Biomedical subjects
Publications and source records attributed to W L Miller.
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The first and rate-limiting step in the synthesis of all steroid hormones is the conversion of cholesterol to pregnenolone by the mitochondrial enzyme, P450scc. Tropic hormones such ACTH and gonadotropins induce steroidogenesis via cAMP by elaborating intracellular cAMP which stimulates P450scc activity in two distinct ways. Chronic stimulation (h to days) occurs through the induction of P450scc gene transcription leading to increased P450scc protein and consequent increased steroidogenic capacity. Acute regulation, over minutes, occurs through the phosphorylation of preexisting StAR and the rapid synthesis of new StAR protein. StAR, the steroidogenic acute regulatory protein, increases the flow of cholesterol into mitochondria, thus regulating substrate availability to whatever amount of P450scc is available. In the absence of StAR, up to 14% of maximal StAR-induced level of steroidogenesis persists as StAR-independent steroidogenesis. Congenital lipoid adrenal hyperplasia, an autosomal recessive disorder in which conversion of cholesterol to pregnenolone is severely impaired, results in female genitalia in 46,XY genetic males, variable onset of a severe salt-losing crisis in the first months of life, but normal feminization and cyclical vaginal bleeding in 46,XX females. Lipoid CAH was once thought to be due to P450scc mutations, but in fact homozygous P450scc mutations cannot exist in human beings as they would prohibit placental progesterone production, causing spontaneous abortion of the affected fetus. Lipoid CAH is caused by StAR mutations, which result in tropic hormone-induced intracellular accumulation of cholesterol in the adrenals and gonads. Our two-hit model, which considers the persistence of StAR-independent steroidogenesis and the differences in the fetal and postnatal ages at which the testis, adrenal zona glomerulosa, adrenal zona fasciculata and ovary are stimulated, predicts and explains all of the various clinical manifestations of lipoid CAH. Structure function studies of StAR show that the critical domains for biological activity reside in the protein's carboxy-terminus. When the N-terminal mitochondrial targeting sequences are deleted and the resulting N-62 StAR remains in the cytoplasm, it retains the ability to stimulate steroidogenesis both in intact cells or when added to isolated mitochondria in vitro. These observations suggest that StAR acts on the outer mitochondrial membrane to promote sterol translocation to P450scc, and that the importation of StAR into mitochondria terminates its action. Data from circular dichroism and Fourier-transform infrared spectroscopy show that the mutant StAR proteins in lipoid CAH are misfolded, suggesting disrupted interaction with another protein. Preliminary data suggest that StAR facilitates cholesterol desorption from membranes, stimulating transfer from the outer mitochondrial (donor) membrane to the inner mitochondrial (acceptor) membrane.
Insulin-like growth factor II (IGF-II) is regulated developmentally and hormonally in human fetal gonads and adrenals. The abundance of IGF-II mRNA is greatest in RNA from human fetal adrenals, followed by fetal liver, testis, placenta, and ovaries. Fetal testicular IGF-II mRNA decreases significantly with increasing gestational age, in parallel with our previous measurements of the mRNAs for the steroidogenic enzymes P450scc (cholesterol side-chain cleavage enzyme) and P450c17 (17 alpha-hydroxylase/17,20 lyase) (J. Clin. Endocrinol. Metab. 63, 1145, 1986). The abundances of P450scc and P450c17 mRNAs in cultured fetal testis cells rose 2.5-fold (p less than 0.01) and 9.2-fold (p less than 0.001), respectively, in response to 0.5 mM cAMP, but the abundance of IGF-II mRNA was not affected. This suggests that the IGF-II gene is regulated differently in fetal testes than it is in fetal adrenals, placenta, or adult granulosa cells, where we have previously shown that ACTH, cAMP, and gonadotropins, respectively, increase IGF-II mRNA accumulation (Proc. Natl. Acad. Sci. USA 84, 1590, 1987). Exogenously added IGF-I and IGF-II had no effect on mRNAs for P450c17 or P450c21 (21-hydroxylase), but decreased IGF-II mRNA in ACTH-stimulated fetal adrenal cells. Thus, the IGFs appear to exert short-loop feedback inhibition on accumulation of IGF-II mRNA.
OBJECTIVE: Health care professionals are faced with the ongoing challenge of improving performance. From physicians and nurses to process improvement experts, health care professionals are discovering new approaches to increasing the overall effectiveness of procedures used in clinical areas. One way to collect data useful for benchmarking specific clinical practices is through the use of prevalence studies. DESIGN: A 1-day pressure ulcer prevalence survey was performed in March 1999. Acute care facilities across the United States volunteered to participate in the data collection process. Patients' demographic information, pressure ulcer stages, locations, and support surfaces were noted. SETTING: 356 acute care facilities. PARTICIPANTS: 42,817 patients. RESULTS: The overall pressure ulcer prevalence was 14.8%, with a nosocomial pressure ulcer prevalence of 7.1%. CONCLUSIONS: Benchmarking is one of the tools that enables health care professionals to measure and identify inconsistencies in patient care practices. Understanding these inconsistencies enables the health care team to develop processes that are innovative and efficient. National pressure ulcer prevalence surveys provide a benchmark to evaluate an individual facility's care and treatment of patients at risk for pressure ulcer development. Success, however, lies in the health care professional's ability to take the information and apply it to clinical practice. Through the use of a benchmarking approach, performance gaps can be identified, processes can be put into place, and improved patient outcomes can be monitored and maintained.
Human P450c17 catalyzes the 17alpha-hydroxylation of pregnenolone to 17OH pregnenolone and of progesterone to 17alpha-OH progesterone; the same P450c17 enzyme also catalyzes 17,20 lyase activity on the same active site, converting 17OH-pregnenolone to DHEA. Rodent and porcine P450c17 also catalyze 17,20 lyase activity with delta4 substrates, converting 17OH-progesterone to delta4 androstenedione, but human P450c17 catalyzes this reaction very inefficiently, so that virtually all human C19 sex steroids are made via 17OH pregnenolone and DHEA. P450c17 is encoded by a single gene and a single species of mRNA. Many mutations of this gene have been described, but until recently all of these either entirely eliminated both 17alpha-hydroxylase and 17,20 lyase activity, or affected each activity equivalently. We have identified and characterized the first patients with P450c17 mutations that selectively ablate 17,20 lyase activity while retaining 17alpha-hydroxylase activity. Through a combination of enyzmologic experiments in transfected mammalian cells and in genetically manipulated yeast, plus a computer model of human P450c17, we have proven that the responsible mutations, R347H and R358Q lie in the redox-partner binding site of P450c17. This site, through which P450c17 interacts with P450 oxidoreductase to receive the electrons needed for catalysis, can be allosterically influenced by cytochrome b5. These two mutations have contributed substantially to our understanding of the mechanisms by which 17alpha-hydroxylase and 17,20 lyase activities are regulated independently, and thus have contributed to the study of regulated 17,20 lyase activity in adrenarche, aging, and the polycystic ovary syndrome.
The relationship between diet diversity and hypertension was examined in a cross-sectional exploratory study of 82 randomly selected adult residents of Saba Island, Netherlands Antilles, in the eastern Caribbean Basin. Blood pressure measurements, taken over 4 years, and the appropriate use of antihypertensive medications, were used to identify chronic hypertensives. A 24-hour dietary recall, semi-quantitative food frequency interviews, and ethnographic confirmation techniques were used to calculate diet diversity, a measure of the overall dietary pattern. Results suggest hypertension is associated with lack of an overall balance of food groups in the daily diet beyond any imbalance of a particular dietary cation such as sodium, potassium, or calcium. Bivariate analyses found a significant association between a poorly diversified diet and hypertension (odds ratio [OR] = 4.25, 95 percent confidence intervals [CI] = 1.47,12.30). Dietary intake of sodium, potassium, and calcium was also examined and found not to be associated with the presence of hypertension in bivariate analyses. Including these cations individually in logistic regression models, which also included diet diversity, did not diminish the diet diversity-hypertension association. Multiple logistic regression models in which other potential confounding variables were individually entered as a control variable (body fat, skin color, age, sex, perceived stress, alcohol intake, aerobic activity, and socioeconomic status) did not alter this result. Analysis of the presence or absence of individual food groups indicate a lack of legumes in the daily diet is also associated with the diagnosis of hypertension (OR = 4.71, 95 percent CI = [1.71,13.01]).
BACKGROUND: Demands for change in medical practices are coming from multiple sources. Since interventions to change clinical practice continue to have limited success, understanding the functional structure of primary care practices and the dynamics of providing care have become increasingly important. METHODS: To portray and understand the primary care office system, we developed "practice genograms" that describe practice participants and their relationships with each other. Formal organizational structure is evaluated using family systems theory and family of origin genogram techniques. RESULTS: Practice genograms provided a more dynamic, relational model than the organizational chart and promoted identification of relationship strengths and weaknesses within a practice the same way that family genograms identify these characteristics in a family system. CONCLUSIONS: Research implications for the use of the practice genogram include enhanced data gathering, increased understanding of the complexity of practices as adaptive systems, and increased understanding of current and potential approaches to changing practices.