It has been well established that the stress-related neurochemical systems corticotropin-releasing factor (CRF), noradrenaline (NA), and dopamine (DA) mediate stress-induced reinstatement of drug seeking. The three series of experiments presented in this dissertation constitute a further exploration of the role these neurochemical circuits play in reinstatement by providing the first direct exploration of whether central CRF and catecholamine (NA and DA) systems interact to influence reinstatement of cocaine seeking. The primary objective of the first series of experiments was to determine whether NA and CRF systems interact to mediate reinstatement of cocaine seeking and, if so, to determine the direction of this interaction. Results showed that central administration of NA induced reinstatement and up-regulated the expression of c-fos mRNA, a marker of neuronal activation, in brain regions involved in footshock-induced reinstatement. Pretreatment with a CRF antagonist blocked NA-induced reinstatement. In contrast, pretreatment with the α2-adrenoceptor agonist, clonidine, failed to block CRF-induced reinstatement. Taken together, these findings suggest a functional interaction between NA and CRF systems in mediating stress-induced reinstatement of cocaine seeking, whereby activation of CRF receptors occurs subsequent to, and downstream of, the sites of action of NA. A second series of experiments examined the role of D1- and D2-like receptors in CRF-induced reinstatement. Pretreatment with the D1- or D2-like receptor antagonists, SCH23390 and raclopride, respectively, dose-dependently blocked CRF-induced reinstatement of cocaine seeking. Taken together with previous findings, these results suggest that CRF-induced reinstatement of cocaine seeking likely involves DAergic signaling via D1- and D2-like receptors, subsequent to activation of CRF receptors. The final series of experiments investigated the neuropharmacology of yohimbine-induced reinstatement, focusing on the roles of α2-adrenoceptors, D1- and D2-like receptors. These experiments were prompted by an unexpected finding in the first series of experiments, in which a CRF antagonist failed to interfere in yohimbine-induced reinstatement of cocaine seeking. Results showed that pretreatment with the α2-adrenoceptor agonist, clonidine, or raclopride, prior to tests for yohimbine-induced reinstatement failed to influence responding. In contrast, pretreatment with SCH23390 blocked yohimbine-induced reinstatement. Taken together, these findings suggest that yohimbine may act through system(s) other than NA to have its effects.

It has been well established that the stress-related neurochemical systems corticotropin-releasing factor (CRF), noradrenaline (NA), and dopamine (DA) mediate stress-induced reinstatement of drug seeking. The three series of experiments presented in this dissertation constitute a further exploration of the role these neurochemical circuits play in reinstatement by providing the first direct exploration of whether central CRF and catecholamine (NA and DA) systems interact to influence reinstatement of cocaine seeking. The primary objective of the first series of experiments was to determine whether NA and CRF systems interact to mediate reinstatement of cocaine seeking and, if so, to determine the direction of this interaction. Results showed that central administration of NA induced reinstatement and up-regulated the expression of c-fos mRNA, a marker of neuronal activation, in brain regions involved in footshock-induced reinstatement. Pretreatment with a CRF antagonist blocked NA-induced reinstatement. In contrast, pretreatment with the α2-adrenoceptor agonist, clonidine, failed to block CRF-induced reinstatement. Taken together, these findings suggest a functional interaction between NA and CRF systems in mediating stress-induced reinstatement of cocaine seeking, whereby activation of CRF receptors occurs subsequent to, and downstream of, the sites of action of NA. A second series of experiments examined the role of D1- and D2-like receptors in CRF-induced reinstatement. Pretreatment with the D1- or D2-like receptor antagonists, SCH23390 and raclopride, respectively, dose-dependently blocked CRF-induced reinstatement of cocaine seeking. Taken together with previous findings, these results suggest that CRF-induced reinstatement of cocaine seeking likely involves DAergic signaling via D1- and D2-like receptors, subsequent to activation of CRF receptors. The final series of experiments investigated the neuropharmacology of yohimbine-induced reinstatement, focusing on the roles of α2-adrenoceptors, D1- and D2-like receptors. These experiments were prompted by an unexpected finding in the first series of experiments, in which a CRF antagonist failed to interfere in yohimbine-induced reinstatement of cocaine seeking. Results showed that pretreatment with the α2-adrenoceptor agonist, clonidine, or raclopride, prior to tests for yohimbine-induced reinstatement failed to influence responding. In contrast, pretreatment with SCH23390 blocked yohimbine-induced reinstatement. Taken together, these findings suggest that yohimbine may act through system(s) other than NA to have its effects.

INTRODUCTION: Marijuana use, although illegal in the majority of states, is increasingly becoming acceptable for use in the United States. There are dangerous public health consequences associated with marijuana use—including: impaired driving, loss of productivity in workplaces and school settings, as well as mental health impacts. In Atlanta, the majority of residents (54.0%) are African American. Emergency room use is double for African American Fulton County residents compared to their Caucasian counterparts and approximately 1/5 of the total population receiving public health treatment identify marijuana as the primary drug of use, with 57% of those being African Americans. Despite these statistics, the availability of treatment and prevention programs targeting African Americans using marijuana is negligible.AIM: The purpose of this study is to synthesize evidence-based approaches to substance use treatment so that effective components of previous research can be incorporated into an innovative marijuana prevention program to increase post-treatment abstinence targeting a segment of the population that has not been a significant focus in intervention research. METHODS: A review of scientific literature was conducted to identify and appraise evidence based approaches to substance use among young adults. First, the student researcher examined programs targeting marijuana use. Second, the search was expanded to substance use in general. The student researcher identified the population, intervention, control arm, and outcomes of various studies focusing on substance use prevention in a variety of settings. With this appraisal, the most effective components are suggested for a marijuana specific program which could be offered to African-American young adults, as no current programs in Georgia were found. RESULTS: Substance abuse intervention approaches targeting young adult populations were identified. Programs are delivered in a variety of settings: family, school, and community. Evidence supports that cognitive behavioral training, motivational enhancement training, and contingency management are the most effective approaches targeting substance use among young adults. A program that integrates components of each approach would be ideal for targeting African American young adults using marijuana in Metro-Atlanta and assisting them to maintain abstinence post-treatment. DISCUSSION: The results from this study emphasize key program elements that can address marijuana addiction among African American young adults in Metro-Atlanta. As marijuana acceptance increases, the need for prevention programs becomes more urgent. This study’s results can assist program planners in understanding the most strategic interventions that would optimize return on investment when addressing a largely silent public health threat: marijuana use among Africa American young adults in Metro-Atlanta.

Syftet med studien var att undersöka vilken grad av intern motivation och extern reglering till fysisk aktivitet som motionärer har, samt vilka barriärer de upplever till fysisk aktivitet och vilka strategier de använder sig av för att övervinna barriärerna. Bakgrunds variabler var kön och aktivitetsstadie. Försökspersonerna (n=199) i studien var män (n=96) och kvinnor (n=103) och samtliga medlemmar på träningsanläggningar i Halland. Högaktiva (n=165) och lågaktiva (n=34). Datainsamling skedde via ett testbatteri bestående av mätinstrumenten The Behavioral Regulation in Exercise Questionnaire-2, Physical Activity Stages of change och Motivation Till Upprätthållande Av Motionsvanor vilka delades ut på träningsanläggningarna. Resultatet visade att både högaktiva (n=165) och lågaktiva (n=34) har en högre grad av intern motivation än extern reglering. De mest frekventa barriärerna till fysisk aktivitet var stress/tidsbrist samt brist på motivation och de mest använda strategierna var tanken på känslan efteråt och tanken på förväntade resultat. Interventioner för att främja långsiktiga motionsbeteenden bör fokusera på att skapa glädje, välbefinnande och självbestämmande hos individen som leder till högre grad intern motivation som visat sig vara eftersträvansvärt för en fysiskt aktiv livsstil. Framtida studier skulle kunna fördjupa sig mer om hur motivation, barriärer och strategier skiljer sig åt beroende på aktivitetsstadie, genom att utföra ett träningsprojekt med en grupp lågaktiva individer för att kunna jämföra om inställningen skiljer sig åt ju mer fysiskt aktiva de blir. / The purpose of this study was to investigate the degree of internal motivation and external regulation for physical activity that athletes have, and what barriers they perceive to physical activity and what strategies they use to overcome barriers. Background variables were gender and activity stage. The subjects (n=199) in the study were men (n=96) and women (n=103) and all members of fitness centers in Halland. Highly active (n=165) and low-level (n=34). Data collection was done through a test battery consisting of measuring instruments The Behavioral Regulation in Exercise Questionnaire-2, Physical Activity Stages of Change and Exercise Adherence Questionnaire which were handed out at training facilities. The results showed that both high-level (n=165) and low-level (n=34) has a higher degree of internal motivation than external regulation. The most frequent barriers to physical activity were stress / time constraints, lack of motivation and the most frequently used strategies were the idea of feeling afterwards and the idea of expected results. Interventions to promote long-term exercise behaviour should focus on creating happiness, well being and autonomy of the individual that lead to greater internal motivation that proved to be desirable for a physically active lifestyle. Future studies could deepen more in how motivation, barriers and strategies differ depending on activity stage, by performing a training project with a group low-level to compare if the attitudes differ when they get more physical active.

Borderline Personality Disorder (BPD) is one of the more common personality disorder diagnoses observed in psychiatric inpatients and outpatients. Previous studies have found that individuals with BPD may be expected to experience difficulties throughout their lifetimes and they may repeatedly return for psychological treatment. Whereas previous studies have attempted to identify various factors related to relapse in other chronically recurring disorders such as depression, schizophrenia, and substance abuse, studies examining factors associated with relapse in BPD, and personality disorders in general, are absent from the scientific literature. This exploratory study examined whether specific risk and protective factors (dynamic and/or static) identified from the general relapse literature were associated with diagnostic relapse in BPD. Results revealed that variables related to an increased likelihood for BPD relapse included: substance abuse or Major Depressive Disorder, higher Neuroticism, and lower Conscientiousness. In addition, having a steady work or school status after remission was found to protect against a BPD relapse in the presence of various risk factors. Although this study has several limitations, these results provide some of the first insights to the processes of relapse and continued remission in BPD patients. Continued research efforts in this area can help to identify individuals who are at a greater risk for BPD relapse and potentially to design effective relapse-prevention strategies for the treatment of BPD.

Insensitivity to chemotherapy is an ongoing issue in cancer treatment, one that appears to be highly dependent on patient-specific variations. It has been shown clinically that while a subset of patients will successfully respond to a particular chemotherapeutic regimen, there exists another subset of patients who when exposed to the same course of therapy will remain resistant to treatment or exhibit signs of relapse after treatment has been administered. This discrepancy raises interesting questions regarding the role that patient-specific variations play in controlling the efficacy of chemotherapy treatment regimens. Doxorubicin (Dox) is a common chemotherapeutic agent used in the treatment of a variety of solid tumors and leukemias and resistance to Dox treatment is a major issue in cancer chemotherapy, oftentimes leading to patient relapse. To gain a deeper understanding of the processes that influence Dox resistance, we must first understand the mechanisms that underlie and contribute to Dox's toxicity. To this end, the metabolic reactions that activate Dox have been implicated as major determinants of Dox cytoxicity and as possible factors that control Dox resistance in cancer cells. There are several lines of evidence that redox-dependent metabolism plays a large role in Dox toxicity. The Dox bioactivation network is comprised of a system of reduction/oxidation (redox) reactions that lead to the formation of toxic Dox metabolites and reactive oxygen species (ROS). Moreover, multi-drug resistant acute lymphoblastic leukemia cells derived from relapsed patients have elevated levels of the antioxidant glutathione and show insensitivity to Dox treatment. The redox dependence of Dox bioactivation, the understanding that Dox treatment generates ROS, and the evidence that Dox resistant cells exhibit increased antioxidant capacity, suggest the possibility that redox pathways modulate the efficacy of Dox treatment in cancer cells. The overall objectives of the proposed dissertation, therefore, were to investigate how the redox properties of the Dox bioactivation network influence Dox toxicity in acute lymphoblastic leukemia cells, and to provide evidence that cell-specific variations in the intracellular levels of these redox components influences the degree to which Dox treatment will induce cancer cell death. The significant findings of this study are that the redox reactions involved in Dox metabolism are dual-natured, containing a toxicity-generating module characterized by nicotinamide adenine dinucleotide phosphate (NADPH)-dependent Dox reductive conversion, as well as an ROS signal-generating module characterized by NADPH- and oxygen-dependent Dox redox cycling. The balance between the coupled redox reactions that comprise the toxicity- and ROS signal-generating modules of Dox bioactivation determines the sensitivity-phenotype of leukemia cells and phenotypic changes in the Dox-sensitivity of leukemia cells can be induced by the successful modulation of the Dox bioactivation network through the pharmacological inhibition of NADPH in a concentration- and cell type-dependent manner. This study highlights the importance of the intracellular redox network in controlling chemotherapy-induced ROS. The unequal distribution in antioxidant burden across the various intracellular antioxidant enzymes suggests a significant role for NADPH supply, as controlled by the enzyme glucose-6-phosphate dehydrogenase (G6PD), to the intracellular ROS buffering capacity of cells during instances of oxidative stress. Changes in G6PD activity were shown to promote protein-S-glutathionylation during oxidative stress conditions, thereby implicating G6PD in the modulation of redox-sensitive signal transduction pathways. The intracellular glutathione redox balance, a measure of the intracellular redox environment, can effectively regulate Dox-induced NF-κB signal transduction in leukemia cells. The systematic modulation of intracellular glutathione redox balance in leukemia cells by N-acetylcysteine (NAC) revealed an important role for protein S-glutathionylation mechanisms in the control of NF-κB signal transduction induced by Dox treatment. These findings identify the glutathione redox network as a potential therapeutic target for the systematic modulation of Dox sensitivity in cancer cells and elucidate the complex role that antioxidants such as NAC can play in modulating the effectiveness of Dox chemotherapy treatment regimens. Lastly, this study highlights the need for and the capacity of computational models to accurately describe the complex redox-reactions that contribute to Dox metabolism in leukemia cells. This study is groundbreaking in its use of computational modeling to analyze reversible electron transfer events between proteins using mass-action kinetics. The models developed in this study can accurately explain cytosolic doxorubicin bioactivation, intracellular hydrogen peroxide clearance, and kinase-specific S-glutathionylation, thereby showing that the use of comprehensive and/or relatively simple computational models can provide semi-quantitative predictions about the behavior of redox systems in mammalian cells as they relate to Dox-induced toxicity and Dox-induced cell signaling.

Autoimmune hepatitis (AIH) was identified as an entity by the Swedish professor Jan Waldenström in the 1950s. It was then denoted lupoid hepatitis, characterized by liver inflammation and most often affecting young women. During the years the diagnosis has become more defined (as the non A non B hepatitis has been identified as Hepatitis C) and now can be safely separated from other diseases with liver inflammation. Studies of epidemiological data and long term prognosis have been scarce in the literature. Within a collaboration between the university hospitals in Sweden, we collected what we believe is the largest cohort in the world of patients with AIH. Data from the medical records of 473 individuals was, after AIH-score calculations where the diagnosis was confirmed, collected in a data base, in which most of the analysis was done. Data from the Swedish national registers of cancer, death cause, and birth register was searched for these patients as well as controls. The aim of the thesis was to explore epidemiological and clinical outcome of AIH.The onset of AIH may be at any age, but the incidence seems to increase after 50 years of age; 75% are females, the overall incidence (0.85/ 100,000 inhabitants and year) and prevalence (11/100,000 inhabitants) are figures that are within the range of another but smaller Scandinavian study. Approximately 30 % had cirrhosis already at diagnosis and 87% displayed at some time positive auto-antibodies indicating AIH (Smooth muscle ab and or antinuclear ab).  Indications of future risk for liver transplantation or death is an advanced AIH at diagnosis with liver cirrhosis, decompensated liver disease, elevated PK INR as well as age. Acute hepatitis-like onset seems to carry a lower risk for later liver transplantation or death. Current Swedish national therapy traditions with immune suppression seem to be well tolerated. Five and ten years overall life expectancy does not differ from controls. Thirty-five women gave birth to 63 children, for 3 after liver transplantation of the mother. Thirteen of the women had liver cirrhosis. Current pharmacological treatment seems to be safe both for the patient and the foetus. Thirty percent of the patients experienced flair after delivery. It has been supposed that there is an overrisk for hepatocellular cancer (HCC) associated with AIH. Our figures are the first in the world to be presented that confirms a twenty-three fold overrisk (95% Confidence Interval 7.5-54.3) for hepatobiliar cancer. We found as well an overrisk of non-Hodgkin lymphomas of 13.09 (95% CI 4.2-30.6).Conclusion:  Our epidemiological results confirm that AIH is a fairly uncommon disease, and that many already at time of diagnosis have an advanced disease with liver cirrhosis. There is a clear overrisk for HCC and lymphoma. For those women with AIH who become pregnant the prognosis for the child as well as for the mother is good, even for those women who already have compensated cirrhosis. There is a risk for relapse after delivery. The overall survival for AIH patients with current therapy is good.

The overall aim of the study was to examine relapse among participants in the DWI Prevention Programme and those who get prison sentence after driving when influenced by alcohol and to examine the participants’ attitudes towards drunk – driving, risk behavior and traffic safety. A direct evaluation of the sentence and penal accomplishment is also examined. The sample of the survey study (see article 1) was 44 from the DWI – sample and 44 from the prison – sample that completed a questionnaire answering about their attitudes towards drunk – driving, risk behavior and traffic safety. The results presented in article 2 are based on transcripts of criminal convicts that participated in the DWI Prevention Programme during the period of 1998 – 2002 in the Salten District ( n = 68) and a sample of convicts to an unconditional sentence for drunk - driving in the same time periode (n = 112). The 1st analysis revealed that the DWI – sample had more ideal attitudes towards drunk – driving, risk behavior and traffic safety. There were also significant differences in how they evaluated their sentence and penal accomplishment. The DWI - sample were generally more satisfied with the penal accomplishment, the way they was treated and how the relationships around them were. They were also more satisfied with the contents of the penal accomplishment. Multivariate analysis, Kaplan – Meier and Cox regression was used in the 2nd analysis calculating if there were significant differences between the samples, survival time and to investigate effects of several variables upon the time a specified event takes to happen. In this study the relapse time was shorter for men than for women and the youngest age – groups had a shorter relapse time than the oldest age – groups. The Kaplan – Meier plot revealed that the prison – group have a shorter relapse time compared to the DWI – group. Based on the results of the two articles we can conclude that the DWI Prevention Programme had a very good effect on the participants compared to those who get traditional prison – sentence. The participants in the programme had the most ideal attitudes and the longest survival time after participating. When it comes to survival time among gender and age, women and the older age – groups had the longest survival time.

Tiriamoji problema. Šiame darbe gvildenama alternatyvių laisvės atėmimui bausmių veiksmingumo problema. Esminis nagrinėjamų bausmių aspektas yra pažeidėjo elgesio kontrolės galimybės laisvėje. Asmens kontrolė laisvėje grindžiama žmogaus gebėjimo keisti savo elgesį idėja. Problemų, padidinančių nusikalstamo elgesio recidyvo riziką sprendimas, pasikeitimas reikalauja iš nuteistojo valios ir pastangų (motyvacijos keistis). Vadinasi, alternatyvių laisvės atėmimui bausmių poveikis nuteistajam turi sąlygoti jo elgesio pasikeitimą. Tokiu būdu nuteistajam teismo nustatytos individualios alternatyvios laisvės atėmimui bausmės sąlygos (įpareigojimai ir/ar draudimai) turi formuoti atitinkamą jo elgesio kryptį. Paskirtos bausmės sąlygos turėtų pažeidėjui formuoti užduotį spręsti nusikalstamą elgesį paskatinusias problemas ir riboti elgesį, kuris yra glaudžiai susijęs su nusikalstama veikla. Alternatyvių laisvės atėmimui bausmių veiksmingumo problema atskleidžiama nagrinėjant jų skyrimo ir vykdymo sąlygų gebėjimą paveikti nusikalstamą elgesį paskatinusius veiksnius ir tokiu būdu mažinti nusikalstamų veikų recidyvą. Analizuojant temą įžvelgiama tinkamos alternatyvios laisvės atėmimui bausmės parinkimo (individualizavimo) ir nuoseklaus taikymo problema. Teismui, sprendžiant alternatyvios laisvės atėmimui bausmės skyrimo klausimą, reikia nustatyti ne tik skiriamos bausmės trukmę, bet ir tinkamumą konkrečiam asmeniui: ar paskirtos sąlygos (jų kiekis ir pobūdis) yra pakankamos, kad būtų... [toliau žr. visą tekstą] / The problem under study. The problem of efficiency of alternative to imprisonment (non-custodial) sanctions is investigated in the present study. The fundamental advantage of this kind of punishment is the possibility to control offenders‘ behavior in the community. This idea is based on the personal ability to change, which depends on an offender‘s will and efforts to change himself and to start solving the problems, which have caused the offending behavior (motivation to change). Therefore, imposed alternative sanctions should affect the changes in offenders‘ behavior. The individual conditions (obligation and/or restrictions) of the sanction, imposed by a court, should direct an offender‘s efforts to change. The problem of efficiency of alternative sanctions is discovered, while studying, how the conditions of imposition and execution of these sanctions could affect the criminogenic factors and, therefore, could reduce recidives of crime. Analyzing these aspects we can observe the problem of individualization of punishment, or finding the appropriate sanction, and the problem of coherent application of the sanction. A court, imposing non-custodial sanction, should not only state a term of its application, but also should decide, if the imposed obligations (their amount and character) are sufficient to supervise the offender in the community. The imposition of non-custodial sanctions to a great extend determs the process of execution of it. Particularly, if the conditions... [to full text]

Premolars are the most commonly extracted teeth to provide space to correct crowding and excessive labial protrusion. After treatment, the extraction spaces have to remain closed. Nevertheless, several studies have shown that there is a tendency for some relapse even in patients finished with an adequate occlusion. The objective of this study was to compare the stability of extraction space closure of the first and second premolars. A sample 72 patients´ dental casts were divided into two groups. Group 1, comprised 29 patients (116 extraction spaces) were treated with first premolar extractions at a mean initial age of 13.78 years and group 2, comprised 43 patients (100 extraction spaces) were treated with second premolar extractions at a mean initial age of 15.20 years. The dental casts obtained at pretrement, posttreament and a between 3 to 4 years postretention were digitized using a 3- dimensional scanner (R700; 3Shape,Copenhagen, Denmark). Chi-Square tests were used to compare the numbers of open and closed extraction spaces after treatment and at long-term posttreatment. T tests were used to compare the amount of spaces at posttreatment and at the long-term posttreatment stages. These tests were also performed in subgroups with completely closed extraction sites at posttreatment. The groups showed similar numbers of extraction sites reopening. First and second premolar extraction space closure present a similar tendency for reopening. Considering only the cases that showed completely closed extraction spaces in the final dental models, extraction space reopening was larger in the first premolar extraction group in the maxillary arch. / Os pré-molares são os dentes mais comumente extraídos para corrigir o apinhamento dentário e à protrusão labial excessiva. Após o tratamento, os espaços das extrações deveriam permanecer fechados. Contudo, muitos estudos demostraram que existe uma tendência à reabertura dos espaços de extrações em pacientes finalizados com uma oclusão adequada. O objetivo deste estudo foi comparar a estabilidade dos espaços de extrações de primeiro e segundo prémolares. A Amostra deste estudo foi composta por 72 modelos dentários dividido em dois grupos. O Grupo 1 composto por 29 pacientes (116 espaços de extração) foram tratados com extrações dos primeiros pré-molares com idade media inicial de 13,78 anos e o grupo 2 composto por 43 pacientes (100 espaços de extração) foram tratados com extrações dos segundos pré-molares com idade media inicial de 15.20 anos. Os modelos dentários obtidos no pré-tratamento, pós-tratamento e 3 a 4 anos de controle e foram digitalizados mediante um scanner 3Shape R700 3D (3Shape A/S, Copenhagen, Dinamarca). Os testes t e do Qui-Quadrado, foram utilizados para comparar o número de espaços de extração abertos e fechados após o tratamento e pós-tratamento em longo prazo. Os resultados demostraram números similares de reabertura do espaço de extração entre os grupos. Concluiu-se que considerando apenas os casos que mostraram espaços de extração completamente fechados no final do tratamento, a quantidade de reabertura dos espaços de extrações dos primeiros pré-molares ocorre mais frequentemente que dos segundos pré-molares no arco superior.