Long-term glucocorticoid use leads to glucocorticoid-induced osteoporosis (GIOP) and fractures which require proper management. Little is known about the "real-world," long-term costs and effectiveness of anti-osteoporotic treatments. A retrospective analysis of data from the 1996-2004 Medical Expenditure Panel Survey was conducted to evaluate the "real-world" outcomes. Markov modeling with Monte Carlo simulations was used to yield long-term estimates of these outcomes. A total of 5,461 subjects met the study criteria for long-term glucocorticoid users (LTGS, average prednisone-equivalent dose=11.0 mg/day, average length=237 days), which represents 2.3% of the non-institutional U.S. population. The study subjects tended to be middle-aged (49.7 years old), female (61.4%) and white (86.2%). Overall 22.4% of LTGS users reported use of any anti-osteoporotic agent. Hormone replacement therapy (HRT) was the most frequently used in women followed by bisphosphonates, while bisphosphonates and calcitonin were used by men. Analyses of variance indicated some significant differences in characteristics of LTGS users among treatment groups which suggest a selection bias. Female LTGS users had higher prevalence rates (6.8%) of osteoporosis than males (1.0%), but the prevalence rates of osteoporotic fractures were similar (3.0%). The logistic regression analyses indicated that the use of oral glucocorticoid tablets does not significantly change the odds of osteoporotic fractures in study subjects (relative risk (RR)=1.146, 95% confidence interval (CI) 0.901-1.458 for subjects in the WELL state; RR=0.55, 95% CI 0.188-1.621 for subjects in the GIOP state; RR=1.241, 95% CI 0.532-2.893 for subjects in the GIFX state). The estimated 10-year and lifetime incremental cost per osteoporotic fracture avoided are $27,253-$35,692 (10-year) and $84,942-$91,075 (lifetime) in hypothetical female glucocorticoid users. HRT is the most cost-effective option for hypothetical females except that calcitonin is preferred for 65-year-old females receiving lifetime treatments. When HRT is excluded, calcitonin is the next most cost-effective option except that raloxifene is preferred for 30- and 50-year-old females receiving 10-year treatments. Calcitonin is the most cost-effective option for male glucocorticoid users. Bisphosphonates are less cost-effective which may be due to selection bias. Anti-osteoporotic treatments are recommended for all long-term glucocorticoid users, but the preferred option depends on gender, age, length of treatments and budgets.

No description available.

Thesis (Ph. D.)--University of Missouri--Columbia, 1996. / "December 1996." Typescript. Vita. Includes bibliographical references (leaves 138-152). Also available on the Internet.

Thesis (Ph. D.)--Rutgers University, 2008. / "Graduate Program in Toxicology." Includes bibliographical references (p. 135-152).

Thesis (M.S.) University of Missouri-Columbia, 2006. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file viewed on (May 18, 2007) Includes bibliographical references.

Glucocorticoids (GC) are powerful metabolic hormones with anti-inflammatory actions. Despite major side effects they remain widely prescribed therapies. GC regulates gene expression through an intracellular receptor (GR), which is a ligand activated transcription factor. Macrophages are innate immune cells and major targets of GC. Traditionally repression of pro-inflammatory genes in the context of an inflammatory stimulus has been considered the primary mode of action of GC in macrophages. The work described in this thesis has demonstrated that GC act primarily as inducers of gene expression in primary macrophages from both mouse and man, but the set of induced genes is very different between the two species. Chromatin immunoprecipitation and sequencing (ChIP-seq) in each species using anti-GR antibodies revealed candidate enhancers in the vicinity of inducible genes that were generally not shared between mouse and man. The differences in binding were correlated with DNA sequence changes at the enhancer sites between the two species, that caused gain or loss of predicted GR receptor-binding motifs. The mechanism of action of GC was investigated by imaging several different target loci using fluorescence in situ hybridisation in macrophage nuclei. Chromatin at specific GC responsive loci was found to decondense within minutes of exposure of macrophages to the ligand. The apparent decondensation was effect was maintained for at least 24 hours and was not prevented by inhibitors of transcription. The general principles of the GC response were shared between species. However the divergence found underlines the caution that must be used when translating specific findings from mouse to man. Additionally, the data support a role for GR driven changes to chromatin structure in gene regulation in macrophages.

Human plasma contains cortisol (F) and corticosterone (B) at a ratio of ~10:1. B is well studied in mice and rats, which do not produce F due to absent adrenal Cyp17, but is largely neglected in humans. Differential transmembrane export of F > B by ABCB1 may account for accumulation of B in the CNS. Conversely, ABCC1, expressed in human adipose tissue, preferentially exports B>F. Here we tested the hypotheses that: (i) negative feedback suppression of the hypothalamic-pituitary-adrenal (HPA) axis is disproportionately sensitive to B; (ii) adipose tissue is disproportionately sensitive to F; and (iii) low plasma B contributes to impaired HPA axis negative feedback and increased F action in metabolic syndrome. We validated a stable isotope tracer for B in vitro and demonstrated distinct kinetics of B and F in vivo. In a randomised crossover study, we undertook ramped steady state infusion of B or F in 10 patients with Addison’s disease. Although levels of B were marginally lower than F, ACTH was similarly suppressed, and yet glucocorticoid-responsive transcripts in adipose tissue were much higher following F than B (PER1 2.2-fold and LPL 1.3-fold; p < 0.05). We assessed associations of ACTH-stimulated plasma B and F with features of metabolic syndrome in a cross-sectional study (n=279). Glucose tolerance was impaired with higher F (β=0.146, p=0.01) but lower B (β = -0.056, p = 0.05). These data support the concept of differential tissue sensitivity to B and F, whereby B suppresses the HPA axis more effectively than it induces adverse effects in adipose tissue. Enhanced CYP17 activity, causing ‘relative B deficiency’, may contribute to HPA axis activation and enhanced F action in adipose tissue in obesity. B therapy might allow control of HPA axis activation without inducing adverse metabolic effects. The ‘neglected second glucocorticoid’, corticosterone, may optimise glucocorticoid action in the human CNS, and simultaneously limit adverse metabolic effects driven by cortisol excess.

Glucocorticoids are known to affect metabolic activities of cells. The mechanism of glucocorticoid actions in adult human dermal and mouse L-929 fibroblasts have yet to be fully ascertained. This study endeavors to examine the effects of one glucocorticoid, triamcinolone acetonide, on cellular proliferation and collagen synthesis and to compare such effects in the human and mouse cell lines. Cellular proliferation and collagen synthesis are analyzed and quantitated by cell counts and selective digestion of the protein by bacterial collagenase, respectively. Further analysis of collagen synthesis is provided by polyacrylamide gel electrophoresis. One-tenth triamcinolone acetonide per ml suppresses cellular proliferation of mouse L-929 fibroblasts. Proline incorporation into total and collagenase-sensitive protein is enhanced in the cell layer; that of medium is altered inconsistently. Polyacrylamide gel electrophoresis of proteins treated with pepsin show the abolition of total and collagenase-sensitive protein in the cell layer. Aberrations in hydroxylation and/or deformation in physical structure of protein may confer greater susceptibility to pepsin digestion. Cellular proliferation and proline incorporation into total and collagenase-sensitive protein of adult human dermal fibroblasts are affected inconsistently by the same dose of triamcinolone acetonide. Except for the consistent suppression of cellular proliferation in the murine L-929 fibroblasts by triamcinolone acetonide, all observations pertaining to human dermal fibroblasts are incompatible with those obtained by other workers. Manipulation of culture conditions and glucocorticoid treatment dictate, to a large extent, the kind of responses observed. This could account for the wide variability and frequent contradictory findings reported in the literature. / Pharmaceutical Sciences, Faculty of / Graduate

Accurately examining animal endocrine profiles pose unique challenges due to possible human interaction influencing basal values. Standard methods of gathering information about an animal’s endocrine status are often dependent upon restraint and use of invasive methodologies. However to accurately monitor the influence management practices, blood sampling sometimes requires that hormone measurements be observed from animals in a relaxed state. To this end, methods for non-invasive monitoring (NIM) are greatly needed to obtain basal endocrine measurements. Such methods include fecal collections followed by hormone extraction, and remote sampling technologies for obtaining blood samples without handling. The overall objective of this study was to use NIM techniques to effectively collect and monitor hormone profiles from domestic and non-domestic species in an effort to more completely understand stress responses and reproductive cyclicity in animals in which handling may not be possible or desired.

No description available.