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  • Ran, Wenjun (Helsingfors universitet, 2014)
    The application of the split root fertigation (SRF) on strawberry cv. Elsanta (Fragaria × ananassa Duch.) was tested in a greenhouse. Responses of strawberry plants under SRF treatments were evaluated by investigating plant water use, plant vegetative growth, berry yield, and berry quality. In this experiment. Strawberry plants had their roots separated evenly into two parts and grown in containers with two compartments in peat. In the traditional fertigation (TF), the control in the experiment, irrigation water with equal electrical conductivity (EC) (1.4 mS/cm) was applied to both root compartments. Three levels of SRF treatments with low, medium, and high mean EC in irrigation water were designed for the experiment. In these SRF treatments, half of roots received the irrigation solutions with lower EC value of 0.7 mS/cm, the other half of roots received irrigation solutions with EC values of 1.4 mS/cm (SRF1), 2.8 mS/cm (SRF2), and 4.2 mS/cm (SRF3). For plant growth, leaf number, petiole length, runner number and dry weight, plant dry weight, leaf nutrient contents, and flowering date were examined. For yield and berry quality, total fresh yield, total berry number, average berry fresh and dry weight, shelf life, contents of total soluble solids (TSS), titratable acid (TA), total phenolics, and ascorbic acid were measured. For plant water use, substrate water content (?) and EC, leakage amount and EC were recorded; water use efficiency (WUE) and water uptake percentage were calculated to investigate the water use. Compared to TF, plants under SRF treatments showed differences in some parameters. Plants grown under SRF2 had highest total leaf area, although no differences in total plant dry weight were observed; leaf Mg was improved by SRF treatments, leaf N increased by SRF with high EC (SRF3), and leaf B and Mn decreased in SRF with low EC (SRF1). More lateral roots were found of plants under SRF treatment. Plant flowering was accelerated in the medium SRF treatment. For fruit quality, berry size was reduced in SRF3, which was in consistent with the response of strawberry grown under salinity stress. TSS/TA decreased in SRF3. In all SRF treatments, more water was taken up from root compartment with the lower EC value. However, the total water uptake amount had no differences. As a conclusion, SRF treatments affected the plant water uptake distribution, plant vegetative growth, yield and yield quality in some parameters, but results were not consistent in this experiment. Treatments with more EC combinations in a wider range are recommended for further studies.
  • Shahbazi, Mohammad-Ali (2015)
    Porous silicon nanoparticles (PSi NPs) have recently drawn increasing interest for therapeutic applications due to their easily modifiable surface, large pore volumes, high surface area, nontoxic nature, and high biocompatibility. Nevertheless, there is no comprehensive understanding about the role of the surface chemistry of these NPs on the biological interactions and the therapeutic effect of the PSi-based nanosystems. Therefore, extensive attempts are still needed for the development of optimal PSi-based therapeutics. The first step for evaluating the biological activity of the NPs was to investigate the potential toxic effects. Accordingly, the immunotoxicity and hemocompatibility of the PSi NPs with different surface chemistries were assessed at different concentrations on the immune cells and red blood cells, since these are the first biological cells in contact with the NPs after intravenous injection. PSi NPs with positively charged amine functional groups showed higher toxicity compared to negatively charged particles. The toxicity of the negatively charged particles was also highly dependent on the hydrophobic nature of the NPs. Moreover, RBC hemolysis and imaging assay revealed a significant correlation between the PSi NP surface chemistry and hemotoxicity. To further understand the impact of the surface chemistry on the immunological effects of the PSi NPs, the immunostimulatory responses induced by a non-toxic concentration of the PSi NPs were evaluated by measuring the maturation of dendritic cells, T cell proliferation and cytokine secretion. Overall, the results suggested that all the PSi NPs containing higher amounts of nitrogen or oxygen on the outermost surface layer have lower immunostimulatory effects than the PSi NPs with higher amounts of C‒H structures on the NPs surface. Combination cancer therapy by the PSi NPs was then studied by evaluating the synergistic therapeutic effects of the nanosystems. Sorafenib-loaded PSi NPs were biofunctionalized with anti-CD326 monoclonal antibody on their surface. The targeted PSi NPs showed a sustained drug release and increased interactions with the breast cancer cells expressing the CD326 antigen on their surface. These NPs also showed higher antiproliferation effect on the CD326 positive cancer cells compared to the pure drug and sorafenib-loaded PSi NPs, suggesting CD326 as an appropriate receptor for the antibody-mediated drug delivery. In addition, anti-CD326 antibody acted as an immunotherapeutic agent by inducing antibody-dependent cellular cytotoxicity and enhancing the interactions of immune cells with cancer cells for the subsequent phagocytosis and cytokine secretion. Next, the development of a stable PSi NP with low toxicity, high cellular internalization, efficient endosomal escape, and optimal drug release profile was tested by using a layer-by-layer method to covalently conjugate polyethyleneimine and poly(methyl vinyl ether-co-maleic acid) copolymers on the surface of the PSi NPs, forming a zwitterionic nanocomposite. The surface smoothness and hydrophilicity of the polymer functionalized NPs improved considerably the colloidal and plasma stability of the NPs. Moreover, the double layer conjugation sustained the drug release from the PSi NPs and improved the cytotoxicity profile of the drug-loaded PSi NPs. In conclusion, this work showed that the surface modification of the PSi NPs with different chemical groups, antibodies and polymers can affect the toxicological profiles, the cellular interactions and the therapeutic effects of the NPs by modifying the charge, stability, hydrophilicity, the drug release kinetics and targeting properties of the PSi NPs.
  • Partti, Susanna (2014)
    Blood-brain barrier (BBB) is a physical barrier between the blood and the brain. BBB restricts drugs transport from blood stream to the brain, which sets challenges in drug delivery to the brain. Nanoparticles can be utilized in drug delivery to the central nervous system (CNS). Nanoparticles are internalized via endocytosis. However it remains unknown which endocytic pathways are active in brain endothelial cells. The characterization of BBB cells would help light on the exact mechanism of nanoparticle delivery into the brain, which would enable the design of targeted nanoparticles to deliver drugs to the CNS. In present study we characterized human brain endothelial cells, hCMEC/D3, which are widely utilized as BBB in vitro model. As brain endothelial cells are polarized in vivo, the aim of the study was to demonstrate the cell polarization of hCMEC/D3 cells and to study the activity and functionality of different endocytic pathways as a function of cell polarization. The level of cell polarization in cells grown on transwell permeable supports was characterized at multiple timepoints with four different methods: transepithelial electrical resistance (TEER) measurement, lucifer yellow permeability assay, alkaline phosphatase expression and ZO-1 expression. To characterize hCMEC/D3 cells for the presence of specific endocytic pathways, proteins involved into each pathway were selected. Expression of these proteins at mRNA level was assessed by quantitative real-time polymerase chain reaction (qRT-PCR). For clathrin-mediated endocytosis, mRNA level of CHC protein was further correlated with the protein level of this protein, and the activity of clathrin-mediated endocytosis was analyzed by fluorescence activated cell sorting (FACS). Our results showed that hCMEC/D3 cells are best polarized after growing on transwell permeable support for 7 days. At the later timepoints, the cell polarization started to decrease, probably due to multilayer formation. We concluded that measuring TEER alone is not a reliable method to determine polarization status of the cells. mRNA levels of endocytosis-related proteins did not change remarkably as a function of cell polarization. In case of clathrin-mediated endocytosis, there was lack of correlation between CHC mRNA and protein level, but good correlation between mRNA level and activity of the pathway.
  • Miao, Zefeng Jr (Helsingfors universitet, 2014)
    Gemfibrozil is a fibric acid derivative used in the treatment of dyslipidemia. It activates peroxisome proliferator activated receptor ? (PPAR?) and alters lipoprotein metabolism gene expression. PPAR? may also regulate the expression of drug disposition genes (e.g., CYP3A4). The aim of this study was to investigate possible effects of gemfibrozil on drug transporter gene expression in human whole blood. In a randomized crossover study, 10 healthy volunteers took 600 mg gemfibrozil or placebo twice daily for 6 days (Filppula et al. 2013). On the morning of day 3, a venous blood RNA sample was collected from each participant into a PaxGene® tube. The expression of 18 ABC, 24 SLC and 10 SLCO transporters was investigated using reverse transcription quantitative real-time PCR (RT-qPCR) with OpenArray® technology on a QuantStudio™ 12 K Flex Real-Time PCR system (Life Technologies, Paisley, UK). FPGS, TRAP1, DECR1 and PPIB served as reference genes. A total of 31 transporters, including 15 ABC transporters, 13 SLC transporters and 3 SLCO transporters were significantly expressed in whole blood during the placebo phase. Gemfibrozil appeared to alter the expression of three transporters. The expression of SLCO3A1 was increased by 34% by gemfibrozil (P=0.004), but gemfibrozil reduced the expression of ABCG2 and ABCC3 by 31% (P=0.018) and 50% (P=0.045), respectively. However, none of the differences remained statistically significant after correction for multiple testing. In conclusion, these data suggest that gemfibrozil might alter the gene expression of certain drug transporters in human blood.
  • Pyöriä, Lari (Helsingfors universitet, 2014)
    In our research we studied if the overexpression of VEGF-A would save the impaired tumor growth in PROX1 silenced colorectal cancer xenografts. We conducted both small hairpin PROX1 and VEGF-A gene transfers to SW1222 colorectal cancer cells using lentiviral vectors. SW1222 cell lines were then injected to Nod scid gamma mice and grown for 14 days for analysis. We also established 3D cocultures of genetically modified SW1222 cell line together with lymphatic endothelial cells or blood endothelial cells to analyze lymphangiogenesis and angiogenesis in vitro. We found out that overexpression of VEGF-A rescues the growth of PROX1 silenced tumors. Large necrotic areas in the central of the PROX1 silenced tumors remain even though VEGF-A overexpression induces greater vascularity in these xenografts. In 3D cocultures silencing of PROX1 did not affect in vitro lymphangiogenesis or angiogenesis. (135)
  • Hirvonen, Johanna (Helsingin yliopisto, 2007)
    Although the principle of equal access to medically justified treatment has been promoted by official health policies in many Western health care systems, practices do not completely meet policy targets. Waiting times for elective surgery vary between patient groups and regions, and growing problems in the availability of services threaten equal access to treatment. Waiting times have come to the attention of decision-makers, and several policy initiatives have been introduced to ensure the availability of care within a reasonable time. In Finland, for example, the treatment guarantee came into force in 2005. However, no consensus exists on optimal waiting time for different patient groups. The purpose of this multi-centre randomized controlled trial was to analyse health-related quality of life, pain and physical function in total hip or knee replacement patients during the waiting time and to evaluate whether the waiting time is associated with patients health outcomes at admission. This study also assessed whether the length of waiting time is associated with social and health services utilization in patients awaiting total hip or knee replacement. In addition, patients health-related quality of life was compared with that of the general population. Consecutive patients with a need for a primary total hip or knee replacement due to osteoarthritis were placed on the waiting list between August 2002 and November 2003. Patients were randomly assigned to a short waiting time (maximum 3 months) or a non-fixed waiting time (waiting time not fixed in advance, instead the patient followed the hospitals routine practice). Patients health-related quality of life was measured upon being placed on the waiting list and again at hospital admission using the generic 15D instrument. Pain and physical function were evaluated using the self-report Harris Hip Score for hip patients and a scale modified from the Knee Society Clinical Rating System for knee patients. Utilization measures were the use of home health care, rehabilitation and social services, physician visits and inpatient care. Health and social services use was low in both waiting time groups. The most common services used while waiting were rehabilitation services and informal care, including unpaid care provided by relatives, neighbours and volunteers. Although patients suffered from clear restrictions in usual activities and physical functioning, they seemed primarily to lean on informal care and personal networks instead of professional care. While longer waiting time did not result in poorer health-related quality of life at admission and use of services during the waiting time was similar to that at the time of placement on the list, there is likely to be higher costs of waiting by people who wait longer simply because they are using services for a longer period. In economic terms, this would represent a negative impact of waiting. Only a few reports have been published of the health-related quality of life of patients awaiting total hip or knee replacement. These findings demonstrate that, in addition to physical dimensions of health, patients suffered from restrictions in psychological well-being such as depression, distress and reduced vitality. This raises the question of how to support patients who suffer from psychological distress during the waiting time and how to develop strategies to improve patients initiatives to reduce symptoms and the burden of waiting. Key words: waiting time, total hip replacement, total knee replacement, health-related quality of life, randomized controlled trial, outcome assessment, social service, utilization of health services
  • Autio, Maiju (2011)
    Generation of raw materials for dry powder inhalers by different size reduction methods can be expected to influence physical and chemical properties of the powders. This can cause differences in particle size, size distribution, shape, crystalline properties, surface texture and energy. These physical properties of powders influence the behaviour of particles before and after inhalation. Materials with an amorphous surface have different surface energy compared to materials with crystalline surface. This can affect the adhesion and cohesion of particles. Changes in the surface nature of the drug particles results in a change in product performance. By stabilization of the raw materials the amorphous surfaces are converted into crystalline surfaces. The primary aim of the study was to investigate the influence of the surface properties of the inhalation particles on the quality of the product. The quality of the inhalation product is evaluated by measuring the fine particle dose (FPD). FDP is the total dose of particles with aerodynamic diameters smaller than 5,0 μm. The secondary aim of this study was to achieve the target level of the FPD and the stability of the FPD. This study was also used to evaluate the importance of the stabilization of the inhalation powders. The study included manufacturing and analysing drug substance 200 μg/dose inhalation powder batches using non-stabilized or stabilized raw materials. The inhaler formulation consisted of micronized drug substance, lactose <100μm and micronized lactose <10μm. The inhaler device was Easyhaler®. Stabilization of the raw materials was done in different relative humidity, temperature and time. Surface properties of the raw materials were studied by dynamic vapour sorption, scanning electron microscopy and three-point nitrogen adsorption technique. Particle size was studied by laser diffraction particle size analyzer. Aerodynamic particle size distribution from inhalers was measured by new generation impactor. Stabilization of all three raw materials was successful. A clear difference between nonstabilized and stabilized raw materials was achieved for drug substance and lactose <10μm. However for lactose <100μm the difference wasn’t as clear as wanted. The surface of the non-stabilized drug substance was more irregular and the particles had more roughness on the surface compared to the stabilized drug substances particles surface. The surface of the stabilized drug particles was more regular and smoother than non-stabilized. Even though a good difference between stabilized and non-stabilized raw materials was achieved, a clear evidence of the effect of the surface properties of the inhalation particles on the quality of the product was not observed. Stabilization of the raw materials didn’t lead to a higher FPD. Possible explanations for the unexpected result might be too rough conditions in the stabilization of the drug substance or smaller than wanted difference in the degree of stabilization of the main component of the product <100μm. Despite positive effects on the quality of the product were not seen there appears to be some evidence that stabilized drug substance results in smaller particle size of dry powder inhalers.
  • Stenberg, Jan-Henry (Helsingin yliopisto, 2014)
    Schizophrenia is a severe, psychiatric illness with neurocognitive deficits as its major component, and affects about 1% of the world population. Improving impaired neurocognitive function is one of the pivotal treatment goals in this patient population. In the treatment of schizophrenia, only a partial treatment response is typically achieved with dopamine antagonists; i.e., antipsychotics . The antidepressant mirtazapine has a unique mechanism of action with, in theory, an ability to enhance neurocognition and provide added value to antipsychotic treatment. This study explored whether or not adjunctive mirtazapine has the potential to improve neurocognitive performance and alleviate clinical symptoms in patients with schizophrenia who demonstrated a suboptimal treatment response to first-generation antipsychotics (FGAs). This study was a neurocognitive arm of a single-center, randomized, add-on, double-blinded, placebo-controlled study, which was carried out in the Karelian Republic, Petrozavodsk, Russia. Patients with schizophrenia or a depressive type schizoaffective disorder, according to the Diagnostic and Statistical Manual of Mental and Behavioral Disorders 4th edition (DSM-IV) criteria, who received stable doses of FGA with inadequate treatment response were enrolled into the trial. Twenty patients were assigned to mirtazapine and 21 to placebo. After a one-week single-blind placebo run-in period, the participants were randomized to receive either 30 mg of mirtazapine or the placebo four times a day (QID) in a double-blind fashion for 6 weeks. Subsequently, those who were eligible to continue entered the following 6-week open-label phase, where they were treated with mirtazapine 30 mg QID. At study weeks 0, 6, and 12, a senior psychologist performed neuropsychological examinations to evaluate neurocognitive functioning. Verbal and visual memory, visuo-spatial and executive functions, verbal fluency and both general mental and psychomotor speeds were assessed by commonly used, validated neuropsychological tests for different neurocognitive domains. Clinical examinations were conducted at week 1 (screening), week 0 (baseline) and after 1, 2, 4, 6, 7, 8, 10, and 12 weeks of treatment. Within group and between group differences were analyzed on a Modified Intent-to Treat (MITT) basis with Last Observations Carried Forward (LOCF). After 6 weeks of treatment, 5/21 neurocognitive parameters (i.e. Wechsler Adult Intelligence Scale Revised (WAIS-R) Block Design, p=0.021; Wechsler Memory Scale (WMS) Logical Memory, p=0.044; WMS Logical Memory Delayed, p=0.044; Stroop Dots, p=0.044; Trail Making Test Part A (TMT-A), p=0.018) were improved with statistical significance in the mirtazapine group. In contrast, only 1 of the 21 parameters changed significantly (WMS Logical Memory, p=0.039) in the placebo group. Add-on 6-week mirtazapine treatment was superior when compared with placebo in the neuropsychological domains of visuo-spatial ability and general mental speed/attentional control (Block Design mirtazapine group vs. placebo and Stroop dots mirtazapine group vs. placebo, p=0.044 for both comparisons). The enhancing effect on the Block Design-measured visuo-spatial functioning was mediated through changes in positive, depressive symptoms and parkinsonism-like side effects, but not via changes in negative symptoms. Moreover, higher doses of FGAs, longer duration of illness and lower initial Block Design scores predicted this effect. During the 6 weeks extension phase, individuals who continued mirtazapine treatment and those who were switched from placebo to mirtazapine showed significant improvements on several neurocognitive tests. Those who switched from placebo to open label mirtazapine treatment achieved similar results in the 6 following weeks as the mirtazapine group during their first 6 weeks of mirtazapine treatment. From week 0 to week 12, the continuation group demonstrated improvements in 17/21 neurocognitive parameters, while the switch group improved in 8/21 of the measured parameters. Twelve weeks of mirtazapine treatment indicated an advantage over a shorter, 6-week mirtazapine treatment on Stroop Dots time (p=0.035) and Trail Making Test part B (TMT-B), and number of mistakes (p=0.043). During the 6-week open-label phase, significant improvements on several clinical parameters, which included the Positive and Negative Syndrome Scale (PANSS) total score, were observed. In the total population (i.e., pooled switch and continuation groups), the effect size was 0.94 (CI 95%=0.451.43) as determined by the PANSS total score. Conclusions. Adjunctive mirtazapine treatment might offer added value as a neurocognitive enhancer, and may augment the antipsychotic effect in FGA-treated schizophrenia patients with inadequate treatment response. The ability to generalize these results for a larger population may be limited by the small sample size of the present study.
  • Jauhiainen, Johanna (Helsingin yliopisto, 2013)
    Within the framework of a national science and mathematics education development program a long-term physics teachers training program was organized. The aim of the program was to enhance teachers pedagogical content knowledge, especially regarding the role of experiments in physics education. The role of experiments was discussed based on a practical teaching philosophy called perceptional approach. The research aimed at exploring teachers experience of the training program, as well as the effect it had on their beliefs about the role of experiments and the concept of interaction (interacting bodies) in teaching Newtonian mechanics. Moreover, the goal was to examine the influence of teachers' beliefs about interaction on students conceptual understanding of force. The model of pedagogical content knowledge and the model of practical conceptual change formed the frameworks for the research. The results of the teacher survey showed that teachers considered the training valuable for their daily teaching practice. The laboratory course was regarded to be most valuable. The course dealing with theoretical principles of the perceptional approach was less advantageous. Approximately 20% of the teachers had changed their beliefs in the use of experiments after the ideas represented in the training program. There were no significant differences between the experimental and control groups in the views regarding the reasons for using experiments in teaching physics. The most important objective for practical work was to enhance students learning of concepts. According to teacher interviews, some teachers were influenced by the program and the way experiments could be used in supporting the creation of meanings for concepts. However, some teachers strongly held to their previous beliefs. The effect of the training program on teachers beliefs about the concept of interaction as an organizing principle in teaching mechanics was examined using teacher interviews. The results showed no remarkable effects. However, the explicit use of interaction as a guiding principle in teaching Newtonian mechanics enhanced students conceptual understanding of force as measured with the Force Concept Inventory, which was translated into Finnish.
  • Rawlings, Anna (Helsingin yliopisto, 2014)
    Aims. The Behavioural Inhibition/Behavioural Approach System (BIS/BAS) is a neurological approach-avoidance system, where BIS depicts inhibition, anxiety, and fear of failure. The BAS system was in this study divided into BAS Inter (seeking social approval and rewards), BAS Impulse (impulsivity, immediate rewards), and BAS Intra (excitement at novel situations, own successes as a reward). Achievement goal orientations describe motivational tendencies to choose certain types of goals in a learning situation. Of the achievement goal orientations, mastery intrinsic describes the aim to learn with subjective, and mastery extrinsic with absolute criteria of success, performance approach the aim to outperform others and performance avoidance to avoid situations where one can fail. The avoidance orientation describes a disinterest in academic achievements and the goal of exerting as little effort as possible on school. The aim of the study was to examine how dispositional sensitivities affect the motivational aims of students. The research hypothesis is that BIS/BAS sensitivities predict the achievement goal orientations students adopt and exhibit. The research task is to examine how the Motivation and Sensitivity to Reward and Punishment questionnaire (MSRP) not yet used in published research succeeds in defining and measuring aspects of BIS/BAS. Method. The data was collected from five classes of eighth-graders in a school in Helsinki (N=78) in 2008 as a self-response survey, where BIS/BAS was measured using the new MSRP questionnaire, and achievement goal orientations with the achievement goal orientation questionnaire. The effects of BIS/BAS on the achievement goal orientations were examined by means of regression analyses. The MSRP was evaluated by examining the construct validity of the measurement, considering its descriptive capacity in relation to the background theories, and comparing the results with those from research conducted with other instruments. Results. The MSRP functioned relatively well. The mastery orientations were related to a tendency for low impulsivity, mastery intrinsic also to sensitivity to enjoy novel situations and challenges. The performance-approach orientation was predicted by the tendency to seek social approval, and performance-avoidance was connected to the punishment-sensitive inhibitory system. The avoidance orientation was linked with high impulsivity and low levels of excitement in personal successes and novelty in situations. Dispositional tendencies and sensitivities have a predictive effect on motivational achievement goal orientations, and generalised attitudes towards learning at school are to some degree affected by individuals inherent qualities. These effects should be considered in school practices, to support and meet the needs of students of all dispositions.
  • Rodewald, Petra (Helsingin yliopisto, 2013)
    An increasing number of programs are releasing animals to nature to conserve threatened populations or to reintroduce animal populations that are extinct from the wild. Crucial to the success of these programs is the survival of the animal. Animals reared in captivity show often maladaptive behaviour and low survival in the wild. Genetic domestication and adaptation to the rearing environment are influencing the development of animals. It has been shown that enriching the rearing environment by e.g. adding structure is promoting animal behaviour and survival. Many studies are now investigating the effects of genetic domestication and the effects of rearing environment on behavioural development of animals and survival in the wild. However, few studies have addressed the effects of genetic domestication and enriched rearing on behaviour and survival simultaneously. The main aim of this thesis was therefore to investigate the effects of broodstock origin (wild vs. captive) and rearing environment (enriched vs. standard) of endangered Atlantic salmon (Salmo salar) on important life skills (e.g. foraging and antipredation), migration and survival after release to the wild. Survival after release is not only thought to be influenced by the quality of fish, but partly due to the release methods. Handling and transportation to a release site represent major stressors for animals and can impair important survival traits. Methods that aim at decreasing stress before release to the wild have been developed and are used in many animal taxa with promising results. The second part of this thesis was therefore designed to investigate the effects of stocking procedures on stress and if so-called soft release methods (acclimatization after transport to decrease stress levels) could benefit post-release performance. The results showed that enriched rearing improved foraging capacity and decreased maladaptive behaviour after release to semi-natural environments of salmon parr. Enriched rearing also promoted migration and survival after release to the wild of salmon smolts. The effects of genetic domestication were less clear. Acclimatization after transport (soft release) proved important for lowering stress before release, but no direct evidence on survival was found. These results show clearly that conventional rearing does not produce fish that are prepared for a life in the wild and indicates that environmental enrichment can improve life skills and survival of fish significantly.
  • Kivinummi, Tanja (Helsingin yliopisto, 2009)
    Tobacco smoking is a worldwide health problem. Nicotine is generally accepted as the addictive substance in tobacco smoke. In addition to causing cancer, cardiac, vascular and pulmonary diseases, tobacco smoking has been suggested to act as a gateway drug to other drugs of abuse. The purpose of this study was to find out, whether chronic nicotine administration and its cessation potentiate the effects of morphine, and the mechanisms behind this. The study was performed in mice that received nicotine chronically via drinking water. This method of administration mimics human smoking in that the mice receive nicotine intermittently during their active time and that their plasma nicotine concentrations resemble those found in human smokers. First, we found that after chronic oral nicotine treatment mice are sensitized to the locomotor activity increasing effects of morphine. However, cocaine s stimulating effect was not enhanced after chronic nicotine treatment, suggesting that the enhanced stimulation is due to changes in the regulation of dopaminergic system. Second, we noticed that mice pretreated chronically with nicotine required smaller doses of morphine to display place conditioning than control mice, suggesting that chronic nicotine treatment enhances morphine s reinforcing effects. However, we found no changes in the number, affinity or functional activity of the µ-opioid receptors, which mediate morphine s effects, suggesting a minor role for the alterations of this receptor in the enhanced effects of morphine. Third, we found that nicotine pretreatment enhances the morphine-induced increase in nigrostriatal and mesolimbic extracellular dopamine levels, which are likely involved in the behavioural changes observed after chronic nicotine treatment. Furthermore, morphine s effect on GABAergic transmission in the ventral tegmental area/substantia nigra after chronic nicotine treatment was opposite to that in controls; morphine increased extracellular GABA in nicotine-pretreated mice. No changes in GABAB-receptor function were found after nicotine treatment. The changes in GABA transmission are possibly involved in the alterations in the morphine-induced dopamine transmission after chronic nicotine treatment. Last, chronic nicotine treatment altered cerebral levels of brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP response element binding protein (pCREB), which are markers of neuronal plasticity. Chronic nicotine decreased BDNF and pCREB levels in the ventral tegmental area and nucleus accumbens, respectively. BDNF levels increased during nicotine abstinence, suggesting that mechanisms of neuronal plasticity are activated after the cessation of chronic nicotine treatment, which could be related to the long-lasting neuronal changes behind addiction. We also found nicotine-morphine interactions in pCREB levels in the soma areas of dopaminergic neurons, showing that nicotine and morphine interact also at the molecular level. These alterations may be involved in the behavioural and neurochemical nicotine-morphine interactions. In conclusion, these experiments suggest that chronic nicotine treatment profoundly enhances morphine s effects on striatal dopaminergic pathways and thereby enhances its effects on locomotion and reinforcement. The alterations in neuronal plasticity markers found in dopaminergic brain areas most probably are involved in these changes. Also, alterations in midbrain GABAergic systems may contribute. These experiments indicate that chronic nicotine exposure leads to cerebral neurochemical and molecular changes that facilitate the addictive properties of morphine. Thus, tobacco smoking may alter the addictive properties of other drugs of abuse.
  • Elo, Aija-Riitta (Helsingin yliopisto, 2007)
    To a large extent, lakes can be described with a one-dimensional approach, as their main features can be characterized by the vertical temperature profile of the water. The development of the profiles during the year follows the seasonal climate variations. Depending on conditions, lakes become stratified during the warm summer. After cooling, overturn occurs, water cools and an ice cover forms. Typically, water is inversely stratified under the ice, and another overturn occurs in spring after the ice has melted. Features of this circulation have been used in studies to distinguish between lakes in different areas, as basis for observation systems and even as climate indicators. Numerical models can be used to calculate temperature in the lake, on the basis of the meteorological input at the surface. The simple form is to solve the surface temperature. The depth of the lake affects heat transfer, together with other morphological features, the shape and size of the lake. Also the surrounding landscape affects the formation of the meteorological fields over the lake and the energy input. For small lakes the shading by the shores affects both over the lake and inside the water body bringing limitations for the one-dimensional approach. A two-layer model gives an approximation for the basic stratification in the lake. A turbulence model can simulate vertical temperature profile in a more detailed way. If the shape of the temperature profile is very abrupt, vertical transfer is hindered, having many important consequences for lake biology. One-dimensional modelling approach was successfully studied comparing a one-layer model, a two-layer model and a turbulence model. The turbulence model was applied to lakes with different sizes, shapes and locations. Lake models need data from the lakes for model adjustment. The use of the meteorological input data on different scales was analysed, ranging from momentary turbulent changes over the lake to the use of the synoptical data with three hour intervals. Data over about 100 past years were used on the mesoscale at the range of about 100 km and climate change scenarios for future changes. Increasing air temperature typically increases water temperature in epilimnion and decreases ice cover. Lake ice data were used for modelling different kinds of lakes. They were also analyzed statistically in global context. The results were also compared with results of a hydrological watershed model and data from very small lakes for seasonal development.
  • Vainio, Petri J. (Helsingin yliopisto, 2000)