Herpes simplex virus type 1 (HSV-1) binds to cells through interactions of viral glycoproteins gB and gC with heparan sulfate chains on cell surface proteoglycans. This binding is not sufficient for viral entry, which requires fusion between the viral envelope and cell membrane. Here, we show that heparan sulfate modified by a subset of the multiple D-glucosaminyl 3-O-sulfotransferase isoforms provides sites for the binding of a third viral glycoprotein, gD, and for initiation of HSV-1 entry. We conclude that susceptibility of cells to HSV-1 entry depends on (1) presence of heparan sulfate chains to which virus can bind and (2) 3-O-sulfation of specific glucosamine residues in heparan sulfate to generate gD-binding sites or the expression of other previously identified gD-binding receptors.

Mammographic breast density and age are important predictors of the accuracy of screening mammography. Although HRT use is not an independent predictor of accuracy, it probably affects accuracy by increasing breast density.

CD39, or vascular adenosine triphosphate diphosphohydrolase, has been considered an important inhibitor of platelet activation. Unexpectedly, cd39-deficient mice had prolonged bleeding times with minimally perturbed coagulation parameters. Platelet interactions with injured mesenteric vasculature were considerably reduced in vivo and purified mutant platelets failed to aggregate to standard agonists in vitro. This platelet hypofunction was reversible and associated with purinergic type P2Y1 receptor desensitization. In keeping with deficient vascular protective mechanisms, fibrin deposition was found at multiple organ sites in cd39-deficient mice and in transplanted cardiac grafts. Our data indicate a dual role for adenosine triphosphate diphosphohydrolase in modulating hemostasis and thrombotic reactions.

Using cultured cells from bovine and rat aortas, we have examined the possibility that endothelial cells might regulate the growth of vascular smooth muscle cells. Conditioned medium from confluent bovine aortic endothelial cells inhibited the proliferation of growtharrested smooth muscle cells. Conditioned medium from exponential endothelial cells, and from exponential or confluent smooth muscle cells and fibroblasts, did not inhibit smooth muscle cell growth . Conditioned medium from confluent endothelial cells did not inhibit the growth of endothelial cells or fibroblasts . In addition to the apparent specificity of both the producer and target cell, the inhibitory activity was heat stable and not affected by proteases . It was sensitive to Flavobacterium heparinase but not to hyaluronidase or chondroitin sulfate ABC lyase. It thus appears to be a heparinlike substance. Two other lines of evidence support this conclusion . First, a crude isolate of glycosaminoglycans (TCA-soluble, ethanol -precipitable material) from endothelial cell-conditioned medium reconstituted in 20% serum inhibited smooth muscle cell growth ; glycosaminoglycans isolated from unconditioned medium (i .e ., 0.4% serum) had no effect on smooth muscle cell growth . No inhibition was seen if the glycosaminoglycan preparation was treated with heparinase . Second, exogenous heparin, heparan sulfate, chondroitin sulfate B (dermatan sulfate), chondroitin sulfate ABC, and hyaluronic acid were added to 20% serum and tested for their ability to inhibit smooth muscle cell growth . Heparin inhibited growth at concentrations as low as 10 ng/ml . Other glycosaminoglycans had no effect at doses up to 10 tug/ml . Anticoagulant and non-anticoagulant heparin were equally effective at inhibiting smooth muscle cell growth, as they were in vivo following endothelial injury (Clowes and Karnovsk . Nature (Lond.) . 265:625-626,1977; Guyton et al . Circ . Res. 46 :625-634, 1980), and in vitro following exposure of smooth muscle cells to platelet extract (Hoover et al . Circ. Res. 47 :578-583, 1980) . We suggest that vascular endothelial cells may secrete a heparinlike substance in vivo which may regulate the growth of underlying smooth muscle cells.A characteristic feature of the normal, healthy arterial wall is that the intimal endothelial cells form a continuous quiescent monolayer, and the underlying medial smooth muscle cells also remain in a quiescent growth state . If the endothelium is damaged, smooth muscle cell proliferation occurs until the endothelium regenerates (9, 29). The regulation of cell growth in the vascular wall is poorly understood . Ross (15, 28) and others (10,25) (11) have shown that endothelial cells produce a factor which stimulates the growth of smooth muscle cells. Eisenstein et al . (8) have found that extracts from the inner arterial wall can be fractionated to produce both stimulators and inhibitors of smooth muscle cell growth .We present evidence demonstrating that cultured endothelial cells produce both positive a...

Abstract-Murine models of atherosclerosis, such as the apolipoprotein E (apoE) or the LDL receptor knockout mice, usually do not exhibit many of the cardinal features of human coronary heart disease (CHD), eg, spontaneous myocardial infarction, severe cardiac dysfunction, and premature death. Here we show that mice with homozygous null mutations in the genes for both the high density lipoprotein receptor SR-BI and apoE (SR-BI/apoE double knockout [dKO] mice) exhibit morphological and functional defects with similarities to those seen in human CHD. When fed a standard chow diet, these hypercholesterolemic animals developed significant atherosclerotic lesions in the aortic sinus as early as 4 to 5 weeks after birth. We now show that they also exhibited extensive lipid-rich coronary artery occlusions and spontaneously developed multiple myocardial infarctions and cardiac dysfunction (eg, enlarged hearts, reduced ejection fraction and contractility, and ECG abnormalities). Their coronary arterial lesions, which were strikingly similar to human atherosclerotic plaques, exhibited evidence of cholesterol clefts and extensive fibrin deposition, indicating hemorrhage and clotting. All of the dKO mice died by 8 weeks of age (50% mortality at 6 weeks). Thus, SR-BI/apoE dKO mice provide a new murine model for CHD and may help better define the role of lipoprotein metabolism and atherosclerosis in the pathogenesis of myocardial infarction and cardiac dysfunction. Furthermore, these animals may be useful for preclinical testing of potential genetic and/or pharmacological therapies for CHD. Key Words: SR-BI/apolipoprotein E knockout mice Ⅲ atherosclerosis Ⅲ myocardial infarction Ⅲ coronary artery disease Ⅲ lipoprotein metabolism O ne of the best understood risk factors for coronary artery atherosclerosis, a leading cause of myocardial infarction (MI) and death, is hypercholesterolemia. Unfortunately, few hypercholesterolemia and atherosclerosis rodent models spontaneously develop MIs and cardiac dysfunction. Fat-fed LDL receptor (LDLR) knockout (KO) 1 and chow-fed apolipoprotein E (apoE) KO mice, 2-4 standard models for hypercholesterolemia/atherosclerosis, do not usually exhibit MI or reduced lifespans; although 24-to 40-week-old, fat-fed apoE KO mice can develop coronary arterial plaques and, occasionally, small areas of myocardial fibrosis. 4,5 ApoE/LDLR double KO mice fed a high-fat/high-cholesterol diet for 7 months have occlusive coronary arterial atherosclerotic lesions and some associated perivascular myocardial scarring. 6 Severe stress exacerbates the small ECG abnormalities seen in these mice at rest and can induce endothelin-dependent MIs, 6 although such MIs were not reported to be lethal. Dahl salt-sensitive, hypertensive rats expressing high levels of human cholesteryl ester transfer protein 7 and atherosclerosisprone male JCR:LA-corpulent rats, 8 which have hyperlipidemia and atherosclerosis, develop coronary artery lesions and MIs.It would be useful to have additional, genetically manipulable, murine models of...

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Breast density is a strong additional risk factor for breast cancer, although it is unknown whether reduction in breast density would reduce risk. Our risk model may be able to identify women at high risk for breast cancer for preventive interventions or more intensive surveillance.

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