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Graphical abstract

We isolated and characterized immunoreactive apolipoprotein B (apoB) -containing lipoproteins from human atherosclerotic plaque and plasma to determine whether verylow-density lipoprotein (VLDL) can enter and become incorporated into the atherosclerotic lesion and how plaque apoBcontaining lipoproteins differ from apoB-containing lipoproteins isolated from plasma. Atherosclerotic plaques were obtained during aortic surgery and processed immediately. Lipoproteins were extracted from minced plaque in a buffered saline solution (extract A). In selected cases a second extraction was done after plaque was incubated with collagenase (extract B). Lipoproteins were then isolated from the extracts by anti-apoB immunosorption and separated into VLDL+intermediate-density lipoprotein (IDL) (d< 1.019 g/mL) and low-density lipoprotein (LDL) (1.019«f< 1.070 g/mL) fractions by ultracentrifugation. The VLDL+IDL fractions from plaque contained more than one third of the total apoB-associated lipoprotein cholesterol in both extracts A and B. The lipid composition of VLDL+IDL in both extracts was related to that of plasma VLDL+IDL By electron microscopy L ipoprotein infiltration into the artery wall is an essential event in the pathogenesis of atherosclerosis, but little is known about the process of lipoprotein infiltration and eventual entrapment in plaque. Even the identity of the lipoproteins involved has not been conclusively determined. It is generally agreed that low-density lipoproteins (LDL) have access to the artery wall, but very-low-density lipoproteins (VLDL) also may infiltrate the artery wall and directly contribute to atherogenesis. VLDL, particularly VLDL remnants, certainly have atherogenic potential.1 -2 Particles resembling VLDL remnants can be taken up by macrophages to produce foam cells, 3 -3 stimulate endothelial cells to express a monocyte-specific chemotactic factor, 6 and increase monocyte adherence to the endothelium. 7 Furthermore, varying amounts of labeled © 1994 American Heart Association, Inc.mean particle diameters of VLDL+IDL from extracts A and B were 9% and 23%, respectively, greater than VLDL+IDL diameters from plasma. Mean diameters of LDL from extracts A and B were 11% and 31% greater than LDL diameters from plasma. The apoE-apoB ratio of extract A VLDL+IDL was nearly twice that of plasma VLDL+IDL and severalfold higher than that of extract A LDL. Immunoblots of both VLDL+IDL and LDL from extract A demonstrated minimal fragmentation of apoB. These results demonstrate that (1) VLDL, VLDL remnants, or both, can enter human atherosclerotic plaque and become bound to the connective tissue matrix; (2) apoB-containing lipoproteins from plaque differ from plasma lipoproteins in size and apoE content; and (3) there appears to be minimal fragmentation of buffer-extractable apoB in plaque lipoproteins. (Arterioscler Thromb.

Parasitic helminths cause significant disease in animals and humans. In the absence of alternative treatments, anthelmintics remain the principal agents for their control. Resistance extends to the most important class of anthelmintics, the macrocyclic lactone endectocides (MLs), such as ivermectin, and presents serious problems for the livestock industries and threatens to severely limit current parasite control strategies in humans. Understanding drug resistance is important for optimizing and monitoring control, and reducing further selection for resistance. Multidrug resistance (MDR) ABC transporters have been implicated in ML resistance and contribute to resistance to a number of other anthelmintics. MDR transporters, such as P-glycoproteins, are essential for many cellular processes that require the transport of substrates across cell membranes. Being overexpressed in response to chemotherapy in tumour cells and to ML-based treatment in nematodes, they lead to therapy failure by decreasing drug concentration at the target. Several anthelmintics are inhibitors of these efflux pumps and appropriate combinations can result in higher treatment efficacy against parasites and reversal of resistance. However, this needs to be balanced against possible increased toxicity to the host, or the components of the combination selecting on the same genes involved in the resistance. Increased efficacy could result from modifying anthelmintic pharmacokinetics in the host or by blocking parasite transporters involved in resistance. Combination of anthelmintics can be beneficial for delaying selection for resistance. However, it should be based on knowledge of resistance mechanisms and not simply on mode of action classes, and is best started before resistance has been selected to any member of the combination. Increasing knowledge of the MDR transporters involved in anthelmintic resistance in helminths will play an important role in allowing for the identification of markers to monitor the spread of resistance and to evaluate new tools and management practices aimed at delaying its spread.