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A: Electron microscopy of the wild-type BY4742 left ; and the mutant his-YEH2 right ; was performed as described in the Methods section. Noteworthy, the structure of the plasma membrane is significantly disturbed in the mutant. B: Drug sensitivity of strains was tested on solid medium. Whereas both his-YEH2 and YEH2-protA are sensitive against nystatin 2g ml ; , yeh2 is characterized by an elevated nystatin tolerance.
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Hypertension Lennart Hansson, Uppsala, Sweden, gave an update on the outcome of hypertension treatment in diabetes. The frequency of cardiovascular disease CVD ; is two to three times higher among patients with diabetes versus patients without diabetes 1 ; , and data compiled by the World Health Organization show that CVD is a major cause of death 2 ; . According to the Multiple Risk Factor Intervention Trial study, the frequency of CVD-related mortalities was three- to fourfold higher among patients with diabetes, regardless of their blood pressure levels; in particular, diabetic patients with low blood pressure levels appeared to be at increased risk for hypertension 3 ; . Normal blood pressure m e a rements are considered to be 130 85 mmHg, and optimal blood pressure measurements are considered to be 120 80 mmHg. In total, there are 50 million people in the U.S. who are hyper.
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29. Delany AM, Canalis E. Transcriptional repression of insulin-like growth factor I by glucocorticoids in rat bone cells. Endocrinology. 1995; 136: 4776 Delany AM, Gabbitas BY, Canalis E. Cortisol downregulates osteoblast 1 I ; procollagen mRNA by transcriptional and posttranscriptional mechanisms. J Cell Biochem. 1995; 57: 488 Voisard R, Seitzer U, Baur R, Dartsch PC, Osterhues H, Hoher M, Hombach V. Corticosteroid agents inhibit proliferation of smooth muscle cells from human atherosclerotic arteries in vitro. Int J Cardiol. 1994; 43: 257267. Naito M, Yasue M, Asai K, Yamada K, Hayashi T, Kuzuya M, Funaki C, Yoshimine N, Kuzuya F. Effects of dexamethasone on experimental atherosclerosis in cholesterol-fed rabbits. J Nutr Sci Vitaminol. 1992; 38: 255264. Asai K, Funaki C, Hayashi T, Yamada K, Naito M, Kuzuya M, Yoshida F, Yoshimine N, Kuzuya F. Dexamethasone-induced suppression of aortic atherosclerosis in cholesterol-fed rabbits: possible mechanisms. Arterioscler Thromb. 1993; 13: 892 Hagihara H, Nomoto A, Mutoh S, Yamaguchi I, Ono T. Role of inflammatory responses in initiation of atherosclerosis: effects of antiinflammatory drugs on cuff-induced leukocyte accumulation and intimal thickening of rabbit carotid artery. Atherosclerosis. 1991; 91: 107116. Villa AE, Guzman LA, Chen W, Golomb G, Levy RJ, Topol EJ. Local delivery of dexamethasone for prevention of neointimal proliferation in a rat model of balloon angioplasty. J Clin Invest. 1994; 93: 12431249. Nashel DJ. Is atherosclerosis a complication of long-term corticosteroid treatment? J Med. 1986; 80: 925929. Troxler RG, Sprague EA, Albanese RA, Fuchs R, Thompson AJ. The association of elevated plasma cortisol and early atherosclerosis as demonstrated by coronary angiography. Atherosclerosis. 1977; 26: 151162. Tenenbaum HC, Heersche JN. Dexamethasone stimulates osteogenesis in chick periosteum in vitro. Endocrinology. 1985; 117: 22112217. Shanahan CM, Cary NR, Metcalfe JC, Weissberg PL. High expression of genes for calcification-regulating proteins in human atherosclerotic plaques. J Clin Invest. 1994; 93: 23932402. Stein GS, Lian JB, Stein JL, van Wijnen AJ, Frenkel B, Montecino M. Mechanisms regulating osteoblast proliferation and differentiation. In: Bilezikian JP, Raisz LG, Rodan GA, eds. Principles of Bone Biology. New York, NY: Academic Press; 1996: 69 86. Balica M, Bostrom K, Shin V, Tillisch K, Demer LL. Calcifying subpopulation of bovine vascular smooth muscle cells is responsive to 17 -estradiol. Circulation. 1997; 95: 1954 Nakano T, Raines EW, Abraham JA, Wenzel F, Higashiyama S, Klagsbrun M, Ross R. Glucocorticoid inhibits thrombin-induced expression of platelet-derived growth factor A-chain and heparin-binding epidermal growth factor-like growth factor in human aortic smooth muscle cells. J Biol Chem. 1993; 268: 2294122947. Petrichenko IE, Daret D, Kolpakova GV, Shakhov YA, Larrue J. Glucocorticoids stimulate cholesteryl ester formation in human smooth muscle cells. Arterioscler Thromb Vasc Biol. 1997; 17: 11431151 and fexofenadine.
A. KUMAR AND T. C. FOSTER POTIER B, RASCOL O, JAZAT F, LAMOUR Y, AND DUTAR P. Alterations in the properties of hippocampal pyramidal neurons in the aged rat. Neuroscience 48: 793 806, SANDLER VM AND BARBARA JG. Calcium-induced calcium release contributes to action potential-evoked calcium transients in hippocampal CA1 pyramidal neurons. J Neurosci 19: 4325 4336, SCHIESS MC, JOELS M, AND SHINNICK-GALLAGHER P. Estrogen priming affects active membrane properties of medial amygdala neurons. Brain Res 440: 380 385, SHANKAR S, TEYLER TJ, AND ROBBINS N. Aging differentially alters forms of long-term potentiation in rat hippocampal area CA1. J Neurophysiol 79: 334 341, SHARROW KM, KUMAR A, AND FOSTER TC. Calcineurin as a potential contributor in estradiol regulation of hippocampal synaptic function. Neuroscience In press. SHELDON JH AND ARGENTIERI TM. Acute administration of 17 beta-estradiol inhibits calcium currents in isolated guinea pig detrusor myocytes. J Pharmacol Exp Ther 274: 723729, 1995. SHERWIN BB. Can estrogen keep you smart? Evidence from clinical studies. J Psychiatry Neurosci 24: 315321, 1999. THIBAULT O AND LANDFIELD PW. Increase in single L-type calcium channels in hippocampal neurons during aging. Science 272: 10171020, 1996. THIBAULT O, PORTER NM, CHEN KC, BLALOCK EM, KAMINKER PG, CLODFELTER GV, BREWER LD, AND LANDFIELD PW. Calcium dysregulation in neuronal aging and Alzheimer's disease: history and new directions. Cell Calcium 24: 417 433, VALVERDE MA, ROJAS P, AMIGO J, COSMELLI D, ORIO P, BAHAMONDE MI, MANN GE, VERGARA C, AND LATORRE R. Acute activation of Maxi-K channels hSlo ; by estradiol binding to the beta subunit. Science 285: 1929 1931, VERKHRATSKY A AND TOESCU EC. Calcium and neuronal ageing. Trends Neurosci 21: 27, 1998. VOUIMBA RM, FOY MR, FOY JG, AND THOMPSON RF. 17beta-estradiol suppresses expression of long-term depression in aged rats. Brain Res Bull 53: 783787, 2000. WARREN SG, HUMPHREYS AG, JURASKA JM, AND GREENOUGH WT. LTP varies across the estrous cycle: enhanced synaptic plasticity in proestrus rats. Brain Res 703: 26 30, ZHANG F, RAM JL, STANDLEY PR, AND SOWERS JR. 17-beta-Estradiol attenuates voltage-dependent Ca2 currents in A7r5 vascular smooth muscle cell line. J Physiol 266: C975C980, 1994.
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Our results show a significant rise in serum estradiol levels in the 2 weeks following commencement of Vagifem in six of the seven women, usually with a decrease after 1 month of therapy Table 1, Figure 1 ; but with a return to pre-Vagifem levels in only two women after 7 and 12 weeks, respectively. Intersubject variability was high and reflects the difficulty of accurately measuring the low estradiol levels seen in women on AIs. FSH and LH were not seen to greatly change during the study. Our experience in this small group of women on AIs and Vagifem raises concerns over the appropriateness of such a combination for effective breast cancer control since the efficacy of aromatase inhibition depends on near total suppression of estrogenic stimulation. The third generation inhibitors that inhibit aromatase by 97% are more effective in controlling breast cancer than earlier agents achieving only 90% inhibition [13], suggesting that even a small increase in systemic estrogen may be detrimental.
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The concentration of immunoreactive CART peptide was determined in blood and pituitary gland by RIA. The procedure was carried out generally as previously described 13 ; but with a commercially available 125 I-RIA kit Phoenix Pharmaceuticals, Belmont, MA ; . The RIA kit was validated before use with tissue extracts and dose-response curves, and increasing concentrations of authentic rat CART 55102 standard Peptide International, Louisville, KY ; added to tissue extracts were parallel to the standard curve. The assay sensitivity was 10 pg tube, and intraassay variability was 5%. To determine the efficiency of the procedure, internal standards 80 pg tube ; of authentic CART 55102 were added and were recovered to a level of 57%, and the values deviated less than 5%. All values are corrected for the loss of CART peptide using the recovery factor. Samples were purified by Sep Pak C18-E columns Phoenix Pharmaceuticals ; . The eluates were freeze-dried overnight using a lyophilizer and later were dissolved in RIA buffer and flagyl.
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Submitted, revised, 11 May 2005. From the David Geffen School of Medicine at UCLA, Beverly Hills, California HL Centre for Integrated Health Care Research, University of Durham, United Kingdom PH Outcomes Research, AstraZeneca R&D, Molndal, Sweden IW and Department of Public Health and Primary Health Care, The University of Bergen, Norway IW ; Conflict of interest: HL has acted as an advisor to AstraZeneca, where proton pump inhibitors are manufactured for the treatment of GERD. PSH has acted as advisor and has received funding for research and academic activities from several gastrointestinal product companies, including AstraZeneca, Wyeth, Takeda, Altana, and GlaxoSmithKline. IW is employed by AstraZeneca. Corresponding author: Harley Liker, MD, MBA, David Geffen School of Medicine at UCLA, 9675 Brighton Way Suite 350, Beverly Hills, CA 90210 e-mail: hliker mednet. ucla and fluconazole.
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19. Bruning PF. Droloxifene, a new anti-estrogen in postmenopausal breast cancer: preliminary results of a double-blind dose-finding Phase II trial. Eur J Cancer 1992; 28A: 14041407. Johnston SRD, Riddler S, Haynes BP, et al. The novel anti-estrogen idoxifene inhibits the growth of human MCF-7 breast cancer xenografts and reduces the frequency of acquired anti-estrogen resistance. Br J Cancer 1997; 75: 804809. Thiebaud D, Secrest RJ. Selective estrogen receptor modulators: mechanism of action and clinical experience. Focus on raloxifene. Reprod Fertil Dev 2001; 13: 331336. Morris C, Wakeling A. Fulvestrant `Faslodex' ; a new treatment option for patients progressing on prior endocrine therapy. Endocr-Relat Cancer 2002; 9: 110. Fornander T, Rutqvist LE, Wilking N, et al. Estrogenic effects of adjuvant tamoxifen in postmenopausal breast cancer. Eur J Cancer 1993; 29A: 497500. MacGregor JI, Jordan VC. Basic guide to the mechanisms of anti-estrogen action. Pharmacol Rev 1998; 50: 151196. Plotkin D, Lechner JJ, Jung WE, Rosen PJ. Tamoxifen flare in advanced breast cancer. J Med Assoc 1978; 240: 26442646. Kauffman RF, Bryant HU. Selective estrogen receptor modulators. Drug News Perspect 1995; 8: 531539. Santen RJ, Harvey HA. Use of aromatase inhibitors in breast carcinoma. Endocr-Relat Cancer 1999; 6: 7592. Njar VC, Brodie AMH. Comprehensive pharmacology and clinical efficacy of aromatase inhibitors. Drugs 1999; 58: 233255. Wakeling AE, Bowler J. Steroidal pure anti-estrogens. J Endocrinol 1987; 112: R7R10. 30. Wakeling AE, Bowler J. Biology and mode of action of pure anti-estrogens. Steroid Biochem 1988; 30: 141148. Bowler J, Lilley TJ, Pittam JD, Wakeling AE. Novel steroidal pure anti-estrogens. Steroids 1989; 54: 7199. Nique F, van de Velde P, Bremaud J, et al. 11b-amidoalkoxyphenyl estradiols, a new series of pure anti-estrogens. J Steroid Biochem Mol Biol 1994; 50: 2129. Levesque C, Merand Y, Dufour JM, et al. Synthesis and biological activity of new halosteroidal anti-estrogens. J Med Chem 1991; 34: 16241630. Wakeling AE, Dukes M, Bowler J. A potent specific pure anti-estrogen with clinical potential. Cancer Res 1991; 51: 38673873. Beato M. Gene regulation by steroid hormones. Cell 1989; 56: 335344. Horwitz KB, Jackson TA, Bain DL, et al. Nuclear receptor co-activators and co-repressors. Mol Endocrinol 1996; 10: 11671177. Brzozowski AM, Pike ACW, Dauter Z, et al. Molecular basis of agonism and antagonism in the estrogen receptor. Nature 1997; 389: 753758. Tzukerman MT, Esty A, Santiso-Mere D, et al. Human estrogen receptor transactivational capacity is determined by both cellular and promotor context and mediated by two functionally distinct intramolecular regions. Mol Endocrinol 1994; 8: 2130. Katzenellenbogen JA, O'Malley BW, Katzenellenbogen BS. Tripartite steroid hormone receptor pharmacology: interaction with multiple effector sites as a basis for the cell- and promotor-specific action of these hormones. Mol Endocrinol 1996; 10: 119. McDonnell DP, Clemm DL, Hermann T, et al. Analysis of estrogen receptor function in vitro reveals three distinct classes of anti-estrogens. Mol Endocrinol 1995; 9: 659669 and glibenclamide.
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Background: Although the role of the osteoclast in bone resorption is becoming better understood, much remains to be learned about osteoclastogenesis and the exact mechanism of action of anti-resorbing agents such as 17-estradiol. This study investigated bone and morphologic osteoclast alterations following long-term estrogen administration to the B6D2F1 mouse. B6D2F1 mice aged 4-5 weeks were exposed to high levels of estrogen via implanted silastic tubing for at least 12 weeks; controls received empty tubing. Femurs of control and treated mice were assessed with radiology, quantitative histomorphometry and transmission electron microscopy. Results: After 8 weeks of treatment, there was radiologic evidence of severe osteosclerosis and 86% of femoral marrow space was replaced with bone. After 12 weeks histologic studies of treated animals revealed that osteoclasts were positive for tartrate-resistant acid phosphatase but showed markedly abnormal ultrastructure which prevented successful bone resorption. Conclusions: Findings extend our understanding of osteoclast structure and function in the mouse exposed in vivo to high doses of estrogen. Ultrastructural examination showed that osteoclasts from estrogen-treated mice were unable to seal against the bone surface and were unable to form ruffled borders and inderal.
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