Background: Preeclampsia is a potentially devastating disorder of hypertension in pregnancy for which there is currently no definitive treatment short of delivery. The bufadienolide, marinobufagenin (MBG), an inhibitor of Na⁺/K⁺ ATPase, has been found to be elevated in extracellular fluid volume-expanded hypertensive patients, a condition similar to preeclampsia. Thus, these studies sought to examine the role of MBG in our rat model of preeclampsia. Methods and Results: Pregnant female rats were injected intraperitoneally with deoxycorticosterone acetate (DOCA) and given 0.9% saline as drinking water for the duration of their pregnancy. Urinary MBG was measured using a DELFIA immunoassay. Blood pressure was measured via the tail-cuff method. Injections of anti-MBG antibody were given intraperitoneally or intravenously to hypertensive pregnant rats. MBG was given intraperitoneally to pregnant rats. Uterine arterioles were dissected free and their diameters were measured before and after perfusion of MBG, ouabain, or digoxin. MBG was found to be elevated in the pregnant + DOCA + saline (PDS) rats compared to normal pregnant animals. In addition, when PDS rats were injected with anti-MBG antibody, there was a subsequent reduction in blood pressure. Administration of MBG in normal pregnant rats caused an elevation in blood pressure equivalent to the PDS model. Also, uterine vessel measurements showed an increased vasoconstrictive reactivity to MBG in the PDS animals vs. the normal pregnant controls; while no changes were observed with perfusion of digoxin or ouabain at the same concentration. Conclusion: These results suggest a relationship between MBG and a syndrome in rats resembling preeclampsia. Armed with these promising results, it would seem logical to further examine the role of MBG in human preeclampsia.

Preeclampsia/eclampsia is a disorder of human pregnancy that continues to exact significant maternal morbidity and mortality and fetal wastage. Therapy of these disorders has not changed in over 50 years and there are no proven preventive measures. We describe a model of the development of a syndrome in the pregnant rat that resembles preeclampsia, which results from the imposition of excessive volume expansion early in gestation. We administered desoxycorticosterone acetate (DOCA) to pregnant animals whose drinking water had been replaced with saline. We compared the results obtained in these animals with those resulting from the study of control, virgin animals, virgin animals receiving DOCA and saline, and normal pregnant (NP) animals. The virgin animals given DOCA and saline did not become hypertensive. The experimental paradigm in the DOCA plus saline pregnant (PDS) animals provides many of the phenotypic characteristics of the human disorder including the development of hypertension, proteinuria, and intrauterine growth restriction. In addition, the mean blood nitrite/nitrate concentration was reduced in the PDS rats compared with their NP counterparts. We propose that this model may prove to be useful in the study of the human condition.

Background: Breast cancers that overexpress the human epidermal growth factor receptor 2 (HER2) are eligible for effective biologically targeted therapies, such as trastuzumab. However, accurately determining HER2 overexpression, especially in immunohistochemically equivocal cases, remains a challenge. Manual analysis of HER2 expression is dependent on the assessment of membrane staining as well as comparisons with positive controls. In spite of the strides that have been made to standardize the assessment process, intra-and inter-observer discrepancies in scoring is not uncommon. In this manuscript we describe a pathologist assisted, computer-based continuous scoring approach for increasing the precision and reproducibility of assessing imaged breast tissue specimens.

The study of the pathogenesis of preeclampsia has been hampered by a relative dearth of animal models. We developed a rat model of preeclampsia in which the excretion of a circulating inhibitor of Na/K ATPase, marinobufagenin (MBG), is elevated. These animals develop hypertension, proteinuria, and intrauterine growth restriction. The administration of a congener of MBG, resibufogenin (RBG), reduces blood pressure to normal in these animals, as is the case when given to pregnant animals rendered hypertensive by the administration of MBG. Studies of Na/K ATPase inhibition by MBG and RBG reveal that these agents are equally effective as inhibitors of the enzyme.

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