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Earlier we have demonstrated a prothrombotic state in spontaneously atherogenic rodents kept on Western-style high fat diet. The aim of the present study was to investigate the cellular mechanism of such prothrombotic state.Two kinds of diets, Western-style high fat diet containing 20% fat (w/w) and 0.05% cholesterol (w/w) and low fat diet containing 7% fat without cholesterol based on AIN93G, were added to diet-sensitive apolipoprotein E and low-density lipoprotein receptor double deficient male mice for 12 or 18 weeks from 6 weeks of age. Atherosclerosis was assessed by morphometry of the aortic wall or lipid-stained lesions. Endothelial function was measured by flow-mediated vasodilation (FMV) of the femoral artery. Platelet reactivity was measured ex vivo by a shear-induced platelet aggregation test.12 weeks feeding of mice with high fat diet significantly impaired FMV, as compared with mice fed with low fat diet (P0.05). In contrast, there was no significant difference in the lipid-stained areas and in the reactivity of platelets between the two groups. 18 weeks feeding with high fat diet significantly impaired FMV (P0.05) and enhanced both lipid-stained areas (P0.05) and platelet reactivity (P0.01). These findings show that in high fat diet-induced prothrombotic state, endothelial dysfunction precedes both the morphologically detectable lesions and the enhancement of platelet reactivity.

We used a new test (the Gorog Thrombosis Test) for assessing the effect of aging, smoking and exercise habits on the overall thrombotic status including platelet reactivity and spontaneous thrombolytic activity of 30 healthy young males (mean, 21.1 +/- 0.4 years) and 34 elderly males (64.5 +/- 1.1 years). The occlusion time (OT) and the lysis time (LT) were measured from a single native blood sample. The OT is an index of platelet activation and subsequent occlusive thrombus formation by high shear stress, while the LT is an index of the resumption of blood flow due to thrombolysis. The LTs in the elderly group were significantly longer than in the young group (P < 0.001). The LTs of elderly smokers were significantly longer than those of non-smokers (P < 0.001). Exercise did not affect the LT significantly. Platelet reactivity to shear stress (OT) was not affected either by aging, smoking or exercise habits. Suppressed spontaneous thrombolytic activity in elderly males and smokers could be a mechanism of acute thrombotic events in these people.

In vivo and in vitro studies were carried out in a 37-year old female with cyclical Cushing's disease. Preoperative studies revealed periodic secretions of urinary corticosteroids occurring with a cyclicity of 2-3 weeks. On transsphenoidal surgery, a microadenoma was visualized in the anteroinferior portion of the anterior pituitary. Gel filtration analyses of the adenoma and surrounding tissues revealed increased concentrations of beta-endorphin and an activated conversion of beta-lipotropin to beta-endorphin in the adenoma compared with the surrounding tissues. These findings were in agreement with the characteristics previously reported for corticotroph adenomas. However, unexpectedly, concentrations of ACTH and beta-lipotropin in the adenoma were only slightly higher than those in the surrounding tissues. Precise mechanisms underlying this unusual finding were elusive, but it may have been due to the periodic nature of her hypercortisolism. In addition, this patient was reproducibly responsive to bromocriptine (2.5 mg, per os) with a reduction of the plasma cortisol level. Although this may suggest an intermediate lobe subtype of Cushing's disease as proposed by Lamberts' group, our case did not have any other characteristic suggestive of this proposed variant. However, it is tempting to speculate that cyclical changes in the central dopaminergic tone may have been at least a partial trigger for the periodic hormonogenesis in this patient.