As a first attempt at exploring an association between histaminergic and serotoninergic neuronal phenotypes in glucose regulation, the influence of the histamine H 3 receptor antagonist thioperamide on glucose uptake by brain was determined in rats in which the serotoninergic innervations of brain was largely destroyed perinatally. Male Wistar rats were initially treated on the 3rd day after birth with the serotoninergic neurotoxin 5,7- dihydroxytryptamine (5,7-DHT) (75 μg icv) or saline vehicle (10 μl icv). At 8 weeks lesioned and control rats were terminated in order to validate the effectiveness of 5,7-DHT: reduction in 5-HT and 5-HIAA by 83-91% and 69-83% in striatum, frontal cortex, and hippocampus (HPLC/ED method). Other groups of rats were pretreated with thioperamide (5.0 mg/kg ip) or saline vehicle 60 min prior to 6-[ 3 H]-D-glucose (500 μCi/kg ip). Fifteen-min later rats were decapitated and brains were excised and dissected to remove frontal cortex, striatum, hippocampus, thalamus/hypothalamus, pons, and cerebellum. Liquid scintillation spectroscopy was used to determine that [ 3 H]glucose uptake, which was enhanced in 5,7-DHT lesioned rats in cortex (by 88%), hippocampus, thalamus/hypothalamus, pons and cerebellum (each by 47-56%), and in striatum (by 35%). In contrast, thioperamide prevented the enhancement in [ 3 H]glucose uptake in all brain regions of 5,7-DHT neonatally lesioned rats; and [ 3 H]glucose levels were significantly different in all brain regions (except thalamus/hypothalamus) in thioperamide-versus saline-treated rats. These findings indicate a functional association between histaminergic and serotoninergic systems in brain in relation to glucose regulation.

Oxidative cell death contributes to neuronal cell death in many neurological diseases such as stroke, brain trauma, and Alzheimer's disease. In this study, we explored the involvement of poly(ADP-ribose)-polymerase (PARP) in oxidative stress-induced necroptosis. We showed that PJ34, a potent and specific inhibitor of PARP, can completely inhibit glutamate-induced necroptosis in HT-22 cells. This protective effect was still observed 8 h after glutamate exposure followed by PJ34 treatment. These results suggest that PARP activation plays a critical role in glutamate-induced necroptosis. We also examined the interaction between PARP and a necroptosis inhibitor called necrostatin-1 (Nec-1). Previously, we showed that Nec-1 protects against glutamate-induced oxytosis by inhibiting the translocation of cellular apoptosis-inducing factor (AIF), a downstream target of PARP-1 activation. In this study, Nec-1 reduced PARP activity but had no effect on the expression of PARP-1 in cells treated with glutamate. Nec-1 also did not protect against cell death mediated by the PARP activator N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), although PJ34 did protect against MNNG-mediated cell death. These findings suggest that Nec-1 is not a direct PARP inhibitor and that its signaling target is located upstream of PARP.

This study examines the effects of the selective serotonin reuptake inhibitor (SSRI), fluoxetine (PROZAC), on the ontogeny of spontaneous swimming activity (SSA) in developing zebrafish. The development of zebrafish motor behavior consists of four sequential locomotor patterns that develop over 1-5 days post fertilization (dpf), with the final pattern, SSA, established at 4-5 dpf. In stage specific experiments, larvae were exposed to 4.6 μM fluoxetine for 24 h periods beginning at 24 h post fertilization (hpf) and extending through 5 dpf. From 1-3 dpf, there was no effect on SSA or earlier stages of motor development, i.e., spontaneous coiling, evoked coiling and burst swimming. Fluoxetine exposure at 3 dpf for 24 h resulted in a transient decrease in SSA through 7 dpf with a complete recovery by 8 dpf. Larvae exposed to 4.6 μM fluoxetine for 24 h on 4 or 5 dpf showed a significant decrease in SSA by day 6 with no recovery through 14 dpf. Although SSA was significantly affected 24 h after fluoxetine exposure, there was little or no effect on pectoral fin movement. These results demonstrate both a stage specific and a long term effect of 4.6 μM fluoxetine exposure in 4 and 5 dpf larvae. Reverse transcriptase polymerase chain reaction (RT-PCR) was performed to determine the relative levels of a serotonin transporter protein (SERT) transcript and the serotonin 1A (5-HT1A) receptor transcript in developing embryos/larvae over 1-6 dpf. Both transcripts were present at 24 hpf with the relative concentration of SERT transcript showing no change over the developmental time range. The relative concentration of the 5-HT1A receptor transcript, however, showed a two-tiered pattern of concentration. RT-PCR was also used to detect potential changes in the SERT and 5-HT1A receptor transcripts in 6 dpf larvae after a 24 h exposure to 4.6 μM fluoxetine on 5 dpf. Three separate regions of the CNS were individually analyzed, two defined brain regions and spinal cord. The two brain regions showed no effect on transcript levels subsequent to fluoxetine exposure, however, the spinal cord showed a significant decrease in both transcripts. These results suggest a correlation between decreased concentration of SERT and 5-HT1A receptor transcripts in spinal cord and decreased SSA subsequent to fluoxetine exposure.

Parkinson's disease is a progressive neurodegenerative movement disorder, affecting mainly the elderly. One of the most important hallmarks of Parkinson's disease is the loss of neuronal cell bodies containing neuromelanin in the substantia nigra zona compacta, and subsequently, loss of dopamine terminals in basal ganglia nuclei of the brain. The discovery by Hornykiewicz and co-workers that levodopa could successfully treat Parkinson's disease in humans was one of the most important events of medicine in the 20th century. Since loss of nigrostriatal dopaminergic function is the basic underlying pathophysiology of this disease, drugs that enhance dopaminergic function in the striatum, including the exogenous precursor levodopa, remain the most effective symptomatic agents in the treatment of Parkinson's disease. However, there are some areas of controversy about levodopa-evoked motor complications (dyskinesias, on-off phenomena) as well as neuroprotective or neurotoxic activity of this drug, etc. In this article the authors try to clarify the molecular mechanisms involved in levodopa action, such as volume transmission - a crucial process for successful levodopa therapy, evidence that serotoninergic neurons may accumulate levodopa and convert it into dopamine as well as some aspects of neuroprotective action of levoda.

Institutional factors affecting implementation of policies are a reflection of the larger political context and setting of money in education. This has an impact on implementing accommodations for English Language Learners in standardized testing under No Child Left Behind. To see if this is true, four states: Indiana, New York, Tennessee and Wisconsin were chosen as examples of state policy adoption and their test contracts were collected from a test company. State accommodations for ELL in testing policy and state costs for standardized tests were analyzed in a comparative review. The diversity of methods in accommodation and lack of correlation between state standardized test costs to product illustrates institutional factors affecting NCLB implementation. Therefore it becomes essential for professional development to support states in implementing NCLB within an institutional context. Addressing these factors will lead to greater educational progress in U.S. federal policies.

To explore associations of neostriatal (NST) endogenous levels of dopamine (DA) and serotonin (5-HT) with sensitivity of their receptors, graded doses of 6-hydroxydopamine HBr (0 to 400 μg, ICV; 6-OHDA; desipramine pretreatment, 20 mg/kg IP) were given to rats between birth (P 0) and P 42. Numbers of vacuous chewing movements (VCMs) induced by SKF 38393 or m-chlorophenylpiperazine (m-CPP), respective DA D1 and 5-HT2 agonists, were subsequently determined. Enhanced SKF 38393-induced VCMs occurred when NST DA was reduced 97%-98% by high dose 6-OHDA (100-134 μg) at P 0 or P 3, but not in rats with 95%-97% loss in DA produced by 6-OHDA at P7 (134 μg) or P3 (67 μg). Enhanced m-CPP-induced VCMs occurred even when NST 5-HT content was not elevated after 6-OHDA (134 μg at P 10). Accordingly, D1 and 5-HT receptor sensitivity is not correlated with respective NST DA and 5-HT contents. The stage of ontogeny at the time of DA denervation may be the governing influence on receptor sensitivity.

Carotid body (CB) receptor type I cells transduce blood-borne chemical stimuli into electrical signals and release the excitatory neurotransmitter ATP onto afferent terminals that project to the breathing centre located in the brainstem. Within the CB, type I cells are ensheathed by glial-like processes of type II cells. Recently, it was hypothesized that type II cells have a paracrine function in CB chemotransduction by acting as an ATP amplifier and enhancing chemoexcitation (Zhang et al. 2012). Given this recent development, the primary goal of this thesis was to further elucidate the paracrine function of type II cells and characterize the signalling mechanisms involved in type I and type II cell interactions. Ratiometric calcium imaging was used to investigate type II cell sensitivity to two prominent CB neuromodulators, angiotensin II (ANG II) and 5-HT, in rat CB cultures. Both ANG II and 5-HT elicited large rises in intracellular Ca<sup>2+<sup> that were present in the absence of extracellular Ca<sup>2+<sup> and were inhibited by intracellular store depletion agents. ANG II and 5-HT acted on their respective G-protein coupled receptors, AT<sub>1<sub> receptor and 5-HT<sub>2A<sub> receptor, to initiate these Ca<sup>2+<sup> responses presumably via a PLC-IP<sub>3<sub> mediated mechanism. Interestingly, these Ca<sup>2+<sup> responses were required to activate pannexin-1 channels (Panx-1), a channel that has been previously shown to be a conduit for ATP in type II cells (Zhang et al. 2012). We were also interested in determining whether type II cells were capable of indirectly responding to a chemostimulus such that the stimulus would elicit neurosecretion from type I cells and result in a secondary Ca<sup>2+<sup> responses in type II cells. Isohydric hypercapnia and a depolarizing stimulus (30 mM KCl saline) were capable of eliciting indirect Ca<sup>2+<sup> responses in type II cells. These secondary Ca<sup>2+<sup> responses in type II cells were partially inhibited by suramin, a purinergic P2Y2 receptor antagonist, suggesting that ATP was the predominant neurotransmitter responsible for type I to type II crosstalk. Similarly, a selective agonist for type II cells, UTP, evoked indirect Ca<sup>2+<sup> responses in nearby type I cells. Type II to type I cell communication was dependent on Panx-1 channels since the secondary Ca<sup>2+<sup> responses in type I cells were inhibited by the Panx-1 blocker, carbenoxolone (5 µM). UTP-evoked indirect Ca<sup>2+<sup> in type I cells were partially inhibited by adenosine A<sub>2<sub> receptor antagonists suggesting that the neuromodulator, adenosine, governs cross-talk between type II and type I cells. This study elucidates the importance of purinergic signalling in the bi-directional cross-talk between receptor type I cells and glial-like type II cells. / Thesis / Master of Science (MSc)

Cette thèse porte sur l'étude des goûts, odeurs et la perception relative à l'eau potable. Le cas à l'étude est l'eau distribuée dans un réseau d'aqueduc de la Ville de Québec. La thèse est divisée en quatre volets. Le premier volet fait la revue de la problématique des composés responsables des goûts et odeurs en réseau de distribution. Plus spécifiquement, les aspects concernant l'origine de ces composés et leurs analyses physico-chimiques et sensorielles sont abordés. Le second chapitre traite de la perception des consommateurs par rapport à l'eau distribuée. Cette étude a été réalisée au moyen de l'information spatialisée d'une enquête postale et des suivis de la qualité physico-chimique et microbiologique de l'eau réalisés entre 2003 et 2005 par la Ville de Québec. Les résultats de ces suivis ont été agrégés dans un indice de qualité d'eau. Les résultats indiquent qu'environ le tiers de la population ne consomme pas l'eau du robinet du réseau à l'étude. L'analyse par régression logistique des résultats de l'enquête montre que l'emplacement de la résidence dans le réseau, l'indice de qualité de l'eau distribuée et les risques perçus par le consommateur sont les principaux facteurs qui 'expliquent le profil de consommation de l'eau du robinet et le choix de consommer ou non l'eau distribuée. Le troisième volet porte sur la détermination des zones sensibles aux goûts et odeurs dans le réseau de distribution. Ces zones ont été établies au moyen d'une analyse multicritère combinant l'information spatialisée des plaintes des consommateurs relatives à l'eau du robinet entre 2002 et 2004, et de la perception de la population concernant l'eau distribuée. Les résultats de cette analyse ont permis de déterminer six secteurs sensibles aux goûts et odeurs dans l'eau potable répartis en 15 zones distinctes. Le dernier volet s'intéresse à l'évolution spatio-temporelle des goûts et odeurs dans le réseau d'aqueduc. Les résultats montrent que les goûts et odeurs en réseau sont liés à certains précurseurs comme les algues, le chlore et le fer. De plus, la variation saisonnière de l'intensité de la flaveur de l'eau est principalement attribuable à la présence des algues diatomées, des algues vertes et des algues bleu-vert (cyanobactéries), leurs sous-produits (géosmine et 2-méthylisoboméol) et au chlore total résiduel. L'intensité de la flaveur de l'eau varie aussi selon l'emplacement dans le réseau. L ' analyse des données en régression linéaire multiple montre que les goûts et odeurs dans l' eau distribuée sont fortement tributaires des variations saisonnières et spatiales. Ils sont aussi directement liés à la présence de cyanobactéries dans l' eau distribuée et inversement liés à la teneur en chlore dans le réseau. Ce qui démontre l'effet masquant du chlore sur les autres flaveurs dans l' eau potable.

Certains épisodes de contamination, autant chimique que bactériologique, ont été très médiatisés et ont éveillé la population face à l’enjeu de la qualité de l’eau potable qui lui est livrée par ses municipalités. Depuis quelques années, le suivi en continu de la qualité de l’eau a commencé à prendre sa place dans les stratégies de surveillance de la qualité de l’eau dans les réseaux de distribution. Ce portrait de l’utilisation du suivi en continu de la qualité de l’eau potable est basé sur une enquête par questionnaire, distribuée à l’ensemble des municipalités opérant un réseau de distribution d’eau potable (810 municipalités). L’analyse descriptive des données montre que le type de source d’eau et la taille de la population influencent le plus l’utilisation du suivi en continu. L’analyse multivariée fait ressortir l’utilisation de la filtration et de la désinfection comme catalyseurs d’utilisation du suivi en continu. Les répondants ont signifié comme facteurs favorisant l’utilisation du suivi en continu la rapidité d’exécution des équipements et la possibilité de créer un portrait de base de la qualité de l’eau. Comme facteurs limitant l’utilisation du suivi en continu, ils ont cité les coûts élevés des équipements, le trop faible risque de contamination et dans certains cas, l’absence d’une obligation réglementaire d’utiliser la technologie. Tous ces facteurs d’utilisation du suivi en continu sont aussi influencés par la règlementation aux articles 5, 22 et 22.1 du Règlement sur la qualité de l’eau potable du Québec (RQEP). Le portrait a permis d’identifier certaines lacunes du suivi de la qualité de l’eau potable et d’évaluer la conformité aux normes de suivi en continu du RQEP. / Chemical and bacteriological contamination of drinking water has been highly publicized through the media and has raised public awareness of drinking water quality in municipal utilities. Online and real-time monitoring of drinking water quality has grown in popularity in the last few years, carving its place in drinking water quality surveillance. This portrait of the use of online monitoring of drinking water quality is based on a survey conducted in all of Quebec municipalities that operate a drinking water utility (810 municipalities). Descriptive analysis of the data has shown that source type and population size as the main factors influencing the use of online monitoring. Multivariate analysis added the use of filtration and disinfection in the water treatment process as main factors of the use of online monitoring. Respondents mentioned early warning capabilities and water baseline creation possibilities as reasons encouraging the use of online monitoring. High cost, low contamination risk and, in some cases, absence of regulation as reasons discouraging the use of these technologies. All of these factors and reasons are influenced by legislation, specifically articles 5, 22 and 22.1 of Province of Quebec’s Drinking Water Quality Regulation (DWQR). The portrait has identified some problems in drinking water quality monitoring and has made possible an evaluation of online monitoring regulations contained in the DWQR.

Heart valve disease is currently one of the leading forms of heart disease. Current literature has shown that endothelin I, angiotension II and 5-HT are vasoactive agents which cause concentration dependent contractions in aortic valve leaflet tissue. This study tested the mechanical properties of leaflets cut in the radial direction after they were exposed to the agents at varied concentrations or for 0.5, 6 or 24 hours. The elastic modulus, ultimate tensile strength and the yield strength were calculated. In the time trials the elastic modulus and the ultimate tensile strength both showed a significant increase at 24-hours. However, there were no significant differences found between the concentrations. Indicating the amount of vasoactive agent is not as significant as the length of exposure.