This study examined the effects of low to moderate doses of manganese (0, 250, or 750 _g per day from PD 1-21) on a comprehensive battery of behaviors in rats during the neonatal period, preweanling period, and in adulthood.

The purpose of this study was to examine forensic social workers' levels of knowledge about skepticism toward Dissociative Identity Disorder (DID) in light of the controversy that surrounds the diagnosis. Relationships between demographic and professional practice variables and workers' levels of knowledge and skepticism were analyzed to assess the possible etiology of skepticism toward DID.

[pt] Nesta tese, à luz do prisma filosófico, empreendemos um olhar que abrangeu o pensamento médico filosófico desde a Antiguidade até a Revolução Terapêutica. Nosso olhar contemplou: na Antiguidade, uma época em que houve uma estreita colaboração entre Filosofia e Medicina, baseada na pesquisa mútua dos aspectos etiológicos, quer da enfermidade da alma, quer daquela do corpo; foi a época do nascimento e apogeu da Analogia Médica; na Idade Média, identificou um estado de hibernação da Analogia Médica no século XII, seguido de um leve despertar no século XIII, a volta a um estado de adormecimento e o despertar definitivo, no século XV; na Renascença, captou a retomada dos textos médicos e a queda do saber galênico tradicional; na Modernidade, finalmente, diagnosticou o início do distanciamento entre os saberes filosófico e médico, com o respectivo definhamento da Analogia Médica. Desde então, nosso olhar aprofundou se nas idas e vindas do saber médico filosófico, especulando as causas e consequências desse distanciamento, e chegou à conclusão de que o legado deixado pelo pensamento médico moderno orientou e orienta a Medicina contemporânea para um sentido de desumanização em relação à pessoa do paciente. Por fim, depois de tanto ver, nossa razão assentiu para a necessidade de uma reforma na Medicina, principalmente em sua paidéia, baseada numa próxima colaboração com a Filosofia a fim de receber subsídios quando à questão central de qualquer procedimento terapêutico: qual é o ser do ser humano? / [en] In this Thesis, using the light of the philosophical prism, we undertake an examination embracing medical philosophical thought beginning in antiquity, continuing up until the Therapeutic Revolution. Our view contemplates: in antiquity, a time during which there was a strict collaboration between Philosophy and Medicine, based upon mutual research of the etiological aspects of disease not only of the soul but also of the body; it was the time of the birth and apogee of the Medical Analogy; during the Middle Ages it was possible to identify that the Medical Analogy had entered a state of hibernation in the twelfth century, followed by a slight awakening in the thirteenth century, returning to a state of sleep, with the final awakening occurring in the fifteenth century; during the Renaissance it captured a return to the medical texts and the fall of traditional Galenic knowledge; finally during the Modern era we have diagnosed the initial phases of a distancing between philosophical and medical knowledge, with a respective weakening of Medical Analogy. Since the Modern era our examination has focused upon the vacillations of medical philosophical knowledge, speculating upon the causes and consequences of this distancing, and our examination found that the legacy left by modern medical thought has oriented and continues to orient Modern Medicine towards a dehumanization in relation to the person of the patient. Finally, we concluded that medical reform is needed, principally, in its Paideia, based upon a closer collaboration with philosophy, with the intent to provide subsidies to help answer the central question of any therapeutic procedure, which is: what is the nature of the being of the human being?

La pancréatite, qui désigne l’inflammation du pancréas, est une condition grave qui survient lorsque les enzymes pancréatiques, servant normalement à la digestion des aliments, digèrent le pancréas. Les causes les plus fréquentes sont la consommation excessive d’alcool et la migration de lithiases vésiculaires dans les voies biliaires. On reconnait également des formes moins fréquentes qui contribuent au fardeau de la maladie et la pancréatite induite par un médicament est l’une d’entre elles. En cours d’hospitalisation et lors du suivi, cette étiologie cause des difficultés aux médecins et aux pharmaciens qui doivent travailler de concert pour d’abord la diagnostiquer, mais également identifier le médicament déclencheur afin d’éviter la récurrence. Néanmoins, cette identification se voit complexifiée, dû à un manque de données probantes fiables et récentes concernant d’une part l’épidémiologie, mais aussi l’étiologie de cette condition. L’objectif principal de ce projet est d’étudier les cas de pancréatites aiguës médicamenteuses hospitalisés au Centre intégré universitaire de santé et services sociaux du Saguenay–Lac-Saint-Jean afin d'obtenir un portrait réel de cette étiologie en plus d’ajouter de nouvelles preuves à la littérature. La méthodologie repose sur la révision des dossiers médicaux des cas hospitalisés pour au moins une pancréatite médicamenteuse dans les six hôpitaux du Saguenay–Lac-Saint-Jean entre 2006 et 2014. Les données recueillies et leurs analyses ont permis de documenter les médicaments ayant causé une pancréatite aiguë médicamenteuse au Saguenay–Lac-Saint-Jean en plus de participer à l’avancement des connaissances actuelles par l’identification de médicaments non associés à la pancréatite aiguë jusqu’à maintenant. / Pancreatitis, which refers to the inflammation of the pancreas, is a serious medical condition in which the pancreatic enzymes, that normally digest food, start to digest the pancreas. The most common causes are excessive alcohol consumption and gallstone migration into the bile ducts. Less common causes also contribute to the burden of the disease and drugs are one of them. Diagnosis of drug-induced pancreatitis and identification of the triggering drug in order to avoid recurrence is a challenge to both physicians and pharmacists. Moreover, identification of the causative drug is complex due to a lack of reliable and recent evidence concerning the epidemiology and the etiology of this condition. The main objective of this project is to study drug-induced acute pancreatitis cases hospitalized at the Centre intégré universitaire de santé et services sociaux of the Saguenay–Lac-Saint-Jean in order to obtain an accurate representation of this etiology in addition to adding new evidences to the literature. The methodology relies on the review of medical records of hospitalized cases for at least one drug-induced acute pancreatitis in the six hospitals of the Saguenay–Lac-Saint-Jean between 2006 and 2014. The data collected and their analyzes document drugs involved in acute pancreatitis in the Saguenay–Lac-Saint-Jean region in addition to participating in the advancement of our current knowledge by describing drugs that had not been associated with acute pancreatitis until now.

Indiana University-Purdue University Indianapolis (IUPUI) / My thesis comprises of two individual projects which revolve around the importance of post-transcriptional regulation in liver. My first project is studying the integrated miRNA – mRNA network in NAFLD. For fulfillment of the study we conducted a genome-wide study to identify microRNAs (miRs) as well as the miR-mRNA regulatory network associated with hepatic fat and NAFLD. Hepatic fat content (HFC), miR and mRNA expression were assessed in 73 human liver samples. Liver histology of 49 samples was further characterized into normal (n=33) and NAFLD (n=16). Liver miRNome and transcriptome were significantly associated with HFC and utilized to (a) build miR-mRNA association networks in NAFLD and normal livers separately based on the potential miR-mRNA targeting and (b) conduct pathway enrichment analyses. We identified 62 miRs significantly correlated with HFC (p < 0.05 with q < 0.15), with miR-518b and miR-19b being most positively and negatively correlated with HFC, respectively (p < 0.008 for both). Integrated network analysis showed that six miRs (miRs-30b*, 612, 17*, 129-5p, 204 and 20a) controlled ~ 70% of 151 HFC-associated mRNAs (p < 0.001 with q < 0.005). Pathway analyses of these HFC-associated mRNA revealed their key effect (p<0.05) in inflammation pathways and lipid metabolism. Further, significant (p<2.47e-4, Wilcoxon test) reduction in degree of negative associations for HFC-associated miRs with HFC-associated mRNAs was observed in NAFLD as compared to normal livers, strongly suggesting highly dysfunctional miR-mRNA post-transcriptional regulatory network in NAFLD. Our study makes several novel observations which provide clues to better understand the pathogenesis and potential treatment targets of NAFLD. My second project is based on uncovering important players of post-transcriptional regulation (RBPs) and how they are associated with age and gender during healthy liver development. For this study, we performed an association analysis focusing on the expression changes of 1344 RNA Binding proteins (RBPs) as a function of age and gender in human liver. We identify 88 and 45 RBPs to be significantly associated with age and gender respectively. Experimental verification of several of the predicted associations in the mouse model confirmed our findings. Our results suggest that a small fraction of the gender-associated RBPs (~40%) are likely to be up-regulated in males. Altogether, these observations show that several of these RBPs are important developmentally conserved regulators. Further analysis of the protein interaction network of RBPs associated with age and gender based on the centrality measures like degree, betweenness and closeness revealed that several of these RBPs might be prominent players in liver development and impart gender specific alterations in gene expression via the formation of protein complexes. Indeed, both age and gender-associated RBPs in liver were found to show significantly higher clustering coefficients and network centrality measures compared to non-associated RBPs. The compendium of RBPs and this study will help us gain insight into the role of post-transcriptional regulatory molecules in aging and gender specific expression of genes.

Indiana University-Purdue University Indianapolis (IUPUI) / Neuropathic pain is a serious health problem that greatly impairs quality of life. The International Association for the Study of Pain (IASP) defines neuropathic pain as ‘pain arising as a direct consequence of a lesion or disease affecting the nervous system’. It is important to note that with neuropathy the chronic pain is not a symptom of injury, but rather the pain is itself a disease process. Novel interactions between the nervous system and elements of the immune system may be key facets to a chronic disease state. One of particular note is the recent finding supporting an interaction between an immune response protein high mobility group box 1 (HMGB1) and Toll like receptor 4 (TLR4). HMGB1 is an endogenous ligand for TLR4 that influences the induction of cytokines in many non-neuronal cells. After tissue damage or injury, HMGB1 may function as a neuromodulatory cytokine and influence the production of pro-nociceptive mediators altering the state of sensory neurons. Very little is known about the HMGB1-TLR4 interaction in sensory neurons and whether chronic changes in endogenous HMGB1 signaling influence the establishment of neuropathic pain. This thesis aims to determine whether a physiologically relevant neuroimmune interaction involving endogenous HMGB1 and TLR4 in the dorsal root ganglia is altered following a tibial nerve injury model of neuropathic pain. I hypothesized that sensitization of sensory neurons following a peripheral nerve injury is dependent on endogenous HMGB1 and TLR4. The studies presented here demonstrate that HMGB1 undergoes subcellular redistribution from the nucleus to the cytoplasm in primary afferent neurons following peripheral nerve injury. Further, the presence of extracellular HMGB1 may directly contribute to peripheral sensitization and injury-induced tactile hyperalgesia. Though thought to be important as a pivotal receptor for HMGB1 activation, neuronal protein expression of TLR4 does not appear to influence the effects of HMGB1-dependent behavioral changes following peripheral nerve injury. Taken together, these findings suggest that extracellular HMGB1 may serve as an important endogenous cytokine that contributes to ongoing pain hypersensitivity in a rodent model of neuropathic pain.

Indiana University-Purdue University Indianapolis (IUPUI) / LIM homeodomain 3 (LHX3) is an important regulator of pituitary and nervous system development. To date, twelve LHX3 gene mutations have been identified in patients with combined pituitary hormone deficiency disease (CPHD). Understanding the molecular mechanisms governing LHX3/Lhx3 gene regulation will provide critical insights into organ development pathways and associated diseases. DNA methylation has been implicated in gene regulation in multiple physiological systems. This dissertation examines the role of DNA methylation in regulating the murine Lhx3 gene. To determine if demethylation of the Lhx3 gene promoter would induce its expression, murine pre-somatotrope pituitary cells that do not normally express Lhx3 (Pit-1/0 cells) were treated with the demethylating reagent, 5-Aza-2’-deoxycytidine. This treatment lead to activation of the Lhx3 gene and thus suggested that methylation contributes to Lhx3 gene regulation. Proteins that modify chromatin, such as histone deacetylases (HDACs) have also been shown to affect DNA methylation patterns and subsequent gene activation. Pit-1/0 pituitary cells treated with a combination of the demethylating reagent and the HDAC inhibitor, Trichostatin A led to activation of the Lhx3 gene, suggesting crosstalk between DNA methylation and histone modification processes. To assess DNA methylation levels, treated and untreated Pit-1/0 genomic DNA were subjected to bisulfite conversion and sequencing. Treated Pit-1/0 cells had decreased methylation compared to untreated cells. Chromatin immunoprecipitation assays demonstrated interactions between the methyl-binding protein, MeCP2 and the Lhx3 promoter regions in the Pit-1/0 cell line. Overall, the study demonstrates that DNA methylation patterns of the Lhx3 gene are associated with its expression status.

Indiana University-Purdue University Indianapolis (IUPUI) / Purpose: Obesity is a growing public health problem and the second most preventable cause of death in the US. Obesity has been linked as a risk factor for several cancers. However, there are limited studies that have examined the roles of metabolic syndrome (MetS) and C-reactive protein (CRP), as well as change in body composition from early adulthood to late adulthood on the risk of cancer. The overall objective of this dissertation was to determine the association of obesity and obesity-related markers with breast and colorectal cancer occurrence and mortality. Methods: Three datasets were used. The first study used 4,500 asymptomatic adults who were surveyed during a colorectal cancer screening study. The second study was based on the National Health and Nutrition Examination Survey (NHANES) 2005-2010. The dataset had 172 breast cancer survivors and 2,000 women without breast cancer. The last manuscript resulted from the NHANES follow-up study (NHANES III). A total of 120 cancer deaths from breast and colorectal deaths were identified from 10,103 women aged 18 years or older. Results: Overall, obesity and obesity related markers were associated with breast and colorectal cancer occurrence and mortality. BMI change and WC change were positively associated with increased risk of advanced colorectal neoplasia (AN). WC measures (both static and dynamic) were generally a better predictor of AN compared to BMI. In the second study involving breast cancer survivors, neither MetS nor CRP were associated with having a breast cancer diagnosis. Also, none of the individual components of MetS (WC, Triglycerides, HDL, fasting blood glucose and blood pressure) were associated with a breast cancer diagnosis. In the last study, MetS was associated with increased risk of mortality from obesity-related cancers. In addition, all components of MetS, except dyslipidemia, were associated with increased risk of mortality for the obesity-related cancers. Conclusion: Obesity expressed in terms of BMI and WC, or their change, MetS and CRP are important factors in regard to the occurrence, survivorship and mortality of breast and colorectal cancer. The results of this research underscore the importance of maintaining a healthy weight.

Durant la dernière décennie, plusieurs études ont identifié l’agression sexuelle à l’enfance en tant que facteur de risque des troubles psychotiques. Toutefois, la survenue des troubles psychotiques chez les enfants et les adolescents ayant vécu une agression sexuelle à l’enfance a été très peu étudiée à ce jour de façon longitudinale, les études précédentes ayant majoritairement utilisé des devis rétrospectifs, étudiant les traumas à l’enfance chez les adultes ayant un trouble psychotique. Notre compréhension du développement des troubles psychotiques chez cette population est ainsi très limitée. L’objectif général de cette thèse est de mieux comprendre la survenue des troubles psychotiques chez les enfants ayant reçu un signalement d’agression sexuelle corroboré par le DPJ. Le premier article vise à documenter la prévalence des troubles psychotiques chez des jeunes agressés sexuellement entre le premier signalement corroboré d’agression sexuelle et le début de l’âge adulte. Les données administratives médicales de 882 jeunes ayant reçu un signalement d’agression sexuelle corroboré par le DPJ ont été comparées à 882 jeunes de la population générale sur une période de 13 ans. Les résultats obtenus via des modèles linéaires généralisés mixtes démontrent que les jeunes agressés sexuellement sont 10 fois plus à risque de recevoir un diagnostic de trouble psychotique que ceux de la population générale. Le second article documente la trajectoire développementale des troubles psychotiques suite à l’agression sexuelle en termes d’âge de survenue. La même méthodologie que celle du premier article est utilisée. Les analyses de survie réalisées démontrent que l’agression sexuelle et l’abus de substance sont associés à l’âge de survenue des troubles psychotiques. Ainsi, les jeunes de l’étude sont plus à risque de recevoir leur premier diagnostic de trouble psychotique plus tôt 6 dans leur développement lorsqu’ils ont reçu un signalement d’agression sexuelle et lorsqu’ils ont un diagnostic d’abus de substance. Lorsque les groupes sont comparés séparément, l’abus de substance est associé à l’âge de survenue uniquement dans le groupe agressé sexuellement. Le troisième article, de nature exploratoire, vise à identifier les facteurs psychologiques impliqués dans la survenue des troubles psychotiques chez les jeunes agressés sexuellement. Un premier objectif est d’identifier les facteurs psychologiques survenant de façon concomitante aux troubles psychotiques ; un second objectif est d’identifier les facteurs qui contribuent à prédire les troubles psychotiques. Pour cet article, seulement l’échantillon de jeunes agressés sexuellement est inclus. Les régressions logistiques révèlent que les troubles de personnalité sont significativement associés aux troubles psychotiques, les jeunes ayant reçu un tel diagnostic étant 10 fois plus à risque de recevoir également un diagnostic de trouble psychotique, peu importe l’ordre d’apparition des diagnostics. La déficience intellectuelle et l’abus de substance ont été identifiés comme contribuant à la survenue des troubles psychotiques. Les contributions théoriques de cette thèse à la littérature portant sur l’association entre l’agression sexuelle à l’enfance et la psychose ainsi que les implications cliniques pour l’intervention et la prévention auprès de cette population spécifique sont discutées. / In the last decade, several studies identified child sexual abuse as a risk factor for psychotic disorders. However, few longitudinal studies addressed the development of psychotic disorders in sexually abused children and adolescent. Previous studies mostly relied on retrospective designs, studying childhood trauma in adults with psychotic disorders, which limits our comprehension of the development of psychotic disorders in sexually abused children. The present thesis aims to achieve a better understanding of the development of psychotic disorders in youths who received a corroborated report of sexual abuse by the DYP. The first article aims to document the prevalence of psychotic disorders in sexually abused youth between the time of the first corroborated report of sexual abuse and the beginning of adulthood. Administrative databases of 882 youths who received a corroborated report of sexual abuse by the DPY were compared to 882 youths from the general population over a 13-year period. Conditional generalized linear mixed models reveal that sexually abused youth were 10 times more at risk to receive a diagnosis for a psychotic disorder than the general population. The second article documents the developmental trajectory of psychotic disorders following sexual abuse in terms of age at onset. The methods used are the same as the first article. Survival analysis reveal that sexual abuse and substance misuse are associated to the age at onset of psychotic disorder. Thus, studied youth are more at risk of receiving their first diagnosis of psychotic disorder early in their development when they received a corroborated report of sexual abuse or when they received a diagnosis for substance misuse. When the groups are compared separately, substance misuse is associated to the age at onset of psychotic disorder only in sexually abused youth. 8 The third article has an exploratory nature and aims to identify the psychological factors implied in the development of psychotic disorders in sexually abused youth. A first objective is to identify which psychological factors cooccur with psychotic disorder; a second objective is to identify which factors predicts psychotic disorders. For this article, only the sample of sexually abuse youth is used. Logistic regressions reveal that personality disorders are significantly associated to psychotic disorders. Youths with a diagnosis of personality disorders are 10 times more at risk of receiving also a diagnosis of psychotic disorder, regardless of the order in which they received either diagnosis. Intellectual disability and substance misuse are identified as factors who predict the development of psychotic disorders. The theoretical contributions of the present thesis to the literature on the association between childhood sexual abuse and psychotic disorders as well as the clinical implications for intervention and prevention programs offered to this population are discussed.

Indiana University-Purdue University Indianapolis (IUPUI) / Research in the alcohol preferring (P) rat has indicated that peri-adolescent alcohol (EtOH) consumption enhances the acquisition of oral operant EtOH self-administration, inhibits the extinction of responding for EtOH, augments EtOH-seeking behaviors, and increases relative reward value of EtOH during adulthood. Experiment 1 was conducted to determine if these adult effects of peri-adolescent EtOH intake could be observed using an Intracranial Self-Administration (ICSA) model. It was hypothesized that an increased sensitivity to the rewarding actions of EtOH would be manifested in peri-adolescent-EtOH-exposed subjects compared to naive subjects when the opportunity to self-administer EtOH to the posterior ventral tegmental area (pVTA) is available in adulthood. The pVTA is a primary site for EtOH’s reinforcing and rewarding properties in the mesolimbic dopamine (DA) system. Experiment 2 was a dose-response examination of the effects of EtOH administered to the pVTA on downstream DA efflux in the nucleus accumbens shell (AcbSh) via a joint Microinjection-Microdialysis (MicroMicro) procedure. Male P rats were given 24-h free-choice exposure to 15% volume/volume EtOH from postnatal day (PD) 30 to PD 60, or remained experimentally naive, with ad lib food and water. By the end of the periadolescent exposure period, average consumption was 7.3 g/kg/day of EtOH. After PD 75, periadolescent-EtOH-exposed and naïve rats were either implanted with an injector guide cannula aimed at the right pVTA for ICSA (Experiment 1), or two cannulae, one aimed at the right pVTA (injector) and one at the ipsilateral AcbSh (microdialysis) for MicroMicro (Experiment 2). Following one week of recovery from surgery, ICSA subjects were placed in standard two-lever (active and inactive) operant chambers. Test sessions were 60 min in duration and occurred every other day for a total of 7 sessions. Rats were randomly assigned to one of 5 groups (n=4-9/group) that self-infused (FR1 schedule) either aCSF (vehicle, 0 mg%), 50, 75, 100, or 150 mg% EtOH during 4 sessions, aCSF only for sessions 5 and 6 (extinction), and the initial concentration again for session 7 (reinstatement). MicroMicro subjects received six days of recovery from surgery, probe implantation the day before testing, and then continuous microdialysis for DA with 15 min microdialysis samples collected before, during, and then two hrs after 10-min pulse microinjection of either aCSF (vehicle, 0 mg%), 50, 75, 100, or 150 mg% EtOH. Neither EtOH-exposed nor naive groups of P rats self-infused the aCSF or 50 mg% EtOH concentration. While the naive group did not self-infuse the 75 or 100 mg% EtOH concentrations, the peri-adolescent EtOH-exposed group of P rats did readily discriminate the active lever from the inactive lever at these concentrations. Both groups self-infused the 150 mg% EtOH concentration. Pulse microinjections of EtOH during the MicroMicro procedure revealed that 75 and 100 mg% concentrations of EtOH increased downstream DA in the AcbSh of EtOH-exposed, but not naïve, subjects. 150 mg% EtOH increased downstream DA in both adolescent treatment groups. Overall, the results indicate that consumption of EtOH by P rats during peri-adolescence increases the reinforcing properties of EtOH in the pVTA in adulthood. The results also indicate that there were differential effects of peri-adolescent EtOH exposure on DA efflux in the AcbSh. This provides evidence that peri-adolescent EtOH-exposure produces long-lasting alterations in neural circuitry involved in EtOH-reinforcement, during adulthood.