Osteoporosis affects the human skeleton through the direct effects of the disease on the function and structure of bone. Individuals who are affected by osteoporosis may be subject to serious fractures and it is estimated that annually approximately 1.5 million fractures can be attributed to this disease [1]. The disease is categorized as the direct side effect of increased bone porosity and bone loss and is directly linked to estrogen deprivation [2]. Animal models are often used to make initial conclusions about the effects of the disease or pharmacological treatments. In this study, sheep were chosen as a representative animal model due to their similar metabolic characteristics to that of a human. Like most animals, the ovine does not undergo a natural menopause and an ovariectomy was necessary to replicate the condition. The study objective was to quantify compact bone density present in ovine at three months post ovariectomy. The study included 112 ovine separated into different treatment groups. The treatment groups were separated into 4 groups of 28 based on season of surgery: autumn, winter, spring, and summer. Each seasonal group was further divided into 2 groups of 14; the first group underwent an ovariectomy; and the second group underwent a sham surgery, in which the ovaries were visualized and handled but left in the abdomen. One group was sacrificed 3 months post operatively and the other group was sacrificed at 12 months post operatively. This study specifically looks at ewe sacrificed at 3 months. The radius from each sheep was cut into the anatomical sectors: cranial, caudal, craniolateral, craniomedial, caudomedial, and caudolateral. Each anatomical sector was turned into a microradiograph for analysis. Densitometry was performed to determine the density of each specimen using the estimated thickness of aluminum (ETA) as the key. Statistical analysis assessed the resulting data to understand the effects of treatment, season of sacrifice, season of surgery, and anatomical sector by comparing both mean ETA and standard deviation ETA to understand changes in bone density. The results revealed significant differences between the ovariectomy and sham groups as well as variation within season of surgery and season of sacrifice in both groups. Anatomical sector showed no significant variation. The differences in the thickness of aluminum seen in the sheep that underwent a sham operation can be attributed to the presence of estrogen. The sheep that underwent an ovariectomy showed differences in the estimated thickness of aluminum that can be attributed to other seasonal characteristics including the influence of Vitamin D. The results and conclusions within this study can be used to influence bone material characteristics and bone loss test protocols in future osteoporosis and estrogen depletion studies.

The purpose of this study is to characterize the compact bone remodeling of the ovariectomized ewe and its effectiveness as an animal model for studies of postmenopausal osteoporosis. The use of animal models is a beneficial way to evaluate the effectiveness of medical devices and therapeutic agents for treating diseases. The ovine model is an attractive option because of its large size and similar bone remodeling to humans. However, this species, like most animals, does not undergo a natural menopause, making an ovariectomy necessary for studies of estrogen depletion. The OVX (ovariectomized) sheep has been widely accepted as a model for loss of BMD. However, even with its advantages seasonality has been shown to have an effect on the bone remodeling in the ovine model. Thus, this study focused on characterizing the seasonal and anatomical variation in the compact bone remodeling in the ovine model. In doing so, 28 skeletally mature Columbia-Rambouillet cross ewes underwent an ovariectomy. The animals were divided into groups of 7 based on each season: autumn, winter, spring, and summer. During its specified season each group of 7 underwent ovariectomy and then was sacrificed 12 months post-surgery. The radii and ulnae were harvested and then divided into 6 anatomical locations: craniolateral, cranial, craniomedial, craniolateral, caudal, and caudomedial. This allowed for analysis through the fabrication of microradiographs. Histomorphometric analysis involved measurements to quantify the bone volume to tissue volume ratio, the percent of tissue and material remodeling, the mean secondary osteonal radius, and number of tissue and material cement line interfaces. Densitometry analysis was then performed to determine the density of each sector relative to an aluminum step wedge, serving as the key. Using a 2-way repeated measures ANOVA statistical analysis was performed to evaluate for seasonal and anatomical differences as well as a possible interaction between season and anatomical region. The OVX data showed significant seasonal and anatomical differences as well as seasonality within anatomical section in the remodeling parameters. When this data was combined with earlier data from a control, sham-cohort from the same experiment a 3-way ANOVA was also performed to evaluate the effects of season, anatomical sector, and treatment on the remodeling parameters. Again, there was significant seasonal, anatomical, and treatment differences, as well as interactions of all three. The results of this study showed that varying levels of remodeling occurs in the adult OVX ovine model and differences between the control and OVX model can be attributed to seasonal and anatomical variations. Thus, it will be an important consideration when developing new test protocols for research incorporating the sheep model for studying osteoporosis.

Research on the relationship between the oil market and the stock market has been a frequently discussed topic. Regarding the connection between oil and the stock market, there are different opinions about whether there is a relationship or not, therefore there is still room left for further research on the subject matter. In addition, none of the studies we could identify researched the Swedish stock market with the effect on different sectors separately at the stock market. The purpose of this paper is to study the relationship between the return- and volatility of the oil and how it affects the Swedish stock market. We will partly analyze the relationship between oil return and the specific sectors on the Swedish stock market while also studying the relationship with the stock market as a whole. Furthermore, we will also look at the connection between the oil volatility index (OVX) with regards to how it affects both the sectors and the Swedish stock market.  The method used in the study is quantitative consisting of two linear regression models which will be redesigned into two multiple regression models containing our control variables. The data which were used in the study was compiled into time-series data and the estimates were performed with OLS-estimations.  The result of the study was that no statistically significant relationship could be found between the Swedish stock market and oil return- and volatility. Furthermore, in the sectoral analysis, five sectors became statistically significant given their relationship to oil return. When examining the relationship between the oil volatility and the sectors on the Swedish stock market the result gained was three statistically significant sectors. Thus, there is no evidence for a statistically significant relationship between the Swedish stock market and the oil return- and volatility. However, we conclude that the oil return- and volatility have a sectoral effect on the Swedish stock market. / Forskning om relationen mellan oljans pris och aktiemarknaden har varit ett väl diskuterat ämne. Beträffande sambandet mellan oljan och aktiemarknaden råder det skilda meningar om huruvida det finns ett samband eller inte, därav finns det fortfarande utrymme för vidare forskning. Dessutom undersöker ingen av studierna vi identifierat den svenska aktiemarknaden och hur olika sektorer på marknaden påverkas enskilt.  Syftet med denna studie är att studera sambandet mellan avkastningen- och volatiliteten i oljan och hur det påverkar avkastningen på den svenska aktiemarknaden. Dels kommer vi att undersöka förhållandet mellan oljans avkastning och enskilda sektorer på Stockholmsbörsen, såväl som vi undersöker börsen i helhet. Vi kommer också att studera hur oljevolatilitetsindex (OVX) påverkar avkastningen för dessa sektorer och Stockholmsbörsen som helhet.  Studien använder sig av en kvantitativ metod bestående av två initiala linjära regressionsmodeller som sedan omkonstrueras till två multipla regressionsmodeller innehållande kontrollvariabler. Studiens data har sammanställts till tidsseriedata och skattningarna utfördes med OLS-estimeringar.  Resultatet av studien blev att inget statistiskt säkerställt samband kunde hittas mellan Stockholmsbörsen och oljans avkastning respektive volatilitet. Vidare i den sektoriella analysen blev fem sektorer signifikanta vid undersökning av oljans avkastning. Fortsättningsvis undersöktes oljans volatilitet mot sektorerna vilket resulterade i tre signifikanta sektorer. Slutsatsen blir således att det inte finns ett signifikant samband mellan Stockholmsbörsen som helhet och oljans avkastning- samt volatilitet. Däremot kan vi konstatera att oljans avkastning såväl som volatilitet har en sektoriell påverkan.

No description available.

京都大学 / 新制・課程博士 / 博士(農学) / 甲第24651号 / 農博第2534号 / 新制||農||1097(附属図書館) / 学位論文||R5||N5432(農学部図書室) / 京都大学大学院農学研究科応用生物科学専攻 / (主査)教授 太田 毅, 教授 横井 伯英, 教授 舟場 正幸 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

Postmenopausal osteoporosis is a disease characterized by bone loss and increased risk of fracture, and represents a significant burden on the Canadian health care system. Current treatments lack the ability to simultaneously address the therapeutic needs for promoting bone formation and inhibiting resorption. Our approach employs a novel conjugate drug in which an anabolic agent (EP4 receptor agonist) is reversibly joined with an anti-resorptive agent (alendronate) through a linker. This allows the bone-targeting ability of alendronate to deliver the EP4 agonist to bone sites, thereby mitigating the side effects associated with systemic administration of the EP4 agonist. This study investigated the in vivo efficacy of this drug in a curative experiment to treat postmenopausal osteoporosis using an ovariectomized rat model. Results showed that conjugate treatment dose-dependently stimulated bone formation and restored ovariectomy-induced bone loss, and conjugation between alendronate and the EP4 agonist was crucial to the drug’s anabolic effect.

Postmenopausal osteoporosis is a disease characterized by bone loss and increased risk of fracture, and represents a significant burden on the Canadian health care system. Current treatments lack the ability to simultaneously address the therapeutic needs for promoting bone formation and inhibiting resorption. Our approach employs a novel conjugate drug in which an anabolic agent (EP4 receptor agonist) is reversibly joined with an anti-resorptive agent (alendronate) through a linker. This allows the bone-targeting ability of alendronate to deliver the EP4 agonist to bone sites, thereby mitigating the side effects associated with systemic administration of the EP4 agonist. This study investigated the in vivo efficacy of this drug in a curative experiment to treat postmenopausal osteoporosis using an ovariectomized rat model. Results showed that conjugate treatment dose-dependently stimulated bone formation and restored ovariectomy-induced bone loss, and conjugation between alendronate and the EP4 agonist was crucial to the drug’s anabolic effect.

No description available.

Les facteurs de risque des maladies cardiovasculaires, telle, que la détérioration du profil lipidique, deviennent plus prononcés après la ménopause, ce qui fait de la maladie coronarienne, l’une des principales causes de décès chez les femmes ménopausées. Une proportion importante de femmes prennent du poids après la ménopause en particulier dans la région abdominale entraînant par conséquent des perturbations métaboliques. Des données récentes suggèrent également que l’absence des œstrogènes observée à la ménopause favorise le développement de la stéatose hépatique. Cette dernière a été incriminée pour incriminée dans le développement de la résistance à l'insuline, et est de ce fait considérée comme une composante hépatique du syndrome métabolique. Il est impératif d'établir des stratégies visant à contrecarrer l'accumulation de graisse dans le foie et l’accroissement du tissu adipeux chez les femmes ménopausées, en tenant compte que l'utilisation de l'hormonothérapie substitutive est de nos jours moins soutenue. Les quatre études de la présente thèse ont été conduites pour tenter de fournir des informations sur le traitement et la prévention de l’augmentation de la masse graisseuse et de la stéatose hépatique qu’entraîne la suppression des œstrogènes, à travers les modifications du mode de vie (diète et exercice physique) chez la rate ovariectomizée (Ovx); un modèle animal de la ménopause. Dans les deux premières études nous nous sommes concentrés sur l’augmentation de la masse graisseuse et sa reprise suite à une perte de poids. Dans la première étude, nous avons montré que les rates Ovx qui ont suivi un programme de restriction alimentaire (FR) ont diminué significativement (P < 0.01) leur poids corporel, leur contenu en graisses intra-abdominales ainsi que leurs triacylglycérols (TAG) hépatiques, comparativement aux rates Ovx nourries à la diète normale. De plus, l’entraînement en résistance (RT) a prévenu la reprise de poids corporel ainsi que l’accroissement du tissu adipeux et l’accumulation de lipides dans le foie des rates Ovx, après l’arrêt du régime amaigrissant. Les résultats de la deuxième étude ont confirmé l'efficacité de la restriction alimentaire associée à l’entraînement en résistance (FR + RT) dans la réduction du poids corporel, des lipides dans le foie et le tissu adipeux chez les rates Ovx. Tenant compte des résultats de notre première étude, l’entraînement en résistance seulement a constitué un atout pour atténuer le poids corporel et la masse grasse reprise par les rates Ovx suite à un programme de perte de poids (FR + RT); bien que l'impact ait été moindre comparé au maintien seul de la restriction alimentaire. De la même manière que la supplémentation en œstrogènes, les résultats de la troisième étude indiquent que l'entraînement en endurance mené concurremment avec l’ovariectomie a significativement atténué l'accumulation de lipides dans le foie ainsi que dans le tissu adipeux. Toutefois, l’entraînement en endurance effectué avant l'ovariectomie n'a pas protégé contre l'accumulation des graisses qu’entraîne l'ovariectomie, si celui-ci est interrompu après l'ovariectomie. Enfin, pour compléter les résultats antérieurs, nous avons montré dans la quatrième étude que l’expression des gènes impliqués dans la synthèse de lipide; SREBP-1c, SCD-1, ChREBP, et ACC dans le foie a augmenté après le retrait des œstrogènes, tandis qu’une diminution (P < 0.01) des niveaux d'ARNm de PPAR-α a été observée. De plus, l'expression hépatique des gènes des cytokines pro-inflammatoires incluant IKKβ, IL-6 ainsi que le contenu protéinique de NF-кB étaient augmentés (P < 0.01) chez les rates Ovx par rapport aux rates ayant subi une Ovx simulée (Sham). Toutes ces perturbations ont été améliorées avec la supplémentation en œstrogènes seulement, ainsi qu'avec l'entraînement en endurance seulement. Dans l'ensemble, nos résultats indiquent que l'exercice physique (en résistance ou en endurance) a un impact significatif sur la réduction de l'accumulation des lipides dans le foie et dans le tissu adipeux des rates Ovx. De plus, chez les rates Ovx, l’entraînement en endurance mimerait les effets des œstrogènes sur l'expression des gènes impliqués dans l'accumulation de lipides et l’inflammation préclinique dans le foie. / Cardiovascular disease risk factors, such as lipid profile deterioration, become more pronounced after menopause making coronary heart disease a leading cause of death among postmenopausal women. A large proportion of women after menopause gain weight especially in the abdominal region resulting in several metabolic disturbances. Recent evidence also suggests that loss of estrogen function in menopause is associated with the development of a state of hepatic steatosis. Excessive fat accumulation in hepatocytes has been shown to play an important role in the development of insulin resistance and is even considered as a hepatic component of the metabolic syndrome. There is an important need to establish strategies to counteract fat accumulation in adipocyte and liver in postmenopausal women specifically considering the fact that utilization of hormone replacement therapy is now less supported. The four studies of the present thesis have been conducted in an attempt to provide information on the treatment and prevention of estrogen withdrawal-induced fat mass and hepatic steatosis via lifestyle modifications (diet and exercise training) in an ovariectomized (Ovx) rat model of menopause. In the first two studies we focused on fat mass gain and regain following weight loss. In study 1, we showed that food restriction program (FR) decreased (P < 0.01) body mass, intra-abdominal fat pad weight, and liver triacylglycerol (TAG) levels as compared to normally fed Ovx rats. Moreover, resistance training program (RT) was useful in preventing body weight as well as adipose tissue and liver fat regain in Ovx rats, following diet-induced weight loss. Results of study 2 confirmed the efficiency of the FR + RT program in reducing body weight as well as liver and adipocytes fat accretion in Ovx rats. In line with the findings of our first study, continuation of only RT constituted an asset to attenuate body weight and fat mass regain in Ovx rats following a FR + RT weight loss program, although the impact was less than maintaining FR alone. Similar to estrogen supplementation, results of study 3 indicated that endurance exercise training conducted concurrently with the induction of ovariectomy significantly attenuated liver and adipocyte fat accumulation. However, an endurance exercise training state acquired before ovariectomy did not provide any protective effects against ovariectomy-induced fat accumulation if exercise is discontinued after the ovariectomy. Finally, complementing previous findings we showed in study 4 that liver gene expressions of transcription factors SREBP-1c and ChREBP along with downstream lipogenic enzymes SCD-1 and ACC were increased with estrogens withdrawal conversely to reduced PPAR-α mRNA levels (P < 0.01). Furthermore, gene expressions of pro-inflammatory cytokines including IKKβ and IL-6 as well as protein content of NF-кB were higher (P < 0.01) in the liver of Ovx than in Sham animals. All of these responses were corrected with estrogen supplementation alone as well as with endurance exercise training alone in Ovx rats. On the whole, our results indicate that exercise training (resistance or endurance) has a significant impact on reducing fat accumulation in liver and adipocytes in Ovx rats. In addition, it seems that endurance exercise training in Ovx rats stimulates estrogenic-like effects on the expression of genes involved in lipid accumulation and sub-clinical inflammation in the liver.

Les facteurs de risque des maladies cardiovasculaires, telle, que la détérioration du profil lipidique, deviennent plus prononcés après la ménopause, ce qui fait de la maladie coronarienne, l’une des principales causes de décès chez les femmes ménopausées. Une proportion importante de femmes prennent du poids après la ménopause en particulier dans la région abdominale entraînant par conséquent des perturbations métaboliques. Des données récentes suggèrent également que l’absence des œstrogènes observée à la ménopause favorise le développement de la stéatose hépatique. Cette dernière a été incriminée pour incriminée dans le développement de la résistance à l'insuline, et est de ce fait considérée comme une composante hépatique du syndrome métabolique. Il est impératif d'établir des stratégies visant à contrecarrer l'accumulation de graisse dans le foie et l’accroissement du tissu adipeux chez les femmes ménopausées, en tenant compte que l'utilisation de l'hormonothérapie substitutive est de nos jours moins soutenue. Les quatre études de la présente thèse ont été conduites pour tenter de fournir des informations sur le traitement et la prévention de l’augmentation de la masse graisseuse et de la stéatose hépatique qu’entraîne la suppression des œstrogènes, à travers les modifications du mode de vie (diète et exercice physique) chez la rate ovariectomizée (Ovx); un modèle animal de la ménopause. Dans les deux premières études nous nous sommes concentrés sur l’augmentation de la masse graisseuse et sa reprise suite à une perte de poids. Dans la première étude, nous avons montré que les rates Ovx qui ont suivi un programme de restriction alimentaire (FR) ont diminué significativement (P < 0.01) leur poids corporel, leur contenu en graisses intra-abdominales ainsi que leurs triacylglycérols (TAG) hépatiques, comparativement aux rates Ovx nourries à la diète normale. De plus, l’entraînement en résistance (RT) a prévenu la reprise de poids corporel ainsi que l’accroissement du tissu adipeux et l’accumulation de lipides dans le foie des rates Ovx, après l’arrêt du régime amaigrissant. Les résultats de la deuxième étude ont confirmé l'efficacité de la restriction alimentaire associée à l’entraînement en résistance (FR + RT) dans la réduction du poids corporel, des lipides dans le foie et le tissu adipeux chez les rates Ovx. Tenant compte des résultats de notre première étude, l’entraînement en résistance seulement a constitué un atout pour atténuer le poids corporel et la masse grasse reprise par les rates Ovx suite à un programme de perte de poids (FR + RT); bien que l'impact ait été moindre comparé au maintien seul de la restriction alimentaire. De la même manière que la supplémentation en œstrogènes, les résultats de la troisième étude indiquent que l'entraînement en endurance mené concurremment avec l’ovariectomie a significativement atténué l'accumulation de lipides dans le foie ainsi que dans le tissu adipeux. Toutefois, l’entraînement en endurance effectué avant l'ovariectomie n'a pas protégé contre l'accumulation des graisses qu’entraîne l'ovariectomie, si celui-ci est interrompu après l'ovariectomie. Enfin, pour compléter les résultats antérieurs, nous avons montré dans la quatrième étude que l’expression des gènes impliqués dans la synthèse de lipide; SREBP-1c, SCD-1, ChREBP, et ACC dans le foie a augmenté après le retrait des œstrogènes, tandis qu’une diminution (P < 0.01) des niveaux d'ARNm de PPAR-α a été observée. De plus, l'expression hépatique des gènes des cytokines pro-inflammatoires incluant IKKβ, IL-6 ainsi que le contenu protéinique de NF-кB étaient augmentés (P < 0.01) chez les rates Ovx par rapport aux rates ayant subi une Ovx simulée (Sham). Toutes ces perturbations ont été améliorées avec la supplémentation en œstrogènes seulement, ainsi qu'avec l'entraînement en endurance seulement. Dans l'ensemble, nos résultats indiquent que l'exercice physique (en résistance ou en endurance) a un impact significatif sur la réduction de l'accumulation des lipides dans le foie et dans le tissu adipeux des rates Ovx. De plus, chez les rates Ovx, l’entraînement en endurance mimerait les effets des œstrogènes sur l'expression des gènes impliqués dans l'accumulation de lipides et l’inflammation préclinique dans le foie. / Cardiovascular disease risk factors, such as lipid profile deterioration, become more pronounced after menopause making coronary heart disease a leading cause of death among postmenopausal women. A large proportion of women after menopause gain weight especially in the abdominal region resulting in several metabolic disturbances. Recent evidence also suggests that loss of estrogen function in menopause is associated with the development of a state of hepatic steatosis. Excessive fat accumulation in hepatocytes has been shown to play an important role in the development of insulin resistance and is even considered as a hepatic component of the metabolic syndrome. There is an important need to establish strategies to counteract fat accumulation in adipocyte and liver in postmenopausal women specifically considering the fact that utilization of hormone replacement therapy is now less supported. The four studies of the present thesis have been conducted in an attempt to provide information on the treatment and prevention of estrogen withdrawal-induced fat mass and hepatic steatosis via lifestyle modifications (diet and exercise training) in an ovariectomized (Ovx) rat model of menopause. In the first two studies we focused on fat mass gain and regain following weight loss. In study 1, we showed that food restriction program (FR) decreased (P < 0.01) body mass, intra-abdominal fat pad weight, and liver triacylglycerol (TAG) levels as compared to normally fed Ovx rats. Moreover, resistance training program (RT) was useful in preventing body weight as well as adipose tissue and liver fat regain in Ovx rats, following diet-induced weight loss. Results of study 2 confirmed the efficiency of the FR + RT program in reducing body weight as well as liver and adipocytes fat accretion in Ovx rats. In line with the findings of our first study, continuation of only RT constituted an asset to attenuate body weight and fat mass regain in Ovx rats following a FR + RT weight loss program, although the impact was less than maintaining FR alone. Similar to estrogen supplementation, results of study 3 indicated that endurance exercise training conducted concurrently with the induction of ovariectomy significantly attenuated liver and adipocyte fat accumulation. However, an endurance exercise training state acquired before ovariectomy did not provide any protective effects against ovariectomy-induced fat accumulation if exercise is discontinued after the ovariectomy. Finally, complementing previous findings we showed in study 4 that liver gene expressions of transcription factors SREBP-1c and ChREBP along with downstream lipogenic enzymes SCD-1 and ACC were increased with estrogens withdrawal conversely to reduced PPAR-α mRNA levels (P < 0.01). Furthermore, gene expressions of pro-inflammatory cytokines including IKKβ and IL-6 as well as protein content of NF-кB were higher (P < 0.01) in the liver of Ovx than in Sham animals. All of these responses were corrected with estrogen supplementation alone as well as with endurance exercise training alone in Ovx rats. On the whole, our results indicate that exercise training (resistance or endurance) has a significant impact on reducing fat accumulation in liver and adipocytes in Ovx rats. In addition, it seems that endurance exercise training in Ovx rats stimulates estrogenic-like effects on the expression of genes involved in lipid accumulation and sub-clinical inflammation in the liver.