Pharmacoeconomics of Cyclamen europaeum in the management of Acute Rhinosinusitis

Objective. To carry out a pharmacoeconomic analysis of Cyclamen europaeum (CE) in the management of acute rhinosinusitis (ARS) in Spain using data from the PROSINUS study. Study Design. This was a prospective observational study to compare the effectiveness and cost-effectiveness between therapies including CE vs. other therapies in the management of ARS. Methods. The study was carried out as a secondary analysis of the PROSINUS, combining healthcare resource use, productivity loses, and health outcomes from the observational study with costs representative of the Spanish Health System. Results. CE given as monotherapy appears to be more effective (cure rate) than other monotherapies (15.3% higher, p<0.05) and combination (10.3% higher, p<0.05) therapies. The addition of CE to other single-drug or combination therapies showed a statistically significant improvement in terms of cure rates when adding CE to 2-drug combinations (93.9% vs. 76.5%; p<0.05), and no significant effect when added to combinations of three or more drugs (81.1% vs. 79.8; NS). CE based therapies generally showed lower indirect costs, although only the comparison of CE alone vs. other monotherapies, with a net cost savings of 101 per patient, reached statistical significance (331 vs. 432 , p<0.05). In addition, CE-based therapies show lower cost per cured patient in all comparisons except when CE was used in combination with three or more other drugs. Conclusions. The use of Cyclamen europaeum may be associated to better clinical outcomes at no additional cost for the healthcare system, respect to treatments commonly used for ARS in clinical practice.

The development of decision limits for the GH-2000 detection methodology using additional insulin-like growth factor-I and amino-terminal pro-peptide of type III collagen assays.

The GH-2000 and GH-2004 projects have developed a method for detecting GH misuse based on measuring insulin-like growth factor-I (IGF-I) and the amino-terminal pro-peptide of type III collagen (P-III-NP). The objectives were to analyze more samples from elite athletes to improve the reliability of the decision limit estimates, to evaluate whether the existing decision limits needed revision, and to validate further non-radioisotopic assays for these markers. The study included 998 male and 931 female elite athletes. Blood samples were collected according to World Anti-Doping Agency (WADA) guidelines at various sporting events including the 2011 International Association of Athletics Federations (IAAF) World Athletics Championships in Daegu, South Korea. IGF-I was measured by the Immunotech A15729 IGF-I IRMA, the Immunodiagnostic Systems iSYS IGF-I assay and a recently developed mass spectrometry (LC-MS/MS) method. P-III-NP was measured by the Cisbio RIA-gnost P-III-P, Orion UniQ? PIIINP RIA and Siemens ADVIA Centaur P-III-NP assays. The GH-2000 score decision limits were developed using existing statistical techniques. Decision limits were determined using a specificity of 99.99% and an allowance for uncertainty because of the finite sample size. The revised Immunotech IGF-I - Orion P-III-NP assay combination decision limit did not change significantly following the addition of the new samples. The new decision limits are applied to currently available non-radioisotopic assays to measure IGF-I and P-III-NP in elite athletes, which should allow wider flexibility to implement the GH-2000 marker test for GH misuse while providing some resilience against manufacturer withdrawal or change of assays. Copyright © 2015 John Wiley & Sons, Ltd.

Current Sheet Regulation of Solar Near-relativistic Electron Injection Histories

We present a sample of three large near-relativistic (>50 keV) electron events observed in 2001 by both the ACE and the Ulysses spacecraft, when Ulysses was at high-northern latitudes (>60◦) and close to 2 AU. Despite the large latitudinal distance between the two spacecraft, electrons injected near the Sun reached both heliospheric locations. All three events were associated with large solar flares, strong decametric type II radio bursts and accompanied by wide (>212◦) and fast (>1400 km s−1) coronal mass ejections (CMEs). We use advanced interplanetary transport simulations and make use of the directional intensities observed in situ by the spacecraft to infer the electron injection profile close to the Sun and the interplanetary transport conditions at both low and high latitudes. For the three selected events, we find similar interplanetary transport conditions at different heliolatitudes for a given event, with values of the mean free path ranging from 0.04 AU to 0.27 AU. We find differences in the injection profiles inferred for each spacecraft. We investigate the role that sector boundaries of the heliospheric current sheet (HCS) have on determining the characteristics of the electron injection profiles. Extended injection profiles, associated with coronal shocks, are found if the magnetic footpoints of the spacecraft lay in the same magnetic sector as the associated flare, while intermittent sparse injection episodes appear when the spacecraft footpoints are in the opposite sector or a wrap in the HCS bounded the CME structure.

Dual and Opposite Effects of hRAD51 Chemical Modulation on HIV-1 Integration.

The cellular DNA repair hRAD51 protein has been shown to restrict HIV-1 integration both in vitro and in vivo. To investigate its regulatory functions, we performed a pharmacological analysis of the retroviral integration modulation by hRAD51. We found that, in vitro, chemical activation of hRAD51 stimulates its integration inhibitory properties, whereas inhibition of hRAD51 decreases the integration restriction, indicating that the modulation of HIV-1 integration depends on the hRAD51 recombinase activity. Cellular analyses demonstrated that cells exhibiting high hRAD51 levels prior to de novo infection are more resistant to integration. On the other hand, when hRAD51 was activated during integration, cells were more permissive. Altogether, these data establish the functional link between hRAD51 activity and HIV-1 integration. Our results highlight the multiple and opposite effects of the recombinase during integration and provide new insights into the cellular regulation of HIV-1 replication.

Post-transcriptional regulation of circadian gene expression by miRNAs

La grande majorité des organismes vivants ont développé un système d'horloges biologiques internes, appelées aussi horloges circadiennes, contrôlant l'expression de gênes impliqués dans de nombreux processus moléculaires et comportementaux. Au cours de la dernière décennie, des analyses « microarray » et séquençages à haut débit sur divers tissus de mammifères, indiquent que jusqu'à 20% du transcriptome serait sous contrôle circadien. Il était jusqu'à présent admis que la majorité des ARNm ayant une accumulation rythmique était générée par une transcription qui était elle-même rythmique. Toutefois, de récentes études ont suggéré qu'une proportion considérable des ARNm cycliques serait en fait générée par des mécanismes post-transcriptionnelles, incluant une régulation par micro-ARN (miARN). Lorsque j'ai débuté mon travail de thèse, l'influence des miARN sur l'expression des gènes circadiens, au niveau pangénomique, était encore méconnue. Par l'utilisation d'un modèle murin, dont la biogenèse des miARN a été spécifiquement désactivée au niveau des cellules hépatiques (knockout conditionnel pour Dicer), je me suis donc intéressée au rôle que jouaient ces molécules régulatrices sur la rythmicité de l'expression génique dans le foie. Des séquençages sur l'ensemble du transcriptome révèlent que l'horloge interne du foie est étonnement résistante à la perte totale des miARN. Nous avons cependant trouvé que les miARN agissent de façon importante sur la régulation de l'expression des gènes contrôlés par l'horloge moléculaire. La corégulation par les miARN, affectant jusqu'à 30% des gènes transcrits de façon rythmiques, conduit ainsi à une modulation de phase et d'amplitude du rythme de l'abondance des ARNm. En revanche, seuls peu de transcrits dépendent uniquement des miARN pour la rythmicité de leur accumulation. Enfin, mon travail met en évidence plusieurs miARN spécifiques, qui semblent préférentiellement moduler l'expression des gènes cycliques et permet l'identification de voies hépatiques particulièrement sujettes à une double régulation par les miARN et l'horloge biologique interne. La première masse d'analyses a essentiellement porté sur le rôle que jouent les miARN au niveau de l'expression des gènes contrôlés par l'horloge interne. Dans deux études de suivi, je me suis penchée sur deux aspects supplémentaires et complémentaires de la manière dont les miARN et l'oscillation de l'expression des gènes interagissent. Dans les hépatocytes murins, spécifiquement privés de Dicer, je me suis demandée si un phénotype horloge avait pu être masqué, dû à un entraînement stable de l'horloge du foie par l'horloge maîtresse du cerveau. J'ai donc commencé une série d'expériences ambitieuses (impliquant la mesure de la rythmicité du foie in vivo, chez l'animal vivant) afin de déséquilibrer l'entrainement de l'horloge hépatique via l'utilisation d'un protocole nutritionnel spécifique. Les premiers résultats suggèrent que dans des conditions où l'animal subit une restriction alimentaire pendant la journée, les miARN sont importants dans la cinétique d'adaptation des organes périphériques à un nouvel horaire de sustentation. Dans une deuxième ligne de recherche, j'ai plus profondément étudié quels seraient les miARN responsables des rythmes post-transcriptionnels des ARNm, en utilisant le séquençage de « small » ARN sur 24h. L'analyse est en cours et se poursuivra après l'obtention de mon diplôme. De façon générale, mon travail révèle d'importants et nouveaux rôles des miARN dans la modulation de l'expression circadienne des gènes hépatiques. De plus, le set de données générées dans l'étude déjà publiée, peut dorénavant servir de ressource valable pour de prochaines investigations sur le rôle physiologique que les miARN jouent au niveau du foie. -- Most living organisms have developed internal timing systems, called circadian clocks, to drive the rhythmic expression of genes involved in many molecular and behavioral processes. Over the last decade, microarray analyses and high- throughput sequencing from various mammalian tissues have indicated that up to 20% of the transcriptome are under circadian control. It was generally assumed that the majority of rhythmic mRNA accumulation is generated by rhythmic transcription. However, recent studies have suggested that a considerable proportion of mRNA cycling may actually be generated by post-transcriptional mechanisms, including by microRNAs. When I started my thesis work, it was still unknown how miRNAs influence circadian gene expression in a genome-wide fashion. Using a mouse model in which miRNA biogenesis can be inactivated in hepatocytes (conditional Dicer knockout mouse), I have thus addressed the role that these regulatory molecules play in rhythmic gene expression in the liver. Whole transcriptome sequencing revealed that the hepatic core clock was surprisingly resilient to total miRNA loss. However, we found that miRNAs acted as important regulators of clock-controlled gene expression. Co- regulation by miRNAs, which affected up to 30% of rhythmically transcribed genes, thus led to the modulation of phases and amplitudes of mRNA abundance rhythms. By contrast, only very few transcripts were strictly dependent on miRNAs for their rhythmic accumulation. Finally, my work highlights several specific miRNAs that appear to preferentially modulate cyclic gene expression, and identifies pathways in the liver that are particularly prone to dual regulation through miRNAs and the clock. The first bulk of analyses mainly dealt with the role that miRNAs play at the level of rhythmic clock output gene expression. In two follow-up studies I further delved into two additional, complementary aspects of how miRNAs and gene expression oscillations interact. First, I addressed whether a core clock phenotype in the hepatocyte-specific Dicer knockout could have been masked due to the stable entrainment of the liver clock by the animals' master clock in the brain. I thus started a series of ambitious experiments (involving the in vivo recording of liver rhythms in live animals) to bring the stable entrainment of the liver clock out of equilibrium using specific feeding protocols. My first results suggest that under conditions when animals are challenged by food restriction to daytime, miRNAs are important for the kinetics of adapting to unusual mealtime in peripheral tissue. In a second line of research, I have more carefully investigated which miRNAs are responsible for post- transcriptional mRNA rhythms using small RNA sequencing around-the-clock. The analyses are ongoing and will be continued after my graduation. Overall, my work uncovered important and novel roles of miRNA activity in shaping hepatic circadian gene expression; moreover, the datasets collect in the published studies can serve as a valuable resource for further investigations into the physiological roles that miRNAs play in liver. -- L'alternance du jour et de la nuit dirige depuis longtemps la vie quotidienne des êtres humains et de la plupart des organismes sur terre. Ce cycle de 24 heures façonne beaucoup de changements comportementaux et physiologiques tels que la vigilance, la température corporelle et le sommeil. Les rythmes journaliers, appelés rythmes circadiens, sont dirigés par des horloges biologiques tournant dans presque chaque cellule du corps. Une structure dans le cerveau agit en tant qu'horloge maitresse pour synchroniser les horloges internes entre elles et en fonction des signaux de jour/nuit extérieurs. Dans les cellules "les gènes de l'horloge" sont activés et désactivés une fois par jour ce qui déclenche des cycles dans lesquels des protéines sont produites de manière circadienne. Ces rythmes protéiques sont spécialisés pour chaque tissu ou organe et peuvent les aider à réaliser leurs tâches quotidiennes. Les rythmes circadiens peuvent être générés d'autres manières n'impliquant pas directement les composants des gènes de l'horloge. Les ARN messagers (ARNm) sont des molécules intermédiaires dans la production de protéines à partir d'ADN. Dans le foie des souris jusqu'à 20% des molécules d'ARNm sont produites suivant des rythmes circadiens. Le foie réalise des tâches essentielles dans le contrôle du métabolisme incluant celui des hydrates de carbone, des graisses et du cholestérol. Un timing précis est important afin de traiter les substances nutritives correctement lors des repas il en résulte une variation des quantités de certains ARNm et protéines coïncidant avec les repas. Les microARNs constituent une autre classe de molécules ARN de très petite taille qui régulent l'efficacité de traduction des ARNm en protéines et la stabilité des ARNm. Lors de mon travail de thèse, j'ai exploré de manière approfondie l'influence de ces petits régulateurs sur les rythmes circadiens du foie de souris. Ces expériences qui impliquaient le "Knock-out" d'un gène essentiel à la production de microARNs montrent qu'au lieu de générer les rythmes des ARNm, les microARNs les ajustent pour répondre aux besoins spécifiques du foie comme assurer leur pic au bon moment de la journée. Le ciblage de microARNs spécifiques peut révéler de nouvelles stratégies pour rectifier ces rythmes lorsque par exemple les fonctions métaboliques ne fonctionnent plus normalement. -- The rising and setting of the sun have long driven the daily schedules of humans and most organisms on the earth. This 24-hr cycle shapes many behavioural and physiological changes, such as alertness, body temperature, and sleep. These daily rhythms, which are called circadian rhythms, are dictated by biological clocks that are ticking in almost every single cell of the body. A region in the brain acts as a master clock to synchronize the internal clocks with each other and with the outside light/dark cycles. In cells, "core clock genes" are turned on and off once per day, which triggers cycles that cause some proteins to be produced in a circadian manner. The protein rhythms are specialized to a particular tissue or organ, and may help them to carry out their designated daily tasks. However, circadian rhythms might also be produced by other ways that do not involve these core clock components. Messenger RNAs (mRNAs) are intermediate molecules in the production of proteins from DNA. In the mouse liver, up to 20% of mRNA molecules are produced in circadian cycles. The liver performs essential tasks that control metabolism-including that of carbohydrates, fats, and cholesterol. Precisely timing when certain mRNAs and proteins reach peaks and troughs in their activities to coincide with mealtimes is important for nutrients to be properly processed. Other RNA molecules called microRNAs, i.e. RNAs of very small size, regulate at which rate mRNA molecules are translated into proteins. In my thesis work, I have explored at the influence of these small regulators on circadian rhythms in the mouse liver in greater detail. These experiments, which involved "knocking out" a gene that is essential for the production of microRNAs, show that rather than generating the mRNA rhythms, the microRNAs appear to adjust them to meet the specific needs of the liver, such as ensuring that they peak at the right time-of-day. Targeting specific microRNA molecules may reveal new strategies to tweak these rhythms, which could help to improve conditions when metabolic functions go wrong.

Contextual factors multiplex to control multisensory processes.

This study analyzed high-density event-related potentials (ERPs) within an electrical neuroimaging framework to provide insights regarding the interaction between multisensory processes and stimulus probabilities. Specifically, we identified the spatiotemporal brain mechanisms by which the proportion of temporally congruent and task-irrelevant auditory information influences stimulus processing during a visual duration discrimination task. The spatial position (top/bottom) of the visual stimulus was indicative of how frequently the visual and auditory stimuli would be congruent in their duration (i.e., context of congruence). Stronger influences of irrelevant sound were observed when contexts associated with a high proportion of auditory-visual congruence repeated and also when contexts associated with a low proportion of congruence switched. Context of congruence and context transition resulted in weaker brain responses at 228 to 257 ms poststimulus to conditions giving rise to larger behavioral cross-modal interactions. Importantly, a control oddball task revealed that both congruent and incongruent audiovisual stimuli triggered equivalent non-linear multisensory interactions when congruence was not a relevant dimension. Collectively, these results are well explained by statistical learning, which links a particular context (here: a spatial location) with a certain level of top-down attentional control that further modulates cross-modal interactions based on whether a particular context repeated or changed. The current findings shed new light on the importance of context-based control over multisensory processing, whose influences multiplex across finer and broader time scales.

Implementació d’un sistema SCADA a la cèl·lula de fabricació flexible MPS+2000C

L’Escola Politècnica Superior de la Universitat de Vic disposa d’una cèl·lula de fabricació flexible del fabricant Festo, que simula un procés d’emmagatzematge automàtic, aquesta cèl·lula esta composta per quatre estacions de muntatge diferenciades i independents, l’estació palets, l’estació plaques, l’estació magatzem intermedi i l’estació transport. Cada una d’aquestes estacions està formada per sensors i actuadors elèctrics i pneumàtics del fabricant Festo que van connectats a un PLC SIEMENS S7-300.Els quatre PLC’s (un per cada estació) estan connectats entre ells mitjançant el bus de comunicacions industrials Profibus. L’objectiu d’aquest treball consisteix en l’adaptació de la programació dels PLC’s i la realització d’un SCADA per tal de controlar el funcionament del conjunt de la cèl·lula de fabricació a través del software Vijeo Citect, d’aquesta manera es coneixerà el funcionament de la cèl·lula i permetrà treure’n rendiment per la docència. Aquest projecte ha estat realitzat en quatre fases principals. 1. Estudi i coneixement de les estacions, en aquesta fase s’han estudiat els manuals de funcionament de les estacions i s’han interpretat els codis de programació dels seus PLCs, amb l’objectiu de conèixer bé el programa per tal de interaccionar-hi més endavant amb el sistema SCADA 2. Disseny i programació del sistema SCADA, en aquesta fase s’ha realitzat tot el disseny gràfic de les pantalles de la interfície SCADA així com la programació dels objectes, la connexió amb els PLCs i la base de dades. 3. Posada en marxa del sistema complert, quan es coneixia abastament el funcionament de les estacions i el sistema SCADA estava completat s’ha fet la posada en marxa del conjunt i s’ha comprovat el correcte funcionament i interacció dels sistemes. 4. Realització de la memòria del projecte, en aquesta ultima fase s’ha realitzat la memòria del projecte on s’expliquen les característiques i funcionament de totes les estacions i del sistema SCADA. La conclusió més rellevant obtinguda en aquest treball, és la clara visualització de la potència i simplicitat que han aportat els sistemes SCADA al món de l’automatització, anys enrere per la supervisió de l’estat d’un sistema automatitzat era necessari disposar d’un gran espai amb grans panells de control formats per una gran quantitat de pilots lluminosos, potenciòmetres, interruptors, polsadors, displays i sobretot un voluminós i complexa cablejat, gràcies als sistemes SCADA avui en dia tot això pot quedar reduït a un PC o terminal tàctil, amb pantalles gràfiques clares i una gran quantitat d’opcions de supervisió control i configuració del sistema automatitzat.

Current Sheet Regulation of Solar Near-Relativistic Electron Injection Histories

We present a sample of three large near-relativistic (>50 keV) electron events observed in 2001 by both the ACE and the Ulysses spacecraft, when Ulysses was at high-northern latitudes (>60°) and close to 2 AU. Despite the large latitudinal distance between the two spacecraft, electrons injected near the Sun reached both heliospheric locations. All three events were associated with large solar flares, strong decametric type II radio bursts and accompanied by wide (>212°) and fast (>1400 km s-1) coronal mass ejections (CMEs). We use advanced interplanetary transport simulations and make use of the directional intensities observed in situ by the spacecraft to infer the electron injection profile close to the Sun and the interplanetary transport conditions at both low and high latitudes. For the three selected events, we find similar interplanetary transport conditions at different heliolatitudes for a given event, with values of the mean free path ranging from 0.04 AU to 0.27 AU. We find differences in the injection profiles inferred for each spacecraft. We investigate the role that sector boundaries of the heliospheric current sheet (HCS) have on determining the characteristics of the electron injection profiles. Extended injection profiles, associated with coronal shocks, are found if the magnetic footpoints of the spacecraft lay in the same magnetic sector as the associated flare, while intermittent sparse injection episodes appear when the spacecraft footpoints are in the opposite sector or a wrap in the HCS bounded the CME structure.

Correcting Interdevice Bias of Horizontal White-to-White and Sulcus-to-Sulcus Measures Used for Implantable Collamer Lens Sizing.

PURPOSE: To assess the agreement and repeatability of horizontal white-to-white (WTW) and horizontal sulcus-to-sulcus (STS) diameter measurements and use these data in combination with available literature to correct for interdevice bias in preoperative implantable collamer lens (ICL) size selection. DESIGN: Interinstrument reliability and bias assessment study. METHODS: A total of 107 eyes from 56 patients assessed for ICL implantation at our institution were included in the study. This was a consecutive series of all patients with suitable available data. The agreement and bias between WTW (measured with the Pentacam and BioGraph devices) and STS (measured with the HiScan device) were estimated. RESULTS: The mean spherical equivalent was -8.93 ± 5.69 diopters. The BioGraph measures of WTW were wider than those taken with the Pentacam (bias = 0.26 mm, P < .01), and both horizontal WTW measures were wider than the horizontal STS measures (bias >0.91 mm, P < .01). The repeatability (Sr) of STS measured with the HiScan was 0.39 mm, which was significantly reduced (Sr = 0.15 mm) when the average of 2 measures was used. Agreement between the horizontal WTW measures and horizontal STS estimates when bias was accounted for was г = 0.54 with the Pentacam and г = 0.64 with the BioGraph. CONCLUSIONS: Large interdevice bias was observed for WTW and STS measures. STS measures demonstrated poor repeatability, but the average of repeated measures significantly improved repeatability. In order to conform to the US Food and Drug Administration's accepted guidelines for ICL sizing, clinicians should be aware of and account for the inconsistencies between devices.

Evolutionary Ecology of Mountain Birch in Subarctic Stress Gradients: Interplay of Biotic and Abiotic Factors in Plant-Plant Interactions and Evolutionary Processes

In nature, variation for example in herbivory, wind exposure, moisture and pollution impact often creates variation in physiological stress and plant productivity. This variation is seldom clear-cut, but rather results in clines of decreasing growth and productivity towards the high-stress end. These clines of unidirectionally changing stress are generally known as ‘stress gradients’. Through its effect on plant performance, stress has the capacity to fundamentally alter the ecological relationships between individuals, and through variation in survival and reproduction it also causes evolutionary change, i.e. local adaptations to stress and eventually speciation. In certain conditions local adaptations to environmental stress have been documented in a matter of just a few generations. In plant-plant interactions, intensities of both negative interactions (competition) and positive ones (facilitation) are expected to vary along stress gradients. The stress-gradient hypothesis (SGH) suggests that net facilitation will be strongest in conditions of high biotic and abiotic stress, while a more recent ‘humpback’ model predicts strongest net facilitation at intermediate levels of stress. Plant interactions on stress gradients, however, are affected by a multitude of confounding factors, making studies of facilitation-related theories challenging. Among these factors are plant ontogeny, spatial scale, and local adaptation to stress. The last of these has very rarely been included in facilitation studies, despite the potential co-occurrence of local adaptations and changes in net facilitation in stress gradients. Current theory would predict both competitive effects and facilitative responses to be weakest in populations locally adapted to withstand high abiotic stress. This thesis is based on six experiments, conducted both in greenhouses and in the field in Russia, Norway and Finland, with mountain birch (<i>Betula pubescensi> subsp. <i>czerepanovii)i> as the model species. The aims were to study potential local adaptations in multiple stress gradients (both natural and anthropogenic), changes in plant-plant interactions under conditions of varying stress (as predicted by SGH), potential mechanisms behind intraspecific facilitation, and factors confounding plant-plant facilitation, such as spatiotemporal, ontogenetic, and genetic differences. I found rapid evolutionary adaptations (occurring within a time-span of 60 to 70 years) towards heavy-metal resistance around two copper-nickel smelters, a phenomenon that has resulted in a trade-off of decreased performance in pristine conditions. Heavy-metal-adapted individuals had lowered nickel uptake, indicating a possible mechanism behind the detected resistance. Seedlings adapted to heavy-metal toxicity were not co-resistant to others forms of abiotic stress, but showed co-resistance to biotic stress by being consumed to a lesser extent by insect herbivores. Conversely, populations from conditions of high natural stress (wind, drought etc.) showed no local adaptations, despite much longer evolutionary time scales. Due to decreasing emissions, I was unable to test SGH in the pollution gradients. In natural stress gradients, however, plant performance was in accordance with SGH, with the strongest host-seedling facilitation found at the high-stress sites in two different stress gradients. Factors confounding this pattern included (1) plant size / ontogenetic status, with seedling-seedling interactions being competition dominated and host-seedling interactions potentially switching towards competition with seedling growth, and (2) spatial distance, with competition dominating at very short planting distances, and facilitation being strongest at a distance of circa ¼ benefactor height. I found no evidence for changes in facilitation with respect to the evolutionary histories of plant populations. Despite the support for SGH, it may be that the ‘humpback’ model is more relevant when the main stressor is resource-related, while what I studied were the effects of ‘non-resource’ stressors (i.e. heavy-metal pollution and wind). The results have potential practical applications: the utilisation of locally adapted seedlings and plant facilitation may increase the success of future restoration efforts in industrial barrens as well as in other wind-exposed sites. The findings also have implications with regard to the effects of global change in subarctic environments: the documented potential by mountain birch for rapid evolutionary change, together with the general lack of evolutionary ‘dead ends’, due to not (over)specialising to current natural conditions, increase the chances of this crucial forest-forming tree persisting even under the anticipated climate change.

Expertise and decision making among clinicians in investigations of alleged child sexual abuse

The purpose of the present thesis was to explore different aspects of decision making and expertise in investigations of child sexual abuse (CSA) and subsequently shed some light on the reasons for shortcomings in the investigation processes. Clinicians’ subjective attitudes as well as scientifically based knowledge concerning CSA, CSA investigation and interviewing were explored. Furthermore the clinicians’ own view on their expertise and what enhances this expertise was investigated. Also, the effects of scientific knowledge, experience and attitudes on the decision making in a case of CSA were explored. Finally, the effects of different kinds of feedback as well as experience on the ability to evaluate CSA in the light of children’s behavior and base rates were investigated. Both explorative and experimental methods were used. The purpose of Study I was to investigate whether clinicians investigating child sexual abuse (CSA) rely more on scientific knowledge or on clinical experience when evaluating their own expertise. Another goal was to check what kind of beliefs the clinicians held. The connections between these different factors were investigated. A questionnaire covering items concerning demographic data, experience, knowledge about CSA, selfevaluated expertise and beliefs about CSA was given to social workers, child psychiatrists and psychologists working with children. The results showed that the clinicians relied more on their clinical experience than on scientific knowledge when evaluating their expertise as investigators of CSA. Furthermore, social workers possessed stronger attitudes in favor of children than the other groups, while child psychiatrists had more negative attitudes towards the criminal justice system. Male participants held less strong beliefs than female participants. The findings indicate that the education of CSA investigators should focus more on theoretical knowledge and decision making processes as well as the role of beliefs In Study II school and family counseling psychologists completed a Child Sexual Abuse Attitude and Belief Scale. Four CSA related attitude and belief subscales were identified: 1. <i>The Disclosure subscalei> reflecting favoring a disclosure at any cost, 2. <i>The Pro-Child subscale i> reflecting unconditional belief in children's reports, 3. <i>The Intuition subscalei> reflecting favoring an intuitive approach to CSA investigations, and 4. <i>The Anti Criminal Justice System subscale i> reflecting negative attitudes towards the legal system. Beliefs that were erroneous according to empirical research were analyzed separately. The results suggest that some psychologists hold extreme attitudes and many erroneous beliefs related to CSA. Some misconceptions are common. Female participants tended to hold stronger attitudes than male participants. The more training in interviewing children the participants have, the more erroneous beliefs and stronger attitudes they hold. Experience did not affect attitudes and beliefs. In Study III mental health professionals’ sensitivity to suggestive interviewing in CSA cases was explored. Furthermore, the effects of attitudes and beliefs related to CSA and experience with CSA investigations on the sensitivity to suggestive influences in the interview were investigated. Also, the effect of base rate estimates of CSA on decisions was examined. A questionnaire covering items concerning demographic data, different aspects of clinical experience, self-evaluated expertise, beliefs and knowledge about CSA and a set of ambiguous material based on real trial documents concerning an alleged CSA case was given to child mental health professionals. The experiment was based on a 2 x 2 x 2 x 2 (leading questions: yes vs no) x (stereotype induction: yes vs no) x (emotional tone: pressure to respond vs no pressure to respond) x (threats and rewards: yes vs no) between-subjects factorial design, in which the suggestiveness of the methods with which the responses of the child were obtained were varied. There was an additional condition in which the material did not contain any interview transcripts. The results showed that clinicians are sensitive only to the presence of leading questions but not to the presence of other suggestive techniques. Furthermore, the clinicians were not sensitive to the possibility that suggestive techniques could have been used when no interview transcripts had been included in the trial material. Experience had an effect on the sensitivity of the clinicians only regarding leading questions. Strong beliefs related to CSA lessened the sensitivity to leading questions. Those showing strong beliefs on the belief scales used in this study were even more prone to prosecute than other participants when other suggestive influences than leading questions were present. Controversy exists regarding effects of experience and feedback on clinical decision making. In Study IV the impact of the number of handled cases and of feedback on the decisions in cases of alleged CSA was investigated. One-hundred vignettes describing cases of suspected CSA were given to students with no experience with investigating CSA. The vignettes were based on statistical data about symptoms and prevalence of CSA. According to the theoretical likelihood of CSA the children described were categorized as abused or not abused. The participants were asked to decide whether abuse had occurred. They were divided into 4 groups: one received feedback on whether their decision was right or wrong, one received information about cognitive processes involved in decision making, one received both, and one did not receive feedback at all. The results showed that participants who received feedback on their performance made more correct positive decisions and participants who got information about decision making processes made more correct negative decisions. Feedback and information combined decreased the number of correct positive decisions but increased the number of correct negative decisions. The number of read cases had in itself a positive effect on correct positive decision.

Borrelia burgdorferi evades the effects of ceftriaxone treatment in a mouse model of Lyme borreliosis

<i>Borrelia burgdorferii> infektoitujen hiirten antibioottihoidon jälkeinen oireilu Lymen borrelioosi on puutiaisten välittämä monimuotoinen infektiotauti, jonka tunnetuin oire on ns. vaeltava ihottuma eli erythema migrans. Muita tavallisia ilmentymiä ovat erityisesti nivel- ja hermosto-oireet sekä harvemmin sydän- ja silmäoireet. Suurin osa potilaista paranee täysin terveeksi antibioottihoidon avulla, mutta jopa 10 % borrelioosiin sairastuneista oireilee suositusten mukaisesta hoidosta huolimatta. Pitkittyneen oireilun on ajateltu johtuvan mm. infektion laukaisemasta autoimmuunitaudista tai kroonisesta infektiosta, mutta teorioiden tueksi ei ole kyetty esittämään kiistattomia todisteita. Onkin todennäköistä, että antibioottihoidon jälkeisen oireilun takana on useampia mekanismeja eikä yksi teoria selitä kaikkien potilaiden oireilua. Tässä väitöskirjatyössä on tutkittu hoidonjälkeistä borrelioosia hiirimallin avulla. Varhaisvaiheessa (2 viikkoa infektoinnin jälkeen) annettu antibiootti vähensi hiirten nivelturvotusta ja esti B. burgdorferi – bakteerin kasvun kudoksista otetuista näytteissä. Hoidettu¬jen hiirten B. burgdorferi -spesifiset IgG-luokan vasta-aineet pysyivät kuitenkin koholla ja osasta kudosnäytteistä löytyi B. burgdorferi:n DNA:ta PCR-tutkimuksen avulla. Mikäli hiiret hoidettiin myöhäisessä vaiheessa (yli 18 viikkoa infektoinnista) tulokset olivat muuten samanlaiset, mutta keftriaksoni ei vaikuttanut nivelturvotukseen. Näin hiirissä oli aikaansaatu tilanne, joka on hyvin samankaltainen ihmisen hoitoresistentin borrelia-artriitin kanssa: oireet jatkuvat, mutta taudinaiheuttajaa ei saada esiin. Inflammaatiota vaimentavaa anti-TNF-alphaa on käytetty nivelreuman hoidossa menestyksekkäästi huonosti muuhun hoitoon reagoivilla potilailla ja siitä syystä sen ajateltiin voivan vaikuttaa suotuisasti myös <i>B. burgdorferii> -infektoitujen hiirten hoidonjälkeiseen nivelturvotukseen. Sillä ei kuitenkaan ollut vaikutusta nivelturvotukseen, mutta yllättäen hoidon jälkeen osa hiirten kudosnäytteistä osoittautui viljelypositiivisiksi. On siis ilmeistä, että hiirimallissamme osa <i>B. burgdorferii> spirokeetoista pystyy välttämään keftriaksonihoidon vaikutuksen joko hakeutumalla elimistössä kudokseen, jossa antibiootin pitoisuus ei nouse riittävän korkeaksi, tai ne kykenevät muuntautumaan metabolisesti inaktiiviin tilaan eikä mikrobilääke yhdessä immuunipuolustuksen kanssa onnistu tappamaan niitä. Jatkotutkimuksissa selvitimme <i>B. burgdorferi i>- spirokeetan mahdollista piilopaikkaa tutkimalla antibioottihoidon jälkeen useita eri kudoksia PCR-menetelmällä. Tulosten perusteella spirokeetta näyttää suosivan nivelkudosta tai soluja, joita esiintyy nivelessä runsaasti. On kuitenkin edelleen epäselvää, missä muodossa <i>B. burgdorferii> –spirokeetat säilyvät kudoksessa antibioottihoidon jälkeen.

Métodos de reconocimiento del subsuelo

The aim of this workshop is to present the main methods of subsoil studies (namely mechanical and geophysical methods) to the Earth Sciences professorate. These methods frequently involve the use of specific material. The different methods are usually taught in the classroom where there is no real contact between the students and the equipment. Several activities, all of them taking place in surrounding areas of the university campus of Girona, will provide the assistants to the workshop with the opportunity of making measurements with different equipment. These activities will be made in the field so as to contribute to the resolution of a problem which will have been previously proposed. The problems presented are situations, most of them real, when subsoil investigation techniques are usually used. These cases have been employed as teaching-learning strategies with university and second grade students in the area of Girona. Finally, some examples of exercises involving the treatment of data obtained through subsoil investigation techniques are also presented to complement the workshop

Nuorisorikollisuuden esiintyvyys, taustatekijät ja sovittelu

Tausta Vaikka nuorisorikollisuus on kriminologisen tutkimuksen perinteinen kohde, on edelleen tarvetta pitkittäistutkimuksille, joissa on laaja, koko väestöä edustava otos. Kriminaalipolitiikan alalla puolestaan rikosten sovittelu ja muut restoratiivisen oikeuden muodot ovat nousseet Suomessakin haastamaan perinteiset rikoskontrollin paradigmat, rangaistuksen ja hoidon. Tutkimuskysymykset Tutkimuksen pääkysymyksenä oli, mitkä lapsuudessa (8 v.) ja nuoruudessa (18 v.) mitatut psykososiaaliset tekijät ovat yhteydessä nuorisorikollisuuden (16-20 v.) määrään ja lajiin. Lisäksi yhtenä kysymyksenä oli, miten varusmiespalvelun aikaiset psykiatriset diagnoosit liittyvät nuorisorikollisuuteen. Lisäksi tutkimme nuorisorikollisuuden esiintyvyyttä ja palvelujen käyttöä, ja vertailimme eri informanttien (tutkimushenkilöt itse, vanhemmat ja opettajat) vastausten ennusvoimaa lasten tulevan rikollisuuden suhteen. Rikosten sovittelun osalta kysymyksenä oli, miten suomalainen sovittelukäytäntö vastaa restoratiivisen oikeuden teoriaa ja miten sovittelua pitäisi kehittää. Aineisto ja metodit Pitkittäistutkimuksemme aineistona oli valtakunnallisesti edustava satunnaisotos, joka vastasi 10% vuonna 1981 Suomessa syntyneistä suomenkielisistä pojista. Ensimmäinen tiedonkeruu tapahtui 1989, kun pojat olivat 8-vuotiaita. Tietoa kerättiin lomakekyselyin pojilta itseltään sekä heidän vanhemmiltaan ja opettajiltaan. Tietoja saatiin 2946 pojasta. Lasten lomakkeena oli <i>Children’s Depression Inventory, i> vanhemman lomakkeena <i> Rutter A2i> ja opettajan lomakkeena <i>Rutter B2.i> Toinen tiedonkeruu järjestettiin, kun pojat osallistuivat kutsuntoihin 1999. Tietoja saatiin 2330 pojasta. Lomakkeena oli <i >Young Adult Self-Reporti> . Puolustusvoimien rekisteristä saatiin tiedot poikien kutsunnoissa ja palvelusaikana (vuosina 1999-04) saamista psykiatrisista diagnooseista, jotka luokiteltiin kuuteen luokkaan: antisosiaalinen persoonallisuushäiriö, päihdehäiriöt, psykoottiset häiriöt, ahdistuneisuushäiriöt, masennustilat ja sopeutumishäiriöt. Tieto mahdollisesta diagnoosista saatiin 2712 pojasta. Rikollisuus operationalisoitiin poliisin ns. RIKI-rekisteriin vuosina 1998-2001 rekisteröityjen tekojen avulla, kun pojat olivat pääasiassa 16-20-vuotiaita. Rikosten määrän mukaan pojat jaettiin neljään ryhmään: ei rikoksia, 1-2 rikosta (satunnainen rikollisuus), 3-5 rikosta (uusintarikollisuus) ja yli 5 rikosta (aktiivinen uusintarikollisuus). Rikoslajeista muodostettiin viisi kategoriaa: huume-, väkivalta-, omaisuus-, liikenne- ja rattijuopumusrikollisuus. Analyysivaiheessa rekisteridatasta poistettiin liikennerikkomukset. Kaikkiaan tiedot mahdollisista poliisikontakteista saatiin 2866 pojasta. Sovitteludata koostui 16 sovittelujutun havainnoinnista Turussa vuosina 2001- 2003. Tulokset Kaikkiaan 23% pojista oli rekisteröity rikoksesta (poissulkien liikennerikkomukset) nelivuotisen tutkimusperiodin aikana 16-20-vuotiaana. Satunnaisia rikoksentekijöitä oli 15%, uusijoita 4% ja moninkertaisia uusijoita 4%. Rikokset kasautuivat moninkertaisille uusijoille: <i>tämä 4%:n ryhmä teki 72% kaikista rikoksistai> . Omaisuus- ja liikennerikollisia oli eniten (kumpiakin 11%), ja huumerikollisia vähiten (4%). Kaikki rikoslajit korreloivat keskenään tilastollisesti merkitsevästi. Nuorisorikollisuuden itsenäisiä ennustekijöitä lapsuudessa olivat rikkinäinen perherakenne, vanhempien alhainen koulutustaso, lapsen käytösongelmat ja hyperaktiivisuus. Kun verrattiin eri informantteja (lapset itse ja heidän vanhempansa ja opettajansa), etenkin opettajien vastaukset ennustivat lasten tulevaa rikollisuutta. Nuoruudessa rikollisuuden itsenäisiä korrelaatteja olivat pienellä paikkakunnalla asuminen, vanhempien ero, seurustelu, itse ilmoitettu antisosiaalisuus ja säännöllinen tupakointi ja humalajuominen. Ennus- ja taustatekijöille oli tyypillistä se, että ne olivat <i>lineaarisessai> yhteydessä rikosten määrään (ongelmat ja rikosten määrä lisääntyivät käsi kädessä) ja että ne liittyivät useaan rikoslajiin yhtä aikaa. Huumerikollisuudella oli kuitenkin vähemmän itsenäisiä ennus- ja taustatekijöitä kuin muilla rikoslajeilla. Joka kymmenes poika kärsi psykiatrisista häiriöistä. Tämä ryhmä teki noin puolet kaikista rikoksista, ja lähes joka toinen poika, jolla oli psykiatrinen häiriö, oli rekisteröity rikoksista. Rikolliseen käytökseen liittyivät etenkin antisosiaalinen persoonallisuushäiriö ja päihdehäiriöt. Masennustilat olivat kuitenkin ainoa diagnoosiryhmä, joka ei ollut yhteydessä rikollisuuteen. Myös psykiatristen häiriöiden esiintyvyys kasvoi lineaarisesti rikosten määrän kanssa; aktiivisista uusintarikollisista yli puolella (59%) oli psykiatrinen diagnoosi. Rikollisuuden lisäksi erilaiset psykososiaaliset ongelmat kasautuivat pienelle vähemmistölle. Aktiivisten uusijoiden ryhmään olivat tilastollisesti merkitsevästi yhteydessä lähes kaikki ongelmat mitä tutkimme. Kuitenkin tästä ryhmästä vain alle 3% oli käyttänyt mielenterveyspalveluja viimeisen vuoden aikana. Rikossovittelun havainnointitutkimuksen perusteella sovittelussa monet perusasiat ovat kunnossa, ja toiminta on mielekästä niin asianosaisten kuin yhteiskunnankin kannalta. Useimmiten osapuolet kohtasivat ja saivat aikaan sopimuksen, johon he vaikuttivat tyytyväisiltä. Rikoksentekijät olivat motivoituneita korvaamaan aiheuttamansa vahingot. Osapuolet saivat kertoa tarinansa omin sanoin, heitä kuunneltiin ja he ymmärsivät mitä sovittelussa puhutaan ja sovitaan. Sovittelun kuluessa jännitys väheni ja asiat saatiin loppuunkäsiteltyä. Asianosaiset saivat vaikuttaa prosessiin ja sopimukseen, ja uhrin oikeudet olivat sovittelussa keskeisellä sijalla. Restoratiivisen teorian perusteella sovittelussa havaittiin myös kehittämisen varaa: Etenkin nuoria rikoksentekijöitä oli hankala saada osallistumaan tosissaan, ja aikuiset helposti hallitsivat keskustelua. Etukäteistapaamisia ja tukihenkilöitä ei juuri hyödynnetty. Sovitteluja hallitsi puhe sopimuksesta ja rahasta. Työkorvauksia ei käytetty eikä rehabilitaatiota käsitelty. Sekä sovitteluun pääsy että sovittelumenettely riippuivat yksittäisistä henkilöistä. Johtopäätökset Rikosten tekeminen nuoruudessa on melko yleistä ja monimuotoista. Rikokset ja psykososiaaliset ongelmat kasautuvat pienelle ryhmälle ja kulkevat käsi kädessä. Myös psykiatriset häiriöt ovat lineaarisessa yhteydessä rikosten määrään. Rikosriskiä voidaan ennustaa jo lapsuudessa, ja etenkin opettajat ovat tarkkanäköisiä lasten ongelmien suhteen. Eri rikoslajeilla on varsin samanlaisia taustatekijöitä. Aktiiviset rikoksentekijät vastaavat suuresta osasta kokonaisrikollisuutta, tarvitsevat eniten apua, mutta eivät kuitenkaan hakeudu psykososiaalisten palvelujen piiriin. Rikosten sovittelu tarjoaa keinon puuttua ongelmiin varhaisessa vaiheessa ilman leimaamista. Sovittelun kehitystehtävät liittyvät etenkin dialogiin, valmisteluihin, tukihenkilöihin, työkorvauksiin, palveluunohjaukseen ja sovittelun sovellusalaan. Sovittelua ja muita restoratiivisia menettelyjä on kehitettävä ja laajennettava esimerkiksi niin, että niitä voitaisiin käyttää palveluunohjauksen välineenä.

Photoinhibition of Photosystem II. Kinetics, Photoprotection and Mechanism

Photosystem II (PSII) is susceptible to light-induced damage defined as photoinhibition. In natural conditions, plants are capable of repairing the photoinhibited PSII by on-going degradation and re-synthesis of the D1 reaction centre protein of PSII. Photoinhibition is induced by both visible and ultraviolet light and photoinhibition occurs under all light intensities with the same efficiency per photon. In my thesis work, I studied the reaction kinetics and mechanism of photoinhibition of PSII, as well as photoprotection in leaves of higher plants. Action spectroscopy was used to identify photoreceptors of photoinhibition. I found that the action spectrum of photoinhibition <i>in vivoi> shows resemblance to the absorption spectra of manganese model compounds of the oxygen evolving complex (OEC) suggesting a role for manganese as a photoreceptor of photoinhibition under UV and visible light. In order to study the protective effect of non-photochemical quenching, the action spectrum was measured from leaves of wild type <i>Arabidopsis thalianai> and two mutants impaired in nonphotochemical quenching of chlorophyll a excitations. The findings of action spectroscopy and simulations of chlorophyll-based photoinhibition mechanisms suggested that quenching of antenna excitations protects less efficiently than would be expected if antenna chlorophylls were the only photoreceptors of photoinhibition. The reaction kinetics of prolonged photoinhibition was studied in leaves of <i>Cucurbita maximai> and <i> Capsicum annuumi>. The results indicated that photoinhibitory decrease in both the oxygen evolution activity and ratio of variable to maximum fluorescence follows firstorder kinetics <i>in vivoi>. The persistence of first-order kinetics suggests that already photoinhibited reaction centres do not protect against photoinhibition and that the mechanism of photoinhibition does not have a reversible intermediate. When <i>Cucurbita maximai> leaves were photoinhibited with saturating single-turnover flashes and continuous light, the light response curve of photoinhibition was found to be essentially a straight line with both types of illumination, suggesting that similar photoinhibition mechanisms might function during illumination with continuous light and during illumination with short flashes.