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.

Berry polyphenol absorption and the effect of northern berries on metabolism, ectopic fat accumulation, and associated diseases

The prevalence of obesity and type 2 diabetes has increased at an alarming rate in developed countries. It seems in the light of current knowledge that metabolic syndrome may not develop at all without NAFLD, and NAFLD is estimated to be as common as metabolic syndrome in western population (23 % occurrence). Fat in the liver is called ectopic fat, which is triacylglycerols within the cells of non-adipose tissue. Serum alanine aminotransferase (ALT) values correlate positively with liver fat proportions, and increased activity of ALT predicts type 2 diabetes independently from obesity. Berries, high in natural bioactive compounds, have indicated the potential to reduce the risk of obesity-related diseases. Ectopic fat induces common endocrine excretion of adipose tissue resulting in the overproduction of inflammatory markers, which further induce insulin resistance by multiple mechanisms. Insulin resistance inducing hyperinsulinemia and lipolysis in adipocytes increases the concentration of free fatty acids and consequently causes further fat accumulation in hepatocytes. Polyphenolic fractions of berries have been shown to reverse inflammatory reaction cascades in in vitro and animal studies, and moreover to decrease ectopic fat accumulation. The aim of this thesis was to explore the role of northern berries in obesity-related diseases. The absorption and metabolism of selected berry polyphenols, flavonol glycosides and anthocyanins, was investigated in humans, and metabolites of the studied compounds were identified in plasma and urine samples (I, II). Further, the effects of berries on the risk factors of metabolic syndrome were studied in clinical intervention trials (III, IV), and the different fractions of sea buckthorn berry were tested for their ability to reduce postprandial glycemia and insulinemia after high-glucose meal in a postprandial study with humans (V). The marked impact of mixed berries on plasma ALT values (III), as well as indications of the positive effects of sea buckthorn, its fractions and bilberry on omental adiposity and adhesion molecules (IV) were observed. In study V, sea buckthorn and its polyphenol fractions had a promising effect on potprandial metabolism after high-glucose meal. In the literature review, the possible mechanisms behind the observed effects have been discussed with a special emphasis on ectopic fat accumulation. The literature review indicated that especially tannins and flavonoids have shown potential in suppressing diverse reaction cascades related to systemic inflammation, ectopic fat accumulation and insulin resistance development.

Secondary seed dispersal of Ricinus communis Linnaeus (Euphorbiaceae) by ants in secondary growth vegetation in Minas Gerais

In this study, I tested the efficacy of ants as secondary seed dispersers of Ricinus communis in southeastern Brazil. In a natural population of 143 individuals, I determined the ballistic dispersal distance for 62 seeds and 100 additional seeds were experimentally offered to ants in groups of ten seeds along a transect of 50 m. Fifty-three seeds were removed by ants, mainly by the leafcutter Atta sexdens (90.4%). The dispersal distance by ants was high, compared to the global average (4.38 m ± 0.74 m vs. 0.96 m), but was lower than the ballistic distance (7.27 m ± 0.13 m). Ants increased the total dispersal distance (8.66 m ± 0.60 m), but the main benefit for the plant was the directed dispersal, with seed deposition on the enriched soil of ant nests.

Effect of light intensity and growth substratum on plant development and production of secondary metabolites in Cordia curassavica (Jacq.) Roem. & Schult

Cordia curassavica (Jacq.) Roem. & Schult. (Boraginaceae), also referred to as Cordia verbenacea DC, has been traditionally used for medicinal purposes. This study was driven to verify the behavior of the species in similar conditions to its natural environment, such as high light intensity and sandbank soil, and in conditions of low light intensity and fertilized substratum (dystroferric red nitosoil plus earthworm humus). The growth of the plant, the income of leaf crude extracts and, in the alcoholic extract, the number of substances found in thin layer cromatography and the toxicity of the substratum was observed. The results indicated that the growth of the root biomass, stem and leaves in discharge or lower light intensity was similar, but smaller in sandbank soil than in fertilized soil. The relative income of extracts in ether of petroleum and alcohol was larger in high light intensity and fertilized substratum. The light intensity and the substratum type didn't affect the number of substances detected in the alcoholic extract or the toxicity of this extract. Stains corresponding to the rosmarinic acid were only evidenced in some samples of the alcoholic extract, not allowing the verification of the effect of the treatments about its production.

Middle school mediocrity : quality and inequality in secondary education

Centrala teman i min avhandling är parallellskolesystem, linjedelning och segregering i högstadier och gymnasier. Det finns stora skillnader mellan länder gällande den årskurs då eleverna sorteras in i olika nivåer genom skilda klasser eller skolor. I Tyskland och Nederländerna till exempel delas eleverna upp före högstadiet medan Sverige och Finland har enhetsskolor på högstadienivå. Jag argumenterar att parallellskolesystem har en positiv effekt på elevernas testresultat i årskurserna före linjedelningen. Eleverna har incitament att jobba hårdare för att komma på i den akademiska linjen. Jag undersöker incitamentseffekter empiriskt, och hittar mönster konsistenta med incitamentseffekter både i brittisk och i internationell data. Det andra bidraget i avhandlingen är metodologiskt. Nationalekonomer brukar behandla testresultat från t.ex. IQ-tester eller internationella PISA-undersökningar som om absoluta nivån på poängantalen har betydelse i sig. I verkligheten antyder de endast en rangordning. Jag visar att normalfördelade testresultat i många fall ligger tillräckligt nära dess pengavärde på arbetsmarknaden för att ändå kunna tolkas som absoluta.

Litter fall production and decomposition in a fragment of secondary Atlantic Forest of São Paulo, sp, southeastern Brazil

Litter fall consists of all organic material deposited on the forest floor, being of extremely important for the structure and maintenance of the ecosystem through nutrient cycling. This study aimed to evaluate the production and decomposition of litter fall in a secondary Atlantic forest fragment of secondary Atlantic Forest, at the Guarapiranga Ecological Park, in São Paulo, SP. The litter samples were taken monthly from May 2012 to May 2013. To assess the contribution of litter fall forty collectors were installed randomly within an area of 0.5 ha. The collected material was sent to the laboratory to be dried at 65 °C for 72 hours, being subsequently separated into fractions of leaves, twigs, reproductive parts and miscellaneous, and weighed to obtain the dry biomass. Litterbags were placed and tied close to the collectors to estimate the decomposition rate in order to evaluate the loss of dry biomass at 30, 60, 90, 120 and 150 days. After collection, the material was sent to the laboratory to be dried and weighed again. Total litter fall throughout the year reached 5.7 Mg.ha-1.yr-1 and the major amount of the material was collected from September till March. Leaves had the major contribution for total litter fall (72%), followed by twigs (14%), reproductive parts (11%) and miscellaneous (3%). Reproductive parts had a peak during the wet season. Positive correlation was observed between total litter and precipitation, temperature and radiation (r = 0.66, p<0.05; r = 0.76, p<0.05; r = 0.58, p<0.05, respectively). The multiple regression showed that precipitation and radiation contributed significantly to litter fall production. Decomposition rate was in the interval expected for secondary tropical forest and was correlated to rainfall. It was concluded that this fragment of secondary forest showed a seasonality effect driven mainly by precipitation and radiation, both important components of foliage renewal for the plant community and that decomposition was in an intermediate rate.

LITTERFALL ASSESSEMENT IN A FRAGMENT OF SECONDARY TROPICAL FOREST, IBIÚNA, SP, SOUTHEASTERN BRAZIL1

ABSTRACT The present study aimed to analyze the production and decomposition of litterfall in a fragment of secondary Atlantic forest in the region of Ibiúna, SP, from April 2012 to March 2013. The litterfall production was estimated by 30 collectors distributed randomly in an area of 1000 m2, where the deposited material was collected every 15 days. The decomposition of litterfall was estimated through the mass loss in the period of study. After collecting, the material was dried in an oven at 65 °C for seven days to achieve a constant weight. The decomposition constant k was obteined according to Shanks and Oslon (1961) and the time for 50% and 95% of decomposition was estimated. It was found a higher litterfall production in October (454.3 kg ha-1) and lower production in July (164.9 kg ha-1), with a total amount produced of 3.5 Mg ha-1 year-1. A delay of one month in the precipitation and relative humidity showed great influence in the litter production during the study. The decomposition rate (k) was 3.1 and the time to decompose 50% of the material was estimated in 2 and ½ months and for 95% of the litterfall the time was estimated in 11 and ½ months. The production and decomposition values of this work are within the range found in other sites of secondary tropical forests.

Pragmatic competence of Finnish learners of English: Meaning in interaction in secondary and upper secondary schools

Tutkin pro gradu -tutkielmassani englannin kielen oppijoiden pragmaattista kompetenssia. Tarkoitukseni oli selvittää, miten suomalaiset yläkoululaiset ja lukiolaiset osaavat käyttää englannin kieltä erilaisissa kommunikaatiotilanteissa. Tutkielmani voidaan sijoittaa välikielen pragmatiikan tutkimukseen. Halusin selvittää, millä tasolla suomalaisten oppijoiden pragmaattinen kompetenssi on ja kehittyykö se yläkoulun ja lukion välillä. Lisäksi tutkin, vaikuttavatko oppimisympäristö ja oppimismahdollisuudet oppijoiden kykyyn käyttää englannin kieltä. Toisin sanoen vertasin englantipainotteisilla luokilla olevia oppilaita formaalin opetuksen oppijoihin sekä tutkin, vaikuttavatko englanninkieliset vapaa-ajan aktiviteetit ja oppijoiden mahdolliset oleskelut englanninkielisissä maissa heidän pragmaattiseen kompetenssiinsa. Tutkimukseni kohderyhmä koostui yläkoulun kahdeksasluokkalaisista ja lukion toisen vuosikurssin opiskelijoista. Testasin neljä eri ryhmää, joissa oli sekä formaalissa opetuksessa olevia oppijoita (yksi ryhmä kahdeksasluokkalaisia ja yksi ryhmä toisen vuosikurssin opiskelijoita) että kielipainotteisten luokkien oppijoita (yksi ryhmä kahdeksasluokkalaisia ja yksi ryhmä toisen vuosikurssin opiskelijoita). Arvioin kohderyhmäni pragmaattista kompetenssia monivalintatestillä, jossa testattiin oppijoiden kykyä käyttää ja ymmärtää implikaatioita, tilannekohtaisia rutiineja sekä puheakteja. Taustakysymysten avulla selvitin, kuinka usein oppijat käyttivät englantia vapaa-aikanaan ja olivatko he vierailleet englanninkielisissä maissa. Tutkimustulokseni osoittavat, että suomalaisten yläkoululaisten ja lukiolaisten pragmaattinen kompetenssi oli korkea. Pragmaattinen kompetenssi kehittyi kahdeksasluokkalaisten ja lukion toisen vuosikurssin välillä. Kehitys oli suurempaa formaalissa opetuksessa kuin kielipainotteisilla luokilla. Englantipainotteisilla luokilla olevat oppilaat suoriutuivat testistä paremmin kuin formaalin opetuksen oppilaat. Tosin erot olivat tilastollisesti merkitseviä vain yläkoulussa. Tutkimuksessani siis päättelin, että vieraskielinen opetus vaikutti enemmän nuorempiin oppijoihin. Eri oppimismahdollisuudet osoittautuivat haastaviksi analysoida. Tulokset osoittivat, että vain englanninkielisessä maassa oleskelulla oli vaikutusta oppijoiden pragmaattiseen kompetenssiin. Kysyttäessä vapaa-ajan aktiviteettien merkitystä oppijat kuitenkin kertoivat, että ne auttoivat heitä testiin vastaamisessa enemmän kuin englanninopetuksessa käydyt asiat. Kouluissa tulisikin jatkossa painottaa yhä enemmän vuorovaikutteista kieltenopetusta.

Understanding and improving quality of secondary school education : conceptions among teachers in Tanzania

Temat för studien handlar om gymnasielärares uppfattningar om kvalitet och om hur kvalitet kan utvecklas i gymnasieutbildningen in Tanzania. Studien är till sin karaktär kvalitativ och består av utprövade semistrukturerade intervjuer med sammanlagt trettio lärare som arbetar i fyra gymnasieskolor både i urbana och rurala miljöer. Lärarna har varierande arbetserfarenhet och undervisar i olika ämnen. Huvudfokus har gällt identifieringen av variationer i lärares uppfattningar om kvalitet. På basen av två forskningsfrågor avslöjar analysen uppfattningar av hur lärare förstår och önskar utveckla kvaliteten på gymnasieutbildningen. Resultaten visar att lärare förstår kvaliteten på utbildningen i sina skolor som försök att möta skolans och samhällets mål, som individuella prestationer och förmågor som att inneha kompetenser och som att möta utmaningar inom utbildning, Identifierade uppfattningar var baserade på lärarnas personliga kunskap, arbetsmiljön och varierande omständigheter som rådde i deras skolor. Uppfattningar om en förbättring av kvaliteten i gymnasieutbildningen innefattade utveckling av lärares motivation, skolmiljön, arbetet i klassrum, kvaliteten på lärares kunskaper och färdigheter och undervisningsmaterial. Ambitionen bakom studien ar att erbjuda en plattform för strategier för att förbättra kvaliteten på gymnasieutbildningen. Resultaten strävar till att ge en fördjupad insikt i uppfattningar hos en utvald grupp av lärare som arbetar under samma villkor inom gymnasieskolor I Tanzania. Av den här anledningen är den genererade kunskapen därför relevant för att belysa lärares uppfattningar även utanför den studerade gruppen av respondenter.

Metabolism and gene polymorphisms of the folate pathway in Brazilian women with history of recurrent abortion

PURPOSE: To investigate the association between polymorphisms in genes that encode enzymes involved in folate- and vitamin B12-dependent homocysteine metabolism and recurrent spontaneous abortion (RSA).METHODS: We investigated the C677T and A1298C polymorphisms of the methylenetetrahydrofalate reductase gene (MTHFR), the A2756G polymorphism of the methionine synthase gene (MS) and the 844ins68 insertion of the cystathionine beta synthetase gene (CBS). The PCR technique followed by RFLP was used to assess the polymorphisms; the serum levels of homocysteine, vitamin B12 and folate were investigated by chemiluminescence. The EPI Info Software version 6.04 was used for statistical analysis. Parametric variables were compared by Student's t-test and nonparametric variables by the Wilcoxon rank sum test.RESULTS: The frequencies of gene polymorphisms in 89 women with a history of idiopathic recurrent miscarriage and 150 controls were 19.1 and 19.6% for the C677T, insertion, 20.8 and 26% for the A1298C insertion, 14.2 and 21.9% for the A2756G insertion, and 16.4 and 18% for the 844ins68 insertion, respectively. There were no significant differences between case and control groups in any of the gene polymorphisms investigated. However, the frequency of the 844ins68 insertion in the CBS gene was higher among women with a history of loss during the third trimester of pregnancy (p=0.003). Serum homocysteine, vitamin B12 and folate levels id not differ between the polymorphisms studied in the case and control groups. However, linear regression analysis showed a dependence of serum folate levels on the maintenance of tHcy levels.CONCLUSION: The investigated gene polymorphisms and serum homocysteine, vitamin B12 and folate levels were not associated with idiopathic recurrent miscarriage in the present study. Further investigations are needed in order to confirm the role of the CBS 844ins68 insertion in recurrent miscarriage.

Comparison of Classical and Secondary Cytologic Criteria Relative to Hybrid Capture for Diagnosing Cervical-vaginal Infection by Human Papillomavirus

Objective To compare the diagnostic accuracy of the classic Meisels cytologic criteria and the Schneider secondary criteria relative to the hybrid capture method for diagnosing HPV infection. Methods This was a retrospective study performed at a public university hospital. A total of 41 patients with a cytologic diagnosis of HPV infection and 40 HPV-negative patients were selected for review of the cervical-vaginal smears seeking to classical and secondary criteria. A single pathologist reviewed the slides in search of the criteria. The classical and secondary cytologic criteria were compared with the hybrid capture for diagnosing HPV infection. Bartleti test was applied for the age analysis, and Fisher's exact test was used to compare proportions. The tests were considered significant when the probability of rejecting the null hypothesis was less than 5% (p < 0.05). Results The Meisels criteria were less sensitive (34.0%) than the secondary Schneider criteria (57.5%) when compared with the hybrid capture (p < 0.0001), although the specificity of the former criteria was non-significantly higher (91.2% and 67.7%, respectively). In cases of moderate or intense inflammation, the sensitivity and specificity of the Schneider criteria were decreased, 33.3% and 50.0% respectively (p = 0.0115). Conclusions Compared with hybrid capture for diagnosis of HPV infection, the sensitivity of the secondary Schneider criteria was higher than the classical Meisels criteria.Moderate or intense inflammation reduces the sensitivity and specificity of the secondary Schneider criteria for diagnosing HPV infection using the hybrid capture as the gold standard.

Parenteral administration of vitamins A, D and E on the oxidative metabolism and function of polymorphonuclear leukocytes in swine

The weaning period of piglets is characterized by physiological alterations, such as decreased weight gain, increased reactive oxygen species (ROS) and increased serum cortisol levels with possible effects on the immune response. The effect of parenteral administration of vitamins A, D and E on production performance, oxidative metabolism, and the function of polymorphonuclear leukocytes (PMNLs) was assessed in piglets during the weaning period. The sample was comprised of 20 male piglets that were given an injectable ADE vitamin combination (135,000 IU vitamin A, 40,000 IU vitamin D and 40mg vitamin E/ animal) at 20 and 40 days of age. Weight gain, concentration of reduced glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD) and the microbicidal and phagocytic activity of PMNLs were assessed. No difference was observed in the average piglet weight during the study; however, a greater percentage of weight gain was observed after weaning in the treated group. The concentrations of GSH and SOD did not differ between groups, although lipid peroxidation was greater in the control group at 60 days of age. The investigated variables of oxidative metabolism were correlated as follows: -0.41 for GSH and MDA, -0.54 for GSH and SOD and 0.34 for MDA and SOD. The intensity of intracellular ROS production, the percentage of ROS-producing PMNLs and the intensity of phagocytosis by PMNLs did not differ between treatment groups. Administration of the injectable ADE combination improved the percentage of weight gain between 20 and 40 days of age, decreased oxidative stress at 60 days of age and did not influence the function of PMNLs in piglets.