Lee, Hoi Ying. / "September 2010." / Thesis (M.Phil.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 171-189). / Abstracts in English and Chinese. / Abstract (English) --- p.i / Abstract (Chinese) --- p.iii / Acknowledgement --- p.v / Publications --- p.vi / Abbreviations --- p.vii / Table of Content --- p.x / Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Human mast cells and its activation --- p.1 / Chapter 1.2 --- Role of mast cells in inflammation --- p.2 / Chapter 1.3 --- Mast cell heterogeneity --- p.5 / Chapter 1.4 --- Interaction of bone and immune system --- p.1 / Chapter 1.5 --- Introduction of bone system --- p.8 / Chapter 1.6 --- Bone remodeling --- p.9 / Chapter 1.7 --- Regulation of bone remodeling --- p.10 / Chapter 1.8 --- Introduction of Osteoporosis --- p.12 / Chapter 1.9 --- Pathophysiology of osteoporosis --- p.13 / Chapter 1.10 --- Pharmacological interventions in osteoporosis --- p.14 / Chapter 1.11 --- Involvement of mast cells in bone metabolism --- p.18 / Chapter 1.12 --- Aim of study --- p.20 / Chapter 2 --- Materials and Methods --- p.27 / Chapter 2.1 --- Materials --- p.27 / Chapter 2.2 --- Methods --- p.34 / Chapter 2.2.1 --- Human mast cells culture --- p.34 / Chapter 2.2.2 --- Human mast cells characterization --- p.35 / Chapter 2.2.3 --- Histamine release assay --- p.36 / Chapter 2.2.4 --- Immunofluorescence staining of estrogen receptors --- p.37 / Chapter 2.2.5 --- Reverse Transcriptase Polymerase Chain Reaction --- p.37 / Chapter 2.2.6 --- TNF measurement --- p.38 / Chapter 2.2.7 --- Calcium mobilization studies of mast cells --- p.38 / Chapter 2.2.8 --- Statistical analysis --- p.39 / Chapter 3 --- Effects of estrogen and selective estrogen receptor modulators (SERMs) on mediators release from human mast cells --- p.41 / Chapter 3.1 --- Introduction --- p.41 / Chapter 3.2 --- Materials and methods --- p.50 / Chapter 3.3 --- Results --- p.51 / Chapter 3.3.1 --- Characterization of human mast cells --- p.51 / Chapter 3.3.2 --- Effect of estrogen on mediator release from human mast cells --- p.52 / Chapter 3.3.2.1 --- Basal histamine release after treatment of estrogen --- p.52 / Chapter 3.3.2.2 --- Histamine release induced by immunological stimulus --- p.52 / Chapter 3.3.2.3 --- Histamine release induced by chemical secretagogues --- p.54 / Chapter 3.3.3 --- Effect of selective estrogen receptor modulators (SERMs) on mast cell activity --- p.54 / Chapter 3.3.3.1 --- Basal histamine release after SERMs treatment --- p.54 / Chapter 3.3.3.2 --- Histamine release induced by immunological stimulus --- p.55 / Chapter 3.3.3.3 --- Histamine release induced by chemical secretagogues --- p.57 / Chapter 3.3.4 --- Effect of estradiol on TNF-α release from human mast cells --- p.57 / Chapter 3.3.5 --- Effect of SERMs on TNE-α release from human mast cells --- p.58 / Chapter 3.3.6 --- Expression of estrogen receptors on human mast cells --- p.59 / Chapter 3.3.6.1 --- Expression of estrogen receptor after treatment of estradiol --- p.59 / Chapter 3.3.7 --- Expression of various bone remodeling molecules on human mast cells --- p.60 / Chapter 3.3.7.1 --- Expression of bone remodeling molecule after treatment of estradiol --- p.61 / Chapter 3.4 --- Discussion --- p.63 / Chapter 4 --- Effects of anti-osteoporosis Chinese herbal medicines on activity of human mast cells --- p.98 / Chapter 4.1 --- Introduction --- p.98 / Chapter 4.2 --- Materials and methods --- p.103 / Chapter 4.3 --- Results --- p.104 / Chapter 4.3.1 --- Effect of the anti-osteoporosis Chinese herbal formulation ELP on histamine release from human mast cells --- p.104 / Chapter 4.3.1.1 --- Histamine release induced by immunological stimulus --- p.104 / Chapter 4.3.1.2 --- Histamine release induced by chemical secretagogues --- p.105 / Chapter 4.3.2 --- Effect of Herba Epimedii (HEP) on histamine release from human mast cells --- p.105 / Chapter 4.3.2.1 --- Histamine release induced by immunological stimulus --- p.106 / Chapter 4.3.2.2 --- Histamine release induced by chemical secretagogues --- p.106 / Chapter 4.3.3 --- Effect of Fructus Ligustri Lucidi (FLL) on histamine release from human mast cells --- p.107 / Chapter 4.3.3.1 --- Histamine release induced by immunological stimulus --- p.107 / Chapter 4.3.3.2 --- Histamine release induced by chemical secretagogues --- p.107 / Chapter 4.3.4 --- Effect of Fructus Psoraleae (FP) on histamine release from human mast cells --- p.108 / Chapter 4.3.4.1 --- Histamine release induced by immunological stimulus --- p.108 / Chapter 4.3.4.2 --- Histamine release induced by chemical secretagogues --- p.109 / Chapter 4.3.5 --- Effect of various partitions from solvent extraction of HEP on histamine release from human mast cells --- p.109 / Chapter 4.3.5.1 --- Histamine release induced by immunological stimulus --- p.110 / Chapter 4.3.5.2 --- Histamine release induced by chemical secretagogue --- p.111 / Chapter 4.3.6 --- Effect of various partitions from solvent extraction of FLL on histamine release from human mast cells --- p.112 / Chapter 4.3.6.1 --- Histamine release induced by immunological stimulus --- p.113 / Chapter 4.3.6.2 --- Histamine release induced by chemical secretagogue --- p.114 / Chapter 4.3.7 --- Effect of ELP and its herbal constituents on the production of cytokine from human mast cells --- p.115 / Chapter 4.3.8 --- Modulation in calcium mobilization in activated human mast cell by ELP and its herbal constituents --- p.117 / Chapter 4.4 --- Discussion --- p.119 / Chapter 5 --- General discussion --- p.163 / Reference --- p.171

O rápido envelhecimento da população brasileira cria um contexto de assistência prolongada e específica a morbidades que tendem a ampliar a duração do tratamento, as incapacidades dos indivíduos, os gastos com exames complementares, internações hospitalares e medicação. Dentro desse contexto, a osteoporose, doença intimamente relacionada com o envelhecimento, pode ter um aumento considerável nos próximos anos. Conhecer quem são os indivíduos em risco de desenvolver a doença é fundamental, uma vez que a fratura, sua mais importante conseqüência clínica, representa gastos elevados com serviços de saúde e está associada à alta taxa de morbidade e mortalidade. O exame indicado pela Organização Mundial da Saúde (OMS) como padrão-ouro para o diagnóstico da osteoporose é o exame de densitometria óssea (DXA), Devidos aos custos e acesso restrito e assim, selecionar candidatos ao exame é uma questão com importantes implicações clínicas e sócioeconômicas. O objetivo deste estudo foi avaliar a validade diagnóstica da radiografia panorâmica para identificação de mulheres na pós-menopausa com baixa massa óssea. Foram utilizados: questionário baseado nos fatores clínicos de risco para osteoporose, exame de densitometria óssea (fêmur, coluna e antebraço), radiografia panorâmica digital e o São Paulo Osteoporosis Risk Index (SAPORI). O estudo é do tipo observacional transversal. Os valores de sensibilidade e especificidade, valor preditivo positivo e negativo foram calculados. A amostra foi constituída por 88 mulheres na pós-menopausa com média de idade de 61 anos. A baixa massa óssea no quadril foi observada em 62 mulheres (70,5%), na coluna em 61(69,3%), no antebraço em 78 (88,6%) e 52 (59,1%) na mandíbula. Fratura após os 50 anos de idade foi observada em 17 mulheres (19,3%) e 37 (42%) relataram ocorrência de queda nos últimos 12 meses. A radiografia panorâmica é um instrumento válido para a identificação de mulheres na pósmenopausa com baixa densidade mineral óssea / The rapid aging of the Brazilian population creates a context of prolonged and specific assistance to morbidities that tend to increase the time of treatment, disabilities and costs related to clinical tests, hospital admissions and medication. Within this context, the osteoporosis, disease closely related to aging, can have a significant burden in the next years. Identifying people at risk to present the disease is essential, once fracture, its main clinical consequence, represents high costs related to health services and is associated to the high rate of morbidity and mortality. The bone densitometry (DXA) is recommended by the World Health Organization as the gold standard test to the osteoporosis diagnosis. Due to the costs associated and restricted access, to select candidates to the exam is an important issue, with clinical and socioeconomic implications. The objective of this study was to evaluate the diagnostic validity of the panoramic radiography to identify women with low bone density. The following were performed: questionnaire based on clinical risk factors for osteoporosis and fragility fracture, bone densitometry (hip, spine and forearm), digital panoramic radiography and the São Paulo Osteoporosis Risk Index (SAPORI). This is a cross-sectional study. The values sensitivity, specificity, positive and negative predictive values were calculated. The sample was constituted of 88 post-menopausal women with an average age of 61 years. Low bone density in the hip was observed in 62 women (70.5%), in the spine in 61 (69.3%), in the forearm in 78 (88.6%) and 52 (59.1%) in the mandible. Fracture after 50 years old was observed in 17 women (19.3%) and 37 (42%) of the sample reported fall in the last 12 months. The panoramic radiography is a valid instrument to identify postmenopausal women with low bone density

<p>The prevalence of respiratory symptoms and diseases like asthma and chronic obstructive pulmonary disease (COPD), seem to have increased the last decades. The reason for the increase in asthma related symptoms and allergy is uncertain. Some, but not all, of this increase might be ascribed to lowered threshold for use of the diagnosis by medical doctors, change in diagnostic criteria, and increased awareness of symptoms in the population. Studies have indicated that increased prevalence might be explained by a reduction during the last decades in exposure to environmental factors in infancy, These factors are supposed to stimulate the change from Th-2 to TH-1 helper cells (hygiene hypothesis), but even low level of allergen exposure seems to contribute to increase in risk for allergy. The increase in COPD in developed countries is closely related to the smoking pattern during the last two to four decades, and the increased therefore, is mainly seen in women. Further, studies have indicated that women are more vulnerable for the deleterious effects of tobacco smoking than men are; if this is true the current smoking pattern with increased female smoking, is worrying. </p> / Paper 1 reprinted with kind permission of Journal of Epidemiology and Community Health. Papers 2 and 3 reprinted with kind permission of European Respiratory Society Journals Ltd. Paper 4 reprinted with kind permission of John Wiley and Sons Limited.

<p>The present work expose a technique of estimation of optimal direction for placing dental implant. A volumetric computed tomography (CT) scan is used as a help of the following searches. The work offers criteria of the optimal implant placement direction and methods of evaluation on direction’s significance. The technique utilizes structure tensor to find a normal to the jawbone surface. Direction of that normal is then used as initial direction for search of optimal direction.</p><p>The technique described in the present work aimed to support doctor’s decisions during dental implantation treatment.</p>

<p>Primary hyperparathyroidism (pHPT), characterized by elevated serum levels of calcium and parathyroid hormone (PTH), is associated with a number of metabolic derangements causing secondary manifestations. These include osteoporosis and increased risk of fractures, but also risk factors for cardiovascular morbidity and mortality. These risk factors include impaired glucose tolerance (IGT), dyslipidemia, increased body mass index and hypertension. While the skeletal abnormalities are mainly due to elevated PTH, the latter disturbances are still unexplained. Non-insulin dependent diabetes mellitus (NIDDM), IGT, dyslipidemia and hypertension are all included in the metabolic syndrome, also associated with morbidity and mortality in cardiovascular diseases.</p><p>In this thesis, decreased bone mineral density (BMD) and variables of the metabolic syndrome are explored in patients with mild and normocalcemic pHPT before and after parathyroidectomy. To further investigate the relationship between insulin sensitivity and calcium, a community-based cohort was investigated.</p><p>In two different patient cohorts of pHPT, lipoprotein alterations with decreased levels of HDL-cholesterol and elevated triglycerides were found in association with a high frequency of IGT, NIDDM and decreased insulin sensitivity. Parathyroidectomy had effects on the dyslipidemia and in part on the glucose metabolism. The disturbed glucose metabolism in pHPT was substantiated by results from the general population by a negative association between insulin sensitivity, measured by hyperinsulinemic clamp, and serum calcium.</p><p>In conclusion, normocalcemic, mild and overt pHPT are associated with a range of risk factors for cardiovascular diseases, development of NIDDM and decreased BMD in cortical as well as trabecular bone. These findings explain, at least in part, the elevated morbidity and mortality from cardiovascular disease as well as fractures, reported in pHPT patients. Moreover, in the general population, serum calcium is associated with decreased insulin sensitivity. Parathyroidectomy has positive effects on several, but not all, of the investigated metabolic parameters.</p>

The prevalence of respiratory symptoms and diseases like asthma and chronic obstructive pulmonary disease (COPD), seem to have increased the last decades. The reason for the increase in asthma related symptoms and allergy is uncertain. Some, but not all, of this increase might be ascribed to lowered threshold for use of the diagnosis by medical doctors, change in diagnostic criteria, and increased awareness of symptoms in the population. Studies have indicated that increased prevalence might be explained by a reduction during the last decades in exposure to environmental factors in infancy, These factors are supposed to stimulate the change from Th-2 to TH-1 helper cells (hygiene hypothesis), but even low level of allergen exposure seems to contribute to increase in risk for allergy. The increase in COPD in developed countries is closely related to the smoking pattern during the last two to four decades, and the increased therefore, is mainly seen in women. Further, studies have indicated that women are more vulnerable for the deleterious effects of tobacco smoking than men are; if this is true the current smoking pattern with increased female smoking, is worrying. / Paper 1 reprinted with kind permission of Journal of Epidemiology and Community Health. Papers 2 and 3 reprinted with kind permission of European Respiratory Society Journals Ltd. Paper 4 reprinted with kind permission of John Wiley and Sons Limited.

Primary hyperparathyroidism (pHPT), characterized by elevated serum levels of calcium and parathyroid hormone (PTH), is associated with a number of metabolic derangements causing secondary manifestations. These include osteoporosis and increased risk of fractures, but also risk factors for cardiovascular morbidity and mortality. These risk factors include impaired glucose tolerance (IGT), dyslipidemia, increased body mass index and hypertension. While the skeletal abnormalities are mainly due to elevated PTH, the latter disturbances are still unexplained. Non-insulin dependent diabetes mellitus (NIDDM), IGT, dyslipidemia and hypertension are all included in the metabolic syndrome, also associated with morbidity and mortality in cardiovascular diseases. In this thesis, decreased bone mineral density (BMD) and variables of the metabolic syndrome are explored in patients with mild and normocalcemic pHPT before and after parathyroidectomy. To further investigate the relationship between insulin sensitivity and calcium, a community-based cohort was investigated. In two different patient cohorts of pHPT, lipoprotein alterations with decreased levels of HDL-cholesterol and elevated triglycerides were found in association with a high frequency of IGT, NIDDM and decreased insulin sensitivity. Parathyroidectomy had effects on the dyslipidemia and in part on the glucose metabolism. The disturbed glucose metabolism in pHPT was substantiated by results from the general population by a negative association between insulin sensitivity, measured by hyperinsulinemic clamp, and serum calcium. In conclusion, normocalcemic, mild and overt pHPT are associated with a range of risk factors for cardiovascular diseases, development of NIDDM and decreased BMD in cortical as well as trabecular bone. These findings explain, at least in part, the elevated morbidity and mortality from cardiovascular disease as well as fractures, reported in pHPT patients. Moreover, in the general population, serum calcium is associated with decreased insulin sensitivity. Parathyroidectomy has positive effects on several, but not all, of the investigated metabolic parameters.

Scandinavia has among the highest incidence of fragility fractures in the world. The reasons for this are unknown, but might involve differences in genetic and/or environmental factors, such as sunlight exposure and levels of physical activity. Weight-bearing exercise is thought to have a beneficial effect on bone health in the young, but few studies have evaluated whether exercise in older subjects affects bone density and protects against fragility fractures. The initial objective of this thesis was to evaluate whether a combined weight-bearing training programme twice a week would be beneficial as regards bone mineral density (BMD) and neuromuscular function in older women. Forty-eight community living women with a mean age of 73 years were recruited for this 12-month prospective, randomised controlled trial, and were randomly assigned to an intervention group (n=24) or a control group (n=24). The intervention group displayed significant increments in BMD at the Ward’s triangle, maximum walking speed, and isometric grip strength compared to the control group. The second objective was to investigate if training effects were retained in older women five years after the cessation of training. The 40 women who completed the first study included in this thesis were invited to take part in a follow-up assessment five years later, and 34 women (~79 years) agreed to participate. During these five years both groups had sustained significant losses in hip BMD and in all neuromuscular function tests, and the previous exercise-induced intergroup differences were no longer seen. The third and fourth objective of this thesis was to investigate whether exercise and weight-bearing leisure activities in middle-aged women are associated with a decreased risk of sustaining hip or wrist fractures at a later stage. A cohort of women participating in the Umeå Fracture and Osteoporosis (UFO) study, a longitudinal, nested case-control study investigating associations between bone markers, lifestyle, and osteoporotic fractures, was used for the purpose of this investigation. Eighty-one hip fracture cases and 376 wrist fracture cases, which had reported lifestyle data before they sustained their fracture, were identified. These cases were compared with age-matched controls identified from the same cohort. Using conditional logistic regression analysis with adjustments for height, BMI, smoking, and menopausal status, results showed that moderate frequency of leisure physical activities such as gardening and berry/mushroom picking, were associated with reduced hip fracture risk (OR 0.28; 95% CI 0.12 – 0.67), whereas active commuting (especially walking) along with dancing and snow shoveling in leisure time, reduced the wrist fracture risk (OR 0.48; 95% CI 0.27 – 0.88, OR 0.42; 95% CI 0.22 – 0.80 and OR 0.50; 95% CI 0.32 – 0.79 respectively). In summary, this thesis suggests that weight-bearing physical activity is beneficial for BMD and neuromuscular functions such as muscle strength and gait in older women, and that a physically active lifestyle, with outdoor activities, in middle age is associated with reduced risk of both hip and wrist fractures. Possible mechanisms underlying this association include improved muscle strength, coordination, and balance, resulting in a decreased risk of falling and perhaps also direct skeletal benefits.

The mechanical properties of the cancellous bone in the laboratory rat animal model are of great interest to the research community for the evaluation of treatments for osteoporosis. Cancellous bone responds rapidly and dramatically to disuse, various pathologies, nutritional deficiencies, and hormonal deficiencies and hence is often a primary focus in animal studies. Previous methods for evaluating the mechanical properties of cancellous bone in rat test specimens included both cortical and cancellous bone. This thesis introduces a new method to core cancellous specimens using a diamond wire saw in concert with specially designed fixtures. This method has been termed Isolated Cancellous Coring (ICC). The location and the geometry of the cored specimens were determined based on uCT analysis. The isolated cancellous specimens were subjected to uni-axial compression testing to evaluate the mechanical properties. Furthermore, the new method is evaluated by directly applying it to a study investigating the effects of estrogen replacement therapy in post-menopausal osteoporosis as simulated by the ovariectomized rat model. The results show that the ICC method can be applied to bone specimens with a large range in density and micro-architecture parameters. The compression testing of the isolated cancellous specimens provides a sensitive indicator of the effects of osteoporosis and treatment on the mechanical properties of the cancellous bone in the distal rat femur. Also, the results indicate a possible discordant relationship between bone mineral density and bone strength with respect to estrogen treatment. Power law regressions show that approximately 50% of the variation in ultimate strength can be accounted for with bone mineral density and the percent of bone volume per total volume.

During the last years, biomechaniccs, the understanding of the very complex mechanical behavior of living tissue, becomes a very important field of research of the wide bravch of mechanichs. Thia study is very important, for instance , to improve the design of implants, with the important social and economical impact. one of important challenges in implant design is to model the complex material behavior of the bone. Remodeling of the bone due to the lodaing is one of the essential behaviors of the bone which can cause for the dental implants, marginal bone loss accuring particallary in the first years of function. On the other hand the finite element method(FEM) has become the most extended tool for engineers to analyse the mechanical behavior of the products which usualy have a complex material behavior and complicated geometries. The aim of this study is to model the remodeling behavior of the bone using FEM and to use the new bone material method to evaluate the implant performance for some commercial implants, taking account of the bone adaptation.