Excimer laser refractive surgery : corneal wound healing and clinical results

Although the first procedure in a seeing human eye using excimer laser was reported in 1988 (McDonald et al. 1989, O'Connor et al. 2006) just three studies (Kymionis et al. 2007, O'Connor et al. 2006, Rajan et al. 2004) with a follow-up over ten years had been published when this thesis was started. The present thesis aims to investigate 1) the long-term outcomes of excimer laser refractive surgery performed for myopia and/or astigmatism by photorefractive keratectomy (PRK) and laser-in situ- keratomileusis (LASIK), 2) the possible differences in postoperative outcomes and complications when moderate-to-high astigmatism is treated with PRK or LASIK, 3) the presence of irregular astigmatism that depend exclusively on the corneal epithelium, and 4) the role of corneal nerve recovery in corneal wound healing in PRK enhancement. Our results revealed that in long-term the number of eyes that achieved uncorrected visual acuity (UCVA)≤0.0 and ≤0.5 (logMAR) was higher after PRK than after LASIK. Postoperative stability was slightly better after PRK than after LASIK. In LASIK treated eyes the incidence of myopic regression was more pronounced when the intended correction was over >6.0 D and in patients aged <30 years.Yet the intended corrections in our study were higher for LASIK than for PRK eyes. No differences were found in percentages of eyes with best corrected visual acuity (BCVA) or loss of two or more lines of visual acuity between PRK and LASIK in the long-term. The postoperative long-term outcomes of PRK with two different delivery systems broad beam and scanning laser were compared and revealed no differences. Postoperative outcomes of moderate-to-high astigmatism yielded better results in terms of UCVA and less compromise or loss of two more lines of BCVA after LASIK that after PRK.Similar stability for both procedures was revealed. Vector analysis showed that LASIK outcomes tended to be more accurate than PRK outcomes, yet no statistically differences were found. Irregular astigmatism secondary to recurrent corneal erosion due to map-dot-fingerprint was successfully treated with phototherapeutic keratectomy (PTK). Preoperative videokeratographies (VK) showed irregular astigmatism. However, postoperatively, all eyes showed a regular pattern. No correlation was found between pre- and postoperative VK patterns. Postoperative outcomes of late PRK in eyes originally subjected to LASIK showed that all (7/7) eyes achieved UCVA ≤0.5 at last follow-up (range 3 — 11 months), and no eye lost lines of BCVA. Postoperatively all eyes developed and initial mild haze (0.5 — 1) into the first month. Yet, at last follow-up 5/7 eyes showed a haze of 0.5 and this was no longer evident in 2/7 eyes. Based on these results, we demonstrated that the long-term outcomes after PRK and LASIK were safe and efficient, with similar stability for both procedures. The PRK outcomes were similar when treated by broad-beam or scanning slit laser. LASIK was better than PRK to correct moderate-to-high astigmatism, yet both procedures showed a tendency of undercorrection. Irregular astigmatism was proven to be able to depend exclusively from the corneal epithelium. If this kind of astigmatism is present in the cornea and a customized PRK/LASIK correction is done based on wavefront measurements an irregular astigmatism may be produced rather than treated. Corneal sensory nerve recovery should have an important role in the modulation of the corneal wound healing and post-operative anterior stromal scarring. PRK enhancement may be an option in eyes with previous LASIK after a sufficient time interval that in at least 2 years.

Nonlinear mixture autoregressive model: economic applications

The aim of this dissertation is to model economic variables by a mixture autoregressive (MAR) model. The MAR model is a generalization of linear autoregressive (AR) model. The MAR -model consists of K linear autoregressive components. At any given point of time one of these autoregressive components is randomly selected to generate a new observation for the time series. The mixture probability can be constant over time or a direct function of a some observable variable. Many economic time series contain properties which cannot be described by linear and stationary time series models. A nonlinear autoregressive model such as MAR model can a plausible alternative in the case of these time series. In this dissertation the MAR model is used to model stock market bubbles and a relationship between inflation and the interest rate. In the case of the inflation rate we arrived at the MAR model where inflation process is less mean reverting in the case of high inflation than in the case of normal inflation. The interest rate move one-for-one with expected inflation. We use the data from the Livingston survey as a proxy for inflation expectations. We have found that survey inflation expectations are not perfectly rational. According to our results information stickiness play an important role in the expectation formation. We also found that survey participants have a tendency to underestimate inflation. A MAR model has also used to model stock market bubbles and crashes. This model has two regimes: the bubble regime and the error correction regime. In the error correction regime price depends on a fundamental factor, the price-dividend ratio, and in the bubble regime, price is independent of fundamentals. In this model a stock market crash is usually caused by a regime switch from a bubble regime to an error-correction regime. According to our empirical results bubbles are related to a low inflation. Our model also imply that bubbles have influences investment return distribution in both short and long run.

Hyveiden harjoittaminen : edellytykset ja esteet

In the first half of the 20th century, most moral philosophers took the concept of virtue to be secondary to moral principles or emotions, though in various and mutually conflicting ways. In the early 1960s interest in the virtues was restored by the analytic philosophers Elizabeth Anscombe and Georg Henrik von Wright, the younger colleagues and friends of the late Wittgenstein. Later, Alasdair MacIntyre became a leading virtue ethicist. In 1981, MacIntyre introduced in After Virtue the concept of practices, which he based on the Aristotelian distinction between praxis and poiesis. This dissertation examines MacIntyre s characterization of the interconnectedness between practices and virtues, especially in relation to skills, education, and certain emotions. The primary position of the virtues is defended against the tendency in modern moral philosophy to overemphasize the role either of principles and rules or of emotions. The view according to which rational action and acting according to the virtues is best conceptualized as following rules or principles is criticized by arguments that are grounded by some Wittgensteinian observations, and that can be characterized as transcendental. Even if the virtues cannot be defined by, and are not based entirely on, emotions, the role of certain emotions on the learning and education of skills and virtues are studied more carefully than by MacIntyre. In the cases of resentment, indignation, and shame, the analysis of Peter Strawson is utilized, and in the case of regret, the analysis of Bernard Williams. Williams analysis of regret and moral conflict concludes in a kind of antirealism, which this study criticizes. Where education of practices and skills and the related reactive emotions are examined as conditions of learning and practicing the virtues, institutions and ideologies are examined as obstacles and threats to the virtues. This theme is studied through Karl Marx s conception of alienation and Karl Polanyi s historical and sociological research concerning the great transformation . The study includes six Finnish-published articles carrying the titles Our negative attitudes towards other persons , Authority and upbringing , Moral conflicts, regret and ethical realism , Practices and institutions , Doing justice as condition to communal action: a transcendental argument for justice as virtue , and Alienation from practices in capitalist society: Alasdair MacIntyre s Marxist Aristotelianism . The introductory essay sums up the themes of the articles and presents some central issues of virtue ethics by relating the classical Socratic questions to Aristotelian practical philosophy, as well as to current controversies in metaethics and moral psychology.

From Habits to Social Structures : Pragmatism and Contemporary Social Theory

Pragmatism has sometimes been taken as a catchphrase for epistemological stances in which anything goes. However, other authors argue that the real novelty and contribution of this tradition has to do with its view of action as the context in which all things human take place. Thus, it is action rather than, for example, discourses that should be our starting point in social theory. The introductory section of the book situates pragmatism (especially the ideas of G. H. Mead and John Dewey) within the field and tradition of social theory. This introductory also contextualizes the main core of the book which consists of four chapters. Two of these chapters have been published as articles in scientific journals and one in an edited book. All of them discuss the core problem of social theory: how is action related to social structures (and vice versa)? The argument is that habitual action is the explanation for the emergence of social structures from our action. Action produces structures and social reproduction takes place when action is habitualized; that is, when we develop social dispositions to act in a certain manner in familiar environments. This also means that even though the physical environment is the same for all of us, our habits structure it into different kinds of action possibilities. Each chapter highlights these general insights from different angles. Practice theory has gained momentum in recent years and it has many commonalities with pragmatism because both highlight the situated and corporeal character of human activity. One famous proponent of practice theory is Margaret Archer who has argued that the pragmatism of G. H. Mead leads to an oversocialized conception of selfhood. Mead does indeed present a socialized view of selfhood but this is a meta-sociological argument rather than a substantial sociological claim. Accordingly, one can argue that in this general sense intersubjectivity precedes subjectivity and not the other way around. Such a view does not indicate that our social relation would necessarily "colonize" individual action because there is a place for internal conversations (in Archer s terminology); it is especially in those phases of action where it meets obstacles due to the changes of the environment. The second issue discussed has the background assumption that social structures can fruitfully be conceptualized as institutions. A general classification of different institution theories is presented and it is argued that there is a need for a habitual theory of institutions due to the problems associated with these other theories. So-called habitual institutionalism accounts for institutions in terms of established and prevalent social dispositions that structure our social interactions. The germs of this institution theory can be found in the work of Thorstein Veblen. Since Veblen s times, these ideas have been discussed for example, by the economist Geoffrey M. Hodgson. His ideas on the evolution of institutions are presented but a critical stance is taken towards his tendency of defining institutions with the help of rules because rules are not always present in institutions. Accordingly, habitual action is the most basic but by no means the only aspect of institutional reproduction. The third chapter deals with theme of action and structures in the context of Pierre Bourdieu s thought. Bourdieu s term habitus refers to a system of dispositions which structure social fields. It is argued that habits come close to the concept of habitus in the sense that the latter consists of particular kinds of habits; those that are related to the reproduction of socioeconomic positions. Habits are thus constituents of a general theory of societal reproduction whereas habitus is a systematic combination of socioeconomic habits. The fourth theme relates to issues of social change and development. The capabilities approach has been associated with the name of Amartya Sen, for example, and it underscores problems inhering in economistic ways of evaluating social development. However, Sen s argument has some theoretical problems. For example, his theory cannot adequately confront the problem of relativism. In addition, Sen s discussion lacks also a theory of the role of the public. With the help of arguments derived from pragmatism, one gets an action-based, socially constituted view of freedom in which the role of the public is essential. In general, it is argued that a socially constituted view of agency does not necessarily to lead to pessimistic conclusions about the freedom of action.

Volume effects and associations in liquid alloys

The regular associated solution model for binary systems has been modified by incorporating the size of the complex as an explicit variable. The thermodynamic properties of the liquid alloy and the interactions between theA ?B type of complex and the unassociated atoms in anA-B binary have been evaluated as a function of relative size of the complex using the activity coefficients at infinite dilution and activity data at one other composition in the binary. The computational procedure adopted for determining the concentration of clusters and interaction energies in the associated liquid is similar to that proposed by Lele and Rao. The analysis has been applied to the thermodynamic mixing functions of liquid Al-Ca alloys believed to contain Al2Ca associates. It is found that the size of the cluster significantly affects the interaction energies between the complex and the unassociated atoms, while the equilibrium constant and enthalpy change for the association reaction exhibit only minor variation, when the equations are fitted to experimental data. The interaction energy between unassociated free atoms remains virtually unaltered as the size of the complex is varied between extreme values. Accurate data on free energy, enthalpy, and volume of mixing at the same temperature on alloy systems with compound forming tendency would permit a rigorous test of the proposed model.

Jauheiden erottuminen

Partikkelisysteemien segregaatio eli erottuminen on ilmiö, jossa tasalaatuisen jauheseoksen komponenteilla on taipumus erota toisistaan. Jauheen erottumistaipumus riippuu partikkelien ominaisuuksista, ympäröivistä olosuhteista ja partikkelien välisistä vuorovaikutuksista. Segregaatiomekanismeja on esitetty kirjallisuudessa valtava määrä ja pienetkin erot partikkelien välisissä ominaisuuksissa ja vuorovaikutuksissa voivat johtaa täysin eri segregaatiomekanismeihin. Segregaatioilmiö on lääketeollisuuden näkökulmasta hyvin keskeinen, eikä sitä tunneta vielä riittävän hyvin, jotta siltä osattaisiin systemaattisesti välttyä. Nykyinen segregaatiotutkimus perustuu suurelta osin yrityksen ja erehdyksen kautta tapahtuvaan oppimiseen. Todellisen segregaatioilmiön ymmärtämiseen tarvittaisiin innovatiivisia tutkimusmenetelmiä. Kokeellisen osan tarkoituksena oli kehittää ja perustestata menetelmä, jolla voidaan tutkia erilaisten partikkelisysteemien erottumiskäyttäytymistä, ja käyttää tätä menetelmää farmaseuttisten rae- ja pellettiseosten segregaation tutkimiseen. Tavoitteena oli todistaa kehitetyn Babel-laitteen toimintaperiaatteen soveltuvuus partikkelisysteemien erottumiskäyttäytymisen tutkimiseen, mutta suoritetut kokeet olivat lähinnä menetelmän ja laitteen testausta. Ongelmiksi muodostuivat Babel-laitteen asettamat rajoitukset, partikkelien sähköistyminen ja partikkelien väliset vuorovaikutukset. Käytetyt suoraviivaiset lähestymistavat eivät riittäneet segregaation aiheuttamiseen Babel-laitteella. Vertikaalisen ravistelun seurauksena syntynyt konvektiopyörre esti segregaation syntymisen. Johtopäätöksenä voidaan sanoa, että Babel-laite mittaa hyvin ja toistettavasti sekä se kykenee erottamaan erikokoiset partikkelit ja erilaiset kokojakaumat toisistaan. Laitteen kehittämistavoitteena olisi saada segregaatio paremmin näkyviin jauheseoksissa ravistelun seurauksena. Tällöin voitaisiin tehdä päätelmiä jauheseoksen erottumistaipumuksesta ja systeemissä vallitsevista erottumismekanismeista. Laitteen ja menetelmän jatkokehittäminen voisi tuottaa hyödyllistä lisätietoa, mikä edesauttaisi segregaation ymmärtämistä ilmiönä entistä paremmin

Using a botanic garden collection to test a bioclimatic vegetation scheme

Vegetation maps and bioclimatic zone classifications communicate the vegetation of an area and are used to explain how the environment regulates the occurrence of plants on large scales. Many practises and methods for dividing the world’s vegetation into smaller entities have been presented. Climatic parameters, floristic characteristics, or edaphic features have been relied upon as decisive factors, and plant species have been used as indicators for vegetation types or zones. Systems depicting vegetation patterns that mainly reflect climatic variation are termed ‘bioclimatic’ vegetation maps. Based on these it has been judged logical to deduce that plants moved between corresponding bioclimatic areas should thrive in the target location, whereas plants moved from a different zone should languish. This principle is routinely applied in forestry and horticulture but actual tests of the validity of bioclimatic maps in this sense seem scanty. In this study I tested the Finnish bioclimatic vegetation zone system (BZS). Relying on the plant collection of Helsinki University Botanic Garden’s Kumpula collection, which according to the BZS is situated at the northern limit of the hemiboreal zone, I aimed to test how the plants’ survival depends on their provenance. My expectation was that plants from the hemiboreal or southern boreal zones should do best in Kumpula, whereas plants from more southern and more northern zones should show progressively lower survival probabilities. I estimated probability of survival using collection database information of plant accessions of known wild origin grown in Kumpula since the mid 1990s, and logistic regression models. The total number of accessions I included in the analyses was 494. Because of problems with some accessions I chose to separately analyse a subset of the complete data, which included 379 accessions. I also analysed different growth forms separately in order to identify differences in probability of survival due to different life strategies. In most analyses accessions of temperate and hemiarctic origin showed lower survival probability than those originating from any of the boreal subzones, which among them exhibited rather evenly high probabilities. Exceptionally mild and wet winters during the study period may have killed off hemiarctic plants. Some winters may have been too harsh for temperate accessions. Trees behaved differently: they showed an almost steadily increasing survival probability from temperate to northern boreal origins. Various factors that could not be controlled for may have affected the results, some of which were difficult to interpret. This was the case in particular with herbs, for which the reliability of the analysis suffered because of difficulties in managing their curatorial data. In all, the results gave some support to the BZS, and especially its hierarchical zonation. However, I question the validity of the formulation of the hypothesis I tested since it may not be entirely justified by the BZS, which was designed for intercontinental comparison of vegetation zones, but not specifically for transcontinental provenance trials. I conclude that botanic gardens should pay due attention to information management and curational practices to ensure the widest possible applicability of their plant collections.

On the fundamentals of coherence theory

In the thesis I study various quantum coherence phenomena and create some of the foundations for a systematic coherence theory. So far, the approach to quantum coherence in science has been purely phenomenological. In my thesis I try to answer the question what quantum coherence is and how it should be approached within the framework of physics, the metatheory of physics and the terminology related to them. It is worth noticing that quantum coherence is a conserved quantity that can be exactly defined. I propose a way to define quantum coherence mathematically from the density matrix of the system. Degenerate quantum gases, i.e., Bose condensates and ultracold Fermi systems, form a good laboratory to study coherence, since their entropy is small and coherence is large, and thus they possess strong coherence phenomena. Concerning coherence phenomena in degenerate quantum gases, I concentrate in my thesis mainly on collective association from atoms to molecules, Rabi oscillations and decoherence. It appears that collective association and oscillations do not depend on the spin-statistics of particles. Moreover, I study the logical features of decoherence in closed systems via a simple spin-model. I argue that decoherence is a valid concept also in systems with a possibility to experience recoherence, i.e., Poincaré recurrences. Metatheoretically this is a remarkable result, since it justifies quantum cosmology: to study the whole universe (i.e., physical reality) purely quantum physically is meaningful and valid science, in which decoherence explains why the quantum physical universe appears to cosmologists and other scientists very classical-like. The study of the logical structure of closed systems also reveals that complex enough closed (physical) systems obey a principle that is similar to Gödel's incompleteness theorem of logic. According to the theorem it is impossible to describe completely a closed system within the system, and the inside and outside descriptions of the system can be remarkably different. Via understanding this feature it may be possible to comprehend coarse-graining better and to define uniquely the mutual entanglement of quantum systems.

Elämästä autofiktioksi : Lajitradition jäljillä Pirkko Saision romaanisarjassa Pienin yhteinen jaettava, Vastavalo ja Punainen erokirja

Pirkko Saisio's trilogy Pienin yhteinen jaettava (The Smallest Shared Dividend, 1998), Vastavalo (Against the Light, 2000), and Punainen erokirja (The Red Book of Separation, 2003), depicts the development of a masculine girl who at the end of the trilogy comes out as a homosexual women, a mother, and a writer. The main character is named Pirkko Saisio, and many of the events are picked from Saisio's real life. Nevertheless, the author wants the trilogy to be read as a novel, not a memoir. The present study analyses the generic elements of Saisio s trilogy and contextualizes the narrative identity that Saisio is creating in her fiction. Following Alastair Fowler s theory of genres as types without strict borders and a tendency to hybridity, the trilogy is linked to several genres. Serge Doubrovsky s genre concept of autofiction is the basis for the analysis: it explains the trilogy s borderline identity between autobiography and novel, and designates the main elements that render Saisio s autobiographical narrative into fiction. Both Doubrovsky and Saisio emphasize the role of the unconscious in writing, and at the same time stress the importance of a skilled composition. As well as autofiction, the trilogy is analyzed as a Bildungsroman, a confession and conversion narrative, a coming-out -narrative and a portrait-of-the-artist novel. Each genre is illuminated by its paradigmatic work: Wilhelm Meister s Apprenticeship by Goethe, The Confessions by St. Augustine, and The Well of Loneliness by Radclyffe Hall. The parallelisms between Saisio s trilogy and the typical plots of the genres and thematics of the classics show how the tradition works in Saisio s text. The thematic parallelisms highlight Saisio s concern for the conflicts that occur between an individual and the surrounding society, while the similarities in plots question the autobiographicality of Saisio s narrative but also clarify how Saisio refines the traditional genres. Read in the light of Saisio s trilogy, the classics are shown to have their gender-transgressive elements that the non-normative reader can identify with. Saisio s text also challenges universalizing claims about genre and gender. As a narrative of identity it follows the example of 1970s essentialistic coming-out stories, but at the same time depicts the notion of identity in a manner that manifests postmodern ideas about identity as multiple and ever-transforming. Keywords: autobiographicality, autofiction, identity narrative, genre research, Bildungsroman, conversion narrative, confession, coming-out story, a portrait-of-an-artist novel

Effect of colostrum feeding method and presence of dam on the sleep, rest and sucking behaviour of newborn calves

"In rats, sucking milk reduces anxiety and promotes non-rapid eye movement (NREM) sleep, and in calves it induces resting but the effect on sleep is unknown. Here, we investigated how calves' sleep was affected by colostrum feeding methods. Forty-one calves were blocked by birth date and randomly allotted within blocks to the experimental treatments. Calves were housed for four days either with their dam (DAM) or individually with warm colostrum feeding (2 L four times a day) from either a teat bucket (TEAT) or an open bucket (BUCKET). DAM calves suckled their dam freely. Calves' sleeping and sucking behaviour was filmed continuously for 48 h at the ages of two and three days. Behavioural sleep (BS) was defined as calves resting at least 30 s with their head still and raised (non-rapid eye movement) or with their head against their body or the ground (rapid eye movement, REM). Latency from the end of colostrum feeding to the start of BS was recorded. We compared behaviour of TEAT calves with that of DAM and BUCKET calves using mixed models. Milk meal duration was significantly longer for TEAT calves than for BUCKET calves (mean +/- S.E.M.; 8.3 +/- 0.6 min vs. 5.2 +/- 0.6 min), but equal to that of DAM calves. We found no effect of feeding method on the duration of daily BS (12 h 59 min I h 38 min) but we found a tendency for the daily amount of NREM sleep; BUCKET calves had less NREM sleep per day than TEAT calves (6 h 18 min vs. 7 h 48 min, S.E.M. = 45 min) and also longer latencies from milk ingestion to BS (21.9 +/- 2.0 min vs. 16.2 +/- 2.0 min). DAM calves slept longer bouts than TEAT calves (10.8 +/- 1.0 min vs. 8.3 +/- 1.0 min) and less often (78 +/- 4 vs. 92 +/- 4). Sucking colostrum from a teat bucket compared with drinking from an open"

Therapeutic change in interaction

A process of change within a single case of cognitive-constructivist therapy is analyzed by means of conversation analysis (CA). The focus is on a process of change in the sequences of interaction, which consist of the therapist’s conclusion and the patient’s response to it. In the conclusions, the therapist investigates and challenges the patient’s tendency to transform her feelings of disappointment and anger into self-blame. Over the course of the therapy, the patient’s responses to these conclusions are recast: from the patient first rejecting the conclusion, to then being ambivalent, and finally to agreeing with the therapist. On the basis of this case study, we suggest that an analysis that focuses on sequences of talk that are interactionally similar offers a sensitive method to investigate the manifestation of therapeutic change. It is suggested that this line of research can complement assimilation analysis and other methods of analyzing changes in a client’s talk.

Correlations between frequency of infra-red active vibrational modes and copper-oxygen distance in copper oxides. Application to superconductors

The infra-red spectra of a large number of ternary Cu(II) oxides with at least a quasi square-planar coordination of oxygen around the copper ions have been studied. The frequency of the bands with the highest frequency,v max, is found to correlate extremely well with the shortest Cu–O distance.v max increases at an impressive rate of sim20 cm–1 per 0.01 Å when the Cu–O distance becomes less than 1.97 Å, which is the Cu2+–O2– distance in square-planar CuO4 complexes as obtained from empirical ionic radii considerations. The marked sensitivity may be used as a ldquotitrationrdquo procedure not only to assign bands but also to obtain diagnostic information about local coordination in compounds derived, for example, from the YBa2Cu3O7–d structure such as LaCaBaCu3O7–d . The only example where this correlation fails is in the two-layer non-superconducting oxides derived from La2(Ca, Sr)Cu2O6. The significance of this result is discussed. The marked dependence of frequency on the bond-distance is qualitatively examined in terms of an increased electron-phonon coupling to account for the observed tendency of the superconducting transition temperature to go through a maximum as the average basal plane Cu–O distance is decreased.

Effect of amino acid substitutions at the subunit interface on the stabiity and aggregation properties of a dimeric protein: role of Arg 178 and Arg 218 at the dimer interface of thymidylate synthase

The significance of two interface arginine residues on the structural integrity of an obligatory dimeric enzyme thymidylate synthase (TS) from Lactobacillus casei was investigated by thermal and chemical denaturation. While the R178F mutant showed apparent stability to thermal denaturation by its decreased tendency to aggregate, the Tm of the R218K mutant was lowered by 5 degrees C. Equilibrium denaturation studies in guanidinium chloride (GdmCl) and urea indicate that in both the mutants, replacement of Arg residues results in more labile quaternary and tertiary interactions. Circular dichroism studies in aqueous buffer suggest that the protein interior in R218K may be less well-packed as compared to the wild type protein. The results emphasize that quaternary interactions may influence the stability of the tertiary fold of TS. The amino acid replacements also lead to notable alteration in the ability of the unfolding intermediate of TS to aggregate. The aggregated state of partially unfolded intermediate in the R178F mutant is stable over a narrower range of denaturant concentrations. In contrast, there is an exaggerated tendency on the part of R218K to aggregate in intermediate concentrations of the denaturant. The 3 A crystal structure of the R178F mutant reveals no major structural change as a consequence of amino acid substitution. The results may be rationalized in terms of mutational effects on both the folded and unfolded state of the protein. Site specific amino acid substitutions are useful in identifying specific regions of TS involved in association of non-native protein structures.

Treatment of illicit opioid and γ-hydroxybutyrate overdose by Helsinki emergency medical services

Aims: To examine the characteristics, incidence, treatment and outcome of presumed opioid, γ-hydroxybutyrate (GHB) and γ-butyrolactone (GBL) overdoses involving users of illicit drugs in Helsinki. GHB/GBL were included in this study, despite not being opioids, due to the relative ease with which they can cause potentially fatal respiratory depression. The incidence and time interval of recurrent opioid toxicity after prehospital administration of naloxone, an opioid antagonist, was studied in presumed heroin overdose patients. Naloxone has been reported to have many adverse effects and the effects of naloxone administered during an opioid overdose on the cardiovascular system and catecholamine levels in piglets were studied. Materials and methods: Patients included in these published retrospective studies were from the following time periods: Study I: 1995-2002, II: 1997-2000, III: 1995-2000, V: 2006-2007. Presumed opioid overdose patients were examined in studies I, II and III. GHB/GBL overdoses among injecting drug users was examined in study V. Recurrent opioid toxicity after prehospital naloxone administration in heroin overdose patients was examined in study III. The effects of naloxone (80 μg/kg i.v.) on the cardiovascular system and catecholamine levels administered during morphine overdose (8mg/kg i.v.) and under propofol anesthesia with spontaneous breathing were studied in eight piglets (IV). In this thesis, previously unpublished data on the incidence of opioid overdose between 2001-2007 and comparison of the characteristics of buprenorphine and heroin overdose patients encountered in 1995-2005 are also included. Results: Helsinki Emergency Medical Service (EMS) ambulances were dispatched annually to 34,153- 45,118 calls from 1995 to 2007. Of them, 7-8% were coded as intoxications or overdoses. During this time, 436 patients were treated by the EMS for presumed opioid overdose. The peak incidence of opioid overdoses was in the year 2000 (113 cases), after which they declined to 6-26 cases annually. The annual incidence of buprenorphine related overdoses increased from 4 (4% of opioid overdoses) in the year 2000 to 8 (30% of opioid overdoses) in 2007. The annual number of GHB related overdose patients treated by Helsinki EMS increased from 21 to 73 between 2004-2007. There appeared to be a peak in the incidence of both GHB/GBL and opioid related overdoses on Saturdays. Characteristics of opioid overdose patients The median age of opioid overdose patients was 28 years (22;33, 25- and 75-percentiles), and 84% were male. Buprenorphine overdose patients had more polydrug, such as alcohol and/or benzodiazepines, use in comparison with heroin overdose patients, 70% versus 33%, respectively. Severe respiratory depression was reported less often with buprenorphine overdoses compared to heroin overdoses, in 67.0% versus 85.4%, respectively. Outcome of heroin overdose patients with cardiac arrest Ninety four patients suffered cardiac arrest due to acute drug poisoning/overdose and were thus considered for resuscitation. Resuscitation was attempted in 72 cases. Cardiac arrest was caused by heroin overdose for 19 patients of which three (16%) were discharged alive. Other agents also induced cardiac arrest in 53 patients, of which six (11%) were discharged alive. The arrest was either EMS witnessed or occurring after the emergency call for all survivors of heroin induced cardiac arrest. Characteristics of GHB/GBL overdose patients The records of 100 GHB/GBL related overdose patients from 2006-2007 were retrieved. The median age of GHB/GBL overdose patients encountered on weekend nights was 24 years (22;27, 25- and 75-percentiles) and 49% were male. Polydrug use was reported in 62-80% of the cases. Thirty nine patients were encountered on Friday-Saturday or Saturday-Sunday night between 11 pm-6 am. The remaining sixty one patients were outside this time frame. There was a statistically significant difference between these two groups in history of chronic injecting drug use (33% vs. 59%, respectively, p=0.012). Recurrent heroin toxicity after prehospital naloxone administration Study III included 145 presumed heroin overdose patients. After prehospital care, 84 patients refused further care and were not transported to an Emergency Department (ED). Seventy one (85%) of them were administered naloxone by the EMS. During a 12-h follow up period, none of these patients developed severe recurrent opioid toxicity. The remaining 61 patients were transported to an ED. Prior to transportation, 52 (85%) patients were administered naloxone by the EMS. Fifteen of them were administered naloxone also in the ED and recurrent opioid toxicity was evident either on arrival at the ED or shortly thereafter. Prehospital naloxone was administered either intravenously, intramuscularly (i.m.) or subcutaneously (s.c.). There was a tendency for more frequent recurrent heroin toxicity among the patients with only intravenous administration of prehospital naloxone (13/36) compared with the patients with intramuscular or subcutaneous prehospital naloxone (2/16), p=0.106. The effects of naloxone on the cardiovascular system and catecholamine levels in piglets The administration of morphine to piglets resulted in an obvious respiratory depression, which was reversed by naloxone. Two severely hypoxemic piglets developed cardiac arrest after naloxone administration. In the other six animals, the administration of naloxone did not provoke arrhythmias, cardiac ischemia or visible evidence of pulmonary edema. There was a statistically significant (p=0.012) increase in norepinephrine levels after morphine administration and before naloxone administration: from 1.9 (1.3-2.3) ng/ml at baseline, to 31.7 (8.3-83.0) ng/ml (median, 25 and 75 percentiles parentheses) after morphine administration. After the administration of naloxone, the catecholamine levels continued to increase in only one of the animals. Conclusions: The incidence of buprenorphine related overdoses increased during the study period, but was still lower in comparison to those involving heroin. Injecting drug users have also started to use GHB/GBL. While recreational drug users use GHB/GBL during weekend nights, a GHB/GBL overdose patient encounter during weekdays has a more probable history of injecting drug use. Patients with cardiac arrest after heroin overdose have a poor prognosis. It appears to be safe to leave heroin overdose patients on scene after prehospital treatment with naloxone. Although no statistically significant difference was observed, it seems prudent to administer part of the total naloxone dose s.c. or i.m. to reduce the risk of recurrent respiratory depression. If transported to an ED, an observation period of one to two hours after the last naloxone dose seems adequate. The treating physician must be vigilant, however, due to the high prevalence of polydrug use and high morbidity after non fatal heroin overdose. Furthermore, care should be taken regarding possible chronic disorders and drug rehabilitation should be addressed. In the experimental animal study, two animals developed cardiac arrest after receiving naloxone while in hypoxemia and bradycardia. Further studies are required to assess the effect of naloxone during opioid-induced hypercapnia and hypoxemia in animals addicted to opioids.

Progression of diffuse gliomas - from the first diagnosis to recurrence

Gliomas are the most frequent primary brain tumours. The cardinal features of gliomas are infiltrative growth pattern and progression from low-grade tumours to a more malignant phenotype. These features of gliomas generally prevent their complete surgical excision and cause their inherent tendency to recur after initial treatment and lead to poor long-term prognosis. Increasing knowledge about the molecular biology of gliomas has produced new markers that supplement histopathological diagnostics. Molecular markers are also used to evaluate the prognosis and predict therapeutic response. The purpose of this thesis is to study molecular events involved in the malignant progression of gliomas. Gliomas are highly vascularised tumours. Contrast enhancement in magnetic resonance imaging (MRI) reflects a disrupted blood-brain barrier and is often seen in malignant gliomas. In this thesis, 62 astrocytomas, oligodendrogliomas and oligoastrocytomas were studied by MRI and immunohistochemistry. Contrast enhancement in preoperative MRI was associated with angiogenesis, tumour cell proliferation and histological grade of gliomas. Activation of oncogenes by gene amplification is a common genetic aberration in gliomas. EGFR amplification on chromosome 7p12 occurs in 30-40% of glioblastomas. PDGFRA, KIT and VEGFR2 are receptor tyrosine kinase genes located on chromosome 4q12. Amplification of these genes was studied using in situ hybridisation in the primary and recurrent astrocytomas, oligodendrogliomas and oligoastrocytomas of 87 patients. PDGFRA, KIT or VEGFR2 amplification was found in 22% of primary tumours and 36% of recurrent tumours including low-grade and malignant gliomas. The most frequent aberration was KIT amplification, which occurred in 10% of primary tumours and in 27% of recurrent tumours. The expression of ezrin, cyclooxygenase 2 (COX-2) and HuR was studied immunohistochemically in a series of primary and recurrent gliomas of 113 patients. Ezrin is a cell membrane-cytoskeleton linking-protein involved in the migration of glioma cells. The COX-2 enzyme is implicated in the carcinogenesis of epithelial neoplasms and is overexpressed in gliomas. HuR is an RNA-stabilising protein, which regulates the expression of several proteins including COX-2. Ezrin, COX-2 and HuR were associated with histological grade and the overall survival of glioma patients. However, in multivariate analysis they were not independent prognostic factors. In conclusion, these results suggest that contrast enhancement in MRI can be used as a surrogate marker for the proliferative and angiogenic potential of gliomas. Aberrations of PDGFRA, KIT and VEGFR2 genes, as well as the dysregulated expression of ezrin, COX-2 and HuR proteins, are linked to the progression of gliomas.