Publications

Marked reductions in cardiovascular mortality have been reported over the last 2 decades as a result of therapeutic advances in ischemic heart disease. Despite medical advances, case fatality rates are higher for women than men. A critical step toward improving outcomes is early diagnosis of coronary artery disease by noninvasive evaluation. The use of noninvasive testing in women has been controversial because of a perception of diminished accuracy, limited female representation, and compromise of efficacy of testing because of technical limitations (eg, thallium-201 breast artifact). Recent meta analysis and large observational series report marked improvements in the accuracy of results for women undergoing exercise treadmill, echocardiography, and nuclear testing. Exercise treadmill testing has an improved accuracy when multiple risk parameters (eg, ST deviation, chest pain, exercise time) are included in the test interpretation. For women, a low-risk Duke treadmill score is associated with a 97% 5-year survival, with 80% of these patients having no obstructive disease. Multivessel disease (70%) is common for those with a high-risk treadmill score with a 5-year survival of 90%. The diagnostic accuracy of electron beam computed tomography reveals a sensitivity and specificity of 88% and 49%. For exercise echocardiography, test diagnostic sensitivity and specificity are 86% and 79%. For nuclear imaging, 3-year cardiac survival ranged from 99% to 85% for 0 to 3 vascular territories with perfusion abnormalities. A sufficient body of evidence supports the use of noninvasive testing for intermediate-risk, symptomatic women. Diagnostic certainty may be effectively guided by the evaluation of global and regional wall motion, eg, with echocardiography. Risk assessment may be more precise with the evaluation of myocardial perfusion, eg, with stress nuclear imaging. With the use of updated evidence, informed test selection for women may result in improved diagnostic and therapeutic decision-making, with the use of available noninvasive testing modalities.

Glycodelin is an endometrial protein with proposed immunomodulatory activity during human embryonic nidation. In this review we describe the effects of ovarian hormones on glycodelin transcription, synthesis, and secretion by human epithelial cells and focus on the importance of glycodelin in implantation. We demonstrate that glycodelin transcription, synthesis, and secretion by human epithelial cells are stimulated by progestins and antiprogestins but not by estrogen. Sequences localized within a 403-base-pair region flanking the 5' human glycodelin gene promoter appear to be responsible for transcriptional activation of this gene mediated by progesterone receptor-ligand complexes. Relaxin, purported to enhance glycodelin production in vivo and in prior in vitro studies, had no stimulatory effect on the expression of this gene in vitro in our models.

The integrin alpha(9)beta(1) mediates cell adhesion to tenascin-C and VCAM-1 by binding to sequences distinct from the common integrin-recognition sequence, arginine-glycine-aspartic acid (RGD). A thrombin-cleaved NH(2)-terminal fragment of osteopontin containing the RGD sequence has recently been shown to also be a ligand for alpha(9)beta(1). In this report, we used site-directed mutagenesis and synthetic peptides to identify the alpha(9)beta(1) recognition sequence in osteopontin. alpha(9)-transfected SW480, Chinese hamster ovary, and L-cells adhered to a recombinant NH(2)-terminal osteopontin fragment in which the RGD site was mutated to RAA (nOPN-RAA). Adhesion was completely inhibited by anti-alpha(9) monoclonal antibody Y9A2, indicating the presence of a non-RGD alpha(9)beta(1) recognition sequence within this fragment. Alanine substitution mutagenesis of 13 additional conserved negatively charged amino acid residues in this fragment had no effect on alpha(9)beta(1)-mediated adhesion, but adhesion was dramatically inhibited by either alanine substitution or deletion of tyrosine 165. A synthetic peptide, SVVYGLR, corresponding to the sequence surrounding Tyr(165), blocked alpha(9)beta(1)-mediated adhesion to nOPN-RAA and exposed a ligand-binding-dependent epitope on the integrin beta(1) subunit on alpha(9)-transfected, but not on mock-transfected cells. These results demonstrate that the linear sequence SVVYGLR directly binds to alpha(9)beta(1) and is responsible for alpha(9)beta(1)-mediated cell adhesion to the NH(2)-terminal fragment of osteopontin.