by Martin Li. / Year shown on spine: 1997. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1996. / Includes bibliographical references (leaves 150-157). / DECLARATION --- p.II / ABSTRACT --- p.III / ACKNOWLEDGEMENTS --- p.VII / CONTENTS --- p.VIII / LIST OF ABBREVIATIONS --- p.XIV / LIST OF TABLES --- p.XVI / LIST OF CHART --- p.XXIII / LIST OF FIGURES --- p.XXIV / Chapter CHAPTER 1 --- OBSTRUCTIVE AIRWAY DISEASE: PUBLIC HEALTH AND CLINICAL ASPECTS --- p.1 / Chapter 1.1. --- Background --- p.1 / Chapter 1.2. --- Magnitude of the problem --- p.2 / Chapter 1.2.1. --- Asthma --- p.2 / Chapter 1.2.2. --- Chronic obstructive pulmonary disease --- p.3 / Chapter 1.2.3. --- Prevalence of osteoporosis in Hong Kong --- p.4 / Chapter 1.2.4. --- History of asthma care --- p.5 / Chapter 1.2.5. --- Treatment of OAD --- p.5 / Chapter 1.3. --- Side effects of Glucocorticoid in OAD patients --- p.6 / Chapter 1.4. --- Side effccts of inhaled corticosteroids in OAD patients --- p.7 / Chapter 1.5. --- Trend of asthma therapy in Hong Kong --- p.8 / Chapter CHAPTER 2: --- OSTEOPOROSIS: PUBLIC HEALTH AND CLINICAL ASPECTS --- p.11 / Chapter 2.1. --- Bone Biology --- p.11 / Chapter 2.2. --- Skeletal Organisation --- p.11 / Chapter 2.3. --- Bone remodelling --- p.12 / Chapter 2.4. --- Effect of corticosteroids on bone remodelling --- p.13 / Chapter 2.5. --- Corticosteroids induccs osteoporosis --- p.13 / Chapter 2.6. --- Factors affecting BMD --- p.14 / Chapter 2.6.1. --- Peak bone mass --- p.14 / Chapter 2.6.2. --- Ethnic factors --- p.14 / Chapter 2.6.3. --- Aging --- p.15 / Chapter 2.6.4. --- Calcium intake --- p.15 / Chapter 2.6.5. --- Oestrogen --- p.16 / Chapter 2.6.6. --- Alcohol consumption --- p.17 / Chapter 2.6.7. --- Cigarette smoking --- p.17 / Chapter 2.7. --- Physical activity and BMD --- p.17 / Chapter 2.8. --- Body composition in Chinese subjects --- p.18 / Chapter CHAPTER 3 --- "PHASE I: BODY COMPOSITION AND BONE MINERAL DENSITY IN OBSTRUCTIVE AIRWAY DISEASE PATIENT AND NORMAL CONTROL SUBJECTS: OBJECTIVES, SUBJECTS AND METHODS" --- p.20 / Chapter 3.1. --- Objectives --- p.20 / Chapter 3.2. --- Subjects and methods --- p.21 / Chapter 3.2.1 --- OAD patients --- p.21 / Chapter 3.2.1.1 --- Disease definition and selection criteria --- p.21 / Chapter 3.2.1.2. --- Normal Control subjects --- p.21 / Chapter 3.3. --- Power of estimation --- p.22 / Chapter 3.4. --- Survey methods --- p.22 / Chapter 3.5. --- Questionnaire --- p.23 / Chapter 3.6. --- Body composition and bone mineral density measurement --- p.23 / Chapter 3.6.1. --- Body composition analysis --- p.24 / Chapter 3.6.2. --- Lumbar spine and proximal hip bone mineral density analysis --- p.24 / Chapter 3.6.3. --- Routine quality control of measurements --- p.24 / Chapter 3.6.4. --- Precision on patient repositioning --- p.25 / Chapter 3.7. --- Statistical methods --- p.25 / Chapter 3.8. --- Bone mineral density of normal control subjects --- p.25 / Chapter CHAPTER 4 --- PHASE II: FLUORIDE IN THE TREATMENT OF OSTEOPOROSIS --- p.27 / Chapter 4.1. --- Introduction --- p.27 / Chapter 4.2. --- Mechanisms of action --- p.28 / Chapter 4.2.1. --- Antiresorptive effect of fluoride --- p.28 / Chapter 4.2.2. --- Force-oriented osteogenic effect of fluoride --- p.28 / Chapter 4.2.3. --- Biochemical osteogenic effect --- p.29 / Chapter 4.3. --- Effect of fluoride salts on BMD: results of clinical trials --- p.29 / Chapter 4.4. --- Effcct of fluoride on bone histomorphology --- p.30 / Chapter 4.5. --- Compliance with sodium fluoride therapy --- p.31 / Chapter 4.6. --- Contradiction of fluoride treatment --- p.31 / Chapter 4.7. --- Sodium monofluorophosphate preparation --- p.32 / Chapter CHAPTER 5 --- PHASE II: THE EFFECTS OF FLUORIDE ON BONE MINERAL DENSITY OF OAD PATIENTS ON STEROID TREATMENT --- p.37 / Chapter 5.1. --- Objectives --- p.37 / Chapter 5.2. --- Subjects and methods --- p.37 / Chapter 5.2.1. --- Power of the study --- p.37 / Chapter 5.2.2. --- Subjects --- p.37 / Chapter 5.2.3. --- Method of randomisation --- p.38 / Chapter 5.2.4. --- Treatment modalities --- p.39 / Chapter 5.2.4.1. --- Treatment group --- p.39 / Chapter 5.2.4.2. --- Control group --- p.39 / Chapter 5.2.5. --- Bone mineral density measurements --- p.39 / Chapter 5.2.6. --- Routine quality control of measurement and precision on patient repositioning --- p.40 / Chapter 5.2.7. --- Methods of monitoring drug compliance --- p.40 / Chapter 5.2.8 --- Statistical methods --- p.40 / Chapter CHAPTER 6 --- RESULTS FOR PHASE I --- p.42 / Chapter 6.1. --- Statistical power of this phase of the study --- p.42 / Chapter 6.2. --- Clinical features of OAD subjects on inhaled steroid --- p.42 / Chapter 6.3. --- Anthropometric measurements and bone mineral density --- p.45 / Chapter 6.4. --- Analysis of covariance for BMDs differences --- p.48 / Chapter 6.5. --- Multiple regression --- p.50 / Chapter 6.6 --- Correlation --- p.51 / Chapter CHAPTER 7 --- RESULTS FOR PHASE II: FLUORIDE AND CALCIUM TRIAL --- p.81 / Chapter 7.1. --- Factors affects the power of studies --- p.81 / Chapter 7.2. --- Clinical findings --- p.82 / Chapter 7.3. --- Body measurements and bone mineral densitometry --- p.85 / Chapter CHAPTER 8: --- DISCUSSION FOR PHASE I --- p.117 / Chapter CHAPTER 9: --- DISCUSSION FOR PHASE II: TRIDIN AND CALCIUM TRIAL --- p.124 / APPENDIX 1: QUESTIONNAIRE FOR OAD BONE MINERAL DENSITY STUDY --- p.132 / APPENDIX 2: BONE SCANS FROM HOLOGIC QDR2000 --- p.137 / APPENDIX 3. TABLES AND REFERENCE CURVES FOR NORMAL HONG KONG CHINESE FEMALE OR MALE BMD --- p.142 / REFERENCE --- p.150

Este estudo avaliou a eficácia do propionato de clobetasol a 0,05% em pomada, com uso de moldeiras individuais de silicone, em 22 pacientes com lesões gengivais de doenças mucocutâneas auto-imunes e inflamatórias, por meio de um estudo duplo-cego, cruzado, placebo-controlado. Os pacientes foram distribuídos em dois grupos: grupo 1, que consistiu de 5 pacientes em uso de corticosteróide e/ou imunossupressor sistêmico para controle de lesões cutâneas e/ou gengivais associadas às doenças mucocutâneas; grupo 2, que consistiu de 17 pacientes sem utilização de corticosteróide e/ou imunossupressor sistêmico. Os pacientes de cada grupo receberam a bisnaga 1, e foram orientados a utilizá-la no preenchimento das moldeiras. Em seguida, foram instruídos a aplicar a pomada com a moldeira 3 vezes ao dia, durante 20 minutos, por um período de duas semanas. A freqüência de uso da pomada foi reduzida na 3 a semana para 1 vez ao dia (pela manhã), em dias alternados. Após esta fase, foi estabelecido um intervalo de 2 semanas sem tratamento após o qual houve a inversão das pomadas (bisnaga 2), e os pacientes passaram a utilizá-la da mesma maneira que a bisnaga 1. As consultas de avaliações foram realizadas na 2 a , 5 a , 7 a , e na 10 a semana após o início do teste, e a resposta terapêutica foi baseada no percentual da remissão dos sinais classificada como completa (100%), excelente (75% a 99%), boa (50% a 74%), regular (1% a 49%), inalterada e piorada; e da remissão dos sintomas classificada como completa, parcial, inalterada e piorada. Durante as consultas de retorno, os pacientes foram monitorados quanto à ocorrência de efeitos colaterais. Com relação à remissão dos sinais, nos pacientes do grupo 1, 4 pacientes (80%) mostraram resposta regular; e 1 paciente (20%) apresentou piora do quadro clínico após o uso do propionato de clobetasol. Nos pacientes do grupo 2, 13 pacientes (76,5%) apresentaram alguma melhora durante o uso do propionato de clobetasol, e 4 pacientes (23,5%) apresentaram piora do quadro clínico. Com relação aos sintomas, durante o uso do propionato de clobetasol, 3 (60%) pacientes do grupo 1, apresentaram melhora parcial, 1 paciente (20%) não verificou mudança na sintomatologia, e 1 paciente (20%) referiu piora dos sintomas. Nos pacientes do grupo 2, completa melhora dos sintomas foi verificado em 2 pacientes (11,8%) e resposta parcial em 9 pacientes (52,9%) durante o uso do propionato de clobetasol. A diferença dos resultados obtidos entre o período de uso do propionato de clobetasol e placebo, nos dois grupos de pacientes e para os parâmetros analisados, não foi estatisticamente significante (Teste exato de Fisher; p > 0,05). Apenas 2 pacientes (11,8 %) do grupo 2 desenvolveram candidose após o uso do propionato de clobetasol. Os resultados deste estudo demonstraram que a aplicação do propionato de clobetasol 0,05% em pomada, com o auxílio de moldeiras de silicone, apresenta eficácia boa a moderada no controle das lesões gengivais de doenças mucocutâneas, causando mínimo de efeitos colaterais. / This study evaluated the efficacy of 0.05% clobetasol propionate in ointment administered with trays in 22 patients with gingival lesions of autoimmune and inflammatory mucocutaneous diseases. The patients were subdivided into two groups: group 1, which was composed by 5 patients treated systemically with corticosteroid and/or other immunosuppressive drug for control of skin and/or gingival lesions associated to mucocutaneous diseases; and the group 2, which was composed by 17 patients not being under systemic corticotherapy. The patients of each group received the container number 1 and they were instructed to apply the ointment with the tray for 20 minutes, 3 times daily, for 2 weeks. The frequency of use of ointment was reduced in the third week for once a day on alternate days. After that, the patients were instructed to discontinue the treatment for 2 weeks (washout period), and then were given the container number 2, to be used in the same way as that of the container 1. Each patient was examined in the weeks 2, 5, 7, and 10 after the beginning of the study. The therapeutic response was determined according to remission of signs on percentage, and assessed as follow: complete (100%), excellent (75% to 99%), good (50% to 74%), poor (1% to 49%), failed and worsened; and on remission of symptoms assessed as complete, partial, failed and worsened. At every visit, the patients were also examined for the presence of side-effects. In group 1, 4 patients (80%) had a poor response, and 1 patient (20%) had a worse of clinical presentation after the use of clobetasol propionate. In patients of group 2, 13 (76.5%) presented some improvement after the use of clobetasol propionate, and 4 patients (23.5%) presented worse of signals. For symptoms, 3 patients (60%) of the group 1 showed partial improvement while 1 (20%) presented no response, and 1 (20%) had symptoms worsened after the use of corticosteroid. In the group 2, complete improvement of symptoms was observed in 2 (11.8%) and partial in 9 (52.9%) after the use of clobetasol. There was no statistical difference when compared the results obtained with clobetasol propionate and placebo in the two groups of patients for the parameters evaluated (Fisher test; P > 0.05). Only 2 patients (11.8%) of group 2 developed candidosis after the use of clobetasol propionate. This study showed that clobetasol propionate ointment present good to moderate efficacy, with minimal side-effects, in the treatment of gingival lesions of mucocutaneous diseases.

Submitted by Jorge Silva (jorgelmsilva@ufrrj.br) on 2017-11-09T18:21:47Z No. of bitstreams: 1 2016 - Rafael Sonoda C?rtes.pdf: 1476755 bytes, checksum: 8d385f19ac5f844e345d9c74ea4ca89f (MD5) / Made available in DSpace on 2017-11-09T18:21:47Z (GMT). No. of bitstreams: 1 2016 - Rafael Sonoda C?rtes.pdf: 1476755 bytes, checksum: 8d385f19ac5f844e345d9c74ea4ca89f (MD5) Previous issue date: 2016-07-29 / CAPES / Myocardial infarction (MI) is the most prevalent nowadays syndrome. Similarly impressive, depression has caused many damages to health and the global economy. Epidemiologically, these different clinical conditions have a bidirectional relationship. Several studies in rats, in recent years, associated the emergence of analog signals depression post pathophysiological IM changes, among which the activation of pro-inflammatory factors and the activation of the hypothalamic-pituitary-adrenal endocrine axis (HPA). The objective of this study was: to study, in different rat groups, a short-term protocol, four days and a long, twenty-five days, the above features, besides elucidating the involvement of brain-derived neurotrophic factor (BDNF ) and hippocampal neurogenesis in the onset of depression induced experimental IM by ki-67 protein, cell proliferation marker. For this purpose, male Wistar rats (200-250 g) were subjected to IM through ligation of the left coronary artery and underwent preference for sucrose test and the open field test. They were measured: cardiac TNF-?, plasma and hypothalamic concentrations of TNF-? and IL-1?. In endocrine handle, plasma concentrations of adrenocorticotropic hormone (ACTH) and corticosterone and hypothalamic levels of corticotropin releasing hormone (CRH). Finally, we measured plasma concentrations of BDNF to the association with the neurogenesis of the hippocampus, an important region in the pathophysiology of depression. In the long protocol, infarcted animals showed similar signs of depression compared to those operated fake animals. Concomitantly, showed elevated levels of TNF-? and IL-1?, CRH, ACTH and corticosterone plasma levels and reduced BDNF, suggesting decreased proliferation of granule cells in the hippocampus and hence the emergence of depression in response to MI. Although further studies are required, it is believed that this study has translational impact serving experimental basis for the development of more effective future pharmacologic strategies to better quality and life expectancy of patients with myocardial infarction. / O infarto do mioc?rdio (IM) ? a s?ndrome de maior preval?ncia nos dias atuais. Semelhantemente impactante, a depress?o tem causado diversos preju?zos ? sa?de e a economia mundial. Epidemiologicamente, essas diferentes condi??es cl?nicas possuem uma rela??o bidirecional. Diversos estudos em ratos, nos ?ltimos anos, associam o surgimento de sinais an?logos a depress?o a altera??es fisiopatol?gicas p?s IM, dentre as quais a ativa??o de fatores pr?-inflamat?rios e a hiperativa??o do eixo end?crino hipot?lamo-hip?fise-adrenal (HPA). O objetivo deste trabalho foi: estudar, em grupos distintos de ratos, num protocolo a curto prazo, de quatro dias e num longo, de vinte e cinco dias, as caracter?sticas supracitadas, al?m de elucidar a participa??o do fator neurotr?fico derivado do c?rebro (BDNF) e da neurog?nese hipocampal no surgimento da depress?o induzida por IM experimental, atrav?s da prote?na ki-67, marcador de prolifera??o celular. Para tanto, ratos Wistar machos (200-250g) foram submetidos ao IM atrav?s da ligadura da art?ria coron?ria esquerda e submetidos ao teste de prefer?ncia pela sacarose, teste do nado for?ado e ao teste do campo aberto. Foram mensurados: os n?veis card?acos de TNF-? e as concentra??es plasm?ticas e hipotal?micas de TNF-? e IL-1?. Na al?a end?crina, as concentra??es plasm?ticas de horm?nio adrenocorticotr?fico (ACTH) e de corticosterona e os n?veis hipotal?micos de horm?nio liberador de corticotrofina (CRH). Por fim, foi mensurada as concentra??es plasm?ticas de BDNF para a associa??o com a neurog?nese do hipocampo, regi?o importante na fisiopatologia da depress?o. No protocolo longo, os animais infartados apresentaram sinais an?logos a depress?o em compara??o aos animais falso operados. Concomitantemente, apresentaram n?veis elevados de TNF-? e IL-1?, de CRH, ACTH e corticosterona e concentra??es plasm?ticas diminu?das de BDNF, sugerindo diminui??o da prolifera??o de c?lulas granulares no hipocampo e, consequentemente, o surgimento da depress?o em resposta ao IM. Embora sejam necess?rios mais estudos, acredita-se que este trabalho tenha impacto translacional, servindo de base experimental para o desenvolvimento de futuras estrat?gias farmacol?gicas mais eficazes para melhor qualidade e expectativa de vida de pacientes com infarto do mioc?rdio. Palavras chave: Infarto, citocinas, depress?o

Thousands of animal experiments have demonstrated that androgenic hormones, such as testosterone, during the prenatal and early postnatal periods, masculinise and defeminise various neural and behavioural characteristics that differ by sex. Can these findings from animal experiments be generalised to human behaviour? Can early androgen exposure shape subsequent gender-related disorders in humans? Chapter 1 (Introduction) provides an overview of the literature. Chapter 2 (Kung et al., 2016a) is the first study to demonstrate that testosterone concentrations in saliva samples collected during the early postnatal testosterone surge at 1 to 3 months of age can negatively predict subsequent expressive vocabulary size (how many words a child can say) during toddlerhood. Notably, males typically have a smaller expressive vocabulary than do females during toddlerhood and a small expressive vocabulary is predictive of subsequent language difficulties, such as dyslexia and stuttering, which are more common in boys. Chapters 3 (Kung et al., 2016b) and 4 (Kung et al., 2016c) evaluate a popular theory of autism, the extreme male brain theory, which argues that heighted androgen exposure during early development causes the male preponderance in autism. To test the hypothesised relationship, Chapters 3 and 4 use different measures and study populations, including testosterone concentrations in amniotic fluid samples obtained prenatally and saliva samples obtained during the early postnatal testosterone surge in typically developing children, as well as examining the adjustment in children exposed to unusually high levels of androgens prenatally due to congenital adrenal hyperplasia (CAH), a rare clinical condition occurring in approximately 1 in 18,000 births. Findings from these two chapters converge to show that any relationship between early androgen exposure and subsequent development of autistic traits is small, non-existent, or unreliable, providing a much-needed clarification of the role of early androgen exposure in the aetiology of autism. Using data from a general population study, Chapter 5 (Kung et al., 2018a) is the first study to show that male-typical play behaviour in early childhood, a trait that has been linked to increased early androgen exposure in previous research, can positively predict adolescent physical aggression, which is typically higher in males than in females. This positive association between play and aggression supports potential influences of early androgen exposure, as well as socio-cognitive influences involved in gender development. Chapter 6 (Kung et al., 2018b) is the first study to compare emotional and behavioural adjustment in children with CAH, their unaffected siblings, and children in the general population. Findings from this chapter suggest that although within the families with a child with CAH there are generally no differences in emotional or behavioural problems between boys or girls with CAH and their unaffected same-sex siblings, both girls with CAH and their unaffected sisters are at risk of developing behavioural problems when compared with girls in the general population. Familial influences and social stigma may contribute to this gender-specific pattern of behavioural adjustment. Finally, Chapter 7 (Discussion) integrates the findings and previous research and provides directions for further research. Chapter References Chapter 2 Kung, K. T. F., Browne, W. V., Constantinescu, M., Noorderhaven, R. M., and Hines, M. (2016). Early Postnatal Testosterone Predicts Sex-Related Differences in Early Expressive Vocabulary. Psychoneuroendocrinology, 68, 111-116. Chapter 3 Kung, K. T. F., Constantinescu, M., Browne W. V., Noorderhaven, R. M., and Hines, M. (2016). No Relationship Between Early Postnatal Testosterone and Autistic Traits in 18 to 30-Month-Old Children. Molecular Autism, 7:15. Chapter 4 Kung, K. T. F., Spencer, D., Pasterski, V., Neufeld, S., Glover, V., O'Connor, T. G., Hindmarsh, P. C., Hughes, I. A., Acerini, C. L., and Hines, M. (2016). No Relationship Between Prenatal Androgen Exposure and Autistic Traits: Convergent Evidence from Studies of Children with Congenital Adrenal Hyperplasia and of Amniotic Testosterone Concentrations in Typically-Developing Children. Journal of Child Psychology and Psychiatry, 57, 1455-1462. Chapter 5 Kung, K. T. F., Li, G., Golding, J., and Hines, M. (2018). Preschool Gender-Typed Play Behavior at Age 3.5 Years Predicts Physical Aggression at Age 13 Years. Archives of Sexual Behavior, 47, 905-914. Chapter 6 Kung, K. T. F., Spencer, D., Pasterski, V., Hindmarsh, P. C., Neufeld, S. A. S., Hughes, I. A., Acerini, C. L., and Hines, M. (2018). Emotional and Behavioral Adjustment in 4- to 11-Year-Old Boys and Girls with Classic Congenital Adrenal Hyperplasia and Unaffected Siblings. Psychoneuroendocrinology. 97, 104-110.

Xu Li. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 204-242). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Abstract not available

Includes bibliographical references (leaves 228-257). Aims to determine the impact of maternal undernutrition during late gestation and during the periconceptional and gestational periods on fetal growth, fetal blood pressure and the fetal hypothalamo-pituitary adrenal axis in the sheep.

Low birth weight is associated with an increased risk of impaired glucose tolerance and type 2 diabetes and with signs of increased hypothalamic pituitary adrenal axis activity in later life (1, 2). Low birth usually weight reflects a reduction in fetal growth, which largely depends on an adequate supply of nutrients and oxygen. Variations in supply modify the metabolic and neuroendocrine characteristics of the fetus, which in turn modulate the pattern of functional development as well as growth (3). An adverse fetal environment, evident as low birth weight, is therefore proposed to alter functional development with long term effects for the function and risk of disease in the individual later in life (4, 5). Increased HPAA impairs metabolic homeostasis and could therefore mediate effect of prenatal challenge on later metabolic control (6). It was therefore hypothesised that restriction of fetal growth, increases circulating cortisol and/or alters sensitivity to cortisol, which increases fasting blood glucose, and impairs glucose tolerance in the young adult. Large litter size in the guinea pig is characterised by reduced placental and fetal growth, reduced size at birth and insulin resistance in offspring in later life, providing a suitable model to test this hypothesis. Spontaneous restriction of fetal growth in the guinea pig, evident as small size at birth, was associated with increased salivary cortisol, in both sexes but at different stages of postnatal life. In males, salivary cortisol was increased with small size at birth in early and adult life, but reduced later with ageing. In females however, salivary cortisol was increased in juveniles and in aged adults, possibly reflecting the impact of the oestrus cycle on cortisol production in mature cycling females. Altered activity of the HPGA, which can influence that of the HPAA, has also been reported to be programmed by prenatal restriction. In the guinea pig, salivary testosterone in males increased with age and small size at birth in juveniles, young and aged adults. In females, salivary progesterone increased with age up to 300 days, and decreased with size at birth in the young guinea pig. Although testosterone inhibits HPAA activity, in males, mean salivary cortisol correlated positively with mean salivary testosterone at 100 and 300 days of age. In contrast, progesterone may enhance HPAA activity, and consistent with this, in females, mean salivary progesterone correlated with mean salivary cortisol at 400 days of age. Therefore, salivary testosterone in the male and salivary progesterone in the female guinea pig changes with maturation and has previously reported in this or other species, but small size at birth increases salivary testosterone in males with modest effects in early life in females. This together with the unexpected positive associations of salivary cortisol with testosterone in males, suggests that programming of the HPAA makes little contribution to that of the HPAA as indicated by salivary cortisol. Here we show that low birth weight is associated with increased fasting blood glucose and impaired glucose tolerance in both male and female young adult guinea pigs aged 100 days. Fasting and mean (during IVGTT) plasma cortisol was reduced in low birth weight female adult guinea pigs, and is not vary with size at birth at this age in males. This suggests that circulating cortisol does not contribute to the impaired glycaemia associated with small size at birth in the guinea pig. Glucose tolerance was increasingly impaired in males but not females, as mean plasma cortisol increased. This is consistent with cortisol impairing glycaemia in the guinea pig as in other species, in males at least. To assess the role of cortisol in prentally programmed impairment of glycaemia directly, metyrapone or vehicle containing 24% ethanol was administered to young adult guinea pigs for 3 days. Treatment with the latter impaired fasting blood glucose and glucose tolerance in females and the latter in males compared to a previous IVGTT and this was exacerbated in low birth weight females. Metyrapone prevented this impairment of fasting glycaemia and glucose tolerance in the low birth weight adult female guinea pig and in the male guinea pig regardless of birth weight class. Neither vehicle or metyrapone altered plasma cortisol, before or during a second IVGTT. Limited numbers of animals, particularly females, limited this study however and additional investigation is required. Nevertheless this shows for the first time that inhibition of glucocorticoid synthesis in the guinea pig improves glucose control. Furthermore this suggests that the low birth weight guinea pig may be more sensitive to cortisol, have increased cortisol synthesis or reduced inactivation of cortisol in peripheral tissues, leading to increased local cortisol action. In conclusion, alterations in peripheral HPAA activity in the guinea pig due to restricted fetal growth may contribute to their prenatally programmed development of impaired glucose tolerance as young adults, but the extent of that contribution may vary with age and gender. / Thesis (Ph.D.) -- University of Adelaide, School of Paediatrics and Reproductive Health, 2008

Thesis (M.D) -- University of Texas Southwestern Medical Center at Dallas, 2007. / Vita. Bibliography: pp. 35-37.

<p>Persistent environmental pollutants were examined for their interaction with the glucocorticoid hormone system. The focus was placed on interference with the glucocorticoid synthesis and the glucocorticoid-signalling pathway in various <i>in vitro</i> test systems.</p><p>Several aryl methyl sulphones competitively inhibited CYP11B1 activity in mouse adrenocortical Y1 cells. The DDT metabolite, 3-methylsulphonyl-2,2’-bis(4-chlorophenyl)-1,1’-dichloroethene (3-MeSO₂-DDE) had a higher affinity to the enzyme than the endogenous substrate, 11-deoxycorticosterone. In fact, 3-MeSO₂-DDE (K_i 1.6 μM) was almost as potent as the drug metyrapone (K_i 0.8 μM), a well-known inhibitor of the enzyme. 3-MeSO₂-DDE inhibited CYP11B1 activity in human adrenocortical H295R carcinoma cells, and at higher concentrations the CYP21 activity. The human H295R cell line seems to be a useful test system for studies of enzyme activities and could be used to screen endocrine disrupting chemicals interfering with the glucocorticoid hormone synthesis.</p><p>Several chiral PCB methyl sulphones and the fungicide tolylfluanid proved to be antagonists to the glucocorticoid receptor (GR) in rat hepatoma cells and/or Chinese hamster ovary cells stable transformed with a human GR and a responsive reporter vector. The 4-methylsulphonyl-2,3,6,2’,4’,5’-hexachlorobiphenyl (4-MeSO₂-CB149) enantiomers had similar antagonistic effect on the GR. Co-exposure of substances led to additive inhibitory effects on glucocorticoid-regulated protein synthesis in rat hepatoma cells. In general, 4-substituted but not 3-substituted methylsulphonyl-PCBs interacted with the glucocorticoid hormone system.</p><p>In the environment, humans and wildlife are constantly exposed to a wide range of chemicals. Considering the effects of these substances via mechanisms of actions described in this thesis, interference of xenobiotics with the glucocorticoid hormone system deserves further attention. In conclusion, environmental pollutants can interact with the glucocorticoid hormone system <i>in vitro</i>, yet the effects of the tested substances on this hormone system remain to be established <i>in vivo.</i></p>