Publications

Alternative splicing of the fibronectin gene transcript gives rise to forms that include the EIIIA (or ED-A) segment. EIIIA-containing fibronectins are prominently expressed during embryogenesis and wound healing and appear to mediate changes in cell adhesion and gene expression. Nonetheless, integrins that bind the EIIIA segment have not been identified. We previously mapped the epitope for two function-blocking monoclonal antibodies to the C-C' loop region of the EIIIA segment (Liao, Y.-F., Wieder, K. G., Classen, J. M., and Van De Water, L. (1999) J. Biol. Chem. 274, 17876-17884). The sequence of this epitope ((39)PEDGIHELFP(48)) resembles the sequence within tenascin-C to which the integrin alpha(9)beta(1) binds. We now report that either integrin alpha(9)beta(1) or alpha(4)beta(1) can mediate cell adhesion to the EIIIA segment. Moreover, this interaction is blocked both by epitope-mapped EIIIA antibodies as well as by the respective anti-integrins. Deletion mutants of the EIIIA segment that include the C-C' loop and flanking sequence bind cells expressing either alpha(9)beta(1) or alpha(4)beta(1). Adhesion of alpha(4)beta(1)-containing MOLT-3 cells to the EIIIA segment stimulates phosphorylation of p44/42 MAP kinase. Our observation that two integrins bind the EIIIA segment establishes a novel mechanism by which cell adhesion to fibronectin is regulated by alternative splicing.

CONTEXT

Postmenopausal hormone therapy is commonly used by women for disease prevention, but its effects on quality of life have not been well documented.

OBJECTIVE

To determine the effect on quality of life of estrogen plus progestin therapy used as secondary prevention in women with coronary artery disease.

DESIGN, SETTING, AND PARTICIPANTS

A total of 2763 postmenopausal women with documented coronary artery disease (mean age, 67 years) in the Heart and Estrogen/Progestin Replacement Study, a randomized, placebo-controlled, double-blind trial conducted from January 1993 to July 1998 at outpatient and community settings at 20 US clinical centers.

INTERVENTION

Participants were randomly assigned to receive either 0.625 mg/d of conjugated equine estrogen plus 2.5 mg/d of medroxyprogesterone acetate (n = 1380) or placebo (n = 1383) for 36 months.

MAIN OUTCOME MEASURES

Physical activity, measured by the Duke Activity Status Index; energy/fatigue and mental health, measured by RAND scales; and depressive symptoms, measured on the Burnam screening scale, at 3 years of follow-up.

RESULTS

In all patients, scores declined significantly over 3 years for physical function (-3.8; P<.001), mental health (-0.6; P =.05), and energy/fatigue (-3.8; P<.001), but depressive symptoms were not significantly changed (P =.20). The effect of hormone therapy on these measures depended on the presence (n = 434) or absence (n = 2325) of flushing at study entry. Women with flushing who were assigned to hormone therapy had improved mental health (+2.6 vs - 0.5; P =.04) and fewer depressive symptoms (-0.5 vs + 0.007; P =.01) over follow-up compared with those assigned to placebo. Women without flushing who were assigned to hormone therapy had greater declines in physical function (-4.2 vs -3.3; P =.04) and energy/fatigue (-4.6 vs -3.1; P =.03) over follow-up. Quality-of-life scores were significantly lower among patients with older age, diabetes, hypertension, chest pain, or heart failure. These differences in quality of life among women classified by clinical characteristics were much greater than the effects of hormone therapy.

CONCLUSION

Hormone therapy has mixed effects on quality of life among older women. The effects of hormone therapy depend on the presence of menopausal symptoms; women without flushing had greater declines in physical measures, while women with flushing had improvements in emotional measures of quality of life.