The current study utilized an early-stage translational approach (Tashiro & Mortensen, 2006) to empirically test the immediate effect of a 15-minute mindfulness intervention on acute pain experience. The study employed a three-group, repeated measures experimental design with two active control conditions (sham mindfulness and attention control) and an analogue pain induction procedure (cold-pressor test). The sample consisted of 165 university students. Repeated measures analyses found an interaction effect between condition and time for subjective pain intensity and an interaction effect between gender and time for pain tolerance. Trends show that attention control increased pain intensity, whereas mindfulness decreased pain intensity. Females exhibited greater pain tolerance at post-intervention across conditions. Analyses yielded no significant differences between conditions among dependent variables of pain tolerance, state affect, or state anxiety. A moderate relationship was found between fear of pain and pain tolerance at pre-intervention, but failed to significantly moderate outcome in main analyses. Post-hoc analyses revealed a subset of "high pain tolerant" participants, who endorsed significantly higher trait mindfulness, lower fear of pain, and lower pain catastrophizing compared to the remainder of participants. Negative affect was related to increased pain intensity within the attention control condition. Suggestions for future research and clinical implications of research in this area are discussed.

Contexto. A impulsividade é um conceito formado a partir de diversas dimensões comportamentais. Desta forma a avaliação do comportamento impulsivo apresenta características complexas e distintas, que devem ser levadas em conta durante o processo de diagnóstico ou pesquisa. Objetivo. Este artigo de revisão apresenta os principais instrumentos de avaliação do comportamento impulsivo tanto em animais, quanto em humanos, relacionando as indicações e limitações de cada instrumento, assim como apontando referências de artigos empíricos que exemplificam cada protocolo. Método. Foram realizadas buscas nos sistemas Medline, PsycINFO e BVS/Bireme durante o período de 2007 a 2012. Resultados. Para humanos foram apontados quatro questionários e oito tarefas, e para animais foram apontadas seis tarefas. Entre os questionários a Escala de Impulsividade Barrat 11 se destaca, assim como a tarefa Delay Discounting, tanto para humanos quanto para animais. Conclusão. Estudos que utilizam instrumentos de modelos diferentes são sugeridos, assim como validação de escalas de impulsividade para diferentes populações brasileiras. / Background. The concept of impulsivity encompasses several behavioral dimensions. Therefore, the evaluation of impulsive behavior is quite complex and can vary greatly. Hence, such complexity should be considered during research or while establishing a diagnosis. Objectives. The objective of the present review article was to describe the main impulsive behavior assessment instruments both in animals and humans, including the indications and limitations of each instrument, and to suggest references of empirical articles that illustrate each protocol. Methods. The following databases were searched from 2007 to 2013: MEDLINE, PsycINFO and BVS/Bireme. Results. Our search retrieved four questionnaires and eight tasks for humans, and six tasks for animals. Among the most frequently used questionnaires and tasks, we found the Barratt Impulsiveness Scale-11 and the Delay Discounting Task, both for humans and animals. Conclusion. It is recommended that further research be undertaken using different models of instruments. In addition, impulsivity scales should be validated for different Brazilian populations.

Contexto. A impulsividade é um conceito formado a partir de diversas dimensões comportamentais. Desta forma a avaliação do comportamento impulsivo apresenta características complexas e distintas, que devem ser levadas em conta durante o processo de diagnóstico ou pesquisa. Objetivo. Este artigo de revisão apresenta os principais instrumentos de avaliação do comportamento impulsivo tanto em animais, quanto em humanos, relacionando as indicações e limitações de cada instrumento, assim como apontando referências de artigos empíricos que exemplificam cada protocolo. Método. Foram realizadas buscas nos sistemas Medline, PsycINFO e BVS/Bireme durante o período de 2007 a 2012. Resultados. Para humanos foram apontados quatro questionários e oito tarefas, e para animais foram apontadas seis tarefas. Entre os questionários a Escala de Impulsividade Barrat 11 se destaca, assim como a tarefa Delay Discounting, tanto para humanos quanto para animais. Conclusão. Estudos que utilizam instrumentos de modelos diferentes são sugeridos, assim como validação de escalas de impulsividade para diferentes populações brasileiras. / Background. The concept of impulsivity encompasses several behavioral dimensions. Therefore, the evaluation of impulsive behavior is quite complex and can vary greatly. Hence, such complexity should be considered during research or while establishing a diagnosis. Objectives. The objective of the present review article was to describe the main impulsive behavior assessment instruments both in animals and humans, including the indications and limitations of each instrument, and to suggest references of empirical articles that illustrate each protocol. Methods. The following databases were searched from 2007 to 2013: MEDLINE, PsycINFO and BVS/Bireme. Results. Our search retrieved four questionnaires and eight tasks for humans, and six tasks for animals. Among the most frequently used questionnaires and tasks, we found the Barratt Impulsiveness Scale-11 and the Delay Discounting Task, both for humans and animals. Conclusion. It is recommended that further research be undertaken using different models of instruments. In addition, impulsivity scales should be validated for different Brazilian populations.

Contexto. A impulsividade é um conceito formado a partir de diversas dimensões comportamentais. Desta forma a avaliação do comportamento impulsivo apresenta características complexas e distintas, que devem ser levadas em conta durante o processo de diagnóstico ou pesquisa. Objetivo. Este artigo de revisão apresenta os principais instrumentos de avaliação do comportamento impulsivo tanto em animais, quanto em humanos, relacionando as indicações e limitações de cada instrumento, assim como apontando referências de artigos empíricos que exemplificam cada protocolo. Método. Foram realizadas buscas nos sistemas Medline, PsycINFO e BVS/Bireme durante o período de 2007 a 2012. Resultados. Para humanos foram apontados quatro questionários e oito tarefas, e para animais foram apontadas seis tarefas. Entre os questionários a Escala de Impulsividade Barrat 11 se destaca, assim como a tarefa Delay Discounting, tanto para humanos quanto para animais. Conclusão. Estudos que utilizam instrumentos de modelos diferentes são sugeridos, assim como validação de escalas de impulsividade para diferentes populações brasileiras. / Background. The concept of impulsivity encompasses several behavioral dimensions. Therefore, the evaluation of impulsive behavior is quite complex and can vary greatly. Hence, such complexity should be considered during research or while establishing a diagnosis. Objectives. The objective of the present review article was to describe the main impulsive behavior assessment instruments both in animals and humans, including the indications and limitations of each instrument, and to suggest references of empirical articles that illustrate each protocol. Methods. The following databases were searched from 2007 to 2013: MEDLINE, PsycINFO and BVS/Bireme. Results. Our search retrieved four questionnaires and eight tasks for humans, and six tasks for animals. Among the most frequently used questionnaires and tasks, we found the Barratt Impulsiveness Scale-11 and the Delay Discounting Task, both for humans and animals. Conclusion. It is recommended that further research be undertaken using different models of instruments. In addition, impulsivity scales should be validated for different Brazilian populations.

A utilização do conhecimento científico para promoção da saúde humana é o principal objetivo da ciência translacional. Para que isto seja possível, faz-se necessário o desenvolvimento de métodos computacionais capazes de lidar com o grande volume e com a heterogeneidade da informação gerada no caminho entre a bancada e a prática clínica. Uma barreira computacional a ser vencida é o gerenciamento e a integração dos dados clínicos, sócio-demográficos e biológicos. Neste esforço, as ontologias desempenham um papel essencial, por serem um poderoso artefato para representação do conhecimento. Ferramentas para gerenciamento e armazenamento de dados clínicos na área da ciência translacional que têm sido desenvolvidas, via de regra falham por não permitir a representação de dados biológicos ou por não oferecer uma integração com as ferramentas de bioinformática. Na área da genômica existem diversos modelos de bancos de dados biológicos (tais como AceDB e Ensembl), os quais servem de base para a construção de ferramentas computacionais para análise genômica de uma forma independente do organismo de estudo. Chado é um modelo de banco de dados biológicos orientado a ontologias, que tem ganhado popularidade devido a sua robustez e flexibilidade, enquanto plataforma genérica para dados biomoleculares. Porém, tanto Chado quanto os outros modelos de banco de dados biológicos não estão preparados para representar a informação clínica de pacientes. Este projeto de mestrado propõe a implementação e validação prática de um framework para integração de dados, com o objetivo de auxiliar a pesquisa translacional integrando dados biomoleculares provenientes das diferentes tecnologias omics com dados clínicos e sócio-demográficos de pacientes. A instanciação deste framework resultou em uma ferramenta denominada IPTrans (Integrative Platform for Translational Research), que tem o Chado como modelo de dados genômicos e uma ontologia como referência. Chado foi estendido para permitir a representação da informação clínica por meio de um novo Módulo Clínico, que utiliza a estrutura de dados entidade-atributo-valor. Foi desenvolvido um pipeline para migração de dados de fontes heterogêneas de informação para o banco de dados integrado. O framework foi validado com dados clínicos provenientes de um Hospital Escola e de um banco de dados biomoleculares para pesquisa de pacientes com câncer de cabeça e pescoço, assim como informações de experimentos de microarray realizados para estes pacientes. Os principais requisitos almejados para o framework foram flexibilidade, robustez e generalidade. A validação realizada mostrou que o sistema proposto satisfaz as premissas, levando à integração necessária para a realização de análises e comparações dos dados. / The use of scientific knowledge to promote human health is the main goal of translational science. To make this possible, it is necessary to develop computational methods capable of dealing with the large volume and heterogeneity of information generated on the road between bench and clinical practice. A computational barrier to be overcome is the management and integration of clinical, biological and socio-demographics data. In this effort, ontologies play a crucial role, being a powerful artifact for knowledge representation. Tools for managing and storing clinical data in the area of translational science that have been developed, usually fail due to the lack on representing biological data or not offering integration with bioinformatics tools. In the field of genomics there are many different biological databases (such as AceDB and Ensembl), which are the basis for the construction of computational tools for genomic analysis in an organism independent way. Chado is a ontology-oriented biological database model which has gained popularity due to its robustness and flexibility, as a generic platform for biomolecular data. However, both Chado as other models of biological databases are not prepared to represent the clinical information of patients. This project consists in the proposal, implementation and validation of a practical framework for data integration, aiming to help translational research integrating data coming from different omics technologies with clinical and socio-demographic characteristics of patients. The instantiation of the designed framework resulted in a computational tool called IPTrans (Integrative Platform for Translational Research), which has Chado as template for genomic data and uses an ontology reference. Chado was extended to allow the representation of clinical information through a new Clinical Module, which uses the data structure entity-attribute-value. We developed a pipeline for migrating data from heterogeneous sources of information for the integrated database. The framework was validated with clinical data from a School Hospital and a database for biomolecular research of patients with head and neck cancer. The main requirements were targeted for the framework flexibility, robustness and generality. The validation showed that the proposed system satisfies the assumptions leading to integration required for the analysis and comparisons of data.

The central hypothesis supporting the present work is that the effectiveness of radiation therapy for cancer is often limited due to defects in key apoptosis regulators, such as Bcl-2 family members, that contribute to cancer ability to evade apoptosis. One way to bypass this resistance to radiotherapy is to target cell death pathways, aiming to sensitize tumours to radiation and enhance the therapeutic ratio in cancer. To test this central hypothesis, we took a dual approach: one targeted apoptosis and the other targeted autophagy. / First, we focused on the apoptotic signaling. The Bcl-2 family comprises antiapoptotic members, such as Bcl-2, Mcl-1, and Bcl-XL, and proapoptotic members, such as Bax, Bak, and Bid. The Bcl-2 family controls the integrity of the outer mitochondrial membrane and is critical in determining the susceptibility of cells to apoptosis induced by the intrinsic pathway. The balance between cell survival and cell death is modulated by the ratios and interactions of antiapoptotic and proapoptotic Bcl-2 family proteins. Overexpression of Bcl-2 or Bcl-XL is observed in several cancers, including lung, colorectal, prostate, and breast cancers, and has been shown to confer resistance to various anticancer agents, including radiotherapy. In cancer cells, alterations in the amounts of these antiapoptotic Bcl-2 proteins promote cell survival, among others by contributing to their evasion from treatment-induced apoptosis. We made the observation that lung cancer cells have different radiosensitivity. On the basis of their relative response to radiotherapy, we stratified lung cancer cells into two groups (higher or lower sensitivity), and selected a representative cell line of each group for more in-depth study: A549 (resistant) and HCC2429 (sensitive). We found that the expression levels of Bcl-XL expression, which is antiapoptotic, was dramatically higher in A549, whereas almost not detected in HCC2429. We then hypothesized that AT-101, a pan-Bcl-2 inhibitor, had the potential to radiosensitize lung cancer by restoring radiation-induced apoptosis. When administered alone, AT-101 resulted in increased apoptosis in a concentration-dependent manner in both groups, with enhanced activity in HCC2429 even at lower concentration. Furthermore, AT-101 promoted radiosensitivity of A549 and HCC2429 cells (p < 0.005). A549 cells required increased AT-101 dose to achieve the same level of cytotoxicity than HCC2429 cells. These investigations suggest that the Bcl-2 family members may serve as effective therapeutic targets in lung cancer. However, the potential of AT-101 as an agent that enhances the therapeutic ratio of radiotherapy varies depending on the lung cancer clone. / Next, we turned to a different approach, focusing on the inhibition of apoptosis instead of its promotion. This work hypothesis was based on previous observations looking at the role of radiation-induced apoptosis by knockdown of Bak and Bax. The radiosensitivity of breast and lung cancer in vitro was increased through autophagy, an alternate type of programmed cell death. Consistently, radiation-induced apoptosis accounts for a minor portion of cell death in irradiated solid tumors. The hypothesis of our work was that apoptosis inhibition would increase radiation-induced autophagy and tumor sensitivity to radiation. To block apoptosis, we used Z-VAD, a broad-spectrum caspase inhibitor, and examined its in vitro and in vivo effects on breast and lung cancer models. Z-VAD markedly radiosensitized breast and lung cancer cells in vitro, with a radiation dose enhancement ratio of 1.31 (P < 0.003). The enhanced tumor cytotoxicity was associated with induction of autophagy. In both breast and lung cancer mice xenograft models, the administration of Z-VAD concurrent with radiation produced a significant tumor growth delay compared with radiation alone and was well tolerated. Interestingly, Z-VAD also had a dramatic antiangiogenic effect when combined with radiation both in vitro and in vivo. Thus, Z-VAD represents an attractive anticancer therapeutic strategy. We further explored the potential of apoptosis inhibition as a way to sensitize cancer to radiation using a more selective chemical, M867, which is a reversible caspase-3 inhibitor. In an in vivo mouse hind limb lung cancer model, the administration of M867 with ionizing radiation was well tolerated, and produced a significant tumor growth delay compared with radiation alone. A dramatic decrease in tumor vasculature and tumor cell proliferation was observed with M867 despite the reduced levels of apoptosis. The radiosensitizing effect of M867 through the inhibition of caspases was validated using a caspase-3/-7 double-knockout (DKO) mouse embryonic fibroblasts (MEF) cell model. Consistent with our previous results, autophagy contributed to the mechanism of increased cell death, following inhibition of apoptosis. Finally, we investigated the mechanism by which radiation triggers autophagy in caspase-3/7-deficient cells, and found the involvement of endoplasmic reticulum (ER) stress. The ER activates a survival pathway, the unfolded protein response, which involves ER-localized transmembrane proteins such as protein kinase-like ER kinase (PERK), inositol-requiring enzyme-1, and activating transcription factor-6. In this study, we found that PERK is essential for radiation-induced autophagy and radiosensitivity in caspase-3/7 double-knockout cells. Irradiation of these cells increased expression of phosphorylated-eIF2a. Similar results were seen after administration of tunicamycin (TM), a well-known ER stress inducer. We found that the administration of TM with radiation in MCF-7 breast cancer cells, which are lacking functional caspase-3 and are relatively resistant to many anticancer agents, enhances radiation sensitivity. Our findings revealed ER stress as a novel potential mechanism of radiation-induced autophagy in caspase-3/7-deficient cells and as a potential strategy to maximize efficiency of radiation therapy in breast cancer. Our data suggested that caspase-3 has a critical role in modulating the PERK/eIF2a pathway after radiation. / Many cancers exhibit multiple deregulations in cell death pathways, allowing for the subsequent promotion of tumor cell survival, and contributing to a relatively low response rate to therapies based on the use of pro-apoptotic strategies. As we have showed, there is a potential for novel anticancer strategies to overcome resistant cancer cells with defective apoptosis machinery in order to improve overall therapeutic outcomes. Such novel approach is to drive cancer cells towards autophagy, as demonstrated by our experiments that studied the effect of radiation on the induction of autophagy in caspase-deficient models. / Doctorat en Sciences biomédicales et pharmaceutiques (Médecine) / info:eu-repo/semantics/nonPublished

This study explores cognitive impairment and its correlation to early- life adverse experiences in non-patient population between the ages of 50 to 65. This developmental approach and observational study design explores cognition in pre-clinical Alzheimer’s disease (AD). Using a standardized neuropsychological instrument, the Montreal Cognitive Assessment (MoCA) and clinically administered questionnaire, the ACE (Adverse Childhood Experiences), I hypothesized that participants with high ACE scores will inversely have low MoCA scores. My goal was to use a multiple linear regression model with 3 covariates and 1 predictor of interest (ACEs). At 80% power, a sample size of 40 was calculated as needed. This would mean that the results would have 80 % chance of declaring statistical significance. This corresponds to an R-squared value (percentage of variation in MoCA score explained by the predictor) of 17.2%. The desired sample size was not attained successfully due to several barriers in receiving sample data from the collaborating site and the 2017 Hurricane Irma causing a drop in participation rate. Overall 13 participants had successfully participated. The analysis of the results is demonstrated in a line graph indicating a relationship between ACE and MoCA scores. The accuracy of the descriptive statistics could be argued against due to the low sample size. The analysis of the ethnographic interviews brings out some trends in the participant responses. The focus here has been to discuss these responses as to how they advocate for the entanglement theory of aging. In other words, how the exposure to social and environmental factors at various stages of an individual’s lifecourse can interact with one’s physiology, resulting in exposure- specific health conditions at later life stages. Among the period of exposure, my focus through this study is specifically on the early exposures in the lifecourse. This is facilitated by the use of the ACE questionnaire regarding exposures to adverse experiences such as sexual/ physical abuse, familial mental health issues, alcohol/ drug abuse in the family and loss or separation from parents. The entanglement theory further allows for race or culture specific exposures to adversity that raises the question of varying health consequences among cultural or racial groups and the need for a more critical approach in providing access to healthcare and healthcare policy development. Trends in ethnographic results obtained have allowed for the critical discourse in the transgenerational effects of social adversity, effects of resilience- building from adversity and the need for care- giver mental health services. The study brought out critiques on how the ACE module could be made more inclusive of experiences specific to diverse cultures and regions, as well as the need to address the severity of individual experiences. We conclude by discussing how effects of social or environmental experiences can be used toward AD and aging research and what supporting literature and initiatives currently exist. The discussion is also inspired by the existing political discourse around the medicalization of AD and how that influences the reductionist methods in AD research. This new direction of applied and holistic approach derives its perspective from neuroanthropology and applied medical anthropology. The overall aim of this study is to ask questions challenging existing research methods with the ultimate hope to newly influence the allocation of AD research and risk reduction toward interdisciplinary focus and funding, involving early-life lived experiences and life course perspectives.

No description available.

Stem cell treatments for spinal cord injury (SCI) are effective in pre-clinical animal model research but not yet for humans. Two promising stem cell repair strategies involve (1) endogenous neural stem/progenitor cells (NSPCs) and (2) induced pluripotent stem cells (iPSCs). Delineating species differences in spinal cord NSPC biology is essential to inform human SCI endogenous regeneration and repair. Understanding the phenotypic differences between iPSC-derived NSPCs and primary spinal cord NSPCs would also improve the clinical application of iPSC-derived NSPC therapy in human SCI. To directly compare the molecular and functional attributes of spinal cord NSPCs between humans and animal models of SCI, we designed an in vitro model that allows the characterization of primary human, pig, and rat NSPCs under identical conditions. We found an enrichment of transcription factors in NSPCs of either species that may underlie their differentiation and proliferation potentials. Specifically, human NSPCs are neurogenic, whereas pig and rat NSPCs are gliogenic. Also, the proliferation rate of human and pig NSPCs is less than rat NSPCs. Subsequently, we expanded our in vitro model to examine the responses of NSPCs to inflammation and regenerative factors. Surprisingly, inflammation had induced glial scarring mechanisms from pig and rat NSPCs but potentiated neurogenesis of human NSPCs. We also found species-specific responses to regenerative factors that depend on the type of factor used, concentration, and duration of treatment. To assess the extent that iPSC-derived NSPCs phenocopy primary spinal cord NSPCs, we created iPSC-derived NSPCs with a previously reported brain or spinal cord phenotype and directly compared them with isogenic primary NSPCs. We found that iPSC-derived NSPCs exhibit an earlier developmental stage and a greater proliferation rate. We also found that primary NSPCs possess a unique differentiation potential and regional polarity along the rostral-caudal and dorsoventral axes. In summary, we discovered that species differences in NSPC biology exist between human and animal primary spinal cord NSPCs and that iPSC-derived NSPCs do not recapitulate the transcriptional nor functional attributes of primary spinal cord NSPCs. This thesis highlights the translational gap between pre-clinical research and the clinical application of stem cell treatments that target endogenous NSPCs or transplant iPSC-derived NSPCs.

No description available.