Our study provides a uniform survey of the immunomodulatory properties of 10 commonly used herbal products and paves the way for testing these effects in vivo and in clinical setting.

Immunosuppressive drugs common in clinical transplantation are known to have untoward effects on the vascular system. The effects of some drugs, notably cyclosporin A (CyA), have been studied on the vascular system, while those of others have not. In the vascular system, endothelial cells are the predominant cell type exposed to intravascular concentrations of immunosuppressive drugs. We therefore studied the effects of drugs common in clinical transplantation on endothelial cells in a capillary tube assay. The endothelial cells in the capillary tubes are morphologically more similar to those in the microvasculature than endothelial cells in monolayers. We studied the kinetics and extent of capillary tube formation and prostacyclin (PGI2) and endothelin-1 (ET-1) release from the in vitro capillaries to determine the morphological and biochemical effects of five immunosuppressive agents on endothelial function. We found a significant difference in the morphological and biochemical effects of the two common calcineurin inhibitors, CyA and tacrolimus (FK506) on capillary morphology in vitro. The former had a pronounced injurious effect on the morphology of the in vitro capillaries, while the latter did not. CyA also significantly increased ET-1 release by the capillaries, but FK506 did not. Mycophenolate mofetil (MMF) was the only other agent that had a moderately injurious effect on the morphology of the in vitro capillaries. Sirolimus (rapamycin) and dexamethasone, similar to FK506, had no effect on the capillary morphology. All these agents, except dexamethasone, increased PGI2 release. Our data suggest that CyA adversely affects the morphology of the microvasculature and that this is mediated, at least partly, by an increased ET-1 release by endothelial cells exposed to CyA. These findings describe a novel effect of CyA and MMF on endothelial cells that could be relevant to understanding the mechanisms of immunosuppressive drug-mediated endothelial injury in clinical transplantation.

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If increased expression of estrogen receptor ␣ (ER) in benign breast epithelium increases susceptibility to breast cancer, such overexpression should be stable over time. There are no published data regarding this important aspect of ER expression in breast epithelium. We examined the temporal consistency of ER expression in the normal breast tissue of 28 women who had 2 separate breast surgical procedures, at least 6 months apart (mean interval, 2.8 years). Paraffin embedded breast tissue blocks containing an adequate sample of normal breast epithelium and no cancer, were sectioned and processed using the 6F11 antibody and standard immunohistochemical techniques. The ER labelling index (ER LI) was calculated by counting a mean of 2,000 epithelial cells. The median ER LI at first sampling was 13.6 and at second sample 15.5, with R 2 ‫؍‬ 0.34 and p ‫؍‬ 0.001. The ER LI was categorized into high and low values, using a threshold of 10. Twenty-four women (85.7%) showed concordance of high and low expression between the 2 samples (p ‫؍‬ 0.002). There were 11 women who were premenopausal at both time points. Among them, much of the variation in ER LI was explained by differences in the menstrual cycle day at the time of sampling and adding the day of cycle to the regression model substantially improved the correlation between first and second labeling indices. These data suggest that ER expression of normal breast tissue is fairly consistent over time and support the notion that overexpression of ER in normal epithelium is a constant feature of the high risk breast. © 2002 Wiley-Liss, Inc. Key words: estrogen receptor ␣; normal breast epitheliumThe increased expression of estrogen receptor ␣ (ER) protein has been observed in the normal breast epithelium of breast cancer cases 1,2 and lower expression has been shown in women belonging to low risk ethnic groups. 3,4 These findings have raised the possibility that estrogen receptor ␣ overexpression is a risk factor for the development of breast cancer. According to the current paradigm of the role of estrogen in breast cancer development, 1 of the effects of prolonged exposure to estrogen is an increase in the mitotic activity of breast epithelium, thereby increasing the mutation rate and allowing genetic defects to accumulate. 5,6 The role of increased ER expression in this paradigm would be to increase the sensitivity of breast epithelium to ambient estrogen. This model requires that increased ER expression be relatively constant over a period of time, because the cumulative effect of increased estrogen exposure occurs over the long term. There have, to date, been no studies examining the temporal constancy of ER expression in normal breast epithelium over a period of years. Existing crosssectional data point to a trend for estrogen receptor expression to increase with age 2,7 and short term longitudinal studies in premenopausal women have shown that ER expression decreases through the menstrual cycle, 8 although this may not be true in high risk women. 2 This article...

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