Introdução: a proteína mitocondrial codificada pelo gene Nicotinamide Nucleotide Transidrogenase (NNT) regula o processo intramitocondrial de desintoxicação de espécies reativas de oxigênio (EROs). Defeitos na homeostase desse sistema (sistema Redox) podem comprometer a esteroidogênese adrenal. Objetivo: caracterizar o impacto funcional da nova variante missense NNT p.G866D (c.2597G>A) e sua associação com o fenótipo de deficiência familiar de glicocorticoide (DFG). Indivíduos e Métodos: Caso índice: lactente com DFG diagnosticada aos 18 meses, seus pais e irmão assintomáticos e controles saudáveis. O ácido desoxirribonucleico (DNA) genômico do caso índice foi submetido a sequenciamento exômico que revelou, entre algumas variantes gênicas-candidatas, a variante (c.2597G> A; p.G866D) em homozigose no exon 17 do gene NNT. Avaliou-se a segregação familiar dessa variante com o fenótipo de DFG. A análise funcional in vitro dessa variante foi realizada em cultura transitória de células mononucleares sanguíneas do paciente, heterozigotos e controles em condição basal e após a indução do estresse oxidativo com 100?m de H2O2 por cinco horas. A expressão do RNAm do gene NNT nessas células foi realizada por meio de qPCR. Os parâmetros mitocondriais avaliados foram: a produção intracelular de espécies reativas de oxigênio (EROS) detectadas por CMDCFDA, a concentração de glutationa reduzida (GSH) e ATP celular medidos ensaios luminescentes, , além da massa e potencial de membrana mitocondrial avaliados com o probe MitoTracker. Resultados: A análise de segregação familiar confirmou a segregação desta variante em homozigose com o fenótipo de DFG. A expressão do NNT RNAm foi semelhante entre paciente, heterozigotos e controles. Em homozigose a variante p.G866D no gene NNT causa aumento na produção de EROs, diminuição de GSH e diminuição da massa e potencial de membrana mitocondrial, tanto em condições basais, quanto após a indução de estresse oxidativo. Após a indução de estresse oxidativo as concentrações de ATP foram menores no homozigoto NNT p.G866D do que nos controles. Conclusão: este estudo confirma a associação da variante NNT em homozigose com o fenótipo de DFG Tipo quatro. In vitro o mutante homozigoto NNT p.G866D reduz significativamente os mecanismos de defesas antioxidantes, comprometendo o sistema da glutationa redutase, levando ao acúmulo de EROs. / Background: mitochondrial Nicotinamide Nucleotide Transidrogenase (NNT) is essential in the intracellular reactive oxygen species (ROS) detox process. Defects in this system may impair adrenal steroidogenesis by yet not fully understood mechanism. Aim: we sought to characterize the functional impact of the new NNT p.G866D (c.2597G>A) variant and its association with familial glucocorticoid deficiency (FGD). Subjects and Methods: evaluated subjects included the index case diagnosed with FGD at the age of 18 months, his asymptomatic parents and young brother and healthy controls. The Index case genomic DNA was evaluated by whole exome sequencing, which revealed several potential candidate variants, including the homozygous NNT p.G866D. We then analyzed the family pedigree to confirm the segregation of this variant with FDG phenotype. To prove the genotype-phenotype association, this new variant was comprehensive evaluated in vitro. Transient mononuclear cell cultures from the patient, family members and controls were performed both in basal conditions and after oxidative stress induced by 5-hours treatment with 100?m de H2O2. We analyzed NNT RNAm expression by qPCR and mitochondrial parameters including ROS intracellular production by 20, 70-diacetate dichlorodihydrofluorescein, reduced glutathione (GSH) and cellular ATP levels by luminescence, and mitochondrial mass and mitochondrial membrane potential by Mitotraker Probe system. Results: family pedigree analysis confirmed the segregation of the homozygous NNT p.G866D variant with FGD. In vitro, no differences in RNAm expression was found among patients, heterozygous carriers and healthy controls. Both in basal and under stress conditions, the homozygous p.G866D NNT variant exhibited significantly increased ROS production, decreased GSH levels and decreased mitochondrial parameters. In addition, under H2O2 oxidative stress, the homozygous p.G866D NNT also leaded in decreased ATP intracellular . Conclusion: this study clearly confirms the association of the homozygous NNT p.G866D variant with the phenotype of FGD. In vitro, this variant significantly impairs anti-oxidants mechanisms and affects the glutathione reductase systems resulting in increased ROS accumulation.

Le modèle linéaire mixte a été formalisé il y a plus de 60 ans. Celui-ci permet d'estimer un modèle avec des effets fixes équivalents à ceux du modèle linéaire classique et des effets aléatoires. Ce type de modélisation, d'abord utilisé en génétique animale, est depuis quelques années largement utilisé en génétique humaine. Les utilisations de ce modèle sont nombreuses. En effet, il peut être utilisé en étude de liaison, d'association, pour l'estimation de l'héritabilité ou encore dans la recherche d'empreinte parentale et peut s'adapter à des données familiales ou en population.Le but de mon doctorat est d'exploiter différentes méthodes basées sur les modèles mixtes d'abord sur des données génétiques en population puis sur des données génétiques familiales.Dans un premier temps, nous explorons dans ce manuscrit la théorie des modèles linéaires mixtes et leur utilisation en génétique. Nous adaptons aussi certaines méthodes pour les appliquer à notre recherche. Ce travail a donné lieu au développement informatique d'un package R permettant d'utiliser ces modèles dans le cadre des études génétiques.Dans un deuxième temps, nous utilisons les modèles linéaires mixtes pour l'estimation de l'héritabilité dans une étude en population française, l'étude Trois-Cités. Nous disposons dans cette étude des génotypes des tag-SNPs habituellement utilisés dans les études d'association ainsi que des lieux de naissance et de plusieurs traits anthropométriques quantitatifs tels que la taille. L'objectif est alors d'étudier la présence et la prise en compte dans l'analyse de stratification de population dans cette étude. Dans ce manuscrit, nous analysons les coordonnées géographiques des lieux de naissance. Nos résultats mettent en évidence la difficulté pour corriger correctement la stratification de population avec les méthodes classiques dans certains cas. Nous analysons ensuite les traits anthropométriques en particulier la taille dont nous estimons l'héritabilité à 39% dans la population de l'étude Trois-Cités.Dans la dernière partie de ce manuscrit, nous nous concentrons sur les données familiales. Nous montrons le gain d’information que peut apporter ce type de données dans la recherche des variants causaux. Puis, nous explorons l'utilisation des modèles mixtes sur des données familiales en appliquant certaines des méthodes associées dans la recherche de signaux d'association pour la Sclérose en Plaques, une maladie auto-immune, en utilisant un échantillon d’une centaine de familles nucléaires avec au moins deux germains atteints. Nous avons alors mis en évidence l’inadéquation des méthodes classiques basées sur les modèles mixtes à ce type de données. Afin de mieux comprendre ce biais de sélection et de le corriger, plus d’investigations sont nécessaires. / Linear mixed models have been formalized 60 years ago. These models allow to estimate fixed effects, as in the linear models, and random effects. First used in animal genetics, this type of modelling have been widely used in human genetics since a few years. Mixed models can be used in many genetic analysis; linkage and association studies, heritability estimations and Parent-of Origin effects studies for population or familial data.My thesis’ aim is to investigate mixed models based methods, for genetic data in population and, for familial genetic data.In the first part of my thesis, we investigated the mixed model statistical theory and their multiple uses in human genetics. We also adapted methods for our own work. An R package have been created which permits to analyze genetic data in R environment with mixed models.In a second part, we applied mixed models on Three-Cities data, a French longitudinal study, to estimate heritability of several traits. For this analysis, we have access to tag-SNPs typically used in genome-wide association studies, birthplaces and several anthropometric traits. The aim of our study is to analyze presence of population stratification and evaluate methods to correct it. In the one hand, we analyzed birthplace geographic coordinates and showed that the correction for population stratification by classical method is not sufficient in this case. In the other hand, we analyzed anthropometric traits, in particular the height for which we estimated heritability to 39% in Three-Cities study population.In the last part, we focused on family data. In a first work, we exploited familial information in causal variant research. In a second work, we explored mixed models uses for familial data, in particular association study, on Multiple Sclerosis data. We showed that mixed model methods can not be used without taking account the ascertainment scheme: in our data, all families have at least two affected sibs. To understand and correct this phenomenon, more investigations are needed.

The familial aggregation of Major Depressive Disorder (MDD) has been repeatedly demonstrated. Several studies have investigated associations between various clinical characteristics of MDD in probands and overall rates of MDD in relatives. Few studies, however, have considered the familial aggregation of clinical characteristics of MDD. The aim of the present report is to examine mother–offspring associations of a variety of clinical characteristics of MDD in a general population sample. Data were derived from baseline and 4-year-follow-up data of 933 adolescents and their biological mothers of the Early Developmental Stages of Psychopathology (EDSP) study, a prospective-longitudinal community study. MDD and its characteristics were assessed with the Munich-Composite International Diagnostic Interview. We found that children of mothers who had a lifetime history of severe MDD and high number of symptoms, high impairment and/or melancholia, revealed elevated odds of MDD regarding the same characteristics as their mothers (ORs between 5.2 and 13.9). The observed associations did not differ by the children’s sex. DSM-IV melancholia and severity as well as impairment were found to aggregate within families. This finding can be interpreted as a validation of the DSM-IV MDD severity subtypes as well as of the melancholic specifier. Severe and melancholic MDD reveal a considerable high degree of familiar aggregation making the search for mechanisms involved in the familiar transmission of these forms of MDD particularly promising.

Several hundred inherited disorders of the skeleton have been delineated. Individually these conditions are rare, but as a group they cause much crippling and hardship. Several factors, including the rarity and complexity of the manifestations of these conditions, as well as semantic overlap, impede the accurate diagnosis which is essential for effective treatment. In this regard, the adoption of microcomputers warrants evaluation as a high technology aid. Microcomputers have developed tremendous capabilities during recent years. The state of the art has become such that a diagnostic aid facility on such a device has been demonstrated in various disciplines of medicine and may also be feasible in the area of inherited skeletal disorders. The study which forms the basis of this thesis, concerns the investigation of this feasibility and has led to the development of an effective working model which sets the basis for microcomputer-aided diagnosis. The design features followed in this project are similar to those conventionally employed for "Expert systems" on mainframe computers. A comprehensive knowledge base consisting of over 200 skeletal disorders and 700 radiographic and clinical manifestations, has resulted. Furthermore, the application is capable of "learning", although inference as employed by the inference engines of real expert systems, is not employed. In this context learning implies that the knowledge base, with the passage of time, improves considerably when used by experts. Serendipitous findings in this regard are: • 1) Considerable improvement of existing profile descriptions can occur without any increased demands on computer memory and storage space; • 2) Growth of the knowledge base in the form of additional disease profiles can be effected with very modest inroads on memory and storage resources. The computerized diagnostic aid which resulted from this thesis, has been demonstrated to be successful in both the Department of Human Genetics of the University of Cape Town and the Department of Paediatrics of the Johannes Gutenberg University in Mainz. Evaluated both in terms of efficiency and utility, the system provides an enhancement to the specialist genetic diagnostician. These achievements have been effected by means of a unique newly developed application of compressed bit-mapping, attained by writing the applicable programs in Turbo Pascal and 8086- assembler languages. Calculations indicate that much larger data bases may possibly be implemented on present-day microcomputers by means of the methods developed in this project.

Introduction : Ces dernières années, les auteurs se sont attachés à créer une théorie générale de la problématique de la relation d’aide afin de mettre en évidence l’importance de la place occupée par les familles auprès du sujet âgé souffrant de la maladie d’Alzheimer. Il peut toutefois être intéressant de replacer l’aidant dans sa singularité de sujet affecté par d’autres questionnements que ceux relatifs à l’aide, afin de déterminer les facteurs influençant son vécu. Problématique : Dans quelle mesure la personnalité, les représentations du vieillissement, le lien de parenté et la qualité des relations passées vont influencer le vécu du rôle d’aidant principal d’un parent ou conjoint âgé en perte d’autonomie psychique, que ce dernier réside à domicile ou en institution ? Objectifs : Dans un premier temps, ce travail a pour objectif, d’établir les relations entre les différentes dimensions du vécu de l’aidant familial (difficultés, satisfactions et stratégies). Il se propose ensuite d’étudier l’influence sur ce vécu du lien de parenté et de l’entrée en institution d’une part, et de la personnalité (modèle en Cinq dimensions) et des représentations de la vieillesse d’autre part. Méthodologie : Pour ce faire, nous avons mené une étude auprès de 113 participants, dont 80 enfants et 33 conjoints. La première moitié accompagnait un proche à son domicile, la seconde en institution. Dans une première partie de l’étude, les participants ont rempli un questionnaire sociodémographique accompagné d’échelles évaluant la qualité des relations passées (QRASA), le fardeau (ZBI), les difficultés (CADI), satisfactions ressenties (CASI) et stratégies utilisées (CAMI) dans la relation d’aide, la personnalité (NEO PI-R) et la dépression (BDI). Dans un second temps, dix-sept participants ont été vus en entretien semi-directif afin d’appréhender qualitativement leur expérience d’aidant, les relations qu’ils entretiennent avec la personne accompagnée ainsi que leurs représentations de la vieillesse. Résultats : Les résultats de cette étude montrent que les difficultés, satisfactions ressenties et stratégies utilisées dans la relation d’aide sont liées entre elles, créant un équilibre nécessaire pour que l’aidant familial puisse investir son rôle. Cet équilibre est influencé aussi bien par des facteurs situationnels (lieu de résidence de la personne malade), relationnels (qualité des relations avec la personne accompagnée) que personnels (personnalité et représentations liées au vieillissement). Conclusion : Les implications en termes d’accompagnement et de prévention auprès de cette population sont discutées. / Introduction: Over the past years, authors have proposed a general theory of the caregiving relationship in order to highlight the importance of the place occupied by the families, who have an elderly relative suffering from Alzheimer's disease. However, it may be interesting to consider the caregiver with all his specificities, and as an individual affected by other problems than only the caregiving. We wonder to what extent the personality of a caregiver, the representations of the ageing process, the family relationship and the quality of the past relationships can influence the experience of caregiving. The studied caregivers were children or spouses of a patient losing his psychic autonomy, living at home or in an institution. Methods: We realized a study with 113 subjects (80 children and 33 spouses of an Alzheimer’s patient). Half of the patients were living at home and the other half in an institution. First, all caregivers filled a socio-demographic questionnaire and different clinical scales, assessing: the quality of the passed relationships (QRASA) ; the burden (ZBI) ; the difficulties (CADI ), satisfactions (CASI ) and strategies they used (CAMI) in the caregiving situations ; the personality (NEO PI-R) and the depression (BDI ). Second, 17 subjects have been seen in a semi-structured interview in order to qualitatively assess their experience of the caregiving, the past and present relationship they have with their parent or spouse. Results: The results of this study showed that the difficulties, the satisfactions which are experienced, and the strategies which are used in the caregiving relation are linked together. A balance between these variables is required for the family caregiver to invest his role. This balance is influenced by situational factors (the place where the patient lives), relational factors (the quality of the present and past relationship with the patient) as well as personal factors (personality and representations linked to the ageing process). Conclusion: The implications in terms of support and prevention for this population of caregivers are discussed.

Familial adenomatous polyposis (FAP) is a condition caused by germline mutations in tumor suppressor gene APC, inherited in autosomal dominant manner. Patients with FAP develop hundreds to thousands of adenomatous colorectal polyps with extremely high risk of malignant reversal into adenocarcinoma of colon and/or rectum. The aim of this thesis is to re-analyze a cohort of highly suspected FAP probands from years 1993-2004 whose diagnosis previously failed to be confirmed by at that time commonly used methods of molecular diagnostics. Next generation sequencing on MiSeq and NextSeq platforms (Illumina®) was performed on 78 samples of probands' DNA, isolated from peripheral blood, using gene panel CZECANCA version 1.2 (Czech Cancer Panel for Clinical Application). The panel enables sequencing of exons and exon-intron junctions of 226 genes linked to hereditary cancer predispositions, newly also including the diagnostically important promoter 1B region of APC. Pathogenic variant in the APC gene was detected in 18 % of re-analyzed probands, 11 % of probands carry pathogenic variants in other genes associated with colorectal polyps. Additional 13 % of probands are carriers of a variants of unknown clinical significance. NGS gene panel CZECANCA enabled diagnosis confirmation or re-evaluation of 22 FAP...

Thesis advisor: Jane E. Regan / In the contemporary United States, trauma is a significant disruptive force in the lives of families. By its nature, however, traumatic suffering isolates and marginalizes its victims, with the result that the pastoral caregiving needs of suffering people can go unrecognized and unmet. This dissertation proposes that caring for families who struggle to cope in contexts of traumatic suffering and chronic distress is a vital work of mission for the Catholic church in the twenty-first century. It further proposes that this work can best be enacted in the local church setting when configured as a synodal, trauma-aware, relational, caregiving community of practice (a STAR caregiving CoP) ministry. The ministerial model offered here is designed to enable parishes and dioceses to develop compassionate, competent ministerial initiatives that can meet the particular needs of families in their communities. Grounded in the theoretical discourses of theological anthropology, ecclesiology, situated learning theory, the ethic of care, and traumatology, the model also reflects insights drawn from the author’s qualitative doctoral research study of two pastoral caregiving ministries that serve men and women struggling with the personal traumas that erupt in family life. The STAR caregiving CoP model offers the local church a flexible, robust framework to employ in the construction and evaluation of familial pastoral caregiving ministries. / Thesis (PhD) — Boston College, 2023. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Religious Education and Pastoral Ministry.

This study aims to close the gap in the literature on religious minority groups in the Arab Middle East by examining how religion has shaped belief systems and social identities in religious minorities in Jordan. Additionally, the study also examines the role of familial structures and their sphere of influence in society. Previous research has predominantly focused on the religious majority and has usually been examined through quantitative data. By means of semi-structured interviews, the findings indicate how foundational religion is perceived to be in shaping belief systems and social identities in individuals and shows strong dependencies on the family system which governs individual behavior. These findings contribute to the research field on religious minority groups in the Arab Middle East, which has not received sufficient attention, providing insight into how religious minorities attribute meaning to the world around them.

Caregivers of persons with dementia often struggle to sustain meaningful communication and reciprocal emotional connection due to the deterioration in functional memory and the resulting diminishment of social-interactive abilities in their loved one. The very personhood of the care recipient is also often compromised by the reduction in those socio-communicative capacities, which in turn, can impact the function of the caregiving relationship. Emotional, as well as social isolation can increase for the familial caregiver just as it often does for the care recipient. This thesis examines the impact that an individualized, home-based music therapy program had on the emotional connection and reciprocal interactions of four familial caregiving dyads. Data were collected over a month-long period using qualitative research methods including pre and post interview, a caregiver's journal log, researcher's journal log, participation, direct observation, and the observations of the caregiver respondents themselves as they engaged in the therapeutic process with their familial care recipient. Through a cross-case analysis of data collected, four main themes emerged to reflect the experiences of the participants. These were: 1) a longing for reciprocity, 2) the experience of emotional reciprocity, 3) the emergence of personhood through shared musical experiences, and 4) perseverance in the pursuit of meaningful communication. Sub-themes, and themes relating to the researcher's participatory experiences are also included. Implications for further research are discussed.

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