Master of Science / Department of Animal Sciences and Industry / James S. Drouillard / Exogenous growth promotants, such as the synthetic beta agonist zilpaterol hydrochloride (ZH), have been shown to increase carcass weight by repartitioning energy toward increased skeletal muscle at the expense of adipose tissue, which is associated with a decline in tenderness. More recently, essential oils such as menthol have been observed to have growth promoting properties in livestock. The objectives of this research were to determine effects of ZH on blood parameters and long chain fatty acids in plasma and adipose tissue, to determine if the decline in tenderness can be negated by temporary depletion of calcium during ZH supplementation, and to determine effects of crystalline menthol on blood parameters. Blood samples were collected in 7-d intervals during ZH administration. Zilpaterol hydrochloride decreased concentrations of plasma urea nitrogen and whole blood glucose (P < 0.10), but had no effects on concentrations of plasma glucose, lactate, beta-hydroxybutyrate, NEFA, or whole blood lactate (P > 0.10). Total long chain fatty acids of plasma and adipose tissue were unaffected (P > 0.10); however, ZH supplementation increased HCW, dressing percentage, and LM area (P < 0.10). Calcium was temporarily depleted during ZH supplementation in an attempt to increase tenderness of meat. No differences (P > 0.10) were observed for Warner-Bratzler shear force values, live animal performance, or carcass measurements. Addition of 0, 0.003, 0.03, 0.3% menthol (diet DM) to diets of steers resulted in a menthol × time within day interaction (P < 0.01) for IGF-1 concentration and BW; however, glucose, lactate, and PUN concentrations were unaffected (P > 0.05). Furthermore, concentrations of VFA were not different (P > 0.05), but production of fermentative gas was decreased (P < 0.01) when menthol was added at 0, 0.003, 0.03, 0.3% of substrate DM in a 24 h in vitro fermentation trial. Results from these studies suggest ZH improved efficiency of nutrient utilization for increased skeletal muscle growth; however, the decline in tenderness was not negated by the temporary depletion of calcium in the diet. Overall, ZH affected components related to increased skeletal muscle growth, but menthol did not affect blood parameters associated with growth.

M. Tech. / This randomised, comparative study was undertaken in order to evaluate whether a menthol-containing gel (Deep Heat® Rub) combined with Chiropractic adjustments on mechanical low back pain, over a three-week period, is more effective than Chiropractic adjustments and aqueous cream only.Thirty participants who conformed to the specified inclusion and exclusion criteria, were accepted to form part of the study. The thirty participants were placed randomly into two groups of fifteen participants each. The Experimental Group received lumbar spine and/or Sacroiliac adjustment(s) over the restricted joint(s) together with the application of Deep Heat® Gel, and the Control Group received lumbar spine and/or Sacroiliac adjustment(s) over the restricted joint(s) together with the application of non-medicated aqueous cream. All participants received a total of six treatments over a three-week period, i.e. two treatments per week. Each participant was requested to come in for a follow-up consultation one day after the last treatment session used for data capturing only. The subjective data was collected by means of the Revised Oswestry Low Back Pain Disability Questionnaire, taken prior to the first, fourth and at the seventh consultations. The objective data, in the form of lumbar range of motion, was obtained by means of a Digital Inclinometer, taken prior to every consultation. Data was statistically analysed by means of the Friedman and Wilcoxon Signed Rank tests for intra-group comparisons and the Mann-Whitney test for inter-group comparisons.The results indicated that the treatment protocols used in the Control and the Experimental Group were equally effective in reducing low back pain and disability as well as increasing the lumbar range of motion. The Control Group did, however, demonstrate statistically significant differences in three out of six ranges of motion, compared to two out of six for the Experimental Group, although no statistically significant differences were found.The results of this study suggest that Chiropractic adjustive therapy (with non-medicated aqueous cream) alone or when administered with Deep Heat® Rub are equally effective in terms of subjective pain perception and objective clinical findings in the treatment of mechanical low back pain. No statistically significant difference could be seen when participants received diversified spinal adjustive therapy and application of aqueous cream, compared to receiving diversified spinal adjustive therapy and application of Deep Heat® Rub.

No description available.

L’environnement climatique est l’un des facteurs pouvant influencer la performance aérobie. Il existe des températures idéales avec lesquelles les athlètes réalisent de meilleures performances : entre 10 et 12°C en course à pied (Maughan et coll. 2010) ou inférieures à 32°C en cyclisme (Peiffer & Abbiss 2011). Davies et coll. (2016) condensent dans une métaanalyse différentes études portant sur le contre la montre (CLM) en cyclisme en environnement chaud et relèvent que la performance est altérée en climat chaud à partir du milieu de l’épreuve (P < 0,02) et jusqu’à la fin (P = 0,01) par rapport à une condition contrôle.Ce résultat laisse donc apparaitre qu’outre la température environnementale, la durée de l’effort peut également être déterminante dans l’impact du climat sur la performance. L’élévation de la température n’est pas le seul facteur environnemental pouvant influencer la performance. Maughan et coll. (2012) mettent en évidence qu’au plus le taux d’humidité est élevé au plus la performance aérobie est détériorée. Dans cette étude, des athlètes non acclimatés, réalisent une épreuve à vélo à 70% de VO2max jusqu’à épuisement lors de quatre sessions à 24, 40, 60 et 80% d’HR (T: 30°C). Les résultats, montrent que le temps d’exercice diminue significativement avec l’augmentation du taux d’humidité (P < 0,05).A travers ce travail de recherche nous avons donc investigué la question : comment faire pour limiter cet impact du climat sur la performance ?Pour ce faire 3 axes sont développés à travers nos études :a. Etudier l’efficacité de protocoles de refroidissement à plusieurs moments de la performance : avant, pendant et entre deux efforts consécutif.b. Déterminer si les combinaisons de froid peuvent se combiner.c. Déterminer si l’utilisation du menthol peut permettre une optimisation des protocoles de cooling.Les principaux résultats de cette thèse mettent en évidence que l’utilisation de méthodes de cooling est efficace mais que cette efficacité dépend du protocole utilisé. Nous avons ainsi mis en évidence (1) Qu’en pré-cooling il est nécessaire de débuter 1h avant l’effort pour avoir une efficacité de la méthode ; (2) Qu’une immersion avec du menthol est plus efficace qu’une immersion seule entre deux efforts de 20’ mais qu’utilisé sur des vêtements son efficacité n’est pas prouvée; (3) Que le port d’un gilet froid cumulé à une ingestion d’une boisson froide à l’échauffement n’est pas plus efficace qu’un refroidissement interne seul (4) Que le menthol peut influencer les performances en jouant un rôle sur le SNC.L’action du menthol va permettre au SNC de percevoir l’environnement comme étant « plus favorable » et par conséquent entrainer une modification de la rétroaction thermorégulatrice, et ainsi permettre une meilleure performance. Cela sans que le menthol ne joue un rôle délétère à la thermorégulation. / The climatic environment is one of the factors that can influence the aerobic performance. There are an ideal temperatures with which athletes realize better performance: between 10 and 12°C in running (Maughan et al. 2010) below 32°C in cycling (Peiffer & Abbiss 2011). Davies et al. (2016) condense in a meta-analysis different studies on time trial (TT) in cycling and note that the performance is impaired in hot weather from middle of the test (P <0.02) and until the end (P = 0.01) compared to a condition control. This result therefore shows that in addition to the environmental temperature, the duration of the effort can also be decisive in the impact of climate on the performance.Rising temperature is not the only environmental factor that can influence the performance. Maughan et al. (2012) highlight that at the highest level of humidity is high at most aerobic performance is deteriorated. In this study, non-athletes acclimatized, perform a 70% VO2max bike test until exhaustion four sessions at 24, 40, 60 and 80% RH (T: 30 ° C). The results show that time exercise decreased significantly with increasing humidity (P <0.05). Through this research work we therefore investigated the question: how to do to limit this impact of climate on performance?To do this, 3 axes are developed through our studies: a. Study the effectiveness of cooling protocols at several points in the performance: before, during and between two consecutive efforts.b. Determine if cold combinations can combine.c. To determine if the use of menthol can allow optimization of the protocols of cooling.The main results of this thesis highlight that the use of cooling is effective but this efficiency depends on the protocol used. We havehighlighted (1) That in pre-cooling it is necessary to start 1 hour before the effort to have an efficiency of the method;(2) Immersion with menthol is more effective only a single immersion between two efforts of 20 'but that used on clothes its effectiveness is not proven; (3) That wearing a cold vest combined with ingestion from a cold drink to warm up is no more effective than an internal cooling only (4) That menthol can influence performance by playing a role on the CNS. The action of menthol will allow the CNS to perceive the environment as being "More favorable" and therefore result in a change in the feedback thermoregulatory, allow higher performance. This without the menthol isplayed a deleterious role to thermoregulation.

Le développement des nanotechnologies dans le domaine médical a suscité un engouement considérable ces dernières années, notamment l’utilisation de nanoparticules pour la vectorisation de principes actifs. Les nanoparticules offrent des perspectives uniques pour la vectorisation et la délivrance de principes actifs qu’ils soient des gènes (thérapie génique),des anti-cancéreux (chimiothérapie) ou encore des agents photosensibilisateurs (photothérapie dynamique, TPD). Le défi majeur reste cependant l’acheminement des molécules thérapeutiques jusqu’à leur site d’action, tout en gardant leur intégrité ainsi que leur effet thérapeutique.L’axe de recherche de cette thèse est l’utilisation des nanocapsules lipidiques comme plateforme multifonctionnelle pour la délivrance de principes actifs. Un des objectifs étant le développement de nanocapsules lipidiques, stables de point de vue physico-chimique, et fonctionnalisées avec du polyéthylèneimine capables de délivrer efficacement un plasmide ADN et un anti-cancéreux (paclitaxel) dans le cadre d’une thérapie combinée. Les applications de ces nanovecteurs pour la transfectionde gènes et la vectorisation de chimiothérapeutique in vitro ont été réalisées.Par ailleurs, l’aptitude de nanocapsules lipidiques à vectoriser des agents photosensibilisants pour la thérapie photodynamique a été aussi étudiée in vitro, et les résultats ont montré que l’encapsulation de deux molécules de PS dans les nanocapsules permet une synergie de l’effet photodynamique tout en gardant les propriétés physico-chimiques de chaque PS. Enfin, l’encapsulation d’un agoniste au canal ionique TRPM8, le menthol, fait l’objet du dernier chapitre. L’étude par imagerie calcique du relargage de cette molécule lipophile in vitro a permis de confirmer le potentiel des NCL comme nanovecteurs de principes actifs. / The development of nanotechnology in the medical field has attracted considerable interest in recent years, including the use of nanoparticles for drug delivery. Nanoparticles offer unique opportunities for delivery of active drugs such as genes (gene therapy), anti-cancer (chemotherapy) or photosensitizers (photodynamic therapy, PDT). The major challenge, however, remains the delivery of therapeutic molecules to their site of action while keeping their integrity and their therapeutic effect.The research focus of this thesis is the use of lipid nanocapsules as a multifunctional platform for the delivery of drugs. One goal is the development of stable lipid nanocapsules, functionalized with polyethyleneimine and capable of effectively delivering a plasmid DNA and an anti-cancer (paclitaxel) as part of a combination therapy. The applications of these nanocarriers for transfection and delivery of chemotherapeutic were performed in vitro.Moreover, the ability of lipid nanocapsules to encapsulate photosensitizers for photodynamic therapy has been studied in vitro, and the results showed that the encapsulation of two molecules of PS in the nanocapsules allows a synergy photodynamic effect while protecting the PS from photo degradation.Finally, encapsulating an ion channel TRPM8 agonist (menthol) is the subject of the last chapter. The study by calcium imaging of the release of this lipophilic molecule in vitro confirmed the potential of lipid nanocapsules as nanocarriers of drugs.

Objectives: Menthol is an organic compound synthesized or naturally obtained from peppermint or other mint oils and once added to cigarettes, is believed to have caused extra adverse health consequences (Kolawole S. Okuyemi 2004) compared with non-menthol cigarettes. This review has multi-purposes: First, to review and summarize the causes of African Americans’ high preference over menthol cigarettes; Second, to review smoking cessation studies and determine the association between menthol cigarettes and reduced quitting rates for African American smokers; Third, to gather information of evidence-based interventions for menthol cigarette smoking cessation. Methods: This article reviewed 16 journal articles through PubMed search using the following key words: menthol cigarette, smoking cessation, African American. And only one Chinese article was found by searching the key word “薄荷?” in CNKI Chinese database. Further search was done by using Google search engine and got 11 electronic articles or webpages for this topic. According to the objectives of this article, 3 journal papers were reviewed for examining the causes of African American smokers’ high preference over menthol cigarettes; 8 journal papers were reviewed for determining the association between menthol cigarettes and reduced quitting rates for African American smokers. In this section, the inclusion criteria include: age (18-65); gender (male, female); study design (cohort, cross-sectional, RCT). At last, 5 journal papers and 5 electronic resources including news were reviewed to gain an up-to-date insight for possible interventions of menthol cigarette smoking. Results: The leading causes for African American smokers’ high preference over menthol cigarettes include: like the minty/cool flavor; perceive menthol cigarette as having medicinal effects; menthol smokers’ influences from one’s social network; tobacco companies’ tailored marketing strategies. Overall, there were lower quitting rates for menthol cigarette smokers compared to non-menthol cigarette smokers at least among African American smokers. For menthol cigarettes and smoking cessation among African American smokers, 4 studies got significant results. For menthol cigarette and non-menthol cigarette smoking cessation among African American smokers: study 1 (TABLE 2), 6 weeks abstinence rate 28.3% vs. 41.5%, p=0.006; study 2 (TABLE 2), 4 weeks abstinence OR=0.32, 95% CI [0.16, 0.62], p<0.05, 6 months abstinence OR=0.48, 95% CI [0.25, 0.9], p<0.05; study 3 (TABLE 2), 6 months abstinence OR=0.23, 95% CI [0.17, 0.31], p<0.05. Study 4 (TABLE 2) compared African menthol cigarette smokers to Whites non-menthol cigarette smokers, OR=0.72, 95% CI [0.53, 0.97], p=0.031. For another 4 studies, they got non-significant results but still revealed such an association. Conclusions: Causes for African American smokers’ high preference over menthol cigarettes were identified as: tailored marketing strategies; physical properties of menthol cigarette (taste, smell); and demographic/social/psychological/cultural/attitudinal causes. There were significantly lower quitting rates for menthol cigarette smokers compared to non-menthol cigarette smokers at least among African American smokers. For menthol cigarette smoking cessation interventions, whether or not a ban on menthol would be implemented or not, comprehensive programs that include educational program, clinical menthol cigarette smoking cessation aids, taxation for price control, and smoke free and related regulations are needed. At last, China should learn experiences from the US regarding analysis of preference and possible clinical, educational, and policy interventions for menthol cigarette smoking cessation and prevention. / published_or_final_version / Medicine / Master / Master of Public Health

nÃo hà / O mentol, constituinte majoritÃrio da hortelÃ-pimenta, foi avaliado em modelos animais para investigar sua atividade no sistema nervoso central atravÃs de modelos experimentais animais para depressÃo, ansiedade, sedaÃÃo e convulsÃo, tais como, nado forÃado (NF), suspensÃo da cauda (SC), campo aberto, labirinto em cruz elevado (LCE), rota rod, tempo de sono induzido por pentobarbital e convulsÃo induzida por pentilenotetrazol. Dos efeitos comportamentais tambÃm foi avaliado o papel da gastroproteÃÃo, o qual buscou-se investigar os mecanismos de aÃÃo envolvidos, jà que hà indÃcios, mas poucos estudos referentes a esse efeito. (-)- Mentol foi administrado de forma aguda em todos os testes por via intraperitoneal, nas doses de 25 e 50 mg/kg, e no caso do NF tambÃm foi utilizado na dose de 10 mg/kg. Para o estudo da atividade gastroprotetora, (-)-mentol foi administrado por via oral nas doses de 100 e 200 mg/kg. A Ãlcera gÃstrica foi induzida pela administraÃÃo de 0,2 ml de etanol absoluto ou indometacina (20mg/kg). Os resultados mostraram que no NF e SC, (-)-mentol apresentou efeito antiimobilidade em todas as doses. No teste do campo aberto, (-)-mentol aumentou o nÃmero de travessias nas doses de 25 e 50 mg/kg, com nenhum efeito significativo na dose de 10 mg/kg. Houve tambÃm aumento de rearing e diminuiÃÃo de grooming. O mecanismo de aÃÃo de anti-imobilidade do mentol parece estar envolvido com os sistemas dopaminÃrgico e noradrenÃrgico, talvez com uma possÃvel ativaÃÃo dos receptores dopaminÃrgicos do tipo D2, e noradrenÃrgico, provavelmente por ativaÃÃo dos receptores adrenÃrgicos do tipo &#61537;1. No rota rod, em todas as doses, a coordenaÃÃo motora dos animais nÃo foi alterada. No LCE, (-)-mentol nÃo houve alteraÃÃo em nenhum parÃmetro. No tempo de sono induzido por pentobarbital, (-)- mentol reduziu o efeito sedativo/hipnÃtico do pentobarbital sÃdico. Na convulsÃo induzida por pentilenotetrazol aumentou a latÃncia de morte. A administraÃÃo oral de (-)-mentol 100 e 200 mg/kg foi capaz de proteger dos danos na mucosa gÃstrica pelo prÃ-tratamento com etanol e indometacina. AdministraÃÃo prÃvia de glibenclamida (10 mg/kg, i.p.) foi capaz de reverter a gastroproteÃÃo promovido por (-)-mentol 200 mg/kg na Ãlcera induzida por etanol. No entanto, prÃ-tratamento com L-NAME (10 mg/kg, i.p.) nÃo foi capaz de reverter efeito gastroprotetor do (-)-mentol. A dosagem de GSH gÃstrico mostrou que os nÃveis de GSH aumentaram com a administraÃÃo de (-)-mentol. O presente estudo fornece evidÃncias hà uma aÃÃo psicoativa de mentol no NF e esta parece ser dependente da sua interaÃÃo com os sistemas noradrenÃrgico (&#945;1) e dopaminÃrgico (D2). Em conjunto, estes resultados sugerem que o mentol apresenta, provavelmente aÃÃo estimulante no SNC, e à desprovida de efeito ansiolÃtico e tem provÃvel aÃÃo anticonvulsivante. A gastroproteÃÃo promovida por (-)-mentol pode estar associada à abertura dos canais K+ dependentes de ATP e ao aumento da quantidade de GSH. / Menthol, major constituent of peppermint, has been evaluated in animal models to investigate their activity in the central nervous system through experimental animal models for depression, anxiety, sedation and convulsion, such as forced swimming (FS), tail suspension (TS), open field, elevated plus maze (EPM), rota rod, sleeping time induced by pentobarbital and pentylenetetrazol-induced convulsion. Behavioral effects was also evaluated the role of gastroprotective, seeking to investigate the mechanisms involved, since there is evidence, but few studies on this effect. (-) - Menthol was administered acutely in all tests intraperitoneally at doses of 25 and 50 mg / kg, and in the case of NF, it was also used at a dose of 10 mg / kg. To study the gastroprotective activity, (-)-menthol was administered orally at doses of 100 and 200 mg / kg. The gastric ulcer was induced by administration of 0.2 ml of absolute ethanol or indomethacin (20mg/kg). The results showed that the FS and TS, (-)-menthol showed antidepressant effect at all doses. In the open field test, (-)-menthol increased the number of crossings in doses of 25 and 50 mg / kg, with no significant effect on the dose of 10 mg / kg was not significant. There was increased rearing and decreased grooming. The mechanism of action of anti-immobility menthol seems to be involved with the dopaminergic and noradrenergic systems, perhaps with a possible activation of the dopamine D2 and noradrenergic, likely by activation of adrenergic receptors of type &#945;1. The route rod, at all doses, the motor coordination of animals was not changed. In EPM, (-)-menthol did not change in any parameter. In the sleep time induced by pentobarbital, (-) - menthol reduced the sedative / hypnotic of pentobarbital sodium. Convulsion induced by pentylenetetrazol increased the latency of death. Oral administration of (-)-menthol 100 and 200 mg / kg were able to protect the damage to gastric mucosa by pre-treatment with ethanol and indomethacin. Prior administration of glibenclamide (10 mg / kg, ip) was able to reverse the gastroproteÃÃo promoted by (-)-menthol 200 mg / kg in ethanol-induced ulcers. However, pretreatment with L-NAME (10 mg / kg, ip) was not able to reverse gastroprotective effect of (-)-menthol. Measurement of gastric GSH showed that GSH levels increased with the administration of (-)-menthol. In conclusion, this study provides evidence indicating that there is a psychoactive effects of menthol in NC and this seems to be dependent on their interaction with the noradrenergic (&#945;1) and dopamine (D2). Together, these results suggest that menthol has probably stimulating action in the CNS is devoid of anxiolytic and anticonvulsant action is likely. The gastroprotective action promoted by (-)-menthol can be associated with the opening of ATP-dependent K + channels and the increased amount of GSH.

Orientador: Edson Antunes / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-25T08:00:03Z (GMT). No. of bitstreams: 1 Ramos-Filho_AntonioCelsoSaragossa_D.pdf: 3024613 bytes, checksum: a03a80c65d863acd441249f461461216 (MD5) Previous issue date: 2014 / Resumo: Os receptores TRPV4 e TRPM8 são expressos no urotélio e em fibras aferentes sensitivas da bexiga. Fisiologicamente, a ativação mecânica do receptor TRPV4 na parede da bexiga participa do controle miccional. Em doenças de origem inflamatória, esses receptores adquirem funcionalidade importante. As disfunções da bexiga no diabetes podem estar associadas a alterações ao nível de detrusor, inervação e urotélio. A disfunção urotelial parece ser a responsável por desencadear as alterações neurais e musculares da bexiga. Assim, o objetivo do presente estudo foi investigar os mecanismos fisiopatológicos da ativação dos receptores TRPV4 e TRPM8 no estado diabético em camundongos. Para tanto, dividimos o estudo em duas etapas, sendo que na primeira avaliamos a participação dos receptores TRPV4 e TRPM8 nos mecanismos contráteis e relaxantes do detrusor isolado de animais controles e knockout para esses canais. Em uma segunda etapa estudamos a ativação desses canais em camundongos diabéticos pela injeção intraperitoneal de estreptozotocina (180 mg/Kg) por 4 semanas. Em fragmentos do detrusor isolados de camundongos mostramos que o agonista do receptor TRPV4, GSK1016790A, causou resposta contrátil dependente da concentração. Por outro lado, quando os tecidos foram contraídos com solução despolarizante de KCl, o GSK1016790A causou relaxamento da preparação. No detrusor isolado de animais TRPV4-/- verificamos hipercontratilidade ao carbacol (agonista muscarínico) e à estimulação elétrica, assim como redução no relaxamento ao agonista ?-adrenérgico não-seletivo, isoprenalina. Estes efeitos não foram obtidos com os antagonistas dos receptores TRPV4, RN1734 e HC067047. A indução do diabetes causou nocicepção mecânica e aumento da proporção entre bexiga e peso corpóreo após 4 semanas da injeção. A avaliação miccional dos animais diabéticos mostrou aumento da capacidade, frequência urinária e das contrações involuntárias da bexiga. Observamos ainda hipercontratilidade do detrusor ao carbacol, à estimulação elétrica e ao KCl. A indução do diabetes em animais TRPV4-/- não modificou as disfunções "in vivo" e "in vitro" observadas nos animais wyld type diabéticos, mostrando que a ausência crônica dos receptores TRPV4 desencadeia alterações miccionais que são anteriores as causadas pelo diabetes. Também verificamos que os animais TRPM8-/- não apresentam alteração na resposta contrátil ao carbacol e à estimulação elétrica. Por outro lado, o mentol, mas não a icilina, reduziu significativamente as respostas contráteis nestes animais. O mentol inibiu o influxo de cálcio extracelular em cultura de células da musculatura lisa da bexiga por mecanismo inibitório direto nos canais Cav1.2. O tratamento agudo com mentol, intraperitoneal e intravesical, atenuou as disfunções miccionais observadas nos camundongos diabéticos. "In vitro" o pré-tratamento com mentol reduziu a hipercontratilidade ao carbacol no grupo diabético, sem alterar a resposta no grupo controle. Concluímos que o mentol impede a resposta contrátil da bexiga por mecanismo independente do receptor TRPM8 bloqueando o influxo de cálcio extracelular nos canais Cav1,2, podendo ser utilizado como tratamento na hiperatividade de bexiga de origem miogênica / Abstract: The TRPV4 and TRPM8 receptors are expressed in bladder urothelium and sensitive afferent fibers. Physiologically, the mechanical activation of TRPV4 receptor in the bladder wall is involved in micturition control. In inflammatory diseases, these receptors may have important roles. The bladder dysfunction in diabetes may be associated with changes at the level of detrusor, innervation and urothelium. The urothelial dysfunction triggers neural changes, modifying consequently the smooth muscle contractility. Thus, the goal of the present study was to investigate the pathophysiological mechanisms of TRPV4 and TRPM8 receptor activation in physiological and diabetic conditions in mice. For this purpose we divided the study in two phases, the first of which we evaluated the participation of TRPV4 and TRPM8 receptors in detrusor contractile and relaxing mechanisms in control and knockout animals for these channels. In the second phase we studied the activation of these channels in diabetic mice induced by intraperitoneal injection of streptozotocin (STZ; 180 mg / kg, 4 weeks). The TRPV4 agonist GSK1016790A produced concentration-dependent detrusor contractions. On the other hand, in detrusor pré-contracted with KCl (80 mM), GSK1016790A caused relaxation responses. In TRPV4-/- animals, we verified hypercontractility to carbachol (muscarinic agonist) and electrical-field stimulation, as well as a decreased relaxation to isoprenaline (non-selective ?-adrenergic agonist). These effects were not obtained with the TRPV4 antagonists, RN1734 and HC067047. Induction of diabetes with STZ caused hyperglycemia, mechanical nocicepton, and increased ratio between bladder and body weight after 4 weeks. The miccturition evaluationin diabetic animals showed increased capacity, urinary frequency, and non-voiding contractions. Hypercontractility to carbachol, electrical-field stimulation and KCl in isolated detrusor were lso observed. The induction of diabetes in TRPV4-/- animals did not change the urinary dysfunctions. Our data are consistent with the proposal that TRPV4 receptor has a physiological function in micturition control by decreasing muscarinic-induced contractions and increasing ?-adrenergic-mediated relaxations. Moreover, the bladder contractions to carbachol and EFS in TRPM8-/- did not significantly change compared to TRPM8+/+. However, menthol (300 ?M), but not icilin (1 ?M), significantly inhibited these contractile responses. The menthol (300 ?M) inhibited extracellular calcium influx in bladder smooth muscle cell culture by direct mechanism though Cav1.2 channels. In addition the acute treatment with menthol, intraperitoneal and intravesical, atenuated the micturition dysfunctions observed in diabetic mice. Also, detrusor preparations pre-treated with menthol decreased carbachol hypercontractility, without changing the responses in normoglycemic group. Menthol reduces bladder contractions by mechanisms independent of TRPM8 receptor activation, inhibiting extracellular calcium influx through Cav1.2 channel, thus been considered as treatment for bladder overactivity of myogenic origin / Doutorado / Farmacologia / Doutor em Farmacologia

Hauptaufgabe dieser Promotionsarbeit war es, eine neue Sol-Gel basierte Syntheseroute zur Darstellung edelmetallbeladener (Pd, Pt, Ag und Au) Aluminiumhydroxidfluoride zu entwickeln. Derartige Katalysatoren besitzen sowohl Lewis- als auch Brønsted-saure, sowie hydrogenierungsaktive Zentren. Solche multifunktionellen Katalysatoren können für mehrstufige Umsetzungen von Substraten in Eintopfverfahren eingesetzt werden. Das Potential der dargestellten Katalysatoren wurde in der zweistufigen Umsetzung von Citronellal zu Mentholen und der dreistufigen Reaktion von Citral zu Mentholen gezeigt. / The main aim of this thesis was to develop a new sol gel based synthesis route to noble metal loaded (Pd, Pt, Ag and Au) aluminium hydroxide fluorides. These catalysts provide Lewis as well as Brønsted acidity and hydrogenation ability. Those multifunctional catalysts can be used for multi step conversions of substrates performed in a one pot process. The potential of the synthesized catalysts was shown in the two step conversion of citronellal to menthols and in the three step conversion of citral to menthols.

Objectives The objective of the present study was to investigate the usefulness of time-frequency analysis (TFA) of olfactory-induced EEG change with a low-cost, portable olfactometer in the clinical investigation of smell function. Materials & methods A total of 78 volunteers participated. The study was composed of three parts where olfactory stimuli were presented using a custom-built olfactometer. Part I was designed to optimize the stimulus as well as the recording conditions. In part II EEG-power changes after olfactory/trigeminal stimulation were compared between healthy participants and patients with olfactory impairment. In Part III the test-retest reliability of the method was evaluated in healthy subjects. Results Part I indicated that the most effective paradigm for stimulus presentation was cued stimulus, with an interstimulus interval of 18-20s at a stimulus duration of 1000ms with each stimulus quality presented 60 times in blocks of 20 stimuli each. In Part II we found that central processing of olfactory stimuli analyzed by TFA differed significantly between healthy controls and patients even when controlling for age. It was possible to reliably distinguish patients with olfactory impairment from healthy individuals at a high degree of accuracy (healthy controls vs anosmic patients: sensitivity 75%; specificity 89%). In addition we could show a good test-retest reliability of TFA of chemosensory induced EEG-power changes in Part III. Conclusions Central processing of olfactory stimuli analyzed by TFA reliably distinguishes patients with olfactory impairment from healthy individuals at a high degree of accuracy. Importantly this can be achieved with a simple olfactometer.