevant legislation; internal plans and policies; funding and their allocation; the practices of web archiving; arrangements for the use of the archive; and issues rising from data security, sensitive materials, &c.

The influence of strategic entrepreneurship on firm performance

In the study the recently developed concept of strategic entrepreneurship was addressed with the aim to investigate the underlying factors and components constituting the concept and their influence on firm performance. As the result of analysis of existing literature and empirical studies the model of strategic entrepreneurship for the current study is developed with the emphasis on exploration and exploitation parts of the concept. The research model is tested on the data collected in the project ―Factors of growth and success of entrepreneurial firms in Russia‖ by Center for Entrepreneurship of GSOM in 2007 containing answers of owners and managers of 500 firms operating in St. Petersburg and Moscow. Multiple regression analysis showed that exploration and exploitation presented by entrepreneurial values, investments in internal resources, knowledge management and developmental changes are significant factors constituting strategic entrepreneurship and having positive relation to firm performance. The theoretical contribution of the work is linked to development and testing of the model of strategic entrepreneurship. The results can be implemented in management practices of companies willing to engage in strategic entrepreneurship and increase their firm performance.

Removal of organic matter and nutrients from slaughterhouse wastewater by using Eichhornia crassipes and evaluation of the generated biomass composting

The objective of this research was to evaluate the performance of the aquatic macrophyte Eichhornia crassipes applied in situ in a slaughter house treatment system, located in the west of the Paraná state, Brazil, regarding the nutrients removal and organic matter. Moreover, it aimed to obtain data from the production, management and composting practices of the biomass generated in the system. During 11 months of macrophytes development, physic and chemical parameters were monitored and plant density was controlled by periodical removal of excess biomass, which was weekly monitored and it is expressed in kg of aquatic plant per m² covered area. The degradation of the macrophytes removed from the treatment system was evaluated at the pilot scale in eight composting piles of 0.60 m³ that underwent four different treatments and two repetitions: T1 - water hyacinth (Eichhornia crassipes); T2 - water hyacinth and swine excrement (7:1), T3 - water hyacinth, swine excrement and earth (7:1:0,67), and T4 - water hyacinth, swine excrement and cellulosic gut (7:1:0,67), for a period of 90 days. The results indicated maximum removal efficiencies of 77.2% for COD; 77.8% for BOD, 87.9% for total nitrogen, 47.5% for ammonia nitrogen and 38.9% for total phosphorus for a five-day retention time. For biomass stabilization by composting, considering the C:N ratio as an indicator of compost maturity, it was observed that treatment T4 resulted in the shortest stabilization period (60 days). No difference was verified in the biostabilization rates at 5% level by the F test.

Relations between communication and development of family farmers

This research investigates relations between communication and the development of family farmers from the Pontal do Paranapanema region (state of São Paulo), mainly in the municipality of Teodoro Sampaio. Family agriculture in this municipality is represented basically by beneficiaries the Agrarian Reform program. The main hypothesis is that communication contributes positively to the development of those family farmers. Thus, this study aimed to understand communication practices of these farmers and relate them with the development of their families. Quantitative and qualitative research methods were used. Development proxy is understood as the combination between the family living conditions and production. Among the main results, it was found that the effect of communication for "life and production conditions" increases as farmers at superior levels of "development" are analyzed; thus the main hypothesis should not be rejected for those farmers with higher development condition. For the others, communication did not have the same effect because many settled families are not focused on agricultural activities. The main suggestion is to improve ways for producers and professionals from public services related to them to access information.

Cognitive Development of Very Low Birth Weight Children from Infancy to Pre-school Age

The survival of preterm born infants has increased but the prevalence of long-term morbidities has still remained high. Preterm born children are at an increased risk for various developmental impairments including both severe neurological deficits as well as deficits in cognitive development. According to the literature the developmental outcome perspective differs between countries, centers, and eras. Definitions of preterm infant vary between studies, and the follow-up has been carried out with diverse methods making the comparison less reliable. It is essential to offer parents upto-date information about the outcome of preterm infants born in the same area. A centralized follow-up of children at risk makes it possible to monitor the consequences of changes in the treatment practices of hospitals on developmental outcome. This thesis is part of a larger regional, prospective multidisciplinary follow-up project entitled “Development and Functioning of Very Low Birth Weight Infants from Infancy to School Age” (PIeniPAinoisten RIskilasten käyttäytyminen ja toimintakyky imeväisiästä kouluikään, PIPARI). The thesis consists of four original studies that present data of very low birth weight (VLBW) infants born between 2001 and 2006, who are followed up from the neonatal period until the age of five years. The main outcome measure was cognitive development and secondary outcomes were significant neurological deficits (cerebral palsy, CP, deafness, and blindness). In Study I, the early crying and fussing behavior of preterm infants was studied using parental diaries, and the relation of crying behavior and cognitive and motor development at the age of two years was assessed. In Study II, the developmental outcome (cognitive, CP, deafness, and blindness) at the age of two years was studied in relation to demographic, antenatal, neonatal, and brain imaging data. Development was studied in relationship to a full-term born control group born in the same hospital. In Study III, the stability of cognitive development was studied in VLBW and full-term groups by comparing the outcomes at the ages of two and five years. Finally, in Study IV the precursors of reading skills (phonological processing, rapid automatized naming, and letter knowledge) were assessed for VLBW and full-term children at the age of five years. Pre-reading skills were studied in relation to demographic, antenatal, neonatal, and brain imaging data. The main findings of the thesis were that VLBW infants who fussed or cried more in the infancy were not at greater risk for problems in their cognitive development. However, crying was associated with poorer motor development. The developmental outcome of the present population was better that has been reported earlier and this improvement covered also cognitive development. However, the difference to fullterm born peers was still significant. Major brain pathology and intestinal perforation were independent significant risk factors for adverse outcome, also when several individual risk factors were controlled for. Cognitive development at the age of two years was strongly related with development at the age of five years, stressing the importance of the early assessment, and the possibility for early interventions. Finally, VLBW children had poorer pre-reading skills compared with their full-term born peers, but the IQ was an important mediator even when children with mental retardation were excluded from the analysis. The findings suggest that counseling parents about the developmental perspectives of their preterm infant should be based on data covering the same birth hospital. Neonatal brain imaging data and neonatal morbidity are important predictors for developmental outcome. The findings of the present study stress the importance of both short-term (two years) and long-term (five years) follow-ups for the individual, and for improving the quality of care.

Optimization as a method of search engine marketing

This study is dedicated to search engine marketing (SEM). It aims for developing a business model of SEM firms and to provide explicit research of trustworthy practices of virtual marketing companies. Optimization is a general term that represents a variety of techniques and methods of the web pages promotion. The research addresses optimization as a business activity, and it explains its role for the online marketing. Additionally, it highlights issues of unethical techniques utilization by marketers which created relatively negative attitude to them on the Internet environment. Literature insight combines in the one place both technical and economical scientific findings in order to highlight technological and business attributes incorporated in SEM activities. Empirical data regarding search marketers was collected via e-mail questionnaires. 4 representatives of SEM companies were engaged in this study to accomplish the business model design. Additionally, the fifth respondent was a representative of the search engine portal, who provided insight on relations between search engines and marketers. Obtained information of the respondents was processed qualitatively. Movement of commercial organizations to the online market increases demand on promotional programs. SEM is the largest part of online marketing, and it is a prerogative of search engines portals. However, skilled users, or marketers, are able to implement long-term marketing programs by utilizing web page optimization techniques, key word consultancy or content optimization to increase web site visibility to search engines and, therefore, user’s attention to the customer pages. SEM firms are related to small knowledge-intensive businesses. On the basis of data analysis the business model was constructed. The SEM model includes generalized constructs, although they represent a wider amount of operational aspects. Constructing blocks of the model includes fundamental parts of SEM commercial activity: value creation, customer, infrastructure and financial segments. Also, approaches were provided on company’s differentiation and competitive advantages evaluation. It is assumed that search marketers should apply further attempts to differentiate own business out of the large number of similar service providing companies. Findings indicate that SEM companies are interested in the increasing their trustworthiness and the reputation building. Future of the search marketing is directly depending on search engines development.

Aging based maintenance and reinvestment scheduling of electric distribution

The maintenance of electric distribution network is a topical question for distribution system operators because of increasing significance of failure costs. In this dissertation the maintenance practices of the distribution system operators are analyzed and a theory for scheduling maintenance activities and reinvestment of distribution components is created. The scheduling is based on the deterioration of components and the increasing failure rates due to aging. The dynamic programming algorithm is used as a solving method to maintenance problem which is caused by the increasing failure rates of the network. The other impacts of network maintenance like environmental and regulation reasons are not included to the scope of this thesis. Further the tree trimming of the corridors and the major disturbance of the network are not included to the problem optimized in this thesis. For optimizing, four dynamic programming models are presented and the models are tested. Programming is made in VBA-language to the computer. For testing two different kinds of test networks are used. Because electric distribution system operators want to operate with bigger component groups, optimal timing for component groups is also analyzed. A maintenance software package is created to apply the presented theories in practice. An overview of the program is presented.

Administration of Bifidobacterium animalis subsp. lactis BB-12 and xylitol with a novel pacifier in early childhood

Probiotic bifidobacteria are used in the prevention and treatment of childhood diseases. On the other hand, these bacteria are also connected to dental caries. The purpose of the present work was to test a food supplement containing Bifidobacterium animalis subsp. lactis BB-12 (B. lactis BB-12) and xylitol, and to investigate its health effects, properties and safety when used in a novel pacifier in early childhood. In a double-blind, placebo-controlled trial, newborn infants (n=163) were assigned randomly to receive B. lactis BB-12, xylitol, or sorbitol from the age of 1– 2 monthsto 2 years with a pacifier or a spoon. Children were followed up to four years of age. A part of the parents participating in the clinical trial evaluated the feasibility of the novel administration method. The pattern of tablet release from the pouch of the pacifier was tested in adults. The food supplement tablet containing B. lactis BB-12 and xylitol could be delivered in a safe and controlled way with the novel pacifier. The early administration of B. lactis BB-12 did not result in permanent oral colonization of this probiotic or affect the colonization of mutans streptococci in early childhood. Moreover, B. lactis BB-12 did not increase the occurrence of caries. Controlled administration of B. lactis BB-12 significantly reduced the incidence of respiratory infections during the first eight months of life in a Finnish population with breastfed infants. To conclude, administration of B. lactis BB-12 in early childhood is safe with regard to the future dental health of the child. In addition, B. lactis BB-12 may add to the protection against respiratory infections provided by human breast milk in infancy.

Treatment of low-risk gestational trophoblastic neoplasia comparing biweekly eight-day Methotrexate with folinic acid versus bolus-dose Actinomycin-D, among Brazilian women

PURPOSE: To compare two single-agent chemotherapy (ChT) regimens evaluating, in first-line treatment, response and side effects and, in final single-agent treatment, the outcomes, among Brazilian patients with low-risk gestational trophoblastic neoplasia (GTN), according to International Federation of Gynecology and Obstetrics (FIGO) 2002. METHODS: Retrospective analysis of two concurrent cohorts with 194 low-risk GTN patients: from 1992 to 2012, as first-line treatment, 115 patients received 4 intramuscular doses of methotrexate alternated with 4 oral doses of folinic acid (MTX/FA) repetead every 14 days and, since 1996, 79 patients received an endovenous bolus-dose of actinomycin D (Act-D), biweekly. At GTN diagnosis, patient opinion was taken into consideration when defining the initial single-agent ChT regimen, and when there was resistance or toxicity to one regimen, the other drug was used preferentially. This study was approved by the Irmandade da Santa Casa de Misericórdia de Porto Alegre Ethical Committee. RESULTS: Both groups were clinically similar (p>0.05). In first-line treatments, frequency of complete response was similar (75.7% with MTX/FA and 67.1% with bolus Act-D); the number of ChT courses -median 3 (range: 1-10) with MTX/FA and 2 (range: 1-6) with bolus Act-D - and the time to remission -median 9 weeks (range: 2-16) with MTX/FA and 10 weeks (range: 2-16) with bolus Act-D) - were not different between the groups. In both groups, first-line side effects frequency were high but intensity was low; stomatitis was higher with MTX/FA (p<0.01) and nausea and vomit with Act-D (p<0.01). Final single-agent ChT responses were high in both groups (94.8% with MTX/FA and 83.5% with bolus Act-D; p<0.01) and 13% higher in the group initially treated with MTX/FA. Rates of hysterectomy and of GTN recurrence were low and similar. No patient died due to GTN. CONCLUSION: The two regimens had similar first-line ChT response. Final single-agent response rates were high and similar in both groups but the final single-agent remission rate was higher in the MTX/FA group.

"Cara inchada" of cattle, an infectious, apparently soil antibiotics-dependant periodontitis in Brazil

The objective of this review on the investigation of "cara inchada" in cattle (CI), pursued over the last 30 years, was to elucidate the pathogenicity of the disease and come to proper conclusions on its etiology. CI has been widely considered to be of nutritional origin, caused primarily by mineral deficiency or imbalance. However, the disease consists of a rapidly progressive periodontitis, affecting the periodontal tissues at the level of the premolars and molars during the period of tooth eruption generally starting in young calves. The disease led to great economic losses for farmers in central-western Brazil, after the occupation of new land for cattle raising in the 1960s and 1970s. The lateral enlargement of the maxillary bones of affected calves gave the disease the popular name of "cara inchada", i.e., swollen or enlarged face. The enlargement was found to be due to a chronic ossifying periostitis resulting from the purulent alveolitis of CI. Black-pigmented non-saccharolytic Bacteroides melaninogenicus, always together with Actinomyces (Corynebacterium) pyogenes, were isolated in large numbers from the periodontal lesions. B. melaninogenicus could be isolated in small numbers also from the marginal gingiva of a few healthy calves maintained on CI-free farms. "In vitro"-assays showed that streptomycin and actinomycin, as well as the supernatants of cultivates of actinomycetes from soils of CI-prone farms, applied in subinhibitory concentrations to the bacteria tested, enhanced significantly (up to 10 times) the adherence of the black-pigmented B.melaninogenicus to epithelial cells of the bovine gingiva. The antibiotics are apparently produced in large quantities by the increased number of soil actinomycetes, including the genus Streptomyces, that develop when soil microflora are modified by cultivating virgin forest or "Cerrado" (tree-savanna) for the first time for cattle grazing. The epidemiology of CI now provides strong evidence that the ingestion with the forage of such antibiotics could possibly be an important determinant factor for the onset and development of this infectious periodontitis. The antibiotic enhanced adherence of B.melaninogenicus to the sulcus-epithelium of the marginal gingiva, is thought to allow it to colonize, form a plaque and become pathogenic. There is experimental evidence that this determinant factor for the development of the periodontitis is present also in the milk of the mothers of CI-diseased calves. It has been shown that the bacteria isolated from the periodontal CI-lesions produce enzymes and endotoxins capable of destroying the periodontal tissues. The epidemiology of CI, with its decline in incidence and its disappearance after several years, could be explained by the fact that the former equilibrium of the microflora of the once undisturbed virgin soil has been reached again and that the number of antibiotic producing actinomycetes has been anew reduced. By this reasoning and all the data available, CI should be considered as a multifactorial infectious disease, caused primarily by the anaerobic black-pigmented non-saccharolytic Bacteroides melaninogenicus, always together with the micro-anaerobic Actinomyces pyogenes. Accordingly, the onset and development of the infectious periodontitis is apparently determined by ingestion with the forage of subinhibitory concentrations of antibiotics produced in recently cultivated virgin soils. This hypothesis is supported by the recent observation of renewed outbreaks of CI-periodontitis in former CI-prone areas, following fresh cultivation after many years. The infectious nature of CI is confirmed by trials in which virginiamycin was used efficiently for the oral treatment of CI-diseased cattle. Previously it has been shown, that spiramycin and virginiamycin, used as additives in mineral supplements, prevented CI-periodontitis.

Expression and distribution of connexin 32 in rat liver with experimentally induced fibrosis

The connexin 32 (Cx32) is a protein that forms the channels that promote the gap junction intercellular communication (GJIC) in the liver, allowing the diffusion of small molecules through cytosol from cell-to-cell. Hepatic fibrosis is characterized by a disruption of normal tissue architeture by cellular lesions, and may alter the GJIC. This work aimed to study the expression and distribution of Cx32 in liver fibrosis induced by the oral administration of dimethylnitrosamine in female Wistar rats. The necropsy of the rats was carried out after five weeks of drug administration. They presented a hepatic fibrosis state. Sections from livers with fibrosis and from control livers were submitted to immunohistochemical, Real Time-PCR and Western-Blot analysis to Cx32. In fibrotic livers the Cxs were diffusely scattered in the cytoplasm, contrasting with the control livers, where the Cx32 formed junction plaques at the cell membrane. Also it was found a decrease in the gene expression of Cx32 without reduction in the protein quantity when compared with controls. These results suggest that there the mechanism of intercellular communication between hepatocytes was reduced by the fibrotic process, which may predispose to the occurrence of a neoplastic process, taken in account that connexins are considered tumor suppressing genes.

Parasitism level by helminths and weight gain of calves kept in organic and conventional grazing

Sustainable production is a principle in which we must meet the needs of the present without compromising the capacity of future generations. Despite the successful development of pesticides against endo and ectoparasites found in domestic ruminants, these parasites are still the major problem of the herbivore production system. The purpose of this study was to know the population of gastrintestinal parasites and their influence on weight gain of calves kept in organic and conventional grazing. Thus, organic and conventional calves were randomly selected in 2008 and 2009. The fecal egg count (FEC) indentified the following genders of helminths: Haemonchus, Trichostrongylus, Oesophagostomum, Cooperia, Strongyloides, Trichuris and oocysts of Eimeria. There was no significant difference (p>0.05) between FEC in organic and conventional animals. Calves younger than 6 months showed significant higher infection (p<0.05) than calves between 7 and 12 months of age. The weight gain observed during the study was of 327g/day and 280g/day for conventional and organic systems animals, respectively. Consequently, the combination of sustainable practices of grazing associated with the selective application of anthelmintics may be a feasible alternative for nematode control in a conventional system and in transition to an organic one.

Scaling up stepwise feature introduction to construction of large software systems

Developing software is a difficult and error-prone activity. Furthermore, the complexity of modern computer applications is significant. Hence,an organised approach to software construction is crucial. Stepwise Feature Introduction – created by R.-J. Back – is a development paradigm, in which software is constructed by adding functionality in small increments. The resulting code has an organised, layered structure and can be easily reused. Moreover, the interaction with the users of the software and the correctness concerns are essential elements of the development process, contributing to high quality and functionality of the final product. The paradigm of Stepwise Feature Introduction has been successfully applied in an academic environment, to a number of small-scale developments. The thesis examines the paradigm and its suitability to construction of large and complex software systems by focusing on the development of two software systems of significant complexity. Throughout the thesis we propose a number of improvements and modifications that should be applied to the paradigm when developing or reengineering large and complex software systems. The discussion in the thesis covers various aspects of software development that relate to Stepwise Feature Introduction. More specifically, we evaluate the paradigm based on the common practices of object-oriented programming and design and agile development methodologies. We also outline the strategy to testing systems built with the paradigm of Stepwise Feature Introduction.