Roles of forced nicotine exposure and Comt gene disruption in the development of addiction-related behavioural and neurochemical changes in mice

Activation of midbrain dopamine systems is thought to be critically involved in the addictive properties of abused substances. Drugs of abuse increase dopamine release in the nucleus accumbens and dorsal striatum, which are the target areas of mesolimbic and nigrostriatal dopamine pathways, respectively. Dopamine release in the nucleus accumbens is thought to mediate the attribution of incentive salience to rewards, and dorsal striatal dopamine release is involved in habit formation. In addition, changes in the function of prefrontal cortex (PFC), the target area of mesocortical dopamine pathway, may skew information processing and memory formation such that the addict pays an abnormal amount of attention to drug-related cues. In this study, we wanted to explore how long-term forced oral nicotine exposure or the lack of catechol-O-methyltransferase (COMT), one of the dopamine metabolizing enzymes, would affect the functioning of these pathways. We also wanted to find out how the forced nicotine exposure or the lack of COMT would affect the consumption of nicotine, alcohol, or cocaine. First, we studied the effect of forced chronic nicotine exposure on the sensitivity of dopamine D2-like autoreceptors in microdialysis and locomotor activity experiments. We found that the sensitivity of these receptors was unchanged after forced oral nicotine exposure, although an increase in the sensitivity was observed in mice treated with intermittent nicotine injections twice daily for 10 days. Thus, the effect of nicotine treatment on dopamine autoreceptor sensitivity depends on the route, frequency, and time course of drug administration. Second, we investigated whether the forced oral nicotine exposure would affect the reinforcing properties of nicotine injections. The chronic nicotine exposure did not significantly affect the development of conditioned place preference to nicotine. In the intravenous self-administration paradigm, however, the nicotine-exposed animals self-administered nicotine at a lower unit dose than the control animals, indicating that their sensitivity to the reinforcing effects of nicotine was enhanced. Next, we wanted to study whether the Comt gene knock-out animals would be a suitable model to study alcohol and cocaine consumption or addiction. Although previous work had shown male Comt knock-out mice to be less sensitive to the locomotor-activating effects of cocaine, the present study found that the lack of COMT did not affect the consumption of cocaine solutions or the development of cocaine-induced place preference. However, the present work did find that male Comt knock-out mice, but not female knock-out mice, consumed ethanol more avidly than their wild-type littermates. This finding suggests that COMT may be one of the factors, albeit not a primary one, contributing to the risk of alcoholism. Last, we explored the effect of COMT deficiency on dorsal striatal, accumbal, and prefrontal cortical dopamine metabolism under no-net-flux conditions and under levodopa load in freely-moving mice. The lack of COMT did not affect the extracellular dopamine concentrations under baseline conditions in any of the brain areas studied. In the prefrontal cortex, the dopamine levels remained high for a prolonged time after levodopa treatment in male, but not female, Comt knock-out mice. COMT deficiency induced accumulation of 3,4-dihydroxyphenylacetic acid, which increased further under levodopa load. Homovanillic acid was not detectable in Comt knock-out animals either under baseline conditions or after levodopa treatment. Taken together, the present results show that although forced chronic oral nicotine exposure affects the reinforcing properties of self-administered nicotine, it is not an addiction model itself. COMT seems to play a minor role in dopamine metabolism and in the development of addiction under baseline conditions, indicating that dopamine function in the brain is well-protected from perturbation. However, the role of COMT becomes more important when the dopaminergic system is challenged, such as by pharmacological manipulation.

Routine Measurement of Health-Related Quality of Life in Assessing Cost-Effectiveness in Secondary Health Care

Aims: The aims of this study were 1) to identify and describe health economic studies that have used quality-adjusted life years (QALYs) based on actual measurements of patients' health-related quality of life (HRQoL); 2) to test the feasibility of routine collection of health-related quality of life (HRQoL) data as an indicator of effectiveness of secondary health care; and 3) to establish and compare the cost-utility of three large-volume surgical procedures in a real-world setting in the Helsinki University Central Hospital, a large referral hospital providing secondary and tertiary health-care services for a population of approximately 1.4 million. Patients and methods: So as to identify studies that have used QALYs as an outcome measure, a systematic search of the literature was performed using the Medline, Embase, CINAHL, SCI and Cochrane Library electronic databases. Initial screening of the identified articles involved two reviewers independently reading the abstracts; the full-text articles were also evaluated independently by two reviewers, with a third reviewer used in cases where the two reviewers could not agree a consensus on which articles should be included. The feasibility of routinely evaluating the cost-effectiveness of secondary health care was tested by setting up a system for collecting HRQoL data on approximately 4 900 patients' HRQoL before and after operative treatments performed in the hospital. The HRQoL data used as an indicator of treatment effectiveness was combined with diagnostic and financial indicators routinely collected in the hospital. To compare the cost-effectiveness of three surgical interventions, 712 patients admitted for routine operative treatment completed the 15D HRQoL questionnaire before and also 3-12 months after the operation. QALYs were calculated using the obtained utility data and expected remaining life years of the patients. Direct hospital costs were obtained from the clinical patient administration database of the hospital and a cost-utility analysis was performed from the perspective of the provider of secondary health care services. Main results: The systematic review (Study I) showed that although QALYs gained are considered an important measure of the effectiveness of health care, the number of studies in which QALYs are based on actual measurements of patients' HRQoL is still fairly limited. Of the reviewed full-text articles, only 70 reported QALYs based on actual before after measurements using a valid HRQoL instrument. Collection of simple cost-effectiveness data in secondary health care is feasible and could easily be expanded and performed on a routine basis (Study II). It allows meaningful comparisons between various treatments and provides a means for allocating limited health care resources. The cost per QALY gained was 2 770 for cervical operations and 1 740 for lumbar operations. In cases where surgery was delayed the cost per QALY was doubled (Study III). The cost per QALY ranges between subgroups in cataract surgery (Study IV). The cost per QALY gained was 5 130 for patients having both eyes operated on and 8 210 for patients with only one eye operated on during the 6-month follow-up. In patients whose first eye had been operated on previous to the study period, the mean HRQoL deteriorated after surgery, thus precluding the establishment of the cost per QALY. In arthroplasty patients (Study V) the mean cost per QALY gained in a one-year period was 6 710 for primary hip replacement, 52 270 for revision hip replacement, and 14 000 for primary knee replacement. Conclusions: Although the importance of cost-utility analyses has during recent years been stressed, there are only a limited number of studies in which the evaluation is based on patients own assessment of the treatment effectiveness. Most of the cost-effectiveness and cost-utility analyses are based on modeling that employs expert opinion regarding the outcome of treatment, not on patient-derived assessments. Routine collection of effectiveness information from patients entering treatment in secondary health care turned out to be easy enough and did not, for instance, require additional personnel on the wards in which the study was executed. The mean patient response rate was more than 70 %, suggesting that patients were happy to participate and appreciated the fact that the hospital showed an interest in their well-being even after the actual treatment episode had ended. Spinal surgery leads to a statistically significant and clinically important improvement in HRQoL. The cost per QALY gained was reasonable, at less than half of that observed for instance for hip replacement surgery. However, prolonged waiting for an operation approximately doubled the cost per QALY gained from the surgical intervention. The mean utility gain following routine cataract surgery in a real world setting was relatively small and confined mostly to patients who had had both eyes operated on. The cost of cataract surgery per QALY gained was higher than previously reported and was associated with considerable degree of uncertainty. Hip and knee replacement both improve HRQoL. The cost per QALY gained from knee replacement is two-fold compared to hip replacement. Cost-utility results from the three studied specialties showed that there is great variation in the cost-utility of surgical interventions performed in a real-world setting even when only common, widely accepted interventions are considered. However, the cost per QALY of all the studied interventions, except for revision hip arthroplasty, was well below 50 000, this figure being sometimes cited in the literature as a threshold level for the cost-effectiveness of an intervention. Based on the present study it may be concluded that routine evaluation of the cost-utility of secondary health care is feasible and produces information essential for a rational and balanced allocation of scarce health care resources.

Devolution of forest-related rights: Comparative analyses of six developing countries

The study focused on the different ways that forest-related rights can be devolved to the local level according to the current legal frameworks in Laos, Nepal, Vietnam, Kenya, Mozambique and Tanzania. The eleven case studies represented the main ways in which forest-related rights can be devolved to communities or households in these countries. The objectives of this study were to 1) analyse the contents and extent of forest-related rights that can be devolved to the local level, 2) develop an empirical typology that represents the main types of devolution, and 3) compare the cases against a theoretical ideal type to assess in what way and to what extent the cases are similar to or differ from the theoretical construct. Fuzzy set theory, Qualitative Comparative Analysis and ideal type analysis were used in analysing the case studies and in developing an empirical typology. The theoretical framework, which guided data collection and analyses, was based on institutional economics and theories on property rights, common pool resources and collective action. On the basis of the theoretical and empirical knowledge, the most important attributes of rights were defined as use rights, management rights, exclusion rights, transfer rights and the duration and security of the rights. The ideal type was defined as one where local actors have been devolved comprehensive use rights, extensive management rights, rights to exclude others from the resource and rights to transfer these rights. In addition, the rights are to be secure and held perpetually. The ideal type was used to structure the analysis and as a tool against which the cases were analysed. The contents, extent and duration of the devolved rights varied greatly. In general, the results show that devolution has mainly meant the transfer of use rights to the local level, and has not really changed the overall state control over forest resources. In most cases the right holders participate, or have a limited role in the decision making regarding the harvesting and management of the resource. There was a clear tendency to devolve the rights to enforce rules and to monitor resource use and condition more extensively than the powers to decide on the management and development of the resource. The empirical typology of the cases differentiated between five different types of devolution. The types can be characterised by the devolution of 1) restricted use and control rights, 2) extensive use rights but restricted control rights, 3) extensive rights, 4) insecure, short term use and restricted control rights, and 5) insecure extensive rights. Overall, the case studies conformity to the ideal type was very low: only two cases were similar to the ideal type, all other cases differed considerably from the ideal type. The restricted management rights were the most common reason for the low conformity to the ideal type (eight cases). In three cases, the short term of the rights, restricted transfer rights, restricted use rights or restricted exclusion rights were the reason or one of the reasons for the low conformity to the ideal type. In two cases the rights were not secure.

Molecular Genetics of Age-related Macular Degeneration

Age-related macular degeneration (AMD; OMIM # 603075) is an eye disease of the elderly, signs of which appear after the age of 50. In the Western world it is a leading cause of permanent visual loss with a prevalence of 8.5% in persons under 54 years of age and of 37% in persons over 75 years of age. Early forms of AMD may be asymptomatic, but in the late forms usually a central scotoma in the visual field follows severely complicating daily tasks. Smoking, age, and genetic predisposition are known risk factors for AMD. Until recently no true susceptibility genes had been identified though the composition of drusen deposits, the hallmarks of AMD, has suggested that the complement system might play a role in the pathogenesis of AMD. When four groups reported in March 2005, that, on chromosome 1q32, a Y402H variant in the complement factor H (CFH) gene confers risk for AMD in independent Caucasian samples, a new period in the field of genetic research of AMD started. CFH is a key regulator of the complement system. Thus, it is logical to speculate, that it plays a role in the pathogenesis of AMD. We performed a case-control association study to analyse whether the CFH Y402H variant contain a risk for AMD in the Finnish population. Although the population of Finland represents a genetic isolate, the CFH Y402H polymorphism was associated with AMD also in our patient sample with similar risk allele frequencies as in the other Caucasian populations. We further evaluated the effects of this variant, but no association between lesion subtype (predominantly classic, minimally classic or occult lesion) or lesion size of neovascular AMD and the CFH Y402H variant was detected. Neither did the variant have an effect on the photodynamic therapy (PDT) outcome. The patients that respond to PDT carried the risk genotype as frequently as those who did not respond, and no difference was found in the number of PDT sessions needed in patients with or without the risk genotypes of CFH Y402H. Functional analyses, however, showed that the binding of C-reactive protein (CRP) to CFH was significantly reduced in patients with the risk genotype of Y402H. In the past two years, the LOC387715/ high-temperature requirement factor A1 (HTRA1) locus on 10q26 has also been repeatedly associated with AMD in several populations. The recent discovery of the LOC387715 protein on the mitochondrial outer membrane suggests that the LOC387715 gene, not HTRA1, is the true predisposing gene in this region, although its biological function is still unknown. In our Finnish patient material, patients with AMD carried the A69S risk genotype of LOC387715 more frequently than the controls. Also, for the first time, an interaction between the CFH Y402H and the LOC387715 A69S variants was found. The most recently detected susceptibilty gene of AMD, the complement component 3 (C3) gene, encodes the central component of the complement system, C3. In our Finnish sample, an additive gene effect for the C3 locus was detected, though weaker than the effects for the two main loci, CFH and LOC387715. Instead, the hemicentin-1 or the elongation of very long chain fatty acids-like 4 genes that have also been suggested as candidate genes for AMD did not carry a risk for AMD in the Finnish population. This was the first series of molecular genetic study of AMD in Finland. We showed that two common risk variants, CFH Y402H and LOC387715 A69S, represent a high risk of AMD also in the isolated Finnish population, and furthermore, that they had a statistical interaction. It was demonstrated that the CFH Y402H risk genotype affects the binding of CFH to CRP thus suggesting that complement indeed plays an important role in the pathogenesis of AMD.

Immigrant Associations in the Metropolitan Area of Finland : Forms of Mobilisation, Participation and Representation

This study examines the role of immigrant associations in the societal and political integration of immigrants into Finnish society. The societal focus is on the ability of immigrant associations to mobilise their ethnic group members to participate in the socio-economic, cultural and political domains of Finnish society and in certain cases even beyond. The political integrative aims are the opportunities of immigrant associations to participate and represent the interests of their ethnic group in local and national policy making. This study focuses on associations in the Metropolitan Area of Finland, (Espoo, Helsinki and Vantaa).The qualitative research consisted of 71 interviews conducted with members of immigrant associations and civil servants. These interviews were mainly semi-structured, including some additional open-ended questions. Additional data consisted of documents, planning reports and of follow-up enquiries. -- In the analysis of the data I categorised thirty-two immigrant associations according to the activity forms and the description of the goals by the members. The four categories consisted of integrative, societal, ethno-cultural and transnational immigrant associations. Most of the immigrant associations belonged to the integrative category (15 of 32 associations). On the one hand the aims of these associations are to provide access for their ethnic group members into Finnish society, while on the other to strengthen the ethnic identity of their members by organising ethno-cultural activities. The societal associations only focused on activities with the objective of including immigrants into the Finnish labour market and educational system. The goal of ethno-cultural associations was to strengthen the ethnic identity of their ethnic group members. The transnational associations aimed at improving the living conditions of women and children in the members' country of origin. The possibilities for immigrant associations to mobilise their members depends partly on external financing. Subsidies have been allocated for societal activities in particular. There remains a risk of the crowding out of ethno-cultural activities: something which has already taken place in several European countries. Immigrant associations aim to strengthen the identity of immigrants mainly by organising social and ethno-cultural activities. Another important target was to provide peer support and therapy courses. Additionally, immigrant women's associations offer assistance to women who have encountered violence by providing counselling and in some cases access to shelter. The data showed that there is an ever growing need to pay heed to the well-being of women, children and elderly immigrants. The participation of immigrant associations in the municipalities' integrative issues takes place mainly through cooperative projects. Until the end of the 1990s there had not been much cooperation. The problem with the projects was that they had mainly been managed by civil servants, whereas members from immigrant associations had remained in a more passive position. Representation of immigrant associations in councils has been fairly weak. Immigrant associations are included in the multicultural councils of Espoo and Vantaa, but only in the planning stages. The municipality of Helsinki does not include immigrant associations due to the large number of organisations which causes problems in finding fair, democratic representation. At the national level, the ‘Advisory Board for Ethnic Relations’ – ETNO didn’t chose its members based on membership of ethnic associations, but based on belongingness to one of the larger language groups spoken by the foreign population in Finland. Since ETNO’s third period (2005-2007), the representatives of immigrant associations and ethnic minority groups have been chosen from proposed candidates. Key words: immigrant associations, integration, mobilisation, participation, representation, the Metropolitan area of Finland, immigrant (women), civil servants

Investigations of Noise-Related Tinnitus

Tinnitus is a frequent consequence of noise trauma. Usually, however, the main focus regarding the consequences of noise trauma is placed on hearing loss, instead of tinnitus. The objectives of the present study were to assess various aspects of noise-related tinnitus in Finland, such as to determine the main causes of conscript acute acoustic traumas (AAT) in the military, assess tinnitus prevalence after noise trauma, characterize long-term AAT-related tinnitus prevalence and characteristics, assess occupational tinnitus, and evaluate the efficacy of hearing protection regulations in preventing hearing loss and tinnitus. The study comprised several independent noise-exposed groups: conscripts performing their military duty, former conscripts who suffered an AAT over a decade earlier, bomb explosion victims, and retired army personnel. Tinnitus questionnaires were used to assess tinnitus prevalence and characteristics. For occupational tinnitus, occupational noise-induced hearing loss (NIHL) reports to the Finnish Institute of Occupational Health were reviewed. Tinnitus is a common result of AAT, blast exposure and long-term noise exposure. Despite hearing protection regulations, up to hundreds of AATs occur annually among conscripts in the Finnish Defence Forces (FDF). The most common cause is an accidental shot, accounting for approximately half of the cases. Conscript AATs are mainly due to accidental shots, while the ear is unprotected. Only seldom is an AAT due to negligence. The most common causative weapon of conscript AATs is the assault rifle, accounting for 81% of conscript AATs. After AAT, the majority of tinnitus cases resolve during military service and become asymptomatic. However, in one-fifth of the cases, tinnitus persists, causing problems such as sleeping and concentration difficulties in many. In Finland, occupational tinnitus often remains unreported in conjunction with NIHL reports. In a survey of occupational NIHL cases, tinnitus was mentioned in only four per cent. However, a subsequent inquiry revealed that almost 90% in fact had tinnitus, indicating that most cases remained undetected and unreported. The best way to prevent noise-related tinnitus is prevention of noise trauma. In the military, hearing protection guidelines have been revised several times over the years. These regulations have been effective in reducing hearing loss of professional soldiers. There has also been a reduction in cases with tinnitus, but the decrease was not significant. However, with improved hearing protection regulations, a significant reduction in the risk of more serious, disturbing tinnitus was observed.

The changing role of legislation related to forest conservation and forest resources development.

XVIII IUFRO World Congress, Ljubljana 1986.

The Effect of Food-Related Lifestyle on the Choices of Consumers of Five Food Products

The purpose of this study was to find out whether food-related lifestyle guides and explains product evaluations, specifically, consumer perceptions and choice evaluations of five different food product categories: lettuce, mincemeat, savoury sauce, goat cheese, and pudding. The opinions of consumers who shop in neighbourhood stores were considered most valuable. This study applies means-end chain (MEC) theory, according to which products are seen as means by which consumers attain meaningful goals. The food-related lifestyle (FRL) instrument was created to study lifestyles that reflect these goals. Further, this research has adopted the view that the FRL functions as a script which guides consumer behaviour. Two research methods were used in this study. The first was the laddering interview, the primary aim of which was to gather information for formulating the questionnaire of the main study. The survey consisted of two separate questionnaires. The first was the FRL questionnaire modified for this study. The aim of the other questionnaire was to determine the choice criteria for buying five different categories of food products. Before these analyses could be made, several data modifications were made following MEC analysis procedures. Beside forming FRL dimensions by counting sum-scores from the FRL statements, factor analysis was run in order to elicit latent factors underlying the dimensions. The lifestyle factors found were adventurous, conscientious, enthusiastic, snacking, moderate, and uninvolved lifestyles. The association analyses were done separately for each choice of product as well as for each attribute-consequence linkage with a non-parametric Mann-Whitney U test. The testing variables were FRL dimensions and the FRL lifestyle factors. In addition, the relation between the attribute-consequence linkages and the demographic variables were analysed. Results from this study showed that the choice of product is sequential, so that consumers first categorize products into groups based on specific criteria like health or convenience. It was attested that the food-related lifestyles function as a script in food choice and that the FRL instrument can be used to predict consumer buying behaviour. Certain lifestyles were associated with the choice of each product category. The actual product choice within a product category then appeared to be a different matter. In addition, this study proposes a modification to the FRL instrument. The positive towards advertising FRL dimension was modified to examine many kinds of information search including the internet, TV, magazines, and other people. This new dimension, which was designated as being open to additional information, proved to be very robust and reliable in finding differences in consumer choice behaviour. Active additional information search was linked to adventurous and snacking food-related lifestyles. The results of this study support the previous knowledge that consumers expect to get many benefits simultaneously when they buy food products. This study brought detailed information about the benefits sought, the combination of benefits differing between products and between respondents. Household economy, pleasure and quality were emphasized with the choice of lettuce. Quality was the most significant benefit in choosing mincemeat, but health related benefits were often evaluated as well. The dominant benefits linked to savoury sauce were household economic benefits, expected pleasurable experiences, and a lift in self-respect. The choice of goat cheese appeared not to be an economic decision, self-respect, pleasure, and quality being included in the choice criteria. In choosing pudding, the respondents considered the well-being of family members, and indulged their family members or themselves.