The correlation between sampling site and gene expression in the term human placenta.

Using oligonucleotide microarrays we recently identified a set of transcripts that were up-regulated in hypoxic human trophoblasts. To test the hypothesis that expression of hypoxia-related placental transcripts depends on sampling site we analyzed nine different sites from term human placentas (n=6), obtained after uncomplicated pregnancies. These sites spanned the placental center to the lateral border and the basal to the chorionic plate. Relative gene expression at each site, determined using quantitative PCR, was correlated with villous histology. The expression of vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF), the cytoskeleton proteins lamininA3 and alpha-tubulin, and the signal transduction protein Rad was enhanced in the subchorionic lateral border compared to medial basal site (1.6-2.9 fold, p<0.05). In contrast, the expression of NDRG1, adipophilin and human placental lactogen was unchanged. Enhanced villous maturation, syncytial knots and fibrin deposits were more frequent in the subchorionic placental lateral border, and correlated with up-regulation of hypoxia-related transcripts (p<0.05). The association between sample site and expression level was not observed in placentas with marginal cord insertion. The expression of hypoxia-related genes in the term human placenta is dependent on sampling site within the placental disk, likely reflecting local differences in villous perfusion.

Thromboxane A(2) limits differentiation and enhances apoptosis of cultured human trophoblasts.

Prostanoids influence differentiation in diverse cell types. Altered expression of cyclooxygenase and prostaglandins has been implicated in the pathophysiology of placental dysfunction, which results in preeclampsia and fetal growth restriction. We hypothesized that prostanoids modulate differentiation and apoptosis in cultured human trophoblasts. Villous cytotrophoblasts were isolated from term human placentas and cultured in serum-free medium. The level of human chorionic gonadotropin was used as a marker of biochemical differentiation of primary trophoblasts, and syncytia formation was used as a marker of morphologic differentiation. Of the prostanoids tested, we found exposure to thromboxane A(2) hindered both biochemical and morphologic differentiation of cultured trophoblasts. As expected, human chorionic gonadotropin levels in the media were elevated in a concentration-dependent manner in the presence of the thromboxane synthase inhibitor, sodium furegrelate, or the thromboxane A(2) receptor blocker SQ 29,548. Furthermore, thromboxane A(2) enhanced trophoblast apoptosis, determined using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining, cell morphology, and a concentration-dependent increase in p53 expression. We conclude that thromboxane A(2) hinders differentiation and enhances apoptosis in cultured trophoblasts from term human placenta. We speculate that thromboxane may contribute to placental dysfunction by restricting differentiation and enhancing apoptosis in human trophoblasts.

Market influences on internal medicine residents' decisions to subspecialize.

BACKGROUND: Managed care reduces the demand for internal medicine subspecialists, but little empirical information is available on how increasing managed care may be affecting residents' training choices. OBJECTIVE: To determine whether increased managed care penetration into an area where residents train was associated with a decreased likelihood that residents who completed general internal medicine training pursued subspecialty training. DESIGN: Secondary logistic regression analysis of data from the 1993 cohort of general internal medicine residents. SETTING: U.S. residency training sites. PARTICIPANTS: 2263 U.S. medical school graduates who completed general internal medicine residency training in 1993. MEASUREMENTS: The outcome variable (enrollment in subspecialty training) was derived from the Graduate Medical Education Tracking Census of the Association of American Medical Colleges (AAMC). Health maintenance organization (HMO) penetration (possible range, 0.0 to 1.0; higher values indicate greater penetration) was taken from the Interstudy Competitive Edge Database. Individual and medical school covariates were taken from the AAMC's Student and Applicant Information Management System database and the National Institutes of Health Information for Management Planning, Analysis, and Coordination system. The U.S. Census division was included as a control covariate. RESULTS: 980 participants (43%) enrolled in subspecialty training. Logistic regression analyses indicated a nonlinear association between managed care penetration into a training area and the odds of subspecialization. Increasing managed care penetration was associated with decreasing odds of subspecialization when penetration exceeded 0.15. The choice of subspecialty training increased as HMO penetration increased from 0 to 0.15. CONCLUSIONS: Local market forces locally influenced the career decisions of internal medicine residents, but the influence was small compared with the effects of age and sex. These results suggest that market forces help to achieve more desirable generalist-to-specialist physician ratios in internal medicine.