The Pharmacology of Oxycodone : Studies In Vitro, In Vivo and In Humans

The antinociceptive properties of oxycodone and its metabolites were studied in models of thermal and mechanical nociception and in the spinal nerve ligation (SNL) model of neuropathic pain in rats. Oxycodone induced potent antinociception after subcutaneous (s.c.) administration in all models of nociception used in rats compared with morphine, methadone and its enantiomers. In the SNL model of neuropathic pain in rats, oxycodone produced dose dependent antinociception after s.c. administration. The antinociceptive effects of s.c. oxycodone were antagonized by naloxone but not by nor-binaltorphimine (Nor-BNI) a selective κ-opioid receptor antagonist indicating that the antinociceptive properties of oxycodone are predominantly μ-opioid receptor-mediated. The antinociceptive activity of oxymorphone, noroxycodone, and noroxymorphone, oxidative metabolites of oxycodone, were studied to determine their role in the oxycodone-induced antinociception in the rat. Of the metabolites of oxycodone s.c. administration of oxymorphone produced potent thermal and mechanical antinociception. Noroxycodone had a poor antinociceptive effect and noroxymorphone was inactive. Oxycodone produced naloxone-reversible antinociception after intrathecal (i.t) administration with a poor potency compared with morphine and oxymorphone. This seems to be related to the low efficacy and potency of oxycodone to stimulate μ-opioid receptor activation in the spinal cord in μ-opioid receptor agonist-stimulated (GTP)γ[S] autoradiography, compared with morphine and oxymorphone. All metabolites studied were more potent than oxycodone after i.t. administration. I.t. noroxymorphone induced a significantly longer lasting antinociceptive effect compared with the other drugs studied. The role of cytochrome P450 (CYP) 2D6-mediated metabolites on the analgesic activity of oxycodone in humans was studied by blocking the CYP2D6-mediated metabolism of oxycodone with paroxetine. Paroxetine co-administration had no effect on the analgesic effect of oxycodone compared with placebo in chronic pain patients, indicating that oxycodone-induced analgesia and adverse-effects are not dependent of the CYP2D6-mediated metabolism in humans. Although oxycodone has many pharmacologically active metabolites, they seem to have an insignificant role in oxycodone-induced antinociception in humans and rats.

John Searlen teoria tietoisuudesta

Tutkielmassa esitellään ja arvioidaan John Searlen teoriaa tietoisuudesta. Tietoisuus (consciousness) on Searlen mukaan tärkein mielenfilosofinen käsite. Searle ei määrittele käsitettä tarkasti, vaan tyytyy esittämään sitä kuvaavia esimerkkejä ja analogioita. Tietoisuuden keskeisimmiksi ominaisuuksiksi Searlen teoriassa näyttävät muodostuvan intentionaalisuus (intentionality), subjektiivisuus (subjectivity) ja kausaalinen vaikutus käyttäytymiseen (mental causation). Näihin ominaisuuksiin liittyvät myös Searlen painavimmat tietoisuudesta esittämät argumentit. Argumenttien analysointi on tutkielman tärkein tavoite. Searlen yhteysperiaatteen (Connection Principle) mukaan intentionaalisia tiloja voi olla vain olennolla, jolla voi olla tietoisia intentionaalisia tiloja, ja jokainen alitajuinen intentionaalinen tila on ainakin potentiaalisesti tietoinen. Toisin sanoen intentionaalisuuden ja tietoisuuden välillä vallitsee välttämätön yhteys seuraavasti: on loogisesti välttämätöntä, että jokainen intentionaalinen tila voi ainakin periaattessa päästä tietoisuuteen.Tutkielmassa kuitenkin osoitetaan, että yhteysperiaateeseen on syytä suhtautua epäillen. Searlen yhteysperiaatteen puolesta esittämä argumentti näyttää nimittäin sisältävän dilemman. Jos erottelu intrinsiseen ja näennäiseen intentionaalisuuteen tulkitaan Searlen tavoin, syyllistytään sen olettamiseen, mikä pitäisi todistaa; jos taas erottelu tulkitaan toisin kuin Searle, argumentti ei tue yhteysperiaatetta. Searlen mukaan mentaaliset tilat ovat aina jonkun mentaalisia tiloja. Tästä väitteestä Searle pyrkii johtamaan toisen, paljon radikaalimman väitteen: mielen ilmiöt kuuluvat omaan ontologiseen kategoriaansa, subjektiivisten mentaalisten tilojen kategoriaan. Searlen käsitystä tukee Thomas Nagelin esittämä, hyvin samansisältöinen argumentti. Yksimielisyys ei kuitenkaan ole erehtymättömyyden tae, sillä Paul Churchlandin kritiikki näyttää pahasti horjuttavan Searlen subjektiivisuusargumentin uskottavuutta. Churchland väittää Searlen syyllistyvän intensionaaliseen virhepäätelmään. Yksittäisen henkilön episteemisen pääsyn rajoittuneisuudesta ei Churchlandin mukaan voida tehdä mitään ontologisia johtopäätöksiä, koska tiedetyksi tuleminen ei ole objektin aito ominaisuus. Vastaväite näyttää olevan kohtalokas Searlen subjektiivisuusargumentille. Subjektiivisuuden ongelma näyttää olevan perustava metafyysinen vedenjakaja, joka jakaa mielenfilosofiset teoriat toisaalta materialistisiin, toisaalta dualistisiin. Searle uskoo, että mieli-ruumis -ongelma (mind-body problem) on ratkaistavissa ilman, että tarvitsee valita kumpaakaan. Ratkaisu sisältyy kahteen Searlen näennäisesti yhteensopimattomaan teesiin. Ensimmäisen teesin mukaan mentaaliset tilat ovat todellisia ilmiöitä, eikä niitä voida redusoida mihinkään muuhun tai eliminoida määrittelemällä ne uudestaan. Toisen teesin mukaan aivojen operaatiot aiheuttavat mentaaliset tilat ja mentaaliset tilat ovat aivojen piirteitä. Teeseistä jälkimmäinen osoittautuu ongelmalliseksi syistä, jotka Jaegwon Kim on esittänyt. Jos mentaaliset tilat olisivat aivojen ominaisuuksia, ei mielen ja aivojen välinen suhde voisi olla kausaalinen, koska kausaatiossa (causation) on aina kyse kahden erillisen entiteetin tai tapahtuman välisestä relaatiosta, jossa suhteen osapuolien välillä on oltava ajallista etäisyyttä. Toiseksi Searlen vertaus tietoisuuden ja aivojen suhteesta kappaleen kiinteyden ja sen mikrorakenteen suhteeseen epäonnistuu, koska tietoisuus ja kiinteys kuuluvat Searlen teoriassa eri ontologisiin kategorioihin, eikä niitä siten voi ongelmattomasti rinnastaa. Searlen analogia kiinteyteen murtuu myös siksi, että kappaleen mikrorakenne ei yksinkertaisesti aiheuta sen kiinteyttä. Tietoisuus ei siis voi olla samanaikaisesti aivojen ominaisuus ja aivojen kausaalisen toiminnan seuraus. Tutkielmassa päädytään puolustamaan kantaa, että Searlen argumentit eivät ole vakuuttavia ja että Searle ei ole onnistunut eksplikoimaan teoriaa, joka välttäisi dualismiin ja materialismiin liittyvät tunnetut ongelmat. Kysymys mikä on mielen suhde ruumiiseen, jää siten avoimeksi. Avainsanat: intentionaalisuus, mentaalinen, mieli-ruumis -ongelma, Searle, subjektiivisuus, tietoisuus

Cooperation and conflict in conspecific brood parasitism : an alternative reproductive tactic

Interactions among individuals give rise to both cooperation and conflict. Individuals will behave selfishly or altruistically depending on which gives the higher payoff. The reproductive strategies of many animals are flexible and several alternative tactics may be present from which the most suitable one is applied. Generally, alternative reproductive tactics may be defined as a response to competition from individuals of the same sex. These alternative reproductive tactics are means by which individuals may fine-tune their fitness to the reigning circumstances and which are shaped by the environment individuals are occupying as well as by the behaviour of other individuals sharing the environment. By employing such alternative ways of achieving reproductive output, individuals may alleviate competition from others. Conspecific brood parasitism (CBP) is an alternative reproductive strategy found in several egg laying animal groups, and it is especially common among waterfowl. Within this alternative reproductive strategy, four reproductive options can be identified. These four options represent a continuum from low reproductive effort coupled with low fitness returns, to high reproductive effort and consequently high benefits. It may not be evident how individuals should allocate reproductive effort between eggs laid in their own nest vs. in nests of others, however. Limited fecundity will constrain the number of eggs donated by a parasite, but also the tendency for hosts to accept parasitic eggs may affect the allocation decision. Furthermore, kinship, individual quality and the costs of breeding may play a role in complicating the allocation decision. In this thesis, I view the seemingly paradoxical effects of kinship on conflict resolution in the context of alternative reproductive tactics, examining the resulting features of cooperation and conflict. Conspecific brood parasitism sets the stage for investigating these questions. By using both empirical and theoretical approaches, I examine the nature of CBP in a brood parasitic duck, the Barrow's goldeneye (Bucephala islandica). The theoretical chapter of this thesis gives rise to four main conclusions. Firstly, variation in individual quality plays a central role in shaping breeding strategies. Secondly, kinship plays a central role in the evolution of CBP. Thirdly, egg recognition ability may affect the prevalence of parasitism. If egg recognition is perfect, higher relatedness between host and parasite facilitates CBP. Finally, I show that the relative costs of egg laying and post-laying care play a so far underestimated role in determining the prevalence of parasitism. The costs of breeding may outweigh possible inclusive fitness benefits accrued from receiving eggs from relatives. Several of the patterns brought out by the theoretical work are then confirmed empirically in the following chapters. Findings include confirmation of the central role of relatedness in determining the extent of parasitism as well as inducing a counterintuitive host clutch reduction. Furthermore, I demonstrate a cost of CBP inflicted on hosts, as well as results suggesting that host age reflects individual quality, affecting the ability to overcome costs inflicted by CBP. In summary, I demonstrate both theoretically and empirically the presence of cooperation and conflict in the interactions between conspecific parasites and their hosts. The field of CBP research has traditionally been divided, but the first steps have now been taken toward the acceptance of the opposite side of the divide. Especially the theoretical findings of chapter 1 offer the possibility to view seemingly contrasting results of various studies within the same framework, and may direct future research toward more general features underlying differences in the patterns of CBP between populations or species.

Anterior cruciate ligament reconstruction with special reference to magnetic resonance imaging of the postoperative outcome

Anterior cruciate ligament (ACL) tear is a common sports injury of the knee. Arthroscopic reconstruction using autogenous graft material is widely used for patients with ACL instability. The grafts most commonly used are the patellar and the hamstring tendons, by various fixation techniques. Although clinical evaluation and conventional radiography are routinely used in follow-up after ACL surgery, magnetic resonance imaging (MRI) plays an important role in the diagnosis of complications after ACL surgery. The aim of this thesis was to study the clinical outcome of patellar and hamstring tendon ACL reconstruction techniques. In addition, the postoperative appearance of the ACL graft was evaluated using several MRI sequences. Of the 175 patients who underwent an arthroscopically assisted ACL reconstruction, 99 patients were randomized into patellar tendon (n=51) or hamstring tendon (n=48) groups. In addition, 62 patients with hamstring graft ACL reconstruction were randomized into either cross-pin (n=31) or interference screw (n=31) fixation groups. Follow-up evaluation determined knee laxity, isokinetic muscle performance and several knee scores. Lateral and anteroposterior view radiographs were obtained. Several MRI sequences were obtained with a 1.5-T imager. The appearance and enhancement pattern of the graft and periligamentous tissue, and the location of bone tunnels were evaluated. After MRI, arthroscopy was performed on 14 symptomatic knees. The results revealed no significant differences in the 2-year outcome between the groups. In the hamstring tendon group, the average femoral and tibial bone tunnel diameter increased during 2 years follow-up by 33% and 23%, respectively. In the asymptomatic knees, the graft showed homogeneous and low signal intensity with periligamentous streaks of intermediate signal intensity on T2-weighted MR images. In the symptomatic knees, arthroscopy revealed 12 abnormal grafts and two meniscal tears, each with an intact graft. Among 3 lax grafts visible on arthroscopy, MRI showed an intact graft and improper bone tunnel placement. For diagnosing graft failure, all MRI findings combined gave a specificity of 90% and a sensitivity of 81%. In conclusion, all techniques appeared to improve patients' performance, and were therefore considered as good choices for ACL reconstruction. In follow-up, MRI permits direct evaluation of the ACL graft, the bone tunnels, and additional disorders of the knee. Bone tunnel enlargement and periligamentous tissue showing contrast enhancement were non-specific MRI findings that did not signify ACL deficiency. With an intact graft and optimal femoral bone tunnel placement, graft deficiency is unlikely, and the MRI examination should be carefully scrutinized for possible other causes for the patients symptoms.

Local structure of water studied by Compton scattering

This thesis presents a novel application of x-ray Compton scattering to structural studies of molecular liquids. Systematic Compton-scattering experiments on water have been carried out with unprecedented accuracy at third-generation synchrotron-radiation laboratories. The experiments focused on temperature effects in water, the water-to-ice phase transition, quantum isotope effects, and ion hydration. The experimental data is interpreted by comparison with both model computations and ab initio molecular-dynamics simulations. Accordingly, Compton scattering is found to provide unique intra- and intermolecular structural information. This thesis thus demonstrates the complementarity of the technique to traditional real-space probes for studies on the local structure of water and, more generally, molecular liquids.

Fast in-memory XPath search using compressed indexes

A large fraction of an XML document typically consists of text data. The XPath query language allows text search via the equal, contains, and starts-with predicates. Such predicates can be efficiently implemented using a compressed self-index of the document's text nodes. Most queries, however, contain some parts querying the text of the document, plus some parts querying the tree structure. It is therefore a challenge to choose an appropriate evaluation order for a given query, which optimally leverages the execution speeds of the text and tree indexes. Here the SXSI system is introduced. It stores the tree structure of an XML document using a bit array of opening and closing brackets plus a sequence of labels, and stores the text nodes of the document using a global compressed self-index. On top of these indexes sits an XPath query engine that is based on tree automata. The engine uses fast counting queries of the text index in order to dynamically determine whether to evaluate top-down or bottom-up with respect to the tree structure. The resulting system has several advantages over existing systems: (1) on pure tree queries (without text search) such as the XPathMark queries, the SXSI system performs on par or better than the fastest known systems MonetDB and Qizx, (2) on queries that use text search, SXSI outperforms the existing systems by 1-3 orders of magnitude (depending on the size of the result set), and (3) with respect to memory consumption, SXSI outperforms all other systems for counting-only queries.

Expected Performance of the ATLAS Experiment - Detector, Trigger and Physics

A detailed study is presented of the expected performance of the ATLAS detector. The reconstruction of tracks, leptons, photons, missing energy and jets is investigated, together with the performance of b-tagging and the trigger. The physics potential for a variety of interesting physics processes, within the Standard Model and beyond, is examined. The study comprises a series of notes based on simulations of the detector and physics processes, with particular emphasis given to the data expected from the first years of operation of the LHC at CERN.

Alignment of the ALICE Inner Tracking System with cosmic-ray tracks

ALICE (A Large Ion Collider Experiment) is the LHC (Large Hadron Collider) experiment devoted to investigating the strongly interacting matter created in nucleus-nucleus collisions at the LHC energies. The ALICE ITS, Inner Tracking System, consists of six cylindrical layers of silicon detectors with three different technologies; in the outward direction: two layers of pixel detectors, two layers each of drift, and strip detectors. The number of parameters to be determined in the spatial alignment of the 2198 sensor modules of the ITS is about 13,000. The target alignment precision is well below 10 micron in some cases (pixels). The sources of alignment information include survey measurements, and the reconstructed tracks from cosmic rays and from proton-proton collisions. The main track-based alignment method uses the Millepede global approach. An iterative local method was developed and used as well. We present the results obtained for the ITS alignment using about 10^5 charged tracks from cosmic rays that have been collected during summer 2008, with the ALICE solenoidal magnet switched off.

Faktorer som initierar och påverkar prat i långsiktiga relationer

Den klassiska situationen där konsumentinformationen på ett ensidigt sätt tidigare har levererats av företagen får ge vika för en ny situation där dagens konsument aktivt sprider information för att påverka andra konsumenters köpbeslut genom att prata med andra om köpupplevelser och specifika tjänsteleverantörer t ex genom diskussionsgrupper på Internet. För företagen är situationen kritisk då de håller på att mista sina maktmonopol på informationen. Innehållet i pratet är mycket viktigt för mottagarna av pratet eftersom de flesta kunder om de inte själva har upplevt företaget, skapar sina åsikter och förväntningar om företaget samt om dess varor och tjänster på basen av vad andra berättar om saken. Man kan då säga att pratet har fått en viktigare roll vid formandet av konsumtionsbeslutet. Syftet med denna studie är att skapa förståelse för vilka faktorer som initierar och påverkar prat hos kunder i långsiktiga relationer. På basis av de olika resultaten konstruerades en modell som förklarar sambandet mellan faktorerna. Modellens första del visar att prat initieras på basis av långvariga upplevelser i relationer mellan tjänsteleverantör och kund. Modellens andra del visar att pratet påverkas av kundens personliga karaktäristika och relationsrelaterade faktorer som upplevt engagemang i tjänstekategorin och i tjänsteleverantören samt i relationslängden. Modellens tredje del visar att kundernas prat varierar i aktivitet och omfång beroende på valensen av upplevelserna och beroende på om prataren har starka eller svaga band till pratmottagaren. Det är viktigt och mycket aktuellt att öka förståelsen för kunders kommunikationsbeteende ur ett relationsperspektiv. Ur företagsledningssynvinkel är det viktigt att förstå hur kunders prat påverkar utvecklingen av verksamhetsmiljön. Ur praktiskt tillämpningsperspektiv kan en ökad kunskap om pratet vidare hjälpa företaget att fokusera på vad kunderna anser vara viktigt i en relation. Genom att veta vad kunderna pratar om kan företaget förbättra svagheter i verksamheten, och därigenom minska på andelen negativt prat eller uppmuntra kunder att prata om fördelar som relationen med företaget ger åt kunden.

The Day of the Week Effect and Option Pricing - A Study of the German Option Market

The use of different time units in option pricing may lead to inconsistent estimates of time decay and spurious jumps in implied volatilities. Different time units in the pricing model leads to different implied volatilities although the option price itself is the same.The chosen time unit should make it necessary to adjust the volatility parameter only when there are some fundamental reasons for it and not due to wrong specifications of the model. This paper examined the effects of option pricing using different time hypotheses and empirically investigated which time frame the option markets in Germany employ over weekdays. The paper specifically tries to get a picture of how the market prices options. The results seem to verify that the German market behaves in a fashion that deviates from the most traditional time units in option pricing, calendar and trading days. The study also showed that the implied volatility of Thursdays was somewhat higher and thus differed from the pattern of other days of the week. Using a GARCH model to further investigate the effect showed that although a traditional tests, like the analysis of variance, indicated a negative return for Thursday during the same period as the implied volatilities used, this was not supported using a GARCH model.

Evaluating Option Pricing Models

This study evaluates three different time units in option pricing: trading time, calendar time and continuous time using discrete approximations (CTDA). The CTDA-time model partitions the trading day into 30-minute intervals, where each interval is given a weight corresponding to the historical volatility in the respective interval. Furthermore, the non-trading volatility, both overnight and weekend volatility, is included in the first interval of the trading day in the CTDA model. The three models are tested on market prices. The results indicate that the trading-time model gives the best fit to market prices in line with the results of previous studies, but contrary to expectations under non-arbitrage option pricing. Under non-arbitrage pricing, the option premium should reflect the cost of hedging the expected volatility during the option’s remaining life. The study concludes that the historical patterns in volatility are not fully accounted for by the market, rather the market prices options closer to trading time.

Intraday and Weekend Volatility Patterns- Implications for Option Pricing

This study examines the intraday and weekend volatility on the German DAX. The intraday volatility is partitioned into smaller intervals and compared to a whole day’s volatility. The estimated intraday variance is U-shaped and the weekend variance is estimated to 19 % of a normal trading day. The patterns in the intraday and weekend volatility are used to develop an extension to the Black and Scholes formula to form a new time basis. Calendar or trading days are commonly used for measuring time in option pricing. The Continuous Time using Discrete Approximations model (CTDA) developed in this study uses a measure of time with smaller intervals, approaching continuous time. The model presented accounts for the lapse of time during trading only. Arbitrage pricing suggests that the option price equals the expected cost of hedging volatility during the option’s remaining life. In this model, time is allowed to lapse as volatility occurs on an intraday basis. The measure of time is modified in CTDA to correct for the non-constant volatility and to account for the patterns in volatility.

Volatility Smile Dynamics in Scenario Analysis

The objective of this paper is to suggest a method that accounts for the impact of the volatility smile dynamics when performing scenario analysis for a portfolio consisting of vanilla options. As the volatility smile is documented to change at least with the level of implied at-the-money volatility, a suitable model is here included in the calculation process of the simulated market scenarios. By constructing simple portfolios of index options and comparing the ex ante risk exposure measured using different pricing methods to realized market values, ex post, the improvements of the incorporation of the model are monitored. The analyzed examples in the study generate results that statistically support that the most accurate scenarios are those calculated using the model accounting for the dynamics of the smile. Thus, we show that the differences emanating from the volatility smile are apparent and should be accounted for and that the methodology presented herein is one suitable alternative for doing so.