O Mal de Alzheimer é a causa mais importante de demência em idosos. A progressão dos sintomas da doença está associada com modificações estruturais nas sinapses colinérgicas em determinadas regiões cerebrais e, consequentemente, à diminuição do potencial de neurotransmissão colinérgica. Desta forma, o aumento da capacidade de neurotransmissão colinérgica constitui o mecanismo fundamental dos fármacos utilizados para o tratamento do Mal de Alzheimer. Atualmente, o único tratamento clínico eficaz para o Mal de Alzheimer (MA) é a utilização de inibidores da acetilcolinesterase (AChE). Os anticolinesterásicos são os fármacos mais promissores desenvolvidos até hoje, pois é a única classe terapêutica que mostrou melhora nos sintomas cognitivos do MA. Para esse projeto, foram utilizadas diferentes técnicas de modelagem molecular como estratégia de planejamento racional de fármacos, tendo como base os inibidores de Acetilcolinesterase (AChE) descritos na literatura além dos que possuem estruturas depositadas no PDB, incluindo alguns que já vêm sendo utilizados no tratamento do Mal de Alzheimer. O objetivo foi planejar e testar novos potenciais inibidores desse alvo terapêutico, na tentativa de obter e futuramente otimizar novos protótipos como futuros candidatos a fármacos em Mal de Alzheimer. Os objetivos estendem-se a propostas de novos potenciais protótipos, selecionados de bases de dados de compostos comerciais contendo propriedades de fármacos. Os screenings virtuais foram tendenciados às estruturas dos inibidores já reportados da literatura bem como ao padrão farmacofórico comum a eles, a ser modelado. / Alzheimer\'s disease is the leading cause of dementia in the elderly. The progression of symptoms is associated with structural changes in cholinergic synapses in specific brain regions and consequentely to decrease the potential of cholinergic neurotransmission. Thus, the increased capacity of cholinergic neurotransmission is the fundamental mechanism of the drugs used to treat Alzheimer\'s disease. Currently, the only effective clinical treatment for Alzheimer\'s (MA) is the use of inhibitors of acetylcholinesterase (AChE). Cholinesterase inhibitors are the most promising drugs developed so far, it is the only therapeutic class that showed improvement in cognitive symptoms of MA. For this project, we used different techniques of molecular modeling as a strategy for rational design of drugs based on inhibitors of acetylcholinesterase (AChE) in the literature than those which have structures deposited in the PDB, including some that have already been used in the treatment Alzheimer\'s disease.The objective was to design and test new potential inhibitors of therapeutic target in attempts to obtain and optimize future new prototypes as future drug candidates in Alzheimer\'s disease. The goals extend to proposals from potential new prototypes, selected from databases of commercial compounds containing properties of drugs. The virtual screenings were trends to structures of the inhibitors already reported in the literature as well as the pharmacophoric pattern common to them, to be modeled.

G-quadruplexes are non-canonical nucleic acid secondary structures of increasing biological and medicinal interest due to their proposed physiological functions in transcription, replication, translation and telomere biology. Aberrant G4 formation and stabilisation have been linked to genome instability, cancer and other diseases. However, the specific genes and pathways involved are largely unknown, and the work within this thesis aims to investigate this. Stabilisation of G4s by small molecules can perturb G4-mediated processes and initial studies suggest that this approach has chemotherapeutic potential. I therefore also aimed to identify cell genotypes sensitive to G4-ligand treatment that may offer further therapeutic opportunities. To address these aims, I present the first unbiased genome-wide genetic screen in cells where genes were silenced via short-hairpin RNAs (shRNAs) whilst being treated with either PDS or PhenDC3, two independent G4-stabilising small molecules. I explored gene deficiencies that enhance cell death (sensitisation) or provide a growth advantage (resistance) in the presence of these G4-ligands. Additionally, I present a validation screen, comprising hits uncovered via genome-wide screening, and also the use of this in another cell line of different origin. Sensitivities were enriched in DNA replication, cell cycle, DNA damage repair, splicing and ubiquitin-mediated proteolysis proteins and pathways. Ultimately, I uncovered four synthetic lethalities BRCA1, TOP1, DDX42, GAR1, independent of cell line and ligand. These were validated with three G4-stabilising ligands (PDS, PhenDC3 and CX-5461) using an independent siRNA approach. The latter siRNA methodology was used to screen 12 PDS derivatives with improved medicinal chemistry properties and ultimately identified SA-100-128, as a lead compound. The mechanism behind synthetic lethality with G4-stabilising ligands was explored further for DDX42, which I show has in vitro affinity for both RNA- and DNA-G4s and may represent a previously unknown G4-helicase. Also within this thesis, gene deficiencies that provided a growth advantage to PDS and/or PhenDC3 as uncovered by genome-wide and focused screening were explored. These showed enrichment in transcription, chromatin and lysosome-associated genes. The resistance phenotype of three gene deficiencies, TAF1, DDX39A and ZNF217 was further supported by additional siRNA experiments. Overall, I satisfied the primary aims and established many novel synthetic lethal and resistance interactions that may represent new therapeutic possibilities. Additionally, the results expand our knowledge of G4-biology by identifying genes, functions and subcellular locations previously not known to involve or regulate G4s.

Thesis (MPH.) --University of Limpopo, 2009 / Please refer to the document

African Americans bear a disproportionately high burden of cancer incidence and mortality in this country. The purpose of this dissertation was to investigate factors associated with African-American men, who are incarcerated, making informed health decisions about participation in prostate cancer screening, as well as exploring factors that reduce modifiable risk factors for cancer. The United States incarcerates more people per capita than any country in the world and African American men are overrepresented in the U.S. prison system This dissertation is composed of three manuscripts. The first paper reviews the current literature about the factors that influence African-American males in making informed decisions about whether to participate in prostate cancer screening. The second paper uses existing data from a sample of 129 incarcerated African American men to examine the value of an intervention aimed at reducing modifiable risks for cardiovascular disease – and by extension, cancer – in inmates. The third paper explores predictors of intent to screen (or not) for prostate cancer in incarcerated African-American males, as well as those factors that influence informed decision-making in this population. These papers provide an overview of factors that influence incarcerated African-American men’s health decisions (health literacy, having a relative with previous diagnosis). These findings can be used to guide future research that addresses African-American male decision-making about personal health outcomes.

The purpose of this study was to compare thirty-two childrens' performances on the Daberon-2 Screening for School Readiness and the Early Screening Inventory , as well as determine whether there was a correlation between the tests. This study responded to the needs of the local Portland, Oregon area schools, some of which use these tests, to investigate the tests, and explore the possibility of using the shorter ESI over the longer Daberon. The reasoning behind the goal of the study was to determine that if the two tests showed a strong, positive correlation and identified the same children as needing further assessment, then perhaps the test which was shorter to administer could be used with confidence as a faster, but equally reliable 2 pre-kindergarten screening tool. In other words, if a child "passes" the Daberon, one could assume that the child would most likely "pass" the ESI as well. Based on the results of this study, one can make this assumption with a reasonable amount of confidence. The subjects in this study included 16 males and 16 females. All were preschool students, ranging in age from 4-6 to 5-6 with a mean age of 5-1 years. The subjects were given the two tests in a counterbalanced order, which also varied as to sex so that not all of one sex received one test first. The standard scores and whether or not each subject "passed" or "failed" each screen was determined. The correlation between the two tests was also determined. The Pearson product moment correlation coefficient was used to determine the degree of relatedness between the tests. A high positive correlation of .73 was found between the Daberon and the ESI, with a shared variance

Individuals with developmental disabilities are at high risk for sexual abuse, exploitation, sexually transmitted diseases and unwanted pregnancies. Thorough screening by clinicians in outpatient settings recommending preventative measures to promote reproductive and sexual health, and developing caregiver trust are essential. The aim of this systematic review was to provide screening tools to assist clinicians in assessing the sexual histories of individuals with developmental or intellectual disabilities. The Iowa model and the cognitive behavioral theory were used as the theoretical frameworks that guided and informed this project. A total of 148 articles were sought and, of the 34 articles reviewed, 19 were pertinent to synthesize the literature. Articles were appraised using the John Hopkins evidence-based practice model. Results from the existing literature showed that no screening tools are available to assess the sexual histories of individuals with developmental and intellectual disabilities. Thorough screening the sexual histories of individuals with developmental and intellectual disabilities could empower safe sexual practices and the attainment of a life with personal fulfillment for members of this population. The results of this project can result in positive social change by protecting the population of individuals with developmental and intellectual disabilities from exploitation, unplanned pregnancy, and sexually-transmitted diseases. Future research is needed to fill the gap in the field and develop sexual history screening tools for this population.

African American women tend to have lower attendance rates at cervical cancer screenings compared to the attendance rates of women from other ethnic groups. The purpose of this research project was to understand how perceptions of African American women affects attendance of future cervical cancer screenings. The goal was to understand what contributes to low attendance. Previous research did not focus on factors contributing or interfering with appointment attendance among African American women, aged 30-65. The conceptual framework was based on individual health behavior. The research questions examined lived experiences affecting attendance of cervical cancer screenings, attendance of future screenings, and perceptions of experiences. Data collection was based on a phenomenological approach. Open-ended questions were used to gather descriptions of 5 participants' experiences via telephone interviews. These interviews were recorded, transcribed, and coded for recurring themes and patterns. Findings revealed 3 emergent themes related to the attendance of screenings: being knowledgeable of the purpose of cervical cancer screening, a female examiner performing the screening, and the encouragement of family and friends. The implications for social change would be increased knowledge among African American women aged 30-65 and the medical community.

Until first half of the XX century, sickle cell disease was practically limited to the malaria endemic areas and countries having known an important surge of African slaves. Today, migratory flows and progress of medicine have modified considerably the distribution of sickle cell disease which is from now on a frequent affection in Western Europe. The preventive implementation of medical care makes it possible to reduce morbidity and mortality associated with this pathology. Stake of a medical policy and economic interests, neonatal screening for hemoglobin disorders justifies then fully the implementation of powerful and adapted means. In order to initiate a newborn screening programme in our centre, we developed various immunological tests allowing to identify the sickle hemoglobin. We first of all developed an indirect immunoassay and led a population study on 46082 Belgian newborns and 1825 neonates from Central Africa. The performances of this assay were improved thereafter by conceiving a competitive test. Next, for reasons independent of our will, we had unfortunately to abandon the immunological approach. This methodology was thus supplanted in our center by an innovative method for this indication: the mass spectrometry. Our promising results currently authorize us to perennialize our policy in the neonatal screening for sickle cell disease and open the way for new developments in other fields. / Jusquà la première moitié du XXe siècle, la drépanocytose se limitait pratiquement aux zones dendémie palustre et aux pays ayant connu un important afflux desclaves dorigine africaine. Aujourdhui, les flux migratoires et les progrès de la médecine ont considérablement modifié la distribution de cette maladie qui est désormais une affection fréquente en Europe occidentale. La prise en charge précoce permet de réduire la morbidité et la mortalité associées à cette maladie. Enjeu dune politique sanitaire et dintérêts économiques, le dépistage néonatal de la drépanocytose justifie donc ainsi pleinement la mise en uvre de moyens performants et adaptés. Afin dinitier un programme de dépistage au sein de notre centre, nous avons initialement développé divers tests immunologiques permettant didentifier lhémoglobine anormale. Nous avons tout dabord mis au point un immunoessai indirect et conduit une étude de population sur 46082 nouveau-nés belges et 1825 bébés originaires dAfrique centrale. Les performances de lessai ont par la suite été améliorées en concevant un test compétitif. Lapprovisionnement laborieux danticorps nécessaires aux tests de détection a par la suite entravé notre programme. En effet, la commercialisation en a été interrompue et la production danticorps monoclonaux par nos moyens propres na pas été couronnée du succès escompté. Lapproche immunologique du dépistage néonatal de la drépanocytose a ainsi été supplantée dans notre centre par une méthode novatrice pour cette indication : la spectrométrie de masse. Nos résultats prometteurs nous autorisent actuellement à pérenniser notre nouvelle façon de faire dans le dépistage néonatal de la drépanocytose et ouvre la voie pour de nouveaux développements dans dautres domaines.

The overrepresentation of minority students identified for special education services continues to plague schools and serves as a challenge for researchers and practitioners (Ferri&Conner,2005). Teacher nomination, office discipline referrals (ODR), and functional behavior assessments (FBA) continue to guide referral processes (Bradshaw, Mitchell, O’Brennen, & Leaf, 2010; Eklund, et al., 2009; Mustian, 2010). These methods have been found to be riddled with inconsistencies. Practices used to identify students for behavioral and emotional interventions over-identify students from culturally and linguistically diverse backgrounds. The use of a behavioral and emotional screener to make data-based decisions regarding placement and services could provide an objective assessment of student risk. The first chapter of this dissertation reviews methods used in the identification of students for behavioral and emotional support services. Additionally, the use of universal screening in conjunction with student self-report are proposed as tools for alleviating the overrepresentation of minority students in special education programs for behavioral and emotional disorders. The second chapter of this dissertation explores the measurement equivalence of Behavior Assessment System for Children, Second Edition (BASC-2) Behavioral and Emotional Screening System Student form (BESS Student) across the Black, Hispanic, and White participants in the norming sample. The BESS Student as a universal screening tool is poised to alleviate the disproportionate number of children of color identified by schools as having behavior and emotional disorders. This instrument also provides an avenue to identify students with internalizing disorders who are often overlooked in present referral practices (Bradshaw, Buckley, & Ialongo, 2008; Kataoka, Zhang, & Wells, 2002). The findings of the measurement equivalence study suggests that the BESS Student is, as designed, identifying behavioral and emotional risk across each of the three groups explored. These findings support the use of a universal screening measure as the first step in a multi-step identification and intervention process. Following up with additional assessment to evaluate the specific areas of risk warranting intervention is pivotal to providing appropriate support services and promoting the behavioral and emotional health of students. Implications for research and practice are discussed.

Allt fler barn i Sverige lider av psykisk ohälsa. Det finns ett behov av bättre kunskapsunderlag för att hitta de barn som visar tidiga tecken på psykisk ohälsa. Syftet med studien var att undersöka vad personal inom förskolan har för inställning till att utföra skattning av barns sociala och känslomässiga utveckling med formulär. Tretton intervjuer genomfördes och materialet analyserades med kvalitativ innehållsanalys. Resultatet visade att det fanns en olust bland förskollärare att möta föräldrars reaktion och oro inför en eventuell bedömning. Att redovisa formulärets svar för föräldrarna kändes inte heller helt lätt. Förskollärarna ansåg att förskolan är ett bra forum för att bedöma socialt beteende och att formuläret kan resultera i en tydlig och rättvis bild av barnen. Men lärarna var också rädda för att stämpla barn. En del ansåg att bedömningar av enskilda barns utveckling är ett förlegat arbetssätt. Personalen hade delade meningar i frågan om tidsbrist skulle utgöra ett hinder för skattningsarbetet. I alla intervjuer fanns en vilja från lärarnas sida att se till barnets bästa. Slutsats: Skattning av barns beteende med hjälp av formulär i förskolan är komplext. Ett eventuellt införande av metoden ställer krav på tydlig information om metoden och syftet till såväl förskollärare som föräldrar. / An increasing number of Swedish children suffer from psychiatric disorders. There is a need for better knowledge to detect children that show early signs of psychiatric disorders. The purpose of this study was to investigate what attitude preschool staffs have to perform evaluations of children’s social and mental development using a questionnaire. A total number of thirteen interviews have been performed and the material have been analysed according to a qualitative content analysis. The results showed a discomfort amongst preschool teachers to meet the parents’ reaction and concern in relation to a possible evaluation. The preschool is considered to be a good forum when to assess children´s behaviour and the actual questionnaire is considered to be a useful tool. But the teachers were worried that they would put a label on the children. Some of the teachers believed that assessing children is an outdated way to work. There were different opinions whether lack of time is an obstacle to use the questionnaire. There was generally an intention to ensure the children´s best. Conclusion: Evaluations of the children´s behaviour using the questionnaire in preschool is a complex issue. An implementation of the method requires extensive information to preschool teachers and parents.