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The very low density lipoprotein receptor (VLDLR) has been proposed to play a role in the delivery of fatty acids to peripheral tissues. However, despite reduced adipose tissue mass in VLDLR-deficient (VLDLR(-)(/-)) mice, this has been difficult to substantiate. In the present study, VLDLR-deficient and VLDLR-overexpressing (PVL) mice were cross-bred onto a low density lipoprotein receptor knockout (LDLR(-)(/-)) background to study the VLDLR under conditions of relatively high serum VLDL and triglyceride levels. Absence of the VLDLR resulted in a significant increase in serum triglyceride levels (1.9-fold) when mice were fed a high fat diet. In contrast, overexpression of the VLDLR resulted in a significant decrease in serum triglyceride levels (2.0-fold) under similar conditions. When kept on a chow diet, a period of prolonged fasting revealed a significant increase in serum triglyceride levels in VLDLR(-)(/-); LDLR(-)(/-) mice (2.3-fold) as compared with LDLR(-)(/-) controls. This could not be attributed to altered apolipoprotein B and VLDL triglyceride production rates. Furthermore, no major differences in nascent VLDL triglyceride content were found between VLDLR(-)(/-); LDLR(-)(/-) mice and LDLR(-)(/-) controls. However, the triglyceride content of circulating VLDL of VLDLR(-)(/-); LDLR(-)(/-) mice (63%) was relatively high as compared with LDLR(-)(/-) controls (49%). These observations suggest that the VLDLR affects peripheral uptake of VLDL triglycerides.In conclusion, under conditions of LDLR deficiency in combination with high fat feeding or prolonged fasting, the effect of the VLDLR on VLDL triglyceride metabolism was revealed.

Atherosclerosis is a process initiated by accumulation of macrophages in distinct areas of endothelial cell damage and uptake of large amounts of lipids. Recently, it has been shown that the immune system plays an active part in the progression of the atherosclerotic plaque although its precise role has not yet been elucidated.Anticardiolipin antibodies (aCL) are generally found in the sera of patients with the antiphospholipid syndrome (APS) and are associated with a prothrombotic state. Several authors have demonstrated that aCL can activate platelets and endothelial cells as well as increase oxidized low density lipoprotein (LDL) uptake by macrophages. In the present study we sought to assess the effect of immunization with aCL (Ab1, leading to the production of mouse aCL-Ab3) on the progression of atherosclerosis. Two groups of 8-weeks old female LDL-receptor knockout mice (n = 13 per group) were immunized with IgG purified from the serum of an APS patient or with normal human IgG, respectively. The aCL immunized mice developed high titres of 'self' aCL (detected using the standard aCL ELISA) as compared with the normal human IgG immunized mice, whereas no differences were noted between both study groups with respect to the serum lipid levels. The extent of fatty streak formation was significantly higher in the aCL immunized mice in comparison with the human IgG injected mice (mean aortic lesion size of 5308 ± 471 μm2vs 1027 ± 184 μm2, respectively, P < 0.01). The immunohistochemical analysis of the atherosclerotic plaques from both mouse groups did not display differences in cellular composition.The results of the study show that mouse aCL induced by immunization with human aCL from an APS patient enhance atherogenesis in LDL-RKO mice and imply that these antibodies may play a role in atherosclerosis development in patients with the APS.

Summary A clinical report of a 67-year-old woman who developed reversible acute renal failure due to focal glomerulonephritis with severe nephrotic syndrome is presented. The patient required four weeks' dialysis treatment but recovered completely. The role of temporary dialysis and diuretics on the clinical course and the reversibility of the process in old age is discussed.

VB-111 is an engineered antiangiogenic adenovirus that expresses Fas-c in angiogenic blood vessels and has previously been shown to have significant antitumor activity in vitroand in vivoin Lewis lung carcinoma, melanoma, and glioblastoma models. To evaluate the efficacy of VB-111 in thyroid cancer, we conducted in vivoxenograft nude mouse studies using multiple thyroid cancer-derived cell lines models. VB-111 treatment resulted in 26.6% (P= 0.0596), 34.4% (P= 0.0046), and 37.6% (P= 0.0249) inhibition of tumor growth in follicular, papillary and anaplastic thyroid cancer models, respectively. No toxicity was observed in any model. All tumor types showed a consistent and significant reduction of CD-31 staining (P< 0.05), reflecting a reduction of angiogenic activity in the tumors, consistent with the intended targeting of the virus. A phase 2 clinical trial of VB-111 in patients with advanced differentiated thyroid cancer is ongoing.

Antiphospholipid antibodies (aPL) are found in a variety of autoimmune diseases, and are thought to predispose of arterial and venous thrombosis. These antibodies, when investigated in different assays in vitro, activate endothelial cells and promote uptake of modified LDL to macrophages. These observations suggest that aPL can contribute to atheroma development by targeting some of the sequential steps that constitute early atherogenesis. If substantiated by large-scale clinical trials, the pro-atherogenic properties of aPL may merit screening and intervention programs in selected populations.

The renin-angiotensin system may play a role in the development of atherosclerosis. Nevertheless, results from studies attempting to attenuate the process by inhibiting the converting enzyme were equivocal, and in those who succeed, blood pressure was lowered and/or lipid profile was improved aside the inhibition of the renin-angiotensin axis. Therefore, we investigated the effect of low doses of fosinopril, a converting enzyme inhibitor, on the development of atherosclerosis in LDL-receptor deficient mice. Three group of 15 mice were fed a high fat high cholesterol western diet. The three study groups received either distilled water (“control group”), or water fortified with fosinopril 0.01 mg/kg/day (“low-dose group”) or with 0.1 mg/kg/day (“high-dose group”). Plasma aldosterone levels and lipid profile were measured at the end of the study. After 10 weeks, the mice were sacrificed and atherosclerosis was assessed at the aortic sinus. Plasma aldosterone levels did not change in the control group, and decreased significantly in both treated groups from 74.7 ng/ml to 39.3 ng/ml at the low-dose group (p < 0.003) and from 70.7 ng/ml to 33.6 ng/ml at the high-dose group (p < 0.001). The lipid profile at the end of the study showed a significantly lower levels of cholesterol and triglycerides in the high-dose group as compared to the low-dose group (p < 0.05). There was no difference between the three groups in the area of atherosclerosis at the aortic sinus: 157,000 ± 34,000 µ/m2, 130,000 ± 58,000 µ/m2 and 145,000 ± 26,000 µ/m2 at the control, low-dose and high-dose respectively. Thus, inhibition of the renin-angiotensin-aldosteron axis does not prevent the development of early atherosclerosis in LDL-receptor deficient mice.

Antiphospholipid antibodies (aPL) are found in a variety of autoimmune diseases, and are thought to predispose to arterial and venous thrombosis. These antibodies, when investigated in different assays in vitro, activate endothelial cells and promote uptake of modified LDL to macrophages. These observations suggest that aPL can contribute to atheroma development by targeting some of the sequential steps that constitute early atherogenesis. If substantiated by large-scale clinical trials, the pro-atherogenic properties of aPL may merit screening and intervention programs in selected populations.