When Y-1 mouse adrenal tumor cells were treated with sodium orthovanadate, an intermediate filament (IF) inhibitor in BHK21-F cells, there was no change in the amount of 20α-dihydroprogesterone produced. A neurofilament inhibitor, β, β'-iminodipropionitrile (IDPN), enhanced the ability of Y-1 cells to produce steroid in response to ACTH by acting on the plasma membrane. Electron microscopy of Y-1 cells extracted with Triton X-100 revealed that both vanadate and IDPN caused the aggregation of cytoskeletal and granular structures in the perinuclear area. The steroidogenic effects of IDPN suggest that the perinuclear aggrergation of cytoskeletal structures may result from the detachment of IF from the plasma membrane, while the reason for the cytoskeletal changes by vanadate is unknown.

Orientador: Maria de Lourdes da Silva Marques Ferreira / Banca: Ione Corrêa / Banca: Maria José Sanches Marin / Resumo: A atenção integral à saúde da mulher pressupõe assistência em todas as fases de sua vida. O climatério, por compreender um período relativamente longo da vida da mulher, deve merecer atenção crescente da sociedade, pois a expectativa de vida após a menopausa é atualmente equivalente ao período de vida reprodutiva. A presente pesquisa objetivou avaliar a qualidade de vida das mulheres do município de Promissão/SP que estão passando por essa fase, com ou sem uso da terapia de reposição hormonal. Tratou-se de um estudo epidemiológico longitudinal, com amostra de 99 mulheres para cada grupo. Avaliaram-se as características sociodemográficas, clínicas e comportamentais. Aplicou-se Menopause Rating Scale (MRS) para avaliar a intensidade dos sintomas climatéricos, e o questionário Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) para avaliação da qualidade de vida. Na análise dos dados utilizaram-se os testes t de Student, Qui-quadrado e Tukey. As usuárias de TRH apresentaram média etária de 50,76 ± 3,63 anos e as não usuárias de 48,95 ± 6,27anos (p=0,01). Houve diferença estatisticamente significativa em relação ao estado marital (p=<0,001). As usuárias relataram maior frequência de sintomas climatéricos de intensidade leve a moderada. Dos oito domínios de qualidade de vida avaliados, apenas aspectos sociais apresentou escore abaixo de 50 para os dois grupos. Destaca-se o domínio dor com escores por volta de 60. Fenômenos vasomotores com escores também acima de 50 para o MRS foram evidenciados. Houve diferenças entre os grupos em relação aos componentes do SF-36 e MRS para estado geral de saúde, capacidade funcional, menor capacidade, depressão, insônia e fenômenos vasomotores. As mulheres usuárias e não usuárias de TRH apresentaram boa qualidade de vida / Abstract: The comprehensive care to women's health requires assistance in all phases of his life. The climacteric, it comprises a relatively long period of woman's life, deserves increased attention from society because life expectancy after menopause is currently equivalent to the period of reproductive life. This study aimed to evaluate the quality of life of women in the municipality of Promissão/SP who are going through this phase with or without use of hormone replacement therapy (HRT). This was a longitudinal epidemiological study with a sample of 99 women in each group. We evaluated the sociodemographic, clinical and behavioral. Applied Menopause Rating Scale (MRS) to assess the intensity of climacteric symptoms and the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) to assess quality of life. In the data analysis used the Student t test, chi-square and Tukey. HRT users had a mean age of 50.76 ± 3.63 years and nonusers of 48.95 ± 6.27 years (p = 0.01). There was no statistically significant difference in marital status (p = <0.001). Users reported a higher frequency of climacteric symptoms of mild to moderate intensity. Of the eight domains of quality of life assessed only social scored below 50 for the two groups. It stands out with the pain domain scores around 60. Vasomotor phenomena also with scores above 50 were shown to MRS. There were differences between the groups in relation to the components of the SF-36 and MRS to general health, functional capacity, lower capacity, depression, insomnia and vasomotor phenomena. Women users and nonusers of HRT had good quality of life / Mestre

OBJETIVO: Analisar a sintomatologia climatérica, a função hepática e a hemostasia das pacientes com hepatite crônica pelo vírus C, durante o uso da terapia hormonal. METODOLOGIA: As pacientes foram divididas em dois grupos: Grupo TH (Grupo caso) - 25 pacientes com terapia hormonal transdérmica (50mcg de estradiol e 170 mcg de noretisterona/dia) por 9 meses, e Grupo NT (Grupo controle) - 25 pacientes sem terapia hormonal, ambos com sintomas climatéricos. A menopausa foi confirmada pela dosagem do FSH, LH e estradiol, e a hepatite C foi diagnosticada pela sorologia, PCR (reação em cadeia de polimerase) e biópsia hepática (grau histológico variando de I-IV). Os dois grupos foram avaliados no mês 0, 1,4,7 e 9; sendo a sintomatologia climatérica mensurada através do Índice Menopausal de Kupperman, a função hepática e a hemostasia pelos exames: alanina aminotransferase, aspartato aminotransferase, gama glutamiltransferase, fosfatase alcalina, bilirrubinas, albumina, tempo de protrombina, fator V, fibrinogênio e plaquetas. ANÁLISE ESTATÍSTICA: realizada através do teste t de Student, teste de Mann Whitney e análises de variâncias com medidas repetidas com dois fatores. Após a realização das análises de variâncias, para os efeitos estatisticamente significantes foram realizadas comparações múltiplas através de contrastes ou do método de Dunnett. RESULTADOS: A média da idade das pacientes foi de 53,72 e a da menopausa foi de 47,3 anos. Os escores médios dos sintomas vasomotores, fraqueza, palpitação e a somatória dos valores atribuídos ao índice menopausal de Kupperman sofreram alteração no comportamento ao longo do tempo (p<0,05). Os valores da fosfatase alcalina apresentaram alteração no comportamento ao longo do tempo (p<0,05), entretanto, as demais medidas da função hepática e hemostasia, não apresentaram diferença entre os grupos. CONCLUSÕES: Houve melhora da sintomatologia climatérica. Não houve alteração na hemostasia e na função hepática, exceção feita à fosfatase alcalina que apresentou melhora significativa no Grupo TH a partir do 4º mês; portanto, houve melhora na qualidade de vida, sem interferência na função hepática e na hemostasia. / OBJECTIVE: To analize climacteric symptoms, liver function, hemostasis in patients with chronic viral hepatitis C, during hormone therapy. DESIGN: Patients were divided in two groups: Group TH (Case Group) - 25 patients on transdermal hormone therapy (50mcg of estradiol and 170 mcg of norethisterone/day) for 9 months, and Group NT (Control Group) - 25 hormone-untreated patients, both with climacteric symptoms. Menopause was confirmed by measuring FSH, LH and estradiol, and hepatitis C was diagnosed by serology, PCR (Polymerase Chain Reaction) and liver biopsy (histological type stages I to IV). Both groups were evaluated in the months 0, 1, 4, 7 and 9; and the climacteric symptoms measured by using Kupperman menopausal index, liver function and hemostasis by the following laboratory tests: alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase, alkaline phosphatase, bilirubin, albumin, prothrombin time (PT), factor V, fibrinogen and platelets. STATISTICAL ANALYSIS: Student\'s t test, Mann-Whitney test and two-factor analysis of variance with repeated measures were applied. After analysis of variance, multi-factor analysis of variance was applied for the statistically significant effects using contrasts or Dunnett?s test. RESULTS: The mean age of patients was 53.72 and the mean age of menopause was 47.3 years. The total mean scores for vasomotor symptoms, fatigue, palpitations and the sum of the values attributed to Kupperman menopausal index do change throughout time (p<0.05). Levels of alkaline phosphatase show alteration throughout time (p<0.05), although, other measures for liver function and hemostasis present no mean difference between the groups. CONCLUSION: There was an improvement in climacteric symptoms. No change was found in hemostasis levels or liver function. However, alkaline phosphatase levels significantly improved in Group TH starting in month 4; therefore, an increase in quality of life was observed.

A relação entre risco cardiovascular e terapia hormonal na pós-menopausa é controversa. Ainda que o estrogênio endógeno possa estar associado ao menor risco cardiovascular observado em mulheres na pré-menopausa em relação às pós-menopáusicas, grandes ensaios clínicos, como o WHI, falharam em demonstrar efeito benéfico da terapia hormonal. Estes resultados podem ter sido influenciados por uma série de fatores, sendo os mais importantes: idade média das pacientes e tempo de menopausa superiores às candidatas usuais de terapia hormonal, tipo e dose dos hormônios utilizados. Desenvolvemos ensaio clínico randomizado, cross-over, com objetivo de avaliar os efeitos de dois tipos de tratamento hormonal na menopausa: tratamento oral baixa dose, associação de estradiol 17 β nasal 300 μcg e drospirenona 2 mg, diário e tratamento nâo oral, estradiol 17 β nasal diário e progesterona micronizada vaginal, 200 mg, 14 dias por mês , sobre variáveis relacionadas com inflamação e função endotelial, perfil antropométrico, metabólico e hormonal em mulheres na pós-menopausa recente e sem doença clínica evidente. Quarenta mulheres na pós-menopausa foram alocadas aleatoriamente para iniciar o tratamento hormonal por um dos dois grupos de tratamento: via oral baixa dose (n=20): ou via não oral (n=20). Ao final dos primeiros 2 meses do estudo, o grupo inicialmente tratado com terapia oral passou a receber tratamento não oral por mais 2 meses, e o grupo inicialmente tratado com terapia não oral passou a receber terapia oral também por mais 2 meses. A avaliação laboratorial foi realizada antes e ao final de 2 e 4 meses de tratamento hormonal. A amostra do estudo foi composta por mulheres com média etária de 51,2 ± 2,7 anos e tempo de amenorréia de 23,1 ± 10 meses. Após os primeiros 2 meses de tratamento, não houve diferença significativa entre os tratamentos sobre circunferência da cintura, relação cintura/quadril, índice de massa corporal e níveis de pressão arterial. Colesterol total diminuiu em ambos os tratamentos de forma semelhante. O tratamento oral teve um efeito maior em reduzir os níveis de LDL-C. HDL-C, triglicerídeos, glicemia e insulinemia de jejum, glicemia e insulinemia 2 horas após sobrecarga oral de glicose não se modificaram. PCR e FVWdiminuíram significativamente, e fibrinogênio permaneceu inalterado. Após o período de 4 meses de tratamento hormonal, não houve diferença significativa entre os tratamentos sobre circunferência da cintura, relação cintura/quadril, índice de massa corporal e níveis de pressão arterial. Durante o tratamento oral observou-se redução da circunferência da cintura e da relação cintura/ quadril em relação ao basal. Colesterol total diminuiu em ambos os grupos de tratamento, e HDL-C diminuiu discreta, mas significativamente após o tratamento oral, enquanto triglicerídeos diminuíram durante tratamento não oral. A glicemia 2 horas após sobrecarga oral de glicose apresentou valores mais elevados em relação ao basal após tratamento oral. Em contraste, glicemia e insulinemia em jejum e insulinemia 2 horas após sobrecarga oral de glicose não se modificaram. Níveis de FVW encontraram-se significativamente reduzidos após 4 meses de tratamento hormonal. Em conclusão, os resultados obtidos em nosso estudo sugerem que os tratamentos não induziram efeitos deletérios sobre variáveis relacionadas com risco cardiovascular, a curto prazo, em uma população de mulheres na pós-menopausa recente e aparentemente saudáveis. O tratamento hormonal baixa dose por via oral manteve os efeitos benéficos conhecidos do tratamento hormonal por via oral, a redução do colesterol total e do LDL-C, e evitou os efeitos nocivos tradicionalmente atribuídos à via oral: o aumento de marcadores próinflamatórios, relacionados à disfunção endotelial. O tratamento hormonal por via não oral mostrou-se também uma alternativa segura, não relacionado à modificações no perfil metabólico e nos marcadores de função endotelial. / The relationship between cardiovascular risk and hormone therapy (HT) for menopause is a contemporary and complex issue. While evidences suggest an association between endogenous estrogen and cardiovascular protection among premenopausal women, recent clinical trials have failed in demonstrate a benefic impact of HT on prevention of cardiovascular events. These results seem to be related by several factors, including selection biases like higher mean age of and time since menopause of participants, fixed type and dosages of hormones administered. A cross-over, randomized clinical trial was designed in order to evaluate the effects of two types of HT: low dose oral treatment, estradiol 17 β oral 1 mg and drospirenona 2 mg, by day and non-oral treatment, estradiol 17 β nasal 300 μcg by day and vaginal micronized progesterone, 200 mg/d, 14 days by month on variables associated with endothelial function, anthropometric, metabolic and hormonal variables on early and healthy postmenopausal women.Forty postmenopausal women were randomly allocated to start with one of the treatments: low dose oral treatment or non-oral treatment. At the end of two months, the group that started with low dose oral treatment passed to receive the non oral treatment for additional two months and vice-versa. Laboratory evaluations were performed before, at 1, 2 and 4 months of HT. The sample of the study included postmenopausal women presenting mean age of 51.2 ± 2.7 years and mean time since menopause of 23.1 ± 10 months. After 2 months, no significant differences were observed between treatments on waist circumference, waist to hip ratio, BMI and arterial pressure. Total cholesterol levels were reduced on both treatments. Low oral dose treatment had greater effect in reducing LDL cholesterol. HDL cholesterol, triglycerides, fast and 2 hours glucose and insulin levels did not change with either treatment. PCR and vW factor levels were reduced in both treatment groups and fibrinogen did not change. After 4 months of low oral dose treatment, a reduction on waist circumference and waist/circumference ratio was found. Total cholesterol was lower than basal levels on bothtreatment groups and while HDL cholesterol presented a slight but significant reduction on low oral dose treatment, triglycerides decreased significantly on non oral treatment. Two hours glucose was higher than basal levels but fast glucose and fast or 2 h insulin levels did not change after low oral dose therapy. After 4 months, vW factor decreased only on non oral treatment and PCR and fibrinogens were unchanged on both treatment groups. In conclusion, the present results suggest that the studied treatments did not induce deleterious effects on variables related to cardiovascular risk, at least at short period of time, in early postmenopausal and apparently healthy women. Low dose oral HT has maintained the well known beneficial effects on lipid profile (lower total and LDL cholesterol) and did not induced an increase on pro-inflammatory or endothelial function markers. On the other hand, non oral HT has shown to be a safe alternative, and was not related to changes on metabolic profile or markers of endothelial function.

No description available.

Asthma is a chronic inflammatory disease of the airways. Using a murine model which replicates many characteristic features of human asthma, this study evaluated the effects of treatment with anti-inflammatory drugs on the lesions of chronic asthma, and investigated potential underlying molecular mechanisms. Treatment with dexamethasone, a glucocorticoid, was compared with roflumilast, a novel phosphodiesterase-4 (PDE4) inhibitor. BALB/c mice sensitised to ovalbumin were challenged with a low mass concentration of aerosolised antigen for 30 min/day, 3 days/week for 6 weeks. In weeks 5 and 6, groups of animals were treated with either dexamethasone or roflumilast. Assessment included changes in acute-on-chronic inflammation, structural remodelling of the airways and airway hyper-responsiveness to a bronchoconstrictor stimulus. These were correlated with the expression of pro-inflammatory cytokines and growth factors. Compared to vehicle-treated control animals, dexamethasone- and roflumilast-treated mice exhibited reduced accumulation of intra-epithelial eosinophils and chronic inflammatory cells, including CD3+ T-lymphocytes in the airways. Similarly, both drugs inhibited subepithelial fibrosis and airway epithelial thickening, although only dexamethasone inhibited goblet cell hyperplasia/metaplasia. Airway hyper-reactivity was not diminished by either drug. Both treatments suppressed production of Th2 cytokines by ovalbumin-restimulated peribronchial lymph node cells. In selectively dissected airway tissue from vehicletreated animals, increased expression of mRNA for several pro-inflammatory cytokines (TNF-α, GM-CSF, IL-6) and cytokines characteristic of Th1 (IFN-γ), Th2 (IL-5, IL-13)and Th17 (IL-17A) cells was demonstrated using real-time PCR. Enhanced expression of growth factors (TGF-β1 and FGF-2) was also demonstrated in airway epithelium isolated by laser capture microdissection. Interestingly, whereas treatment with dexamethasone significantly inhibited expression of mRNA for all of the inflammationrelated cytokines examined, roflumilast inhibited only IL-17A, TNF-α, GM-CSF and IL-6. Both drugs inhibited mRNA expression of growth factors by epithelial cells. Because roflumilast was as effective as dexamethasone in suppressing inflammation and most changes of remodelling, the selective suppression of IL-17A, TNF-α, GM-CSF and IL-6 suggests that these mediators, or the cells that produce them, may have critical roles in pathogenesis. Furthermore, they may be particularly appropriate therapeutic targets in chronic asthma.

Low physical activity levels and high serum C-reactive protein (CRP) levels are risk factors for coronary artery disease (CAD) in both men and women. However, postmenopausal women who take hormone replacement therapy (HRT) may have increased risk of CAD because of HRT-related increases in serum CRP. There are two manuscripts in this dissertation. The purpose of the first manuscript was to determine whether higher physical activity energy expenditure was associated with lower serum CRP, independent of oral HRT status and body fatness, in 133 postmenopausal women. Higher physical activity energy expenditures were significantly associated with lower serum CRP levels (r=-0.21, p=0.0l9), independent of oral HRT use, age, smoking behavior, alcohol consumption, aspirin use, and statin use. However, in the complete multivariate model, which included body fat, the association between higher physical activity and lower serum CRP levels was abolished. The purpose of the second study was to quantify the biological variability of insulin resistant CAD risk factors in a sample of 8 postmenopausal women. Risk factor outcomes, including serum total cholesterol, serum triglycerides (TG), serum high-density lipoprotein cholesterol (HDL-C), serum glucose, plasma insulin, serum CRP, waist and hip circumferences, abdominal sagittal diameter, body fat, systolic (SBP) and diastolic blood pressure, and self-reported physical activity energy expenditure, were measured on two occasions, 7-12 days apart. High absolute biological variability values (by standard error of measurement) were observed for serum TG (32.0 mg/dl), serum CRP (5.6 mg/l), SBP (4.0 mmHg), and physical activity (9.4 kcal/kg/week). High relative biological variability (by within-subjects coefficient of variation ���27.3%) was also observed for serum TG, serum CRP, and physical activity. Bland-Altman plots identified individual outliers for serum TG, serum CRP, plasma insulin, and SBP. Together, the results suggest that the correlations between lower levels of serum CRP and higher levels of physical activity, though significant, may have been attenuated by the high biological variability of both serum CRP and physical activity. Thus, the importance of higher levels of physical activity, in decreasing serum CRP and the concomitant risk of heart disease, may be underestimated in the absence of serial measurement of serum CRP and physical activity. / Graduation date: 2002

In the United States, falls are the leading cause of unintentional death with one of every three people 65 years and older falling each year. Falls account for approximately 95% of hip fractures among older adults and falls to the side predominate hip fracture related falls in this population. However, risk factors for side and frequent falls are poorly understood. Furthermore, few data exist to explain differences in bone mineral density among older postmenopausal women. In particular, data regarding the timing of hormone replacement therapy (HRT) among older women is scarce. In the first aim of this dissertation, we examined changes in mobility and balance-related risk factors for side falls as well as differences in these risk factors according to fall status in a population of 107 independent, elderly women (>70 yrs), who were followed over 2 years. We found hip abduction strength decreased (p<.001) in all subjects, with side-fallers exhibiting weaker hip abduction strength (p=.008), greater sway velocity (p=.027), and slower performances on the tandem walk (p=.039) and Get Up and Go (p<.001) compared to non-fallers. For the second study, in the same population, we examined 2-year changes in balance self-efficacy (BSE) and the relationship of BSE to side fall risk factors and falls incidence. Results showed BSE at baseline was predictive of Get Up and Go, hip abduction strength and tandem walk at follow-up (p<.008), but that BSE decreased only among the non-fallers (p=.013). In the third study, we examined 3-yr hip bone mineral density (BMD) changes in women with distinct hormone replacement therapy (HRT) profiles: 1) no hormone replacement therapy (N0HRT), 2) HRT continually since menopause (Continual), 3) HRT begun 10 years after menopause (Late), 4) HRT initiated within 5 years (New), and compared the change in BMD of the hip across HRT groups. Only the NoHRT group lost bone over the 3 years (p=.014). We also assessed BMD of the lateral spine across levels of estrogen use in a sub-sample of participants and found long-term HRT users had significantly higher lateral spine BMD (p=.041) compared to women who had never been on HRT. / Graduation date: 2003

Estrogen therapy (ET) is most effective to reduce menopausal symptoms and prevent other disorders associated with estrogen deficiency. However, Women's Health Initiative studies found that hormone therapy (HT) containing estrogen plus progestogen, but not estrogen-alone increases breast cancer (BC) risk. To prevent the increase in BC risk and yet relieve menopausal symptoms, a novel HT with 17&#946;-estradiol (E2) for symptom relief, progesterone (P4) for uterine protection and melatonin (Mel) for both BC and uterine protection was designed. Inclusion of Mel was postulated to offer uterine protection with lower P4 dose and protect against BC. The goal of this study was to assess the efficacy of E2, P4 and Mel Therapy (EPMT) on mammary cancer (MC) and uterine protection in MMTV-Neu mouse model that mimics HER2 BC. Starting at 2 months age, female mice received Mel in drinking water at night to supplement endogenous Mel surge; while E2 and P4 Therapy (EPT) was provided continuously in diet until 14 months with weekly MC onset and growth monitoring. Normal mammary, uterus and mammary tumors harvested by month 14 were analyzed for potential mechanisms. The results from this study revealed that EPMT delayed tumor onset leading to a decrease in MC incidence. In addition, mice in the EPMT group had no increase in relative uterine weight as opposite to an increase of this parameter in EPT group versus control. The percent tumor-bearing mice with gross metastatic lung lesions were reduced in Mel, EPT and EPMT groups. Mel receptor, estrogen receptor (ER) and progesterone receptor (PR) expression revealed that all tissues examined have Mel receptors. However, ER and PR expression varied. In normal mammary tissue, both ER&#945; and PR were detected by immunohistochemistry. However, no ER&#945; and PR were detected in mammary tumors of same mice. In uterus, mice given Mel or EPMT had significant decreases in PR expression but no change in ER&#945; expression compared to control suggesting that Mel-mediated inhibition of ER binding to estrogen response elements may be involved in the down regulation of uterine PRs. Overall, this study reveal that EPMT prevents mammary cancer and may protect against uterotrophy. / Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences; / Pharmacology / PhD; / Dissertation;

Title from PDF of title page. / Document formatted into pages; contains 165 pages. / Thesis (M.A.)--University of South Florida, 2002. / Includes bibliographical references. / Text (Electronic thesis) in PDF format. / ABSTRACT: The doctrine of informed consent, defined as respect for autonomy, is the tool used to govern the relationship between physicians and patients. Its framework relies on rights and duties that mark these relationships. The main purpose of informed consent is to promote human rights and dignity. Some researchers claim that informed consent has successfully replaced patients&softsign; historical predispositions to accept physicians' advice without much explicit resistance. / Although the doctrine of informed consent promotes ideals worth pursuing, a successful implementation of these ideals in practice has yet to occur. What has happened in practice is that attorneys, physicians, and hospital administrators often use consent forms mainly to protect physicians and medical facilities from liability. Consequently, ethicists, legal theorists, and physicians need to do much more to explain how human rights and human dignity relate to the practice of medicine and how the professionals can promote them in practice. / This is especially important because patients' vulnerability has increased just as the complexity and power of medical science and technology have increased. Certain health care practices can shed light on the difficulties of implementing the doctrine of informed consent and explain why it is insufficient to protect patients' rights and dignity. Defining a normal biological event as a disease, and routinely prescribing hormone drug therapy to menopausal women for all health conditions related to menopause, does not meet the standards of free informed consent. / Clinicians provide insufficient disclosure about risks related to long-term use of hormone therapies and about the absence of solid evidence to support their bias toward hormone therapies as a treatment of choice for menopause related health conditions. The contributing problem is women's failure to act as autonomous agents because they either choose not to take an active part in their own therapy or because they fear to question physicians' medical authority. To insure that patients' autonomy and free choice are a part of every physician-patient interaction, physicians and patients need actively to promote them as values that are absolutely indispensable in physicians' offices, clinics, and hospitals. / System requirements: World Wide Web browser and PDF reader. / Mode of access: World Wide Web.