Master of Science / Department of Animal Sciences and Industry / Evan C. Titgemeyer / Two experiments analyzed effects of zilpaterol-HCl and nitrogen supplementation in the form of either dried distiller’s grains with solubles (DDGS) or urea fed to steers. In Experiment 1, steers were fed corn-based diets: control (CON; 10.2% CP), urea (UREA; 13.3% CP), or DDGS (14.9% CP). Nitrogen intake differed among treatments (99, 151, and 123 g/d for CON, DDGS, and UREA). Urea-N synthesis tended to be greater for DDGS (118 g/d) than for UREA (86 g/d), which tended to be greater than CON (52 g/d). Urinary urea-N excretion was greater ([italics]P[italics]<0.03) for DDGS (35.1 g/d) and UREA (28.6 g/d) than for CON (12.7 g/d). Gut entry of urea-N (GER) was numerically greatest for DDGS (83 g/d), intermediate for UREA (57 g/d), and least for CON (39 g/d). Urea-N returned to the ornithine cycle tended to be greater for DDGS (47 g/d) than for UREA (27 g/d) or CON (16 g/d). The percent of microbial N flow derived from recycled urea-N tended ([italics]P[italics]=0.10) to be greater for DDGS (35%) than for UREA (22%) or CON (17%). The percent of urea production captured by ruminal bacteria was greater ([italics]P[italics]<0.03) for CON (42%) than for DDGS (25%) or UREA (22%). Experiment 2 diets were identical to those used in Experiment 1. In addition, steers were also fed either 0 or 60 mg/d zilpaterol-HCl. Dietary CP was 9.6, 12.4, and 13.7% for CON, UREA, and DDGS, respectively. Zilpaterol increased ([italics]P[italics]<0.01) total DMI and N intake; however, zilpaterol did not affect urea entry rate ([italics]P[italics]=0.80) or GER ([italics]P[italics]=0.94). Urea entry rate and GER were numerically greater for DDGS than CON and UREA. In conclusion, zilpaterol did not influence urea entry rate or GER. This lack of response in the face of greater N intake was interpreted to suggest that zilpaterol may reduce urea production and GER at constant N intake.

Cannabinoids (CBs) and particularly CB2 agonists have been shown to reduce pain andinflammation without eliciting any apparent psychotropic effect conversely to CB1agonist compounds. CBs candidates are usually lipophilic non drug-like compoundswith poor bioavailability. To serve the purpose of evaluating new synthetic CB2 agonistsdeveloped by our group, on in vivo neuropathic pain models, an enabling formulationstrategy has been set up and four Drug Delivery Systems (DDS) developed. Forparenteral administration, cyclodextrin (CD)-based inclusion complexes, liposomes andsurfactants/co-solvents micellar solution have been investigated whereas Self-Emulsifying DDS (SEDDS) was selected for oral administration. A pharmacologicalstudy conducted with lead compound MDA7, formulated in CD-based DDS resulted inthe higher antinociceptive activity. A comprehensive study of the inclusion mechanismof MDA7 in the CD supramolecular complexes prepared was carried out. MDA7pharmacokinetic profile was also generated formulated in micellar solution and SEDDS.Besides, cationic polymeric nanocapsules (NCs) have been designed to serve as aprotective DDS for oral administration of a dietary phytocannabinoid CB2 agonist.Studies were undertaken to characterize and evaluate the influence of differentparameters on NCs formation prepared by nanoprecipitation. The cationic NCsdeveloped have been explored for their property to yield proportion of counterioniccondensation in the presence of macrocycles bearing anionic groups such assulfobutylether-beta-cyclodextrin or to form electrostatic interactions/host-guestcomplexion with cucurbit[n]uril.

L’asthme est l’une des maladies chroniques les plus fréquentes durant la grossesse, affectant environ 4% à 12% des femmes enceintes et ayant une prévalence qui a augmenté au cours des dernières décennies. Plusieurs études ont identifié l'asthme comme un facteur de risque pour plusieurs enjeux de santé défavorables chez le fœtus et la mère. Les lignes directrices de traitement recommandent l’utilisation de médicaments antiasthmatiques pendant la grossesse afin de contrôler l’asthme et d’éviter les problèmes de santé maternels et fœtaux. L’évaluation de la littérature sur l'utilisation maternelle de médicaments antiasthmatiques et le risque de malformations congénitales majeures a relevé plusieurs études sur l’innocuité des bêta2-agonistes inhalés à courte durée d’action (BACA) et des corticostéroïdes inhalés (CSI) pendant la grossesse, mais peu de données sur les bêta2-agonistes à longue durée d’action (BALA) ainsi que sur les thérapies combinées (BALA-CSI). Un programme de recherche en trois volets a été développé pour combler ces lacunes. Dans le premier volet, nous avons entrepris une revue systématique de la littérature sur l'impact de l'utilisation de BACA et de BALA pendant la grossesse sur le risque de différents problèmes périnataux. Vingt et une études originales ont été identifiées. Quatre études ont rapporté une augmentation significative du risque de malformations congénitales avec BACA, une étude a rapporté une augmentation significative du risque de malformations congénitales avec BALA et quatre études ont rapporté un risque significatif accru de malformations congénitales avec bêta2-agonistes (BACA et/ou BALA). Toutefois, aucun risque majeur n’a été trouvé pour les autres complications périnatales. Fait important, la plupart des études récupérées ont subi plusieurs limitations méthodologiques, y compris l'utilisation des femmes non-asthmatiques comme groupe de référence et la faible puissance statistique. De plus, les résultats qui en découlent doivent être interprétés avec prudence. Dans le deuxième volet, nous avons utilisé la base de données Québec Asthma and Pregnancy Database qui comprend toutes les grossesses de femmes asthmatiques et un échantillon aléatoire de femmes non-asthmatiques ayant accouchées entre 1990 et 2010 pour effectuer deux études. La première était une étude comparant la prévalence des malformations congénitales majeures entre les femmes enceintes asthmatiques traitées avec une combinaison de BALA-CSI et celles traitées avec une dose plus élevée de CSI en monothérapie. Dans une sous-cohorte, il y’avait 643 femmes qui utilisaient un BALA plus CSI à dose faible et 305 qui ont utilisé une dose moyenne de CSI ; l'autre sous-cohorte comprenait 198 utilisatrices de BALA plus CSI à dose moyenne et 156 utilisatrices de CSI à dose élevée. La prévalence de malformations majeures a été 6,9% et 7,2%, respectivement. Le risque de malformations congénitales majeures était similaire entre ces deux groupes de femmes avec un odds ratio ajusté (OR) de 1,1 (IC 95%: 0,6-1,9) pour les femmes souffrant d’asthme modéré et un OR ajusté de 1,2 (IC 95%: 0,5-2,7) pour les femmes souffrant d’asthme sévère. La seconde était une étude méthodologique visant à étudier l’impact de six différentes définitions opérationnelles de malformations congénitales qui varient selon la source des données et la méthode de classification sur l’estimation de la prévalence des malformations et de l'association entre l'asthme maternel et les malformations majeures. Sur 467,946 grossesses, 12,3% étaient de femmes enceintes souffrant d’asthme actif. Nous avons démontré que la source des données et la méthode de classification ont eu un impact considérable sur la prévalence des malformations congénitales majeures (augmentation entre 10,0% et 50,4%), alors qu’elles ont eu peu d’influence sur l’association entre l’asthme maternel et les malformations congénitales. Dans le troisième volet du programme de recherche, nous avons développé une procédure systématique pour la classification des médicaments utilisés au cours du premier trimestre de grossesse en agents tératogènes et potentiellement tératogènes dans un contexte de recherche. Nous avons développé une procédure systématique qui s’actualise facilement, avec des composantes objectives dans la plupart de ses processus. Nous avons établi une liste comprenant 91 médicaments tératogènes, et une autre liste comprenant 81 médicaments potentiellement tératogènes. Les résultats présentés dans cette thèse ont fourni des données importantes sur l’innocuité des traitements de l'asthme pendant la grossesse, aidant les cliniciens et les femmes enceintes à choisir un traitement pharmacologique sécuritaire pour maintenir l’asthme sous contrôle. De plus, les données présentées dans cette thèse sur la minimisation du biais d'indication, les définitions opérationnelles de malformations congénitales et l’identification des médicaments tératogènes pourront aisément être utilisées par les chercheurs en pharmacoépidémiologie, en tératologie et en épidémiologie périnatale. / Asthma is one of the most prevalent chronic diseases during pregnancy, affecting about 4% to 12% of pregnant women and shows an increasing prevalence over time. In the past decades, several studies have identified asthma as a risk factor for several poor fetal and maternal outcomes. A consensus exists on favoring the use of asthma medications during pregnancy to maintain asthma under control to prevent adverse maternal and fetal outcomes. An assessment of the published literature on maternal asthma medications and the risk of major congenital malformations revealed more data on the safety of short-acting beta2-agonists (SABA) and inhaled corticosteroids (ICS) during pregnancy compared to long-acting beta2-agonists (LABA), as well as a paucity of data on the fetal safety of combination therapies (e.g. LABA-ICS). A three-part research program was developed to fill this knowledge gap and answer other intriguing questions we faced, adding necessary evidence in this field. In the first part, we summarized the published evidence on the impact of maternal use of SABA and LABA during pregnancy and different perinatal outcomes in a comprehensive systematic review. Twenty-one original studies were identified. Four studies reported a significant increased risk of congenital malformations with SABA, one study reported a significant increased risk of congenital malformations with LABA and four studies reported a significant increased risk of congenital malformations with beta2-agonists (SABA and/or LABA). However, no major increased risk was found for the other perinatal outcomes. Importantly, most of the retrieved studies suffered several methodologic limitations, including using non-asthmatic women as the reference group and low statistical power. Moreover, the non-significant results reported should be interpreted with caution. In the second part, we used the Quebec Asthma and Pregnancy Database – which includes all pregnancies in asthmatic women and a random sample in nonasthmatic women between 1990 and 2010 – to conduct two studies. The first was a comparative safety study examining the prevalence of major congenital malformations in pregnant asthmatic women treated with a combination of LABA-ICS compared to those treated with a higher dose of ICS monotherapy. In one subcohort there were 643 women who used a LABA plus low-dose ICS and 305 women who used a medium-dose ICS; the other subcohort included 198 users of a LABA plus a medium dose ICS and 156 users of a high-dose ICS. The prevalence of major malformations was 6.9% and 7.2%, respectively. The risk of major malformations did not differ when a combination therapy was used among both moderate and severe asthmatic women (aOR: 1.1; 95% CI: 0.6–1.9 and aOR: 1.2; 95% CI: 0.5–2.7 respectively). The second was a methodological study aiming to compare the prevalence of major malformations using six different case ascertainment definitions that vary by the source of data and the classification method, as well as to evaluate the impact of these definitions on the association between maternal asthma and major malformations. From the 467,946 pregnancies, 12.3% were with active asthma. We demonstrated that the source of data and the classification method had a considerable impact on the prevalence of major malformations (increases between 10.0% and 50.4%), but only a small influence on the measure of association. In the third part of the research program, we aimed at constructing a systematic procedure for the classification of proven and potential teratogenic medications during the first trimester of pregnancy to be used for research. We structured a procedure that is both systematic and updatable, with objective components in most of its processes. We identified a substantial list of teratogenic medications, including 91 medications, and an extensive list of potentially teratogenic medications, including 81 medications. The results presented in the current thesis provided essential evidence on the safety of asthma treatments during pregnancy, helping clinicians and mothers to choose the optimal therapeutic regimen to keep asthma under control. The added knowledge on indication bias minimization, congenital malformations ascertainment and teratogenic medications are directly transferable to researchers in pharmacoepidemiology, teratology and other related research fields.

<p>Uvod: Pu&scaron;enje predstavlja jedan od najznačajnijih uzroka lo&scaron;e kontrole astme, zbog iritativnog dejstva duvanskog dima na disajne puteve i razvoja rezistencije na inhalatorne kortikosteroide. Stoga je pu&scaron;ače sa astmom često potrebno lečiti kombinovanom antiinflamatornom terapijom, iako je efikasnost ovakvog tretmana jo&scaron; uvek nedovoljno ispitana. Cilj: utvrditi efikasnost kombinovane antiinflamatorne terapije: inhalatorni kortikosteroidi (ICS) u kombinaciji sa dugodelujućim beta2-adrenergičkim agonistima (DDBA) u odnosu na ICS u kombinaciji sa antagonistima leukotrijenskih receptora (ALTR) u postizanju dobre kontrole astme, pobolj&scaron;anju kvaliteta života i plućne funkcije kod pu&scaron;ača u odnosu na nepu&scaron;ače sa astmom. Metod: Pacijenti starosti od 18-50 godina sa astmom (&ge;6meseci), FEV1 većim od 60%, podeljeni su u grupu nepu&scaron;ača &ndash;NP (N=60) i aktivnih pu&scaron;ača &ndash;PU (&le;2 &ge;15 p/g i &ge;10&le;40 cigareta na dan; N=60). Obe grupe su randomizovane u jednu od dve, otvorene, terapijske grupe (ICS uz dodatak DDBA ili ALTR) u trajanju od 24 nedelje. Rezultati: u svakoj od 4 randomizovane grupe (NP-DDBA, NP-ALTR, PU-DDBA, PU-ALTR) je bilo po 30 pacijenata. Tokom 24 nedelje, PU su imali lo&scaron;ije kontrolisanu astmu od NP (p=0,02), bez ralizke između DDBA vs ALTR (0,677 vs 0,634). Konstantno dobru kontrolu astme (ACQ&lt;0,75) tokom 24 nedelje je postiglo 48% NP i 32% PU (p=0,094), bez značajne razlike u odnosu na terapiju (DDBA vs ALTR; p=1,000). NP su imali bolji kvalitet života od PU, ali razlika nije dostigla statističku značajnost (p=0,056)- Kod NP i kod PU u oba modaliteta lečenja (LABA, ALTR) je do&scaron;lo do statistički značajne promene srednjeg skora AQLQ (p&lt;0,001). Povećanje FEV1(%) je bilo statistički značajno i u grupi NP i u grupi PU (p=0,001 vs. p=0,002). Kod pacijenata lečenih DDBA povećenje FEV(%) je bilo na nivou p=0,001, dok je u grupu ALTR bilo na nivou p=0,005. Multivarijantnom analizom je utvrđeno da su nezavisni faktori postizanja dobre kontrole astme BMI&ge;24, nepu&scaron;ač, FEV1&ge;90%, ACQ&le;2,2 i AQLQ&ge;4,2 Zaključak: Kombinovana antiinflamatorna terapija je efikasnija kod NP u odnosu na PU, dok su u populaciji aktivnih pu&scaron;ača, oba dodatna leka (DDBA, ALTR) bila podjednako efikasna u pobolj&scaron;anju kontrole astme, kvaliteta života i plućne funkcije.</p> / <p>Introduction: Smoking is one of the major causes of a bad asthma control, due to negative effects of the tobacco smoke on the airways and consequent resistance to inhalant corticosteroids. Smoking asthmatics should therefore often be treated with combined anti-inflammatory therapy, although the efficacy of this treatment regimen has not been completely examined yet. Objective: To examine the efficacy of the combined anti-inflammatory therapy (ICS combined to LABA vs.LTRA) in achieving a good asthma control, better quality of life and improved lung function in smoking vs. nonsmoking asthmatics. Method: The patients at 18-50 years of age with asthma (&ge;6 months), FEV1 &gt; 60%, were subclassified into the group of nonsmokers &ndash;NS (N=60), and the group of active smokers - SM (&le;2 &ge;15 p/g and &ge;10&le;40 cigarettes a day; N=60). Both groups were randomized into one of the two open therapy groups (ICS combined to DDBA or ALTR), receiving the selected treatment for 24 weeks. Results: Any of the four randomized groups (NS-LABA, NS-LTRA, SM-LABA, SM-LTRA) consisted of 30 patients. During the 24-week period, SM had a worse control of their asthma than NS (p=0.02), but no difference was registered between DDBA vs. ALTR therapy subgroups (0.677 vs. 0.634). Over the 24-week period, a constantly good asthma control (ACQ&le;0,75) was achieved by 48% of NS and 32% of SM (p=0.094), and no significant difference related to the applied therapy regimen (LABA vs. LTRA; p=1.000). NS had a better life quality than SM, but this difference remained statistically insignificant (p=0.056). Both the NS and the SM group in either treatment modality (LABA, ALTR) had a statistically significant change of the AQLQ score (p&lt;0.001). FEV1 (%) improvement was statistically significant t in both the NS and the SM group (p=0.001 vs. p=0.002). The LABA and LTRA treated patients had their FEV (%) improvement at the level of p=0.001, and p=0.005 respectively. The multivariate analysis has established the following independent factors of a good asthma control: BMI&ge;24, nonsmoker, FEV1&ge;90%, ACQ&le;2.2, and AQLQ&ge;4.2. Conclusion: The combined anti-inflammatory therapy is more efficient in NS than in SM asthmatics, while in the population of active smokers, both additional drugs (LABA, LTRA) were equally efficient in improving asthma control, life quality, and lung function.</p>

Selon les lignes directrices de traitement de l'asthme pendant la grossesse, les beta2-agonistes inhalés à courte durée d’action (SABA) sont les médicaments de choix pour tous les types d’asthme [intermittent, persistant, léger, modéré et sévère] comme médicaments de secours rapide et dans la gestion des exacerbations aiguës. D’autre part, les beta2-agonistes inhalés à longue durée d’action (LABA) sont utilisés pour les patients atteints d'asthme persistant, modéré à sévère, qui ne sont pas entièrement contrôlés par des corticostéroïdes inhalés seuls. Malgré que plusieurs études aient examinées l’association entre les LABA, les SABA et les malformations congénitales chez les nouveau-nés, les risques réels restent controversés en raison de résultats contradictoires et des difficultés inhérentes à la réalisation d'études épidémiologiques chez les femmes enceintes. L'objectif de cette étude était d'évaluer l'association entre l'exposition maternelle aux SABA et LABA pendant le premier trimestre de grossesse et le risque de malformations congénitales chez les nouveau-nés de femmes asthmatiques. Une cohorte de grossesses de femmes asthmatiques ayant accouchées entre le 1er janvier 1990 et le 31 décembre 2002 a été formée en croisant trois banques de données administratives de la province de Québec (Canada). Les issues principales de cette étude étaient les malformations congénitales majeures de touts types. Comme issues secondaires, nous avons considéré des malformations congénitales spécifiques. L'exposition principale était la prise de SABA et/ou de LABA au cours du premier trimestre de grossesse. L'exposition secondaire étudiée était le nombre moyen de doses de SABA par semaine au cours du premier trimestre. L'association entre les malformations congénitales et la prise de SABA et de LABA a été évaluée en utilisant des modèles d’équations généralisées (GEE) en ajustant pour plusieurs variables confondantes reliées à la grossesse, l’asthme de la mère et la santé de la mère et du foetus. Dans la cohorte formée de 13 117 grossesses de femmes asthmatiques, nous avons identifié 1 242 enfants avec une malformation congénitale (9,5%), dont 762 avaient une malformation majeure (5,8%). Cinquante-cinq pour cent des femmes ont utilisé des SABA et 1,3% ont utilisé des LABA pendant le premier trimestre. Les rapports de cotes ajustées (IC à 95%) pour une malformation congénitale associée à l'utilisation des SABA et des LABA étaient de 1,0 (0,9-1,2) et 1,3 (0,9-2,1), respectivement. Les résultats correspondants étaient de 0,9 (0,8-1,1) et 1,3 (0,8-2,4) pour les malformations majeures. Concernant le nombre moyen de doses de SABA par semaine, les rapports de cotes ajustées (IC à 95%) pour une malformation congénitale était de 1.1 (1.0-1.3), 1.1 (0.9-1.3), et 0.9 (0.7-1.1) pour les doses >0-3, >3-10, and >10 respectivement. Les résultats correspondants étaient de 1.0 (0.8-1.2), 0.8 (0.7-1.1), et 0.7 (0.5-1.0) pour les malformations majeures. D'autre part, des rapports de cotes (IC à 95%) statistiquement significatifs ont été observés pour les malformations cardiaques (2.4 (1.1-5.1)), les malformations d'organes génitaux (6.8 (2.6-18.1)), et d'autres malformations congénitales (3.4 (1.4 à 8.5)), en association avec les LABA pris pendant le premier trimestre. Notre étude procure des données rassurantes pour l’utilisation des SABA pendant la grossesse, ce qui est en accord avec les lignes directrices de traitement de l’asthme. Toutefois, d'autres études sont nécessaires avant de pouvoir se prononcer sur l’innocuité des LABA pendant la grossesse. / According to asthma management guidelines during pregnancy, short-acting β2-agonists (SABA) are the drug of choice in all types of asthma [intermittent or persistent, mild, moderate and severe] as a quick reliever medication and in the management of acute exacerbations or emergency hospitalizations. On the other hand, long-acting β2-agonists (LABA) are used for patients with moderate and severe persistent asthma not fully controlled with inhaled corticosteroids alone. While many studies examined their associations with congenital malformations in newborns, the actual risks remain controversial due to the discordance between different risk reports and the difficulties in performing epidemiological studies on pregnant women. The objective of this study is to investigate the association between maternal exposure to SABA and LABA during the first trimester of pregnancy and the risk of congenital malformations in the newborns among asthmatic women. Through the linkage of three administrative databases from Québec, a cohort of pregnancies from asthmatic women insured by the RAMQ drug insurance plan was formed between January 1, 1990 and December 31, 2002. The primary outcomes were major and any congenital malformations and the secondary outcomes were specific malformations. The primary exposure was the separate exposure to SABA and LABA during the first trimester, while the secondary exposure was the average number of doses of SABA per week taken during the first trimester. The association between congenital malformations and SABA and LABA exposure was assessed using generalized estimating equation models while adjusting for sociodemographic, asthma, maternal and fetal variables. We identified 1242 infants with a congenital malformation (9.5%), 762 of which had a major malformation (5.8%) within the cohort formed of 13117 pregnancies. Fifty-five percent of the women used SABA during the first trimester, and 1.3% used LABA. The adjusted odds ratio (95% CI) for any malformation associated with the use of SABA and LABA were 1.0 (0.9-1.2) and 1.3 (0.9-2.1), respectively. The corresponding figures were 0.9 (0.8-1.1) and 1.3 (0.8-2.4) for major malformations. Regarding the average number of doses of SABA per week, the adjusted odds ratio (95% CI) for any malformation were 1.1 (1.0-1.3), 1.1 (0.9-1.3), and 0.9 (0.7-1.1) for doses >0-3, >3-10, and >10 respectively. The corresponding figures were 1.0 (0.8-1.2), 0.8 (0.7-1.1), and 0.7 (0.5-1.0) for major malformations. On the other hand, significant increased risks, odds ratio (95% CI), of cardiac malformations 2.4 (1.1-5.1), genital organ malformations 6.8 (2.6-18.1), and other congenital malformations 3.4 (1.4-8.5) were observed with LABA use in the 1st trimester. Our study adds evidence, in concordance with asthma management guidelines, to the safety of SABA during pregnancy. However, more research is needed before we can decide on the safety of LABA during pregnancy.

Ractopamine hydrochloride (RAC) is a &#946;-agonist additive that has been used in many countries as a repartitioning agent, redirecting nutrients in order to increase leanness and decrease lipid deposition in pigs. Countries from the European Union and Asia question their safety, while American countries and Australia allow their controlled use as an additive added to the feed of pigs in the finishing phase. In Brazil, the Ministry of Agriculture, Livestock and Food Supply together with the national production sector, developed a Program called \"SplitSystem\" to ensure a safe product without RAC in order to meet international sanitary requirements. However, co-products used in animal feed may contain RAC, such as meat and bone meal (MBM), one of the main feed ingredients used in many countries which can partially replace soybean meal to lower costs. As the level of RAC in this protein source has not been established an experiment was under taken to examine the impact on pig tissues of increasing amounts of meat and bone meal (MBM) in four dietary groups: 0, 7, 14 and 21% w/w of MBM-containing RAC (53.5 &#181;g kg-1) in the diet. The purpose was to verify if ractopamine residues remain in pig tissues (muscle, liver, kidneys, and lungs) and how much is eliminated through urine. To address these concerns, gilts were fed RAC via MBM daily, from weaning until slaughter. RAC was determined in muscle, liver, kidneys, and lungs with a limit of detection (LOD) = 0.15, 0.5, 0.5 and 1.0 &#181;g kg-1, respectively), and no RAC residues were quantified above the limit of quantification (LOQ) = 0.5, 2.5, 2.5 and 2.5 &#181;g kg-1, respectively). In urine, RAC concentration remained below 1.35 &#181;g L-1. These values are below the maximum residue limits (MRLs) established by legislation. Therefore, MBM (53.5 &#181;g kg-1 of RAC) can be used up to 21% in pig diets, however when considering restrictive markets, it is recommended not to use MBM. / O cloridrato de ractopamina (RAC) é um aditivo &#946;-agonista que tem sido usado em muitos países para redirecionar nutrientes a fim de aumentar a deposição de tecido muscular e diminuição de lipídios em suínos. Países da União Européia e Ásia questionam sua segurança, enquanto os países da América e a Austrália permitem seu uso controlado como um aditivo adicionado à ração na fase de terminação em suínos. No Brasil, o Ministério da Agricultura, em conjunto com o setor produtivo nacional, desenvolveu um programa chamado \"SplitSystem\" para garantir um produto seguro sem RAC, a fim de atender aos requisitos sanitários internacionais. No entanto, os co-produtos utilizados na ração animal podem conter RAC, como farinha de carne e ossos (FCO), um dos principais ingredientes utilizados em muitos países para substituir parcialmente o farelo de soja, a fim de reduzir os custos de produção. Como o nível de RAC nessa fonte de proteína não foi estabelecido, um experimento foi conduzido para examinar o impacto sobre os tecidos suínos que receberam níveis crescentes de FCO, divididos em quatro grupos: 0, 7, 14 e 21% de FCO contendo 53,5 &#181;g kg-1 de RAC, na dieta dos animais. O objetivo foi verificar se resíduos de RAC permanecem nos tecidos suínos (lombo, fígado, rim e pulmão) e o quanto é eliminado através da urina. Para atender a essas preocupações, as leitoas foram alimentadas com RAC via FCO diariamente, desde o desmame até o abate. A RAC foi determinada em lombos, rins, fígados e pulmões com um limite de detecção (LOD) = 0,15; 0,5; 0,5 e 1,0 &#181;g kg-1, respectivamente, e nenhum resíduo de RAC foi quantificado acima do limite de quantificação (LOQ) = 0,5; 2,5; 2,5 e 2,5 &#181;g kg-1, respectivamente. Na urina, a concentração de RAC permaneceu abaixo de 1,35 &#181;g L-1. Estes valores são inferiores aos limites máximos residuais (LMRs) estabelecidos pela legislação. Concluindo que a FCO (53.5 &#181;g kg-1 de RAC) pode ser utilizada com até 21% em rações para suínos, entretanto, ao considerar mercados restritivos, recomenda-se não usar a FCO.

A filamina A (FLNA) é uma proteína de citoesqueleto com diversas funções, dentre as quais estão motilidade celular e ancoragem de receptores de membrana. A alteração de sua expressão foi anteriormente descrita em diversos tipos de neoplasia. Em tumores hipofisários, demonstrou-se que sua expressão se correlacionou à expressão de receptores de dopamina tipo 2 (DRD2) em prolactinomas, e com a sinalização intracelular do receptor de somatostatina tipo 2 (SSTR2) após ativação por agonista, em somatotropinomas. Neste estudo, avalariam-se a expressão da FLNA, DRD2, SSTR2 e SSTR5 em diversos tumores hipofisários: prolactinomas, somatotropinomas, corticotropinomas e adenomas clinicamente não funcionantes (ACNF). Avaliou-se também a correlação entre a expressão da FLNA e resposta aos tratamentos medicamentosos, com agonista dopaminérgico (AD) ou com ligantes do receptor de somatostatina (LRS), e entre FLNA e as características de invasividade e/ou agressividade tumorais. Houve correlação entre a expressão de FLNA e a expressão de DRD2 e, entre FLNA e a resposta ao AD, nos ACNFs. Nos corticotropinomas, houve correlação entre a expressão da FLNA e critérios de invasividade tumoral. Portanto, o papel da FLNA nos tumores hipofisários pode depender do tipo celular implicado. Além disso, o envolvimento da FLNA nos mecanismos de resistência aos medicamentos utilizados nos tumores hipofisários, AD ou LRS, não deve estar relacionado apenas à sua ação na ancoragem e reciclagem dos receptores DRD2 e SSTRs, mas também à sua ação na motilidade celular, propiciando caratecterísticas de invasividade / Filamin A (FLNA) is a cytoskeletal protein with a variety of functions, including cell motility and membrane receptor anchorage. Changes in FLNA expression has already been described in several types of neoplasia. In pituitary tumors, its expression has been shown to correlate with the expression of dopamine type 2 receptors (DRD2) in prolactinomas and with intracellular somatostatin type 2 receptor (SSTR2) signaling after agonist activation in somatotropinomas. The expression of FLNA, DRD2, SSTR2 and SSTR5 in different pituitary tumors: prolactinomas, somatotrophinomas, corticotrophinomas and clinically nonfunctioning adenomas (CNFA) were evaluated. We also correlate FLNA expression to sensibility to drug treatments with dopamin agonists (DA) or somatostatin receptor ligands (SRL), and to tumor invasiveness and/or aggressiveness. Positive correlation between FLNA expression and DRD2 expression and between FLNA and DA response were found in CNFA. In corticotrophinomas, there was correlation between FLNA expression and tumor invasiveness. Therefore, the role of FLNA in pituitary tumors seems to depend on the cell type involved. Additionally, FLNA involvement in the mechanisms of drug (DA or SRL) resistance in pituitary tumors could not be related only to its action in the anchoring and recycling of DRD2 and SSTR receptors, but also to its action on cellular motility and invasiveness

Fan, Rongrong. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 130-150). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Lu, Zengbing. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 206-217). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Wong Hei Lui. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2001. / Includes bibliographical references (leaves 192-226). / Abstracts in English and Chinese. / Publications Based On The Work In This Thesis --- p.i / Abstract --- p.ii / Acknowledgements --- p.vii / Abbreviations --- p.viii / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Normal joint --- p.1 / Chapter 1.11 --- Biology of joint --- p.1 / Chapter 1.12 --- Structure of synovial joint --- p.1 / Chapter 1.13 --- Components of the mature synovial joint --- p.3 / Chapter 1.131 --- Articular cartilage --- p.3 / Chapter 1.1311 --- Water --- p.4 / Chapter 1.1312 --- Cartilage matrix --- p.4 / Chapter 1.1313 --- Chondrocyte --- p.5 / Chapter 1.132 --- Synovium --- p.5 / Chapter 1.1321 --- Synovium vasculature --- p.6 / Chapter 1.1322 --- Synovial blood flow --- p.7 / Chapter 1.133 --- Synovial fluid --- p.8 / Chapter 1.134 --- Bone --- p.9 / Chapter 1.2 --- Pathological processes of arthritis --- p.11 / Chapter 1.21 --- Activation of immune cells in arthritis --- p.11 / Chapter 1.22 --- Synovial proliferation --- p.13 / Chapter 1.221 --- Synovial lining cell activation --- p.13 / Chapter 1.222 --- Pannus invasion --- p.14 / Chapter 1.23 --- Cartilage and bone degradation --- p.14 / Chapter 1.231 --- Depletion of proteoglycan (GAG) --- p.15 / Chapter 1.232 --- Collagen denature --- p.15 / Chapter 1.3 --- Tachykinins (TKs) --- p.17 / Chapter 1.31 --- History --- p.17 / Chapter 1.32 --- "Synthesis, storage and release of TKs" --- p.17 / Chapter 1.33 --- Tachykinin receptors --- p.18 / Chapter 1.331 --- Characterization of NK1 receptor --- p.19 / Chapter 1.332 --- Characterization of NK2 receptor --- p.19 / Chapter 1.333 --- Characterization of NK3 receptor --- p.20 / Chapter 1.34 --- Effector systems of TKs --- p.21 / Chapter 1.35 --- Termination of TK signals --- p.21 / Chapter 1.351 --- Enzymatic breakdown --- p.21 / Chapter 1.352 --- Receptor desensitization --- p.22 / Chapter 1.353 --- Receptor endocytosis --- p.22 / Chapter 1.36 --- TK receptor antagonists --- p.23 / Chapter 1.361 --- Selective NK1 receptor antagonists --- p.23 / Chapter 1.362 --- Selective NK2 receptor antagonists --- p.24 / Chapter 1.363 --- Selective NK3 receptor antagonists --- p.25 / Chapter 1.4 --- Roles of tachykinins in arthritis --- p.28 / Chapter 1.41 --- Correlation between tachykinins and joint inflammation --- p.28 / Chapter 1.42 --- Roles of tachykinins in immune cell activation --- p.30 / Chapter 1.43 --- Roles of tachykinins in synovial proliferation --- p.31 / Chapter 1.44 --- Roles of tachykinins in cartilage degradation --- p.32 / Chapter 1.5 --- Animal model of arthritis --- p.33 / Chapter 1.51 --- Instability model --- p.33 / Chapter 1.52 --- Immobilization model --- p.34 / Chapter 1.53 --- Noxious agent-induced model --- p.34 / Chapter 1.531 --- Collagen-induced erosive arthritis --- p.34 / Chapter 1.532 --- Cartilage oligometric matrix protein-induced arthritis --- p.35 / Chapter 1.533 --- Oil-induced arthritis --- p.35 / Chapter 1.534 --- Streptococcal cell wall-induced arthritis --- p.35 / Chapter 1.535 --- Adjuvant-induced arthritis --- p.36 / Chapter 1.536 --- Pristane-induced arthritis --- p.36 / Chapter 1.6 --- Current anti-arthritic therapies --- p.39 / Chapter 1.61 --- Non steroid anti-inflammatory drugs --- p.39 / Chapter 1.62 --- Glucocorticoid --- p.44 / Chapter 1.63 --- Second-line treatment --- p.46 / Chapter 1.631 --- Sulfasalazine --- p.46 / Chapter 1.632 --- Gold salts --- p.47 / Chapter 1 633 --- D-penicillamine --- p.48 / Chapter 1.634 --- Antimalarial --- p.49 / Chapter 1 .635 --- Methotrexate --- p.51 / Chapter 1.64 --- New trends for treatment of arthritis --- p.53 / Chapter 1.641 --- Anti-cytokine therapy --- p.53 / Chapter 1.642 --- Anti-angiogenesis therapy --- p.54 / Chapter 1.7 --- Aims of study --- p.57 / Chapter Chapter 2 --- Material and drugs --- p.62 / Chapter Chapter 3 --- Methodology --- p.62 / Chapter 3.1 --- Animals used and anaesthetization --- p.62 / Chapter 3.2 --- Measurement of plasma protein extravasation --- p.63 / Chapter 3.3 --- Measurement of knee joint sizes --- p.64 / Chapter 3.4 --- Measurement of knee joint blood flow --- p.65 / Chapter 3.5 --- Measurement of histological changes --- p.65 / Chapter 3.51 --- Dissection and fixation --- p.65 / Chapter 3.52 --- Decalcification --- p.66 / Chapter 3.53 --- Processing --- p.66 / Chapter 3.54 --- Embedding --- p.67 / Chapter 3.55 --- Sectioning --- p.67 / Chapter 3.56 --- Staining --- p.69 / Chapter 3.6 --- Data analysis --- p.69 / Chapter 3.61 --- Scoring systems --- p.72 / Chapter Chapter 4 --- A model of monoarthritis in rats --- p.72 / Chapter 4.1 --- Introduction --- p.72 / Chapter 4.2 --- Method --- p.73 / Chapter 4.3 --- Results --- p.73 / Chapter 4.31 --- Lewis rats --- p.73 / Chapter 4.32 --- Sprague-Dawley (SD) rats --- p.74 / Chapter 4.33 --- Comparison of FCA-induced changes in Lewis and SD rats --- p.74 / Chapter 4.34 --- Histological studies on arthritic SD rats --- p.75 / Chapter 4.4 --- Discussion --- p.93 / Chapter 4.5 --- Conclusions --- p.95 / Chapter Chapter 5 --- Effect of Substance P on adjuvant-induced arthritis --- p.96 / Chapter 5.1 --- Introduction --- p.96 / Chapter 5.2 --- Method --- p.98 / Chapter 5.3 --- Results --- p.99 / Chapter 5.31 --- Evans blue extravasation --- p.99 / Chapter 5.32 --- Joint size --- p.100 / Chapter 5.33 --- Knee joint blood flow --- p.101 / Chapter 5.34 --- Histology results --- p.102 / Chapter 5.341 --- Infiltration of immune cells in synovial tissue --- p.102 / Chapter 5.342 --- Synovial tissue proliferation --- p.102 / Chapter 5.343 --- Cartilage degradation --- p.103 / Chapter 5.344 --- Bone degradation --- p.103 / Chapter 5.4 --- Discussion --- p.120 / Chapter 5.5 --- Conclusions --- p.125 / Chapter Chapter 6 --- Effects of tachykinin receptor antagonists on FCA-induced arthritis / Chapter 6.1 --- Introduction --- p.126 / Chapter 6.2 --- Method --- p.128 / Chapter 6. 21 --- Intravenous NK1 receptor antagonists on FCA-induced arthritis --- p.128 / Chapter 6. 22 --- Intraperitoneal TK receptor antagonists on FCA-induced arthritis --- p.128 / Chapter 6.3 --- Results --- p.129 / Chapter 6.31 --- Intravenous NK1 227}0اreceptor antagonists on FCA-induced arthritis Evans blue extravasation and joint swelling --- p.129 / Chapter 6.32 --- Intraperitoneal tachykinin receptor antagonists on FCA- induced arthritis Evans blue extravasation and joint swelling --- p.129 / Chapter 6.33 --- Intraperitoneal tachykinin receptor antagonists on FCA- induced immune cell accumulation --- p.130 / Chapter 6.34 --- Intraperitoneal tachykinin receptor antagonists on FCA- induced synovial tissue proliferation --- p.131 / Chapter 6.35 --- Intraperitoneal tachykinin receptor antagonists on FCA- induced cartilage degration and bone erosion --- p.131 / Chapter 6.4 --- Discussion --- p.159 / Chapter 6.5 --- Conclusions --- p.162 / Chapter Chapter 7 --- Individual and combined effects of dexamethasone and TK receptor antagonists on FCA-induced arthritis --- p.163 / Chapter 7.1 --- Introduction --- p.163 / Chapter 7.2 --- Method --- p.166 / Chapter 7.3 --- Results --- p.167 / Chapter 7.31 --- Evans blue extravasation --- p.167 / Chapter 7.32 --- Knee joint size --- p.167 / Chapter 7.33 --- Body weight --- p.168 / Chapter 7.34 --- Cellular infiltration --- p.168 / Chapter 7.35 --- Synovial tissue proliferation --- p.168 / Chapter 7.36 --- Cartilage degradation --- p.169 / Chapter 7.4 --- Discussion --- p.184 / Chapter 7.5 --- Conclusions --- p.187 / Chapter Chapter 8 --- General discussions and conclusions --- p.188 / References --- p.192