In Vivo Profiling and Distribution of Known and Novel Phase I and Phase II Metabolites of Efavirenz in Plasma, Urine, and Cerebrospinal Fluid.

Efavirenz (EFV) is principally metabolized by CYP2B6 to 8-hydroxy-efavirenz (8OH-EFV) and to a lesser extent by CYP2A6 to 7-hydroxy-efavirenz (7OH-EFV). So far, most metabolite profile analyses have been restricted to 8OH-EFV, 7OH-EFV, and EFV-N-glucuronide, even though these metabolites represent a minor percentage of EFV metabolites present in vivo. We have performed a quantitative phase I and II metabolite profile analysis by tandem mass spectrometry of plasma, cerebrospinal fluid (CSF), and urine samples in 71 human immunodeficiency virus patients taking efavirenz, prior to and after enzymatic (glucuronidase and sulfatase) hydrolysis. We have shown that phase II metabolites constitute the major part of the known circulating efavirenz species in humans. The 8OH-EFV-glucuronide (gln) and 8OH-EFV-sulfate (identified for the first time) in humans were found to be 64- and 7-fold higher than the parent 8OH-EFV, respectively. In individuals (n = 67) genotyped for CYP2B6, 2A6, and CYP3A metabolic pathways, 8OH-EFV/EFV ratios in plasma were an index of CYP2B6 phenotypic activity (P < 0.0001), which was also reflected by phase II metabolites 8OH-EFV-glucuronide/EFV and 8OH-EFV-sulfate/EFV ratios. Neither EFV nor 8OH-EFV, nor any other considered metabolites in plasma were associated with an increased risk of central nervous system (CNS) toxicity. In CSF, 8OH-EFV levels were not influenced by CYP2B6 genotypes and did not predict CNS toxicity. The phase II metabolites 8OH-EFV-gln, 8OH-EFV-sulfate, and 7OH-EFV-gln were present in CSF at 2- to 9-fold higher concentrations than 8OH-EFV. The potential contribution of known and previously unreported EFV metabolites in CSF to the neuropsychological effects of efavirenz needs to be further examined in larger cohort studies.

A system to assess the stability of airborne nanoparticle agglomerates under aerodynamic shear

Stability of airborne nanoparticle agglomerates is important for occupational exposure and risk assessment in determining particle size distribution of nanomaterials. In this study, we developed an integrated method to test the stability of aerosols created using different types of nanomaterials. An aerosolization method, that resembles an industrial fluidized bed process, was used to aerosolize dry nanopowders. We produced aerosols with stable particle number concentrations and size distributions, which was important for the characterization of the aerosols' properties. Next, in order to test their potential for deagglomeration, a critical orifice was used to apply a range of shear forces to them. The mean particle size of tested aerosols became smaller, whereas the total number of particles generated grew. The fraction of particles in the lower size range increased, and the fraction in the upper size range decreased. The reproducibility and repeatability of the results were good. Transmission electron microscopy imaging showed that most of the nanoparticles were still agglomerated after passing through the orifice. However, primary particle geometry was very different. These results are encouraging for the use of our system for routine tests of the deagglomeration potential of nanomaterials. Furthermore, the particle concentrations and small quantities of raw materials used suggested that our system might also be able to serve as an alternative method to test dustiness in existing processes.

Validation of a computer-assisted system on classifying lower third molars

Objectives: The present study evaluates the reliability of the Radio Memory® software (Radio Memory; Belo Horizonte,Brasil.) on classifying lower third molars, analyzing intra- and interexaminer agreement of the results. Study Design: An observational, descriptive study of 280 lower third molars was made. The corresponding orthopantomographs were analyzed by two examiners using the Radio Memory® software. The exam was repeated 30 days after the first observation by each examiner. Both intra- and interexaminer agreement were determined using the SPSS v 12.0 software package for Windows (SPSS; Chicago, USA). Results: Intra- and interexaminer agreement was shown for both the Pell & Gregory and the Winter classifications, p<0.01, with 99% significant correlation between variables in all the cases. Conclusions: The use of Radio Memory® software for the classification of lower third molars is shown to be a valid alternative to the conventional method (direct evaluation on the orthopantomograph), for both clinical and investigational applications.

Parallel declines in species and genetic diversity driven by anthropogenic disturbance: a multispecies approach in a French Atlantic dune system.

Numerous studies assess the correlation between genetic and species diversities, but the processes underlying the observed patterns have only received limited attention. For instance, varying levels of habitat disturbance across a region may locally reduce both diversities due to extinctions, and increased genetic drift during population bottlenecks and founder events. We investigated the regional distribution of genetic and species diversities of a coastal sand dune plant community along 240 kilometers of coastline with the aim to test for a correlation between the two diversity levels. We further quantify and tease apart the respective contributions of natural and anthropogenic disturbance factors to the observed patterns. We detected significant positive correlation between both variables. We further revealed a negative impact of urbanization: Sites with a high amount of recreational infrastructure within 10 km coastline had significantly lowered genetic and species diversities. On the other hand, a measure of natural habitat disturbance had no effect. This study shows that parallel variation of genetic and species diversities across a region can be traced back to human landscape alteration, provides arguments for a more resolute dune protection, and may help to design priority conservation areas.

Long-term controlled GDNF over-expression reduces dopamine transporter activity without affecting tyrosine hydroxylase expression in the rat mesostriatal system.

The dopamine (DA) transporter (DAT) is a plasma membrane glycoprotein expressed in dopaminergic (DA-) cells that takes back DA into presynaptic neurons after its release. DAT dysfunction has been involved in different neuro-psychiatric disorders including Parkinson's disease (PD). On the other hand, numerous studies support that the glial cell line-derived neurotrophic factor (GDNF) has a protective effect on DA-cells. However, studies in rodents show that prolonged GDNF over-expression may cause a tyrosine hydroxylase (TH, the limiting enzyme in DA synthesis) decline. The evidence of TH down-regulation suggests that another player in DA handling, DAT, may also be regulated by prolonged GDNF over-expression, and the possibility that this effect is induced at GDNF expression levels lower than those inducing TH down-regulation. This issue was investigated here using intrastriatal injections of a tetracycline-inducible adeno-associated viral vector expressing human GDNF cDNA (AAV-tetON-GDNF) in rats, and doxycycline (DOX; 0.01, 0.03, 0.5 and 3mg/ml) in the drinking water during 5weeks. We found that 3mg/ml DOX promotes an increase in striatal GDNF expression of 12× basal GDNF levels and both DA uptake decrease and TH down-regulation in its native and Ser40 phosphorylated forms. However, 0.5mg/ml DOX promotes a GDNF expression increase of 3× basal GDNF levels with DA uptake decrease but not TH down-regulation. The use of western-blot under non-reducing conditions, co-immunoprecipitation and in situ proximity ligation assay revealed that the DA uptake decrease is associated with the formation of DAT dimers and an increase in DAT-α-synuclein interactions, without changes in total DAT levels or its compartmental distribution. In conclusion, at appropriate GDNF transduction levels, DA uptake is regulated through DAT protein-protein interactions without interfering with DA synthesis.

The role of surface vertical mixing in phytoplankton distribution in a stratified reservoir

We investigated convection caused by surface cooling and mixing attributable to wind shear stress and their roles as agents for the transport of phytoplankton cells in the water column by carrying out two daily surveys during the stratified period of the Sau reservoir. Green algae, diatoms, and cryptophyceae were the dominant phytoplankton communities during the surveys carried out in the middle (July) and end (September) of the stratified period. We show that a system with a linear stratification and that is subject to weak surface forcing, with weak winds , < 4 m S (-1) and low energy dissipation rate values of the order of 1028 m2 s23 or lower, enables the formation of thin phytoplankton layers. These layers quickly disappear when water parcels mix because there is a medium external forcing (convection) induced by the night surface cooling, which is characterized by energy dissipation rates on the order of , 5x10(-8)m2s(-3). During both surveys the wind generated internal waves during the entire diurnal cycle. During the day, and because of the weak winds, phytoplankton layers rise in the water column up to a depth determined by both solar heating and internal waves. In contrast, during the night phytoplankton mixes down to a depth determined by both convection and internal waves. These internal waves, together with the wind-driven current generated at the surface, seem to be the agents responsible for the horizontal transport of phytoplankton across the reservoir.

Chlamydiaceae and Chlamydia-like organisms in the koala (Phascolarctos cinereus)--organ distribution and histopathological findings.

Chlamydial infections in koalas can cause life-threatening diseases leading to blindness and sterility. However, little is known about the systemic spread of chlamydiae in the inner organs of the koala, and data concerning related pathological organ lesions are limited. The aim of this study was to perform a thorough investigation of organs from 23 koalas and to correlate their histopathological lesions to molecular chlamydial detection. To reach this goal, 246 formalin-fixed and paraffin embedded organ samples from 23 koalas were investigated by histopathology, Chlamydiaceae real-time PCR and immunohistochemistry, ArrayTube Microarray for Chlamydiaceae species identification as well as Chlamydiales real-time PCR and sequencing. By PCR, two koalas were positive for Chlamydia pecorum whereas immunohistochemical labelling for Chlamydiaceae was detected in 10 tissues out of nine koalas. The majority of these (n=6) had positive labelling in the urogenital tract related to histopathological lesions such as cystitis, endometritis, pyelonephritis and prostatitis. Somehow unexpected was the positive labelling in the gastrointestinal tract including the cloaca as well as in lung and spleen indicating systemic spread of infection. Uncultured Chlamydiales were detected in several organs of seven koalas by PCR, and four of these suffered from plasmacytic enteritis of unknown aetiology. Whether the finding of Chlamydia-like organisms in the gastrointestinal tract is linked to plasmacytic enteritis is unclear and remains speculative. However, as recently shown in a mouse model, the gastrointestinal tract might play a role being the site for persistent chlamydial infections and being a source for reinfection of the genital tract.

Effects of modern variable frequency drive on the reliability of an old crane induction motor

The work aims to analyze the possibilities of utilizing old crane driving AC induction motors in modern pulse-width-modulated variable frequency drives. Bearing currents and voltage stresses are the two main problems associated with modern IGBT inverters, and they may cause premature failure of an old induction motor. The origins of these two problems are studied. An analysis of the mechanism of bearing failure is proposed. Certain types of bearing currents are considered in detail. The most effective and economical means are chosen for bearing currents mitigation. Transient phenomena of cables and mechanism of over voltages occurring at motor terminals are studied in the work. The weakest places of the stator winding insulation system are shown and recommendations are given considering the mitigation of voltage stresses. Only the most appropriate and cost effective preventative methods are chosen for old motor drives. Rewinding of old motors is also considered.

On Transmission System Design for Wireless Broadcasting

This thesis considers aspects related to the design and standardisation of transmission systems for wireless broadcasting, comprising terrestrial and mobile reception. The purpose is to identify which factors influence the technical decisions and what issues could be better considered in the design process in order to assess different use cases, service scenarios and end-user quality. Further, the necessity of cross-layer optimisation for efficient data transmission is emphasised and means to take this into consideration are suggested. The work is mainly related terrestrial and mobile digital video broadcasting systems but many of the findings can be generalised also to other transmission systems and design processes. The work has led to three main conclusions. First, it is discovered that there are no sufficiently accurate error criteria for measuring the subjective perceived audiovisual quality that could be utilised in transmission system design. Means for designing new error criteria for mobile TV (television) services are suggested and similar work related to other services is recommended. Second, it is suggested that in addition to commercial requirements there should be technical requirements setting the frame work for the design process of a new transmission system. The technical requirements should include the assessed reception conditions, technical quality of service and service functionalities. Reception conditions comprise radio channel models, receiver types and antenna types. Technical quality of service consists of bandwidth, timeliness and reliability. Of these, the thesis focuses on radio channel models and errorcriteria (reliability) as two of the most important design challenges and provides means to optimise transmission parameters based on these. Third, the thesis argues that the most favourable development for wireless broadcasting would be a single system suitable for all scenarios of wireless broadcasting. It is claimed that there are no major technical obstacles to achieve this and that the recently published second generation digital terrestrial television broadcasting system provides a good basis. The challenges and opportunities of a universal wireless broadcasting system are discussed mainly from technical but briefly also from commercial and regulatory aspect

Reliability analysis of medium voltage feeder

Distribution companies are facing numerous challenges in the near future. Regulation defines correlation between power quality and revenue cap. Companies have to take measures for reliability increase to successfully compete in modern conditions. Most of the failures seen by customers originate in medium voltage networks. Implementation of network automation is the very effective measure to reduce duration and number of outages, and consequently, outage costs. Topic of this diploma work is study of automation investments effect on outage costs and other reliability indices. Calculation model have been made to perform needed reliability calculations. Theoretical study of different automation scenarios has been done. Case feeder from actual distribution company has been studied and various renovation plans have been suggested. Network automation proved to be effective measure for increasing medium voltage network reliability.

Haja-asutusalueiden sähkönjakelujärjestelmien kehittäminen – erityisesti 1000 V jakelujännitteen käyttömahdollisuudet

Yhteiskunnan riippuvuus sähköstä on lisääntynyt voimakkaasti viime vuosikymmenien aikana. Sähkönjakelussa esiintyneet lyhyet ja pitkät keskeytykset ovat osoittaneet yhteiskunnan haavoittuvuuden ja yhteiskunta kestää entistä vähemmän sähkönjakelussa tapahtuvia häiriöitä. Keskeytyksistä aiheutuneiden haittojen arvostus on kasvanut ja tämä on luonut taloudelliset perusteet sähkön laatua parantaville investoinneille. Haja-asutusalueiden keskijänniteverkon johdot on rakennettu avojohtoina ja siten ne ovat alttiita sääolosuhteista johtuville myrsky- ja lumikuormavaurioille. Ilmastomuutoksen ennustetaan lisäävän tuulisuutta ja siten ongelmat sähkönjakelussa mahdollisesti lisääntyvät. Taajamissa käytetään enemmän kaapeleita ja johtolähdöt ovat lyhyitä, joten myrskyistä aiheutuvia keskeytyksiä on vähemmän kuin haja-asutusalueella. Olemassa olevat jakeluverkot ovat käytössä vielä vuosikymmeniä, joten uuden tekniikan kehittämisen rinnalla on kehitettävä myös olemassa olevaa jakeluverkkoa ja sen ylläpitoa. Ylläpidon tavoitteena on käyttövarmuuden parantamisen lisäksi huolehtia siitä, että jakeluverkkoihin sitoutunut omaisuus säilyttää arvonsa mahdollisimman hyvin pitoajan loppuun saakka. Jakeluverkkoihin investoitiin paljon 1950–70-luvuilla. Tältä ajalta on yhä käytössä puupylväitä, joiden ikääntymisen takia korvausinvestointien tarve kasvaa. Hyvänä puolena tässä on että käyttövarmuuden parantamiseksi olemassa olevaa jakeluverkkoa ei tarvitse uusia ennenaikaisesti. Tutkimuksessa päähuomio on haja-asutusalueiden 20 kV keskijänniteverkon kehittämisessä, sillä yli 90 % asiakkaiden kokemista keskeytyksistä johtuu keskijänniteverkon vioista. Erityisesti johtorakenteisiin ja johtojen sijoittamiseen on kiinnitettävä huomiota. Käyttövarmuuden lisäksi jakeluverkkojen kehittämistä ohjaavia tekijöitä ovat taloudellisuus, ympäristön huomioiminen, viranomaisvalvonta sekä asiakkaiden ja omistajien odotukset. Haja-asutusalueilla taloudelliset haasteet ovat suuret vakituisen väestön vähenemisen ja mahdollisesti sähköntarpeen pienenemisen takia. Taloudellisuus korostuu ja riskit kasvavat, kun tuottojen määrä supistuu tarvittaviin jakeluverkon investointeihin ja ylläpitokustannuksiin verrattuna. Ristiriitaa aiheuttaa se, että asiakkaat odottavat sähkönjakelulta parempaa luotettavuutta, mutta paremmasta sähkönlaadusta ei olla valmiita maksamaan juurikaan nykyistä enempää. Jakeluverkkojen kehittämistä voi hidastaa myös viranomaisvalvonta, jos tuottoja ei voida lisätä investointien lisätarpeiden suhteessa. Tutkimuksessa on analysoitu yleisellä tasolla kaapeloinnin lisäämistä, korkeiden pylväiden käyttämistä, leveitä johtokatuja, edullisten ja yksinkertaisten sähköasemien rakentamista haja-asutusalueille ja automaatioasemien lisäämistä keskijänniteverkon solmupisteisiin. Erityisesti tutkimuksessa on analysoitu uutena tekniikkana 1000 V jännitteen käyttömahdollisuutta jakeluverkkojen kehittämisessä. Sähköjohtojen siirtäminen teiden varsiin parantaa käyttövarmuutta, vaikka johdot rakennetaan samalla tekniikalla kuin olemassa olevat johdot. Hajaasutusalueille rakennettavilla sähköasemilla pitkät syöttöjohdot voidaan jakaa pienemmiksi syöttöalueiksi, jolloin keskeytyksistä aiheutuvat haitat koskettavat kerrallaan pienempää asiakasmäärää. Samaan tulokseen päästään oikein sijoitetuilla ja toteutetuilla automaatioasemilla. Tutkimuksen mukaan lupaavaksi tekniikaksi jakeluverkkojen kehittämisessä on osoittautumassa 1000 V jänniteportaan ottaminen 400 V pienjännitteen lisäksi. 1000 V verkoilla voidaan korvata häiriöherkkiä 20 kV keskijänniteverkon lyhyitä, alle viiden kilometrin pituisia haarajohtoja ja haarajohtojen jatkeita, missä siirrettävät tehot ovat pieniä. Uudessa jakelujärjestelmässä sähkö tuodaan 1000 V jännitteellä lähelle asiakasta, jossa jännite muunnetaan normaaliksi asiakkaille soveltuvaksi 400/230 V jännitteeksi. Edullisuus perustuu siihen, että rakentamisessa käytetään samoja pienjännitejohtoja kuin asiakkaille menevässä 400 V pienjänniteverkossa. 1000 V jakelutekniikassa sekä investointikustannukset että ylläpitokustannukset ovat pienemmät kuin perinteisessä 20 kV ilmajohtotekniikassa. 1000 V johdot säästävät maisemaa, sillä ne eivät tarvitse leveää johtokatua kuten 20 kV keskijännitejohdot. 1000 V verkkojen käyttö soveltuukin erityisesti vapaa-ajanasuntojen sähköistykseen herkissä ranta- ja järvimaisemissa. 1000 V verkot mahdollistavat kaapeliauraamisen lisäämisen ja näin voidaan vähentää ympäristöä haittaavien kyllästettyjen pylväiden käyttöä. 1000 V jakeluverkkojen osalta tutkimustyön tuloksia on sovellettu suomalaisessa Suur-Savon Sähkö Oy:ssä. Käytännön kokemuksia 1000 V jakelujärjestelmästä on useista kymmenistä kohteista. Tutkimustulokset osoittavat, ettei keskijänniteverkon maakaapelointi hajaasutusalueilla ole taloudellisesti kannattavaa nykyisillä keskeytyksistä aiheutuvilla haitta-arvoilla, mutta jos keskeytyskustannusten arvostus kasvaa, tulee kaapelointi kannattavaksi monissa paikoissa. Myös myrskyisyyden ja myrskyistä aiheutuvien jakelukeskeytysten lisääntyminen tekisi kaapeloinnista kannattavan. Tulevaisuudessa jakeluverkkojen rakentaminen on entistä monimuotoisempi tehtävä, jossa taloudellisuuden ja käyttövarmuuden lisäksi on huomioitava asiakkaat, omistajat, viranomaiset ja ympäristö. Tutkimusta jakelutekniikan kehittämiseksi tarvitaan edelleen. Tulevaisuuden osalta haja-asutusalueiden jakeluverkkojen kehittämiseen liittyy paljon epävarmuuksia. Hajautetun kiinteistökohtaisen sähköntuotannon lisääntyminen voi tehdä jakeluverkoista nykyistä tarpeettomampia, mutta esimerkiksi liikenteen sähköistyminen voi kasvattaa jakeluverkkojen merkitystä. Tästä syystä jakeluverkkojen rakentamisessa tarvitaan joustavuutta, jotta tarvittaessa voidaan helposti sopeutua erilaisiin kehityssuuntiin.

Distribution Patterns of Soil Properties in a Rural Mediterranean Area in Northeastern Spain

Soil properties on the Cap de Creus Peninsula, NE Spain depend primarily on scarce agricultural practices and early abandonment. In the study area, 90% of which is mainly covered by Cistus shrubs, 8 environments representing variations in land use/land cover and soil properties at different depths were identified. In each environment variously vegetated areas were selected and sampled. The soils, collected at different depths, were classified as Lithic Xerorthents according to the United States Department of Agriculture system of soil classification (USDA-NRCS 1975). Differences in soil properties were largely found according to the evolution of the plant canopy and the land use history. To identify underlying patterns in soil properties related to environmental evolution, factor analysis was performed and factor scores were used to determine how the factor patterns varied between soil variables, soil depths and selected environments. The three-factor model always accounted for 80% of the total variation in the data at the different soil depths. Organic matter was the more relevant soil property at 0–2 cm depth, whereas active minerals (silt and clay) were found to be the most relevant soil parameters controlling soil dynamics at the other depths investigated. Results showed that vineyards and olive tree soils are poorly developed and present worse conditions for mineral and organic compounds. Analysis of factor scores allowed independent assessment of soils, depth and plant cover and demonstrated that soils present the best physico-chemical characteristics under Erica arborea and meadows. In contrast, soils under Cistus monspeliensis were less nutrient rich and less well structured

Pharmaceuticals occurrence in a WWTP with significant industrial contribution and its input into the river system

Occurrence and removal of 81 representative Pharmaceutical Active Compounds (PhACs) were assessed in a municipal WWTP located in a highly industrialized area, with partial water reuse after UV tertiary treatment and discharge to a Mediterranean river. Water monitoring was performed in an integrated way at different points in the WWTP and river along three seasons. Consistent differences between therapeutic classes were observed in terms of influent concentration, removal efficiencies and seasonal variation. Conventional (primary and secondary) treatment was unable to completely remove numerous compounds and UV-based tertiary treatment played a complementary role for some of them. Industrial activity influence was highlighted in terms of PhACs presence and seasonal distribution. Even if global WWTP effluent impact on the studied river appeared to be minor, PhACs resulted widespread pollutants in river waters. Contamination can be particularly critical in summer in water scarcity areas, when water flow decreases considerably

Multichannel distribution strategy for electrical equipment marketing

The thesis examines System Integration and original equipment manufacturer (OEM) channel in the St. Petersburg drives market. The aim of the study was to increase understanding the relationship between OEM and SI and producers, problems and ongoing trends. The collected data was analyzed in order to find out which features of a power electronic drive product exercise a significant influence for the Russian companies decision. An essential part of this study was interviews as primary information sources, organized with SI and OEM companies which represented the basic SPb industry segments. The wholesalers and end users are left out from the analysis. The collected data was analyzed in order to find out which features of a power electronic drive product exercise a significant influence for the Russian companies decision.