The human receptor-type protein-tyrosine phosphatase kappa (PTPRK) gene is highly expressed in human brain and was previously associated with an increased risk of neuropsychiatric disorders and cancer. This study investigated the association of 52 single nucleotide polymorphisms (SNPs) in PTPRK with the risk and age at onset (AAO) of Alzheimer's disease (AD) in 791 AD patients and 782 controls. Our data analysis showed that five SNPs (top SNP rs4895829 with p = 0.0125) were associated with the risk of AD based on a multiple logistic regression (p < 0.05); while six SNPs (top SNP rs1891150 with p = 8.02 × 10−6) were associated with AAO by using a multiple linear regression analysis. Interestingly, rs2326681 was associated with both the risk and AAO of AD (p = 4.65 × 10−2 and 5.18 × 10−3, respectively). In a replication study, the results from family-based association test - generalized estimating equation (GEE) statistics and Wilcoxon test showed that seven SNPs were associated with the risk of AD (top SNP rs11756545 with p = 1.02 × 10−2) and 12 SNPs were associated with the AAO (top SNP rs11966128 with p = 1.39 × 10−4), respectively. One additional sample showed that four SNPs were associated with risk of cancer (top SNP rs1339197 with p = 4.1 × 10−3), 12 SNPs associated with LDL-cholesterol (top SNP rs4544930 with p = 3.47 × 10−3), and eight SNPs associated with total cholesterol (top SNP rs1012049 with p = 6.09 × 10−3). In addition, the AD associated rs4895829 was associated with the gene expression level in the cerebellum (p = 7.3 × 10−5). The present study is the first study providing evidence of several genetic variants within the PTPRK gene associated with the risk and AAO of AD, risk of cancer, LDL and total cholesterol levels.

The neuron navigator 2 (NAV2) gene is highly expressed in brain and involved in the nervous system development and may play a role in Alzheimer's disease (AD). We aimed to investigate the associations of 317 single-nucleotide polymorphisms (SNPs) in the NAV2 gene with the risk and age at onset (AAO) of AD using a family-based sample (1266 AD cases and 1279 healthy relatives). Association with the risk of AD was assessed using family-based association test -generalized estimating equations (FBAT- GEE) statistics while the association with AAO as a quantitative trait was evaluated using the FBAT-Wilcoxon statistic. Single marker analysis showed that 20 SNPs were significantly associated with the risk of AD (top SNP rs7112354 with p = 8.46 × 10− 4) and 11 SNPs were associated with AAO (top SNP rs1354269 with p = 2.87 × 10− 3). Interestingly, two SNPs rs17614100 and rs12364788 were associated with both the risk (p = 1.7 × 10− 2 and 2.71 × 10− 2; respectively) and AAO (p = 1.85 × 10− 3 and 6.06 × 10− 3; respectively). Haplotype analyses further supported the results of single marker analyses. In addition, functional analysis showed that NAV2 mRNA had significant expression across ten human brain regions examined and significantly correlated with APOE expression in four of ten regions. The present study is the first study providing evidence of several genetic variants within the NAV2 gene influencing the risk and AAO of AD.

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Witnessing partner violence (WPV) in childhood and adolescence can have significant impact on psychological functioning throughout development. Studies have shown that parenting factors, perceived social support, coping strategies, age at exposure, and gender can influence the relationship between WPV and outcomes. Although WPV can have serious implications towards emotion regulation abilities, empirical research on the link between WPV and emotion regulation is inadequate. The current study examined the associations between the frequency and types of WPV in childhood and adolescence and emotion dysregulation in adulthood. The study further explored the roles of parental bonds, social support, coping strategies, age at exposure, and gender as moderators in the relationship between WPV and emotion dysregulation. Data were collected using an undergraduate sample at Virginia Tech (N = 1040). Results indicated that verbal violence exposure was a significant predictor of emotion dysregulation while physical violence and total WPV were not. Parental warmth moderated the relationship between all three types of WPV and emotion dysregulation, while parental control and age of onset were moderators for total and physical WPV. Social support moderated the relationship between verbal violence exposure and emotion dysregulation. Coping strategies and gender were not found to be significant moderators. Exploratory analyses were conducted to further explore these relationships. The findings and their implications are discussed. / Ph. D.

Background Rheumatoid arthritis (RA) is a systemic progressive destructive joint disease with an increased risk for co-morbidity and premature death if untreated. Cardiovascular disease (CVD) is the main cause of death but also other co-morbid conditions contribute to the patient’s shorter life expectancy. Inflammation is important for the development of CVD, but knowledge of its relationship with other co-morbidities is sparse. Early disease modifying anti rheumatic drugs (DMARDs) can suppress disease activity and improve the long-term outcome. The aim of this thesis was to evaluate prospectively aspects of disease activity and severity in a large cohort of patients with early RA. Predictive and prognostic markers, e.g., antibodies against citrullinated proteins/peptides (ACPAs), occurring in early disease and with implications for disease outcome and co-morbidity were evaluated. Methods Patients with early RA (i.e., symptomatic for ≤12 months) have, since December 1995, been consecutively included in a large survey of prospective and observational studies on the progression of RA and the development of co-omorbidity. Autoantibodies, inflammatory, genetic markers and radiographs have been analyzed. In paper I, 210 RA patients and 102 controls were followed regularly for two years. The predictive value of four different ACPAs in relation to disease activity and radiological progression was evaluated. In Paper II (n = 700) and in Papers III-IV (n =950), patients with early RA from the four northern-most counties of Sweden were followed regularly for 5 years. Data on risk factors and co-morbidity was collected, according to the study protocol, from clinical records and self-reported questionnaires from patients at inclusion into the study cohort and after five years. The predictive value of traditional and potential disease related risk factors for new cardiovascular events (CVE) was evaluated (II). In Paper III, the impact of age at the onset RA, stratified as being young onset RA (&lt;58 years; YORA) and late onset RA (≥58 years; LORA) on disease activity, severity and chosen treatment, was evaluated. In Paper IV, the development of new co-morbidities after RA onset and their relation to inflammatory activity was assessed. Results The presence of anti-mutated citrullinated vimentin (MCV ) antibodies was associated with a more severe disease course, estimated by disease activity score, erythrocyte sedimentation rate (ESR) and swollen joint count after 24 months, compared with anti-CCP2, anti-CCP3, and anti CCP3.1 antibodies. In Paper II, the incidence of a new CVE during 5 years was explained by several of the traditional CV risk factors, and potentiated by a high disease activity. Treatment with DMARDs decreased the risk. In Paper III, LORA patients were associated with greater disease activity/severity at disease onset and over time compared with YORA who were more often ACPA positive. YORA patients were treated earlier with DMARDs, whilst LORA patients were more often treated with corticosteroids and less so with DMARDs early in the course of their disease. In Paper IV, 53%of patients already had one or more co-morbidities already at the onset of RA. After 5 years, 41% of the patients had developed at least one new co-morbidity. ESR at baseline and accumulated disease activity were associated with a new co-morbidity after five years. Conclusion Early RA patients sero-positive for anti- MCV antibodies appeared to have a higher disease activity over time. The occurrence of a new CVE in early RA patients was predicted by traditional risk factors for CVD which were potentiated by a high disease activity. Treatment with DMARDs decreased the risk. Patients with young onset of RA were associated with a higher frequency of ACPA. Late onset of RA was associated with higher disease activity/severity at inclusion and over time. However, LORA patients were more often treated with corticosteroids and less so with DMARDs early in the disease course. Development of a new co-morbidity during the five years following diagnosis was related to ESR.

In an attempt to understand girls' involvement conduct problems, this dissertation first reviews two existing theoretical approaches that provide an explanation for the development of conduct problems. Specifically, the available literature on the development and correlates of conduct problems in boys suggests the subtypes of conduct disorder represent two developmental trajectories. The adolescent-onset pathway is associated with deviant peers and few characterological problems, where as the childhood-onset pathway is associated with emotion regulation deficits, negative parenting, callous and unemotional traits, and neurological deficits. Research also suggests a gender-specific model, the delayed-onset model, for the development of conduct problems in girls. Following this theoretical review, differential predictions made by the competing theoretical models are tested in a community sample of school-aged girls and boys. Participants were 202 children (87 males and 115 females) in grades 5-9. The students ranged in age from 10 to 17 years old (M = 13.16). Similar to the total student body, the ethnic breakdown of the sample was as follows: African-American (60%), Caucasian (24%), Hispanic (6%), and Other (5%). Data was also collected from the students' parents and teachers. Results indicated that girls conduct problems did not follow either model in a consistent manner. Specifically, adolescent-onset conduct problem girls, childhood-onset conduct problem boys, and adolescentonset conduct problem boys differed from non-conduct problem children but did not differ significantly amongst themselves on study variables (e.g., deviant peer association, hyperactivity/impulsivity, emotional dysregulation, callous/unemotional traits). However, results suggest that gender-specific risk factors should be taken into account when developing theoretical models for girls' conduct problems. For example, early pubertal maturation is a particularly salient risk factor for conduct problems in girls, and pubertal development interacts with emotion regulation problems to place girls at high risk for deviant behavior. Finally, implications for prevention and intervention as well as future research are discussed.

Os episódios mistos em pacientes portadores de Transtorno Bipolar são descritos freqüentemente como sendo mais graves que os episódios de mania aguda. Além disso, muitos trabalhos na literatura descrevem os pacientes com TB com história de episódios mistos, como um grupo distinto clínica e demograficamente do grupo com apresentação apenas de episódios de mania pura. Os objetivos deste estudo foram comparar clinicamente episódios agudos mistos versus episódios de mania pura e comparar clínica e demograficamente pacientes que apresentaram em algum momento do seguimento clínico pelo menos um episódio misto com pacientes que apresentaram apenas mania pura. Vinte pacientes apresentando episodio de mania pura foram comparados a 29 pacientes em estado misto de acordo com os critérios do DSM-IV. Não houve diferença na duração destes episódios, presença de hospitalização e tentativas de suicídio. Na comparação dos dados demográficos, não encontramos diferenças na idade, distribuição entre os sexos, classe sócio-econômica, estado civil e anos de escolaridade. Em relação ao curso, nosso estudo mostrou que pacientes com pelo menos um estado misto apresentaram maior freqüência de tentativas de suicídio e de episódios, mais comorbidades e idade de início da doença mais precoce. Foi realizada analise multivariada através de regressão logística para a identificação das variáveis clinicas que melhor distinguem um grupo do outro. Esta analise mostrou que a presença de comorbidades e de tentativas de suicídio foram as variáveis identificadas que mais fortemente estão associadas ao diagnóstico de pacientes com estado misto. / Mixed episodes in patients with bipolar disorder (BD) have been frequently described as more severe than acute manic episodes. Moreover, many papers in the literature have described the patients with BD with history of mixed episodes as a group that is clinically and demographically distinct from the group with clinical presentation of pure manic episodes. The purposes of this study were to compare clinically acute mixed episodes with pure manic episodes and compare clinically and demographically patients that present in any moment of their clinical follow-up at least one mixed episode with patients that present only pure mania. Twenty patients with pure manic episode were compared to 29 patients with mixed episodes according to DSM-IV criteria. There were no differences in episodes duration, presence of hospitalization and suicide attempts. Comparing the demographic data, we did not find differences in age, gender distribution, socio-economic status, marital status and years of education. Regarding the course of illness, our study showed that patients with at least one mixed state presented higher frequency of suicide attempts, younger age of illness onset, more co-morbidities, and higher index of impulsivity. A multi-variate analysis was performed with logistic regression to identify the clinical variables that better distinguish one group from the other. This analysis showed that the presence of co-morbidities and suicide attempts were the identified variables that are strongly associated with the diagnosis of patients with mixed state.

Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2014-08-21T12:48:09Z No. of bitstreams: 2 license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) DISSERTACAO MESTRADO MOYSES PRONTA (1) (1).pdf: 679547 bytes, checksum: cf4dd53c812b868e1a8d7ceb72f62419 (MD5) / Made available in DSpace on 2014-08-21T12:48:09Z (GMT). No. of bitstreams: 2 license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) DISSERTACAO MESTRADO MOYSES PRONTA (1) (1).pdf: 679547 bytes, checksum: cf4dd53c812b868e1a8d7ceb72f62419 (MD5) Previous issue date: 2013-09-30 / There are several studies on the differential diagnosis of Bipolar Disorder (BD), however, further investigation with an emphasis on clinical phenotypes that inaugurate the disease is needed. The aims of this study are to identify the psychiatric disorders most frequently diagnosed before the definitive diagnosis of BD, the time until the correct diagnosis and compare BD I and II for the variables studied. We studied 259 patients with current diagnosis of BD according to the DSM- IV-TR, evaluated by the same psychiatrist. Early psychiatric signs and symptoms were identified through an interview with the patient and family members and were considered suggestive of an initial diagnosis that was coded according to the same diagnostic criteria. The authors analyzed data on patients' age at prodromes suggestive of initial psychiatric diagnosis and time delay to the actual diagnosis of BD. Comparisons were made between sex, schooling and type of BD. The mean age of patients was 41.6 years, with a predominance of adults (19-60 years), women (67.6%), as well as type II BD (68.3%). Patients were on average 24.6 years of age at initial diagnosis, 41.6 years in the diagnosis of BD and the mean time delay between these was 16.9 years. The most common initial diagnoses were depressive disorders (41.3%), anxiety (12.7%), ADHD (8.1%), disorders related to substance abuse (7.7%), somatoform disorders (6 9%), and psychosis (5.4%). BD can be considered a “great imitator” in modern psychiatry, since initial phenotypes can mimic other disorders. BD diagnosis is very delayed in Brazil. / Há diversos estudos sobre o diagnóstico diferencial do Transtorno Bipolar (TB), entretanto, investigações com ênfase nos fenótipos clínicos que inauguram a doença são escassos. Os objetivos deste estudo consistem em identificar as doenças psiquiátricas mais frequentemente diagnosticadas antes do diagnóstico definitivo de TB, assim como o intervalo de tempo até o mesmo; e comparar o pacientes com TB I e II quanto aos diagnósticos iniciais, escolaridade, sexo e faixa etária. Para tanto, estudamos 259 pacientes com diagnóstico atual de TB segundo os critérios do DSM-IV-TR, realizado por um mesmo psiquiatra. Através de entrevistas com o paciente e familiares, identificou-se retrospectivamente os sinais e sintomas precoces considerados sugestivos do primeiro diagnóstico psiquiátrico, segundo os mesmos critérios. Dados relativos à idade dos pacientes no diagnóstico inicial e tempo até o diagnóstico atual de TB foram analisados e comparações foram feitas entre sexo, escolaridade, faixa etária e tipo de TB. A média de idade encontrada foi de 41,6 anos, com predominância de adultos (19-60 anos), do gênero feminino (67,6%), com TB II(68,3%). Os pacientes tinham em média 24,6 anos de idade no diagnóstico inicial, 41,6 anos no diagnóstico de TB e o tempo médio de atraso diagnóstico foi de 16,9 anos. Os diagnósticos iniciais mais frequentemente encontrados foram: transtornos depressivos (41,3%), ansiosos (12,7%), TDAH (8,1%), transtornos relacionados ao abuso de substâncias psicoativas (7,7%), transtornos somatoformes (6,9%) e psicóticos (5,4%). O T pode ser considerado um “grande imitador” moderno da Psiquiatria, posto que fenótipos iniciais podem mimetizar outros transtornos. Há um atraso significativo no diagnóstico do TBno Brasil.