Thesis (Ph. D.)--University of Washington, 1999. / Vita. Includes bibliographical references (leaves [118]-129).

Heritable and environmental factors contribute to an individual’s risk of substance abuse and psychosis. Individuals diagnosed with a mental disorder have greater vulnerability for substance abuse. Our laboratory established that neonatal treatment of rats with quinpirole (NQ), a dopamine (DA) D2-like agonist, results in a significant increase of DAD2 receptor sensitivity throughout the animal’s lifetime. An increase of DAD2 receptor sensitivity is relevant to a model of schizophrenia (SZ), although increases of DAD2 receptor activity also occur in a number of clinical disorders, including bipolar disorder, obsessive-compulsive disorder, panic disorder, and major depression. Common amongst these clinical conditions is a dramatic increase in cigarette smoking compared to the general population. We bred NQ-treated male and female rats with their NQ-treated or neonatal saline (NS)-treated counterparts once they reached adulthood to determine whether increases in DAD2 sensitivity were passed to the next generation. Offspring of these animals, regardless of whether one or both founders received NQ-treatment, also demonstrated increases of DAD2 receptor sensitivity both behaviorally and neurobiologically. RNASeq preliminary data revealed an increase in cortisol synthesis and release in F1 generation animals, demonstrating an enhanced response to stress, consistent with a model of drug abuse vulnerability. Consistent with this finding, F1 generation rats demonstrated enhanced nicotine conditioned place preference (CPP) and had an enhanced brain derived neurotrophic factor (BDNF) response to nicotine in the nucleus accumbens (NAcc), a brain area critical to drug reward. The DAD2 receptor forms a triple heteromer with the adenosine A(2A) and metabotropic glutamate type 5 (mGlu5) receptor, such that stimulation of either receptor results in a decrease of DAD2 activity. Therefore, we analyzed whether use of a positive allosteric modulator (PAM) of mGlu5 in the F1 generation would block nicotine CPP and improve sensorimotor gating deficits, which is a hallmark of psychosis. In both experiments, the mGlu5 PAM effectively blocked the enhanced rewarding effects of nicotine and also alleviated sensorimotor gating deficits in this model. In essence, we demonstrate in results reported here that there may be a common therapeutic target for the dual treatment of substance abuse and psychosis.

No description available.

Utilizing ECLS-K:2011 data, this study compares adopted and biological children to account for the role of heritable characteristics in explaining the relationship between family environments and children's cognitive skills. I find that cognitive skills do not differ across adopted and biological children after adjusting for the systematic differences between them. I also find that the relationship between family environment and children's cognitive skills does not differ across adopted and biological children. Taken together, these results suggest that the relationship between family environment and children's cognitive skills is not spurious.

Background: Carotid body tumor (CBT) is a rare lesion of the neuroendocrine system. Chronic hypoxia has long been recognized as an etiology of CBT and other paragangliomas. Recent biogenetic discoveries reveal that mutations in oxygen-sensing genes are another etiology, accounting for approximately 35% of cases, and that these 2 etiologies are probably additive. Data Sources: (1) A retrospective analysis of fifteen cases of CBT in a 6-year period occurring in the mountains of Southern Appalachia; (2) an extensive review of the literature on the surgery of CBT and on the expansive biogenetic understanding of the disease. Conclusions: Improved imaging, vascular surgical techniques, and understanding of the disease have vastly improved outcomes for patients. The necessities for long-term follow-up and appropriate genetic testing and counseling of patients and their families are documented. Surgeon and institutional competence are critical in achieving maximal outcomes.

N,N'-methylenebisacrylamide (MBA) was studied because of its effectiveness in inducing heritable translocations in germ cells of male mice. The health impact of translocations was studied through anatomical analysis of the progeny of semisterile translocation carriers. As expected, the semisterility of translocation carriers resulted primarily from embryonic death during periimplantation stages due to unbalanced chromosome sperm segregants. Among conceptuses that survived to mid- and late-gestation stages, there was an increased incidence of developmental anomalies including fetal death and phenotypic defects. These abnormalities are associated with unbalanced chromosome complements that allow survival to the later stages of development.

Pulmonary arterial hypertension (PAH) can be caused by pathogenic variants in the gene bone morphogenetic protein receptor 2 (BMPR2). While BMPR2 protein expression levels are known to be reduced in the lung tissue of heritable PAH (HPAH) patients, a systematic study evaluating expression in more easily accessible blood samples and its clinical relevance is lacking. Thus, we analyzed the BMPR2 mRNA expression in idiopathic/HPAH patients and healthy controls in blood by quantitative polymerase chain reaction and protein expression by enzyme-linked immunosorbent assay. Clinical parameters included right heart catherization, echocardiography, six-minute walking test and laboratory tests. BMPR2 variant-carriers (n = 23) showed significantly lower BMPR2 mRNA expression in comparison to non-carriers (n = 56) and healthy controls (n = 30; p < 0.0001). No difference in BMPR2 protein expression was detected. Lower BMPR2 mRNA expression correlated significantly with greater systolic pulmonary artery pressure and pulmonary vascular resistance. Higher BMPR2 mRNA expression correlated with greater glomerular filtration rate, cardiac index and six-minute walking distance. We demonstrated the feasibility to assess BMPR2 expression in blood and, for the first time, that BMPR2 mRNA expression levels are significantly reduced in variant carriers and correlated with clinical parameters. Further studies may evaluate the usefulness of BMPR2 mRNA expression in blood as a new marker for disease severity.

La détection précoce de l’athérosclérose, avant le développement de ses séquellespathologiques, comme l’infarctus du myocarde, l’angine ou l’accident cérébrauxvasculaire(ACV), représente un important défi au niveau de la médecine diagnostiqueactuelle. Malgré les récentes avances technologiques, les maladies cardiovasculairesdemeurent la principale cause de décès dans les pays occidentaux et la détection à unstage plus précoce s’avère nécessaire pour permettre une intervention thérapeutiqueadéquate. Notre étude se concentre sur la détection de l’athérosclérose, plusspécifiquement la vulnérabilité de la plaque, grâce à l’imagerie moléculaire combinée àl’observation pathologique. Afin de prédire la rupture de la plaque, l’imageriemoléculaire a émergé comme outil diagnostique puissant suite au développementcroissant de sondes ayant de l’affinité pour les molécules cibles du processusd’athérosclérose. Comme résultantes, ces molécules sélectives possédant une forteaffinité pour des cibles surexprimées durant le processus de formation de la plaque,comme l’αvβ3 par exemple, devrait représentées des sondes prometteuses pour ladétection de l’athérosclérose.Objectif L’objectif global de notre étude était d’évaluer et de prédire lavulnérabilité de la plaque d’athérome à l’aide de différents marqueurs moléculaires. Leprincipal objectif de notre recherche était d’évaluer la possibilité de détecter précocementla plaque en utilisant une ITOP (integrin targeted optical probe). Cette sonde synthétiquenouvellement développée et ciblant l’intégrine αvβ3 avait déjà démontré une affinité etspécificité particulièrement élevée pour le récepteur de l’αvβ3 dans le cancer. Nousavons également exploré la relation entre cette sonde et l’observation pathologique desplaques d’athéromes sur le modèle animale WHHL et sur des plaques humainesprovenant de différents patients.Procédure et Résultats Les expériences ont été réalisées sur un total de 12 lapinsWatanabe hyperlipidémiques de souche WHHL (Watanabe heritable hyperlipidemic) et 1lapin contrôle NZW (New Zealand White). Premièrement, notre ITOP, marquée avec lafluorescéine isothiocyanate (FITC), a été utilisée pour détecter in vitro et ex vivo laprésence du récepteur de l’αvβ3. La microscopie à fluorescence a révélé un importantmarquage de la plaque d’athérome, lequel était absent dans les tissus provenant des lapinscontrôles NZW. Le marquage a été détecté au niveau de segments de plaques provenantde deux régions distinctes de l’aorte ascendante et descendante dans chaque lapin. Lesignal a été détecté principalement au niveau de l’adventitia et de l’intima proximale desvaisseaux aortiques, correspondant directement à l’expression de l’intégrine αvβ3,déterminée par essai immunochimique avec un anticorps contre l’αvβ3. De plus, uneforte association s’est révélée entre le niveau de marquage de la sonde ciblant l’αvβ3 etl’épaisseur de l’adventitia. Deuxièmement, nous avons évalué notre sonde sur deséchantillons humains affectés par l’athérosclérose et comparé les résultats avec uneévaluation morphologique. Nous avons remarqué la même tendance que chez le lapin, soiun marquage plus important lorsque l’adventitia s’épaissi. Finalement, nous avons testé lasonde sur des artères coronaires provenant d’une autopsie d’un patient affecté par le ADHIESet comparé les résultats avec l’évaluation morphologique de leurs artèrescoronaires. Nous avons trouvé un lien entre la morphologie de la plaque et la prévalenced’anévrysmes coronaires chez ces patients.Conclusion L’expression de l’αvβ3 est reliée à la foi aux processus inflammatoires età la sténose. Notre ITOP à marqué efficacement in vitro le premier type de plaqued’athérome classé comme avancé (type IV) et pouvant produire des manifestationscliniques. En combinaison avec l’imagerie noninvasive détectant la sténose, il pourraits’avéré utile dans la détection de la plaque vulnérable. / Purpose The detection of early atherosclerosis, before the development of its later sequelae of myocardial infarction, angina or stroke, constitutes an important challenge in current diagnostic medicine. Despite all the recent technological advances, cardiovascular disease remains the leading cause of death in the Western World and needs to be detected at an earlier stage to allow for more timely therapeutic intervention. This study is focusing on the detection of atherosclerosis or more specifically plaque vulnerability with the help of molecular imaging and pathological observation. Effectively, to predict plaque rupture, molecular imaging has emerged as a powerful diagnostic tool, consequent to the development of a growing number of new probes with affinity for key molecular targets. As a result, such selective molecule with high affinity for overexpressed target in plaque formation, as αvβ3 integrin, should have promise as a probe for imaging atherosclerosis. With the help of molecular imaging combined with pathological observations, we can better comprehend, predict, and detect plaque vulnerability and rupture. Objectives The overall objective of this study is to evaluate different molecular tools to predict the vulnerability of the atheromatous plaque. The major objective of the research was to investigate the possibility of detecting atherosclerotic plaque by using a newly developed synthetic αvβ3 integrin targeted optical probe (ITOP) showing particularly high affinity and specificity for the αvβ3 receptor. We also investigate the relation between this probe and pathological observation of atherosclerotic plaques from WHHL animal model and different human samples. Procedures and Results For this study, experiments were performed on 12 Watanabe heritable hyperlipidemic (WHHL) rabbits and 1 New Zealand White (NZW) rabbits for control. First, our ITOP labeled with fluorescein isothiocyanate was used for detecting the presence of αvβ3 receptors in vitro and ex vivo on a Watanabe rabbit model. Fluorescence microscopy demonstrated a strong labeling of atherosclerotic plaques, which was absent in tissue from normal NZW rabbits. Segments of plaque accumulation from two distinct regions of ascending and descending aortas were labeled in each rabbit. The signal was found principally in the adventitia and proximal intima of the aortic vessel, corresponding directly to the expression of integrin αvβ3 as determined by antibody assay. Moreover, there was a close association between the level of labeling with the αvβ3 targeted probe and the thickness of the adventitia. Secondly, the ITOP was evaluated on human atherosclerotic samples, and was found to efficiently labeled atherosclerotic plaques. Moreover, we observed the same tendency as in the Watanabe rabbit: the ITOP intensity correlated with the degree of adventitial thickening. Finally, we tested the ITOP on Job's Syndrome coronary arteries, and have been able to detect a plaque corresponding to the first type of advanced atherosclerosis (type IV). We also found a relationship between plaque morphology and predisposition to aneurysms in Job's syndrome. Conclusions αvβ3 expression is related to inflammatory and stenotic processes. Our ITOP can efficiently label in vitro the first type of advanced atherosclerotic plaque. In combination with noninvasive imaging techniques that evaluate stenosis, it has great potential for the detection of vulnerable plaque.