The phytoestrogen genistein suppresses cell-mediated immunity in mice.

The soy phytoestrogen, genistein, induces thymic atrophy when administered to ovariectomized mice by injection or in the diet. Injected genistein also causes decreased humoral immunity, but the effects of genistein on cell-mediated immunity have not been addressed. Here we examined effects of injected and dietary genistein on cell-mediated immune responses. Female C57BL/6 mice (25- to 27-days-old) were ovariectomized, then placed on phytoestrogen-free feed 5 days later. Seven days after ovariectomy, they were given daily subcutaneous injections of either dimethylsulfoxide (DMSO) or genistein (8, 20, 80 mg/kg) for 28 days; some mice were given 80 mg/kg genistein plus the anti-estrogen ICI 182,780 (5 mg/kg/week). Cell-mediated immune response was tested by analyzing the delayed-type hypersensitivity (DTH) response to a hapten, 4-hydroxy-3-nitrophenyl acetyl succinimide (NP-O-SU), at the end of treatment. Reversibility of the effects of genistein was tested by measuring the DTH response in mice that were given genistein (20 or 80 mg/kg) for 28 days, then allowed to recover for 28 days. To determine if dietary genistein could affect cell-mediated immunity, mice ovariectomized as above were fed genistein at 0, 1000 or 1500 parts per million (ppm) for 28 days. There was a 46-67% decrease in the DTH response in the footpads of mice injected with 8-80 mg/kg genistein compared with controls (P<0.05 vs control for all treatment groups); these effects were reversible. On histopathological examination of the feet, there was decreased cell infiltration in genistein-treated animals compared with controls, and the numbers of CD4(+) and CD8(+) T cells in popliteal lymph nodes were reduced. The effects of genistein are mediated through both estrogen receptor (ER) and non-ER pathways, as the anti-estrogen ICI 182,780 only partially blocked the effects of genistein on the DTH response. Dietary genistein (1000 or 1500 ppm) decreased cell-mediated immunity while producing serum genistein concentrations in the physiological range for humans under certain nutritional conditions. Further work is needed to determine if dietary genistein and phytoestrogen exposure can produce effects on cell-mediated immunity in humans or other animals under various nutritional conditions.

Normal development of thymus in male and female mice requires estrogen/estrogen receptor-alpha signaling pathway.

Estrogen receptors (ERs) are expressed in the thymus of both males and females, but their role in thymic development and function is unclear. To determine whether ERalpha plays a role in thymic function of either males or females, we compared thymuses of male and female wild-type (WT) and ERalpha knockout (alphaERKO) mice from birth to adulthood. Although thymic size was similar in both male and female WT and alphaERKO mice at birth (d 0), by postnatal d 5 and at all subsequent ages, both male and female alphaERKO mice had significant (30-55%) reductions in thymic weight. Morphometric analysis revealed a reduction in thymic medullary areas in adult alphaERKO mice compared with age-matched WT controls that paralleled thymic involution. There were changes in relative percentages of CD4+ and CD4+CD8+ T-cells, and large decreases (70-80%) in overall absolute numbers of CD4+ and CD4+CD8+ T-cells. Serum corticosterone and testosterone levels were not different in either neonatal or adult male WT or alphaERKO mice, and serum levels of 17beta-estradiol (E2) were similar in neonatal WT and alphaERKO males, indicating that increases in these thymolytic hormones are not responsible for the decreased thymic weight in alphaERKO males. Additionally, delayed-type hypersensitivity was significantly increased in male alphaERKO mice compared with WT mice. In summary, ERalpha deficiency does not inhibit initial differentiation or fetal thymic development, but the absence of ERalpha results in marked decreases in thymic size in both sexes during the postnatal period. These results are the first direct demonstration that the E2/ERalpha signaling system is necessary for maintenance of normal postnatal function of the female thymus gland. The similar results obtained in males demonstrate a role for the E2/ERalpha signaling system in the male thymus and emphasize that estrogens play a more critical role in the male than previously realized.

Indications and use of the Palmaz-Schatz coronary stent.

Restenosis prevention has been the 'holy grail' of contemporary interventional cardiology. Even though balloon angioplasty has become the standard treatment for ischemic syndromes, it is still plagued by a definite incidence of restenosis. This recidivism has prompted the search for newer, catheter-based modalities of treatment to address this issue. The proliferation of newer devices for intervention has increased the number of options for the interventional cardiology; however, until recently, none has had a significant impact on restenosis. The randomized trials (STRESS and BENESTENT) have both shown a significant reduction in angiographic restenosis with the Palmaz-Schatz stent in de novo coronary lesions. Nonrandomized trials suggest additional benefit in saphenous vein bypass grafts.

Effects of thermal exposure on binding of heparin in vitro to the arterial wall and to clot and on the chronic angiographic luminal response to local application of a heparin film during angioplasty in an in vivo rabbit model.

Experimentally, heparin inhibits mechanisms that promote fibrosis, neointimal cellular proliferation, and thrombin bound to fibrin at the surface of intraluminal thrombus, but only in relatively high concentrations. A preliminary hypothesis was tested and confirmed in vitro that initial binding of 3H-heparin to mechanically injured porcine aorta is concentration-dependent over a 1,000-50,000 units/ml range (r = 0.9). The hypothesis was then tested in vitro that thermal exposure during contact of heparin to arterial tissue and to clot would enhance binding of the drug. 3H-heparin binding to clot, whole blood particulates, and washed erythrocytes was markedly enhanced by exposure to temperatures > 70 degrees C. Thermal exposure (80 degrees C x 40 s) also enhanced tissue persistence of the drug within porcine aorta subjected to a shear rate of 1,100(-1) in an annular Baumgartner chamber perfused with normal saline at 37 degrees C for 48 h. Heparin in vitro anticoagulant activity persisted after thermal exposure and binding to tissues. A new method was developed for local application of a heparin film that provides a maximum concentration with a tolerable systemic dose during an angioplasty procedure. In an in vivo rabbit model of mural fibrosis after iliac artery angioplasty, the 1-month mean angiographic luminal diameter loss (23% compared to the acute postangioplasty result by computer image analysis) in response to conventional balloon angioplasty (BA) and laser balloon angioplasty (LBA) was the same (P > 0.05). Local application of a heparin film (3,000 units at a concentration > 100,000 units/g), however, reduced the mean % loss in diameter 1 month after LBA (12%), but not after BA (29%), compared to arteries subjected to angioplasty without local heparin (P < .05). The results are consistent with the hypothesis that thermal energy enhances heparin binding to tissues and that local application of a heparin film favorably modulates arterial luminal responses to LBA, but not to BA, in this animal model.

An in vitro evaluation of the effect of laser irradiation on the thrombogenicity of thrombus.

The effect of laser irradiation on the thrombogenicity of thrombus was evaluated by treating thrombi, formed in-vitro from canine blood, with two different doses of cw Nd:YAG laser energy at 1064 nm. The thrombi were then incubated with whole blood, and the plasma levels of fibrinogen and thrombin-antithrombin III-complexes were measured. A statistically significant decrease (p < 0.05) in the thrombogenicity was indicated by a reduction in both fibrinogen consumption and levels of thrombin-antithrombin III-complexes in the high dose group (600 joules, 100 degrees C peak temperature) in comparison to the low dose group (300 joules, 70 degrees C peak temperature) and the untreated thrombi. These findings suggest that laser irradiation of thrombus at an appropriate dose may substantially reduce its thrombogenicity and ability to modulate hemostasis.