Thesis (M.A.)--State University of New York at Binghamton, Psychology Department, 2006. / Includes bibliographical references.

Pour avoir une parfaite compréhension dune maladie, il est nécessaire den connaitre la fréquence, la symptomatologie et les causes dapparition. Dans le cas des adénomes hypophysaires, les données de la littérature concernant lépidémiologie de ces tumeurs sont contradictoires certaines études suggérant une haute prévalence, et dautres affirmant quelles sont plutôt rares. En parallèle, la compréhension de la physiopathologie des tumeurs endocrines telles que les adénomes hypophysaires a fait un bond en avant avec lavènement des techniques de biologie moléculaire. Pourtant, leur physiopathologie reste encore très floue. Le fait de se concentrer sur les causes familiales permet dapprocher plus efficacement les causes des tumeurs endocrines. Concernant les adénomes hypophysaires, mis à part les Néoplasies endocriniennes multiples de type I (MEN1) et le Complexe de Carney (CNC), le domaine des adénomes hypophysaires familiaux est peu compris. En effet, mise à part lacromégalie familiale, il ny a eu aucune étude sur dautres types dadénomes hypophysaires entrant dans le cadre familial. Les buts du travail contenu dans cette thèse étaient de décrire des aspects épidémiologiques et génétiques des adénomes hypophysaires. Tout dabord, nous avons étudié la discordance entre les taux de prévalence dadénomes hypophysaires provenant détudes radiologiques/autopsiques (les incidentalomes étant très fréquents) et dautre part ceux provenant de registres de cancers et plus rarement de données de population. Une étude intensive et complète de la prévalence des adénomes hypophysaires a été réalisée dans 3 régions géographiquement parfaitement délimitées dans la province de Liège. Dans cette étude qui a concerné une population de plus de 70 000 habitants, les adénomes hypophysaires diagnostiqués lont été en collaboration avec toute la communauté médicale de ces régions. Les données démographiques, cliniques, hormonales, radiologiques et pathologiques de tous les patients ont été confirmées de façon indépendante. A une date fixe, nous avons montré que les adénomes hypophysaires diagnostiqués suite à des symptômes cliniques surviennent avec une prévalence de 1 cas par 1064 habitants résidants dans les limites géographiques déterminées pour cette étude. Ces résultats montrent que la prévalence des adénomes hypophysaires évidents sur le plan clinique est de 3.5 à 5 fois plus haute que les estimations précédentes se rapportant à des populations ou des registres. Cela suggère que les adénomes hypophysaires significatifs sur le plan clinique surviennent assez fréquemment dans la pratique de tous les jours et ceci peut avoir des implications importantes sur la distribution des ressources de santé. Une étude épidémiologique internationale appliquant la même méthodologie est actuellement en cours. Létude des adénomes hypophysaires familiaux en-dehors du contexte de la polyendocrinopathie de type I ou du Complexe de Carney constitue la deuxième partie de ce travail. Jusquà présent, seule lacromégalie familiale avait été rapportée dans la littérature. Nous avons réalisé une étude internationale pour démontrer que tous les types dadénomes hypophysaires pouvaient survenir dans le cadre dune pathologie familiale différente de la polyendocrinopathie de type I et du complexe de Carney. La suspicion de cette pathologie est née à Liège au cours de la dernière décennie. Cette étude a démontré que les adénomes hypophysaires familiaux isolés (Familial Isolated Pituitary Adenoma ou FIPA) constituent 2% des adénomes hypophysaires et 64 familles FIPA ont été caractérisées cliniquement. Cette étude a démontré pour la première fois que tous les phénotypes dadénomes hypophysaires peuvent survenir dans les mêmes familles. Quelques familles montrent seulement un phénotype parmi les membres atteints (familles FIPA homogènes) et dautres familles montrent différents types de tumeurs chez les patients atteints (famille FIPA hétérogène). Dans les familles FIPA, les adénomes hypophysaires étaient plus agressifs et tendaient à survenir à un âge plus jeune que dans les cas sporadiques. Les familles FIPA montrent une grande proximité familiale entre les membres atteints suggérant un mode dominant de transmission. Les études ultérieures ont été réalisées sur les aspects génétiques et anatomo-pathologiques des adénomes hypophysaires et particulièrement ceux qui survenaient dans le contexte FIPA. La découverte dun gène nouveau aryl hydrocarbon receptor interacting protein (AIP), dont quelques mutations ont été associées avec des adénomes hypophysaires nous a conduit à entreprendre la première étude génétique dans les FIPA. Des mutations AIP ont été découvertes dans 15 % des familles et 50% des familles homogènes dacromégales dans le contexte FIPA. Ceci suggère que dautres gènes peuvent également être responsables du contexte FIPA. Dans les familles FIPA qui portent la mutation AIP, les tumeurs étaient plus importantes et survenaient à un âge plus jeune que dans les familles FIPA sans mutation AIP. Neuf nouvelles mutations AIP ont été identifiées, dont la majorité permet de prédire la perte du ligand ou de la région de AIP qui interagit avec son récepteur. Une mutation AIP dans les FIPA était associée avec différents types dadénomes hypophysaires incluant acromégalie, prolactinomes, adénomes mixtes à GH-prolactine et adénomes nonsécrétants. Nous avons également observé que la même mutation AIP pouvait être responsable de différents phénotypes dans 2 familles FIPA différentes. Un suivi détaillé dune famille FIPA avec mutation AIP a permis de montrer pour la première fois quune anomalie endocrinienne différente dune tumeur hypophysaire pouvait survenir chez des porteurs de mutation AIP (élévation de lIGF1). Une analyse détaillée de lADN germinal et somatique provenant dun grand groupe international européen dadénomes hypophysaires sporadiques (non familiaux) a montré que les mutations AIP surviennent rarement dans cette condition. En conclusion : Le travail entrepris a apporté une nouvelle compréhension de la vraie prévalence des adénomes hypophysaires diagnostiqués de façon clinique dans une population et il a permis de codifier et de caractériser le désordre FIPA, une nouvelle entité clinique qui représente une aire de recherche potentielle pour des études cliniques et génétiques impliquant la fonction de AIP et dautres gènes non encore identifiés. To have a full understanding of a disease, it is necessary to at least know how frequently it occurs, its clinical features and by what means it is caused. In the case of pituitary adenomas, data in the literature on the epidemiology of these tumors is conflicting, with some studies suggesting a high frequency, others that they occur rarely in the clinical setting. In parallel, the understanding of the pathophysiology of endocrine tumors like pituitary adenomas has advanced greatly with the advent of molecular genetic techniques. However, much remains unclear regarding pathophysiology. A valuable avenue for studying the causes of endocrine tumors has been to focus on the familial setting. With respect to pituitary adenomas, apart from multiple endocrine neoplasia type 1 (MEN1) and Carney complex (CNC), the field of familial pituitary tumors is poorly understood. Indeed, apart from familial acromegaly, there have been virtually no studies on other pituitary adenomas occurring in the familial setting. The aims of the work described in this thesis were based on addressing aspects of the epidemiology and genetics of pituitary tumors. Firstly, the disconnect between the prevalence rates for pituitary adenomas from autopsy/radiology studies (incidentalomas being very common) and cancer registries/population data (rare) was studied. An intensive, comprehensive, case-finding study of the prevalence of pituitary adenomas was performed in three tightly-defined geographical areas in the Province of Liège. In this study, which involved a population of more than 70,000 people, diagnosed pituitary adenomas were sought in collaboration with the entire group of community medical practitioners in the study areas, and the demographics and clinical, hormonal, radiological and pathological features of all patients were confirmed independently. On a fixed date, it was found that clinically diagnosed pituitary adenomas occurred with a prevalence of 1 case per 1064 individuals residing within the geographic boundaries of the study. These results report a clinical prevalence of pituitary adenomas that is 3.5 to 5 times higher than previous population/registry estimates. It suggests that clinically relevant pituitary adenomas occur frequently in the everyday clinical setting, which may have important implications for health resource allocations. Also, it is possible to undertake detailed, comprehensive, crosssectional epidemiological studies in well-defined geographic areas, and this methodology can be applied internationally Studying the familial occurrence of pituitary adenomas outside of MEN1 and CNC was the next aim of the work described. Up to this time, only the familial occurrence of acromegaly had been reported with any frequency in the literature. An international study was undertaken to assess whether isolated pituitary adenomas of all types could occur in the familial setting, a suspicion raised in Liège over the past decade. This study demonstrated that familial isolated pituitary adenomas (FIPA) occur in about 2% of pituitary adenoma populations, and 64 FIPA families were characterized clinically. The study demonstrated for the first time that all phenotypes of pituitary adenomas can occur together in families; some families exhibit only one phenotype among affected members (homogeneous FIPA kindreds), others have multiple tumor types among affected family members (heterogeneous FIPA). In FIPA families, pituitary tumors were more aggressive and tended to occur at a younger age than sporadic pituitary adenomas. FIPA families display a high degree of familiality, suggesting a dominant mode of inheritance. Subsequent studies were performed on the genetic and pathological features of pituitary adenomas, particularly those occurring as FIPA. The discovery of a novel gene, aryl hydrocarbon receptor interacting protein ( AIP), mutations in which were associated with isolated pituitary adenomas, led us to undertake the first such genetic studies in FIPA. AIP mutations account for a minority (15%) of FIPA families and 50% of familial acromegaly kindreds in FIPA. This suggests that other genetic causes for FIPA also exist. In AIP mutation carrying FIPA families, tumors were larger and had a younger age at diagnosis than non- AIP mutated FIPA kindreds. A series of 9 novel AIP mutations were identified, the majority of which led to predicted loss of vital ligand and receptor interacting regions of the AIP protein. AIP mutations in FIPA were associated with multiple pituitary adenoma types, including acromegaly, prolactinomas, mixed growth hormone/prolactin secreting adenomas and non-secreting tumors. It was also found that the same AIP mutation was responsible for different pituitary adenoma types in two separate FIPA families. A detailed follow-up study of an individual FIPA kindred with an AIP mutation found for the first time that non-pituitary tumor-associated endocrine abnormalities (elevated circulating insulin-like growth factor-1) occur in AIP mutation carriers. A detailed analysis of germline and somatic DNA from a large international European cohort of sporadic (non-familial) pituitary adenoma cases showed that AIP mutations occur rarely in this setting. In conclusion, the work undertaken has provided new understanding of the true prevalence of clinically-relevant pituitary adenomas in the population, in addition to codifying and characterizing FIPA, a new clinical entity that represents a potentially valuable area for genetic and clinical studies involving the function of AIP and other as yet unidentified associated genetic causes.

Thesis (Ph. D.)--University of Massachusetts Amherst, 2009. / Open access. Includes bibliographical references (p. 89-87). Print copy also available.

This dissertation describes the work done on two distinct projects. In the first part I sought to unravel the mechanisms that underlie the activity-dependent modulation of response in the excitation-secretion coupling of the neurohypophysis. In the second part, I optically monitored and analyzed the secondary structure changes accompanying amyloid fibril formation along multiple pathways, under both denaturing and near-physiological conditions. Neuronal plasticity plays an important role in regulating various biological systems by modulating release of hormones or neurotransmitters. The changing response to the same stimulus, depending on the context and previous stimulation events, is also the basis of learning and all higher order brain functions. The mechanisms behind this modulation are widely varied, and are often poorly understood in specific tissues. In this work, we examined excitation-secretion coupling in the neurohypophysis, a tissue composed of densely packed axons that secretes the hormones arginine vasopressin and oxytocin. The release of hormones depends not only on the overall level of activity in the gland, but also upon the specifics of the temporal pattern of stimulation. By optically monitoring the electrical activity using voltage sensitive dyes, we were able to investigate this plasticity in the intact gland. Varying extracellular potassium concentration in the bath, increasing interstitial space via hypertonic saline, and retarding potassium reuptake with ouabain all showed that extracellular potassium accumulation drives the depression of excitability. This effect is hidden from glass micro-electrode recordings because of the inevitable damage sustained by the surrounding tissue. Furthermore, no calcium mediated release mechanism played any significant role in the depression. Numerical simulations confirmed the findings and give more insight to the details of the mechanism. Deposits of amyloid fibrils, long, unbranched polymeric protein aggregates, are the molecular hallmark for a variety of human diseases, including Alzheimer's disease, Parkinson's disease, and type II diabetes. While the amyloid fibrils all share a characteristic cross-beta sheet structure, the proteins that make up the aggregates have no unifying theme in either native structure or function. In this research, I characterized the structural reordering that accompanies this aggregation using Fourier transform infrared spectroscopy (FTIR). Hen egg white lysozyme forms fibrillar aggregates with two distinct morphologies, depending on the growth conditions. At acidic pH with low ionic concentrations, lysozyme forms the fibrils with standard amyloid morphology. These aggregates are long and stiff but with the cross sectional area of a single monomer. At higher salt concentrations, the aggregation follows another pathway, under which oligomers initially form and later assemble into protofibrils. The oligomeric protofibrils are thicker than the monomeric filaments, but are much more curvilinear. These fibrils are not universally recognized as amyloidogenic aggregates. Using FTIR, I showed that both this aggregates are indeed amyloid structures, but that they are structurally distinct. While it is generally accepted that partial unfolding of the protein is a prerequisite for amyloid fibril formation, we found that native protein can be the substrate for amyloid growth when seeded with preformed oligomeric or protofibrillar aggregates. These seeded fibrils grown under near-physiological conditions are structurally indistinguishable from those grown from partially unfolded protein under denaturing conditions. This incorporation and restructuring of native monomers is characteristic of prion-like assembly.

published_or_final_version / Zoology / Master / Master of Philosophy

published_or_final_version / Physiology / Master / Master of Philosophy

published_or_final_version / Physiology / Master / Master of Philosophy

An experiment was conducted with Brangus cows to evaluate the effect of loss of body weight and condition on pituitary responsiveness to gonadotropin releasing hormone (GnRH) stimulation during late lactation. The treatment groups were lactating intact (LI), lactating ovariectomized (LO), nonlactating intact (NLI), and nonlactating ovariectomized (NLO). The study was carried out in two separate blocks, each one consisting of 3 periods. During period 1 the cows were fed a ration that supplied 90% and 88% of the NRC recommendations for TDN in lactating and nonlactating cows, respectively. This period lasted 170 in block 1 and 130 days in block 2. During period 2 the TDN was reduced to 55% or 52% for lactating and nonlactating cows, respectively. Period 2 lasted 100 days for cows in block 1 and 63 days for cows in block 2. At the beginning of period 3 TDN was further reduced to 25% or 27% for the lactating and nonlactating cows, respectively. Cows in block 1 were challenged with GnRH 40 days after the beginning of the 1st energy reduction, 30 days later and 7 days after the 2nd energy reduction. The cows in block 2 were challenged with GnRH 30 days after the 1st energy reduction, 30 days later and 25 days after the 2nd energy reduction. At the end of the study body composition parameters and organ gland weights were determined. No significant differences in the weights of the cows among the treatment groups were found. All cows were, however, losing weight through the course of this study. The nonlactating cows maintained higher body condition (P < .05) than lactating cows from 31 days after ovariectomies were performed until the end of the study. The pituitary glands were significantly heavier in the lactating ovariectomized (2.3 g vs. 1.7 g, P < .05) than the nonlactating intact cows. The weight of the adrenals per unit of body weight of LO cows was significantly higher (.057 g/kg vs. .040 g, P < .05) than among NLO cows. The percent of carcass lipid was significantly higher (P < .05) in nonlactating as compared to lactating cows. Percent moisture and protein were higher (P < .05) in lactating cows. Amount of LH released after GnRH stimulation tended to be higher in lactating than nonlactating cows. The magnitude of the LH peak did not differ significantly among the treatment groups at each of the dates GnRN was injected. Ovariectomized cows (LO and NLO) responded more rapidly (P < .05) to GnRH stimulation than intact cows (LI and NLI). Time on reduced TDN did not affect cow's response pattern after GnRH injection.

No description available.

No description available.