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Biomedical subjects

M Aviram

Publications and source records attributed to M Aviram.

At least 181 records · Page 10Linked to original sources
PubMed1990

Variations in theophylline concentrations detected by 24-hour saliva concentration profiles in ambulatory children with asthma.

Sustained-release theophylline (SRT) therapy was monitored in ambulatory children with asthma by measuring theophylline in citric acid-stimulated saliva. Ninety-six around-the-clock saliva theophylline profiles were performed in 59 children (median age, 8.3 years) under routine life conditions. Five to seven stimulated saliva samples were collected by parents at home during a 24-hour period. Highest (Cmax) and lowest (Cmin) saliva theophylline concentrations (Sal-TC) were not consistently found after or before medication, respectively. Cmax occurred during morning hours (before or after medication) in 82% of patients. Cmax was found immediately before morning or evening dose in as many as 25% of patients. Cmin occurred in 70% of children during evening hours. Cmin was found 4 hours after morning or evening dose in 19% of patients. Excessive fluctuation in Sal-TC between pre- and post-SRT doses during both day and night hours occurred in six patients (286% +/- 87% (mean +/- SD)). Marked circadian variation in Sal-TC was disclosed in 23% of children. The first profile performed was therapeutically satisfactory in only 39% of patients; satisfactory profiles were achieved in other children after changing daily SRT dose or dosing interval. Determination of theophylline concentration in stimulated saliva specimens obtained frequently during a 24-hour period and under routine life conditions is practical and extremely valuable for close monitoring and individualization of theophylline therapy in ambulatory children with asthma.

Adolescent↗
PubMed1989

Modified forms of low density lipoprotein affect platelet aggregation in vitro.

Modified forms of low density lipoprotein (LDL) unlike native LDL can lead to macrophage cholesterol accumulation and foam cell formation. Since platelets interact with both lipoprotein and macrophages in the atherosclerotic plaque, the present study was designed to analyze the effect of modified LDL on washed human platelet composition and aggregation. Platelet aggregation was increased following 2 h of incubation with native LDL. Phospholipase C modified LDL and hepatic lipase modified LDL but not acetyl LDL further increased collagen induced platelet aggregation in a dose dependent manner by up to 15% (p less than 0.01). Oxidized LDL, however, demonstrated 25% reduction in both collagen and ADP induced platelet aggregation in comparison to the effect of native LDL. Platelet aggregation was found to be directly related to changes in platelet phospholipid content whereas platelet cholesterol content was similarly affected by all lipoproteins. Platelet cholesterol/phospholipid ratio was directly related to platelet aggregation. Our study thus demonstrates that modified forms of LDL significantly affect platelet lipid composition and function and if similar interactions occur in vivo it might also affect the atherogenic process.

Acetic Anhydrides↗
PubMed1989

Familial homozygous hypercholesterolemia: clinical and cardiovascular features in 18 patients.

Homozygous familial hypercholesterolemia (HFH) is a very rare autosomal dominant disease characterized by accelerated severe atherosclerosis. We examined 18 patients from 9 families with HFH. The age range was 6-30 years (mean = 16 years). Male to female ratio was equal. All patients had huge, multiple tuberous xanthomas on the skin and tendons. Mean +/- standard deviation of plasma cholesterol, triglycerides, low-density lipoproteins (LDL), and high-density lipoproteins (HDL) cholesterol levels were 608 +/- 89, 122 +/- 39, 550 +/- 88, and 26 +/- 8 mg/dl, respectively. Five patients (28%) had angina pectoris, two sustained a myocardial infarction, and one died at the age of 15 years. Two-dimensional echocardiography demonstrated supravalvular aortic stenosis in 3 of the 13 patients (23%). Coronary arteriography performed in 11 patients demonstrated significant obstruction in 6 patients, 2 each with single-, double-, and triple-vessel disease. Left main stenosis was present in 3 patients (27%). Supravalvular aortic narrowing was demonstrated in 6 patients (54%) and was associated with a gradient in 2 (25 and 35 mmHg, respectively). Segmental contraction abnormalities were detected in 2 of the 11 patients (18%). It is concluded that coronary artery disease is prevalent in patients with HFH and, based on the data presented, we recommend the performance of noninvasive technique, coronary arteriography and supravalvular aortography at an early age to detect and to follow the progression of the disease.

Adolescent↗
PubMed1989

Intralipid infusion into humans reduces in vitro platelet aggregation and alters platelet lipid composition.

Intralipid (Kabi Vitrum Inc, Alameda, CA) infusion into normal volunteers results in substantial elevation in serum triglyceride, phospholipids, and free cholesterol concentrations. Platelet aggregation induced in vitro in platelet-rich plasma by collagen or ADP was significantly reduced by up to 40% and 45%, respectively, during the infusion period but returned to preinfusion levels 18 hours after the end of the infusion. In parallel, platelet lipid composition was also affected. Platelet free cholesterol content was reduced by up to 20% during the infusion of Intralipid, whereas platelet triglyceride and phospholipid contents increased by 3.5-fold and twofold, respectively. Eighteen hours after the end of the infusion, both platelet cholesterol and triglyceride returned to preinfusion levels, but platelet phospholipid was still elevated. Both components of Intralipid (liposomes and triglyceride-phospholipid particles) were able to decrease in vitro platelet aggregation and platelet cholesterol content. Our results demonstrate decreased platelet function induced by Intralipid infusion into humans, which was associated with reduced platelet cholesterol content. These results suggest possible antiatherogenic effects of infusing Intralipid in humans.

Adenosine Diphosphate↗
PubMed1989

Platelet secretory products enhance LDL receptor activity and inhibit scavenger receptor activity in human monocyte derived macrophages.

Macrophage cholesterol accumulation is an early event in atherogenesis. Platelet secretory products have the potential to affect macrophage cholesterol accumulation through their effect on cellular lipoprotein uptake via the low density lipoprotein (LDL) or the scavenger receptor pathways. Preincubation of human monocyte-derived macrophages (HMDM) for 16 hours at 37 degrees C with serotonin, ADP, fibrinogen, fibronectin and platelet-derived growth factor (PDGF), followed by washout of these substances, significantly enhanced LDL uptake by 25% to 75%, whereas acetyl LDL (AcLDL) degradation (AcLDL is taken up by the scavenger receptor), was substantially reduced by 40% to 60% (except for ADP). The effect of serotonin (0 to 75 mumol/L) on macrophage interaction with lipoproteins was further analyzed and revealed a dose-dependent effect on both stimulation of macrophage LDL degradation and cholesterol esterification by up to 2.5 times, as well as an inhibition of the cellular uptake of AcLDL by up to 1.5 times. Analysis of the regulatory effect of serotonin on macrophage lipoprotein uptake revealed that the main effect of serotonin on the uptake of both lipoproteins was to change the affinity of the lipoproteins toward their specific receptor without a significant effect on the number of binding sites. The next questions addressed are whether substances that are known to be secreted by activated platelets can also modify LDL, and whether this modification can alter the interaction between LDL and macrophages. LDL treated with all of the studied substances demonstrated significantly enhanced cellular degradation compared with untreated LDL. The data thus demonstrate that substances such as those released from activated platelets can selectively affect macrophage LDL and scavenger receptor activities.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Platelets↗
PubMed1989

Low-density lipoprotein and scavenger receptor activities are modulated by secretory products derived from cells of the arterial wall.

The atherosclerotic lesion consists of cholesterol-loaded macrophages, smooth muscle cells, and other cells of the arterial wall. Conditioned medium from human monocyte-derived macrophages (HMDM) stimulated both acetylated and native low-density lipoprotein (Ac-LDL and LDL, respectively) degradation in autologous cells by 25% and 90%, respectively, and this was due to an increase in the number of both LDL and Ac-LDL receptors. Macrophage conditioned medium also resulted in an approximate doubling of LDL degradation by human arterial smooth muscle cells (HASMC), endothelial cells (HEC), and skin fibroblasts (HSF). Macrophage degradation of both Ac-LDL and LDL was enhanced 15% to 45% by conditioned medium derived from HASMC and HSF, respectively, but not by HEC-conditioned medium. Conditioned medium from HASMC, like that from macrophages, could also enhance LDL degradation by smooth muscle cells, fibroblasts, endothelial cells, and macrophages. Thus, the current study demonstrated that arterial wall cells secretory products can affect cellular lipoprotein receptor activities. This phenomenon could lead to increased cellular cholesterol accumulation and foam cell formation.

Aorta↗
PubMed1989

An effective method for plasma lipoprotein separation: studies of various animal species.

1. Plasma lipoprotein separation by density gradient ultracentrifugation largely depends on visual examination based on the natural yellow pigments of lipoproteins. 2. In non-human species and in humans with dyslipoproteinemia, some lipoproteins are not well visualized due to the lack of pigments. 3. Using a fluorescent probe in minute quantity (1,6 diphenyl-1,3,5-hexatriene) we were able to demonstrate an effective plasma lipoprotein separation using a discontinuous density gradient ultracentrifugation technique. 4. Plasma lipoproteins of human, chicken, rat and carp were compared showing the unique character of carp HDL.

Animals↗
PubMed1989

Low-density lipoprotein derived from atherosclerotic patients enhances macrophage cholesterol accumulation and in vitro platelet aggregation.

The aims of our study were to assess the differences between plasma lipoproteins separated from five angiographically normal subjects and five patients with proven CHD. The patients with CHD had significantly higher levels of LDL-cholesterol and apo-B, and reduced levels of HDL-cholesterol and apo-Al. The biological characteristics of LDL and HDL from both groups of patients demonstrated that the LDL from the CHD patients enhanced platelet aggregation and increased cholesterol content and cholesterol esterification in MPM compared to the normal patients. HDL had no significant effect on MPM; however, there was an increased platelet aggregation with HDL derived from the CHD patients, while the HDL from the normal group decreased platelet aggregation. The data suggest that lipoproteins isolated from CHD patients are more atherogenic than lipoproteins from normal patients.

Adult↗
PubMed1989

Modification of LDL by platelet secretory products induces enhanced uptake and cholesterol accumulation in macrophages.

LDL modified by incubation with platelet secretory products caused cholesterol accumulation and stimulation of cholesterol esterification in mouse peritoneal macrophages. Its uptake by the macrophages was a receptor-mediated process, not susceptible to competition by acetyl-LDL or polyanions suggesting independence of the scavenger receptor. Stimulation of the esterification process in macrophages by this modified LDL was inhibited by the lysosomal inhibitor chloroquine, indicating requirement for cellular uptake and lysosomal hydrolysis of the lipoprotein. Within the cell, the modified LDL inhibited cellular biosynthesis of triglycerides in a manner similar to the action of acetyl-LDL but different to the effect of native LDL. In the presence of HDL, acting in the medium as an acceptor for cholesterol, a low rate of cholesterol efflux from cells incubated with this modified LDL as well as with acetyl-LDL was demonstrated. A small reduction in cholesteryl ester synthesis was found in these cells, compared to a 60% reduction in cells incubated with native LDL. Thus it was demonstrated that LDL modified by platelet secretory products could induce macrophage cholesterol accumulation even though it was recognized and taken up via the regulatory LDL receptor.

Adult↗
PubMed1989

Phagocytosis of aggregated lipoprotein by macrophages: low density lipoprotein receptor-dependent foam-cell formation.

Low density lipoprotein (LDL) modified by incubation with phospholipase C (PLC-LDL) aggregates in solution and is rapidly taken up and degraded by human and mouse macrophages, producing foam cells in vitro. Human, mouse, and rabbit macrophages degraded 125I-labeled PLC-LDL (125I-PLC-LDL) more rapidly than native 125I-labeled LDL (125I-LDL), while nonphagocytic cells such as human fibroblasts and bovine aortic endothelial cells degraded 125I-PLC-LDL more slowly than 125I-LDL. This suggested the mechanism for internalization of PLC-LDL was phagocytosis. When examined by electron microscopy, mouse peritoneal macrophages appeared to be phagocytosing PLC-LDL. The uptake and degradation of 125I-PLC-LDL by human macrophages was inhibited greater than 80% by the monoclonal antibody C7 (IgG2b) produced by hybridoma C7, which blocks the ligand binding domain of the LDL receptor. Similarly, methylation of 125I-LDL (125I-MeLDL) prior to treatment with phospholipase C decreased its subsequent uptake and degradation by human macrophages by greater than 90%. The uptake and degradation of phospholipase C-modified 125I-MeLDL by macrophages could be restored by incubation of the methylated lipoprotein with apoprotein E, a ligand recognized by the LDL receptor. These results indicate that macrophages internalize PLC-LDL by LDL receptor-dependent phagocytosis.

Animals↗
PubMed1989

Platelet-modified low density lipoprotein induces macrophage cholesterol accumulation and platelet activation.

Low density lipoprotein (LDL), modified by chemical or biological means, was shown to induce macrophage cholesterol accumulation. The cholesterol and protein contents of LDL were decreased (by 10 and 15%, respectively) by incubation of the LDL for 2 h at 37 degrees C with normal washed platelet suspension or with platelet-conditioned medium; these decreases were not affected by platelet activation. The platelet-modified LDL caused a greater increase (by up to 15%) in collagen-induced, in vitro platelet aggregation than control LDL. Incubation of mouse peritoneal macrophages with platelet-modified LDL for 18 h at 37 degrees C resulted in an elevation of the macrophage cholesterol ester content (by 35-50%) as well as an increase in the cholesterol esterification rate (by 40-70%), compared with the effect of control LDL. Macrophage cholesterol synthesis, however, was significantly decreased (by 40-50%), compared with the effect of control LDL. The effect of LDL treated by platelet-conditioned medium was similar to that of platelet-modified LDL. The effect of platelet-modified LDL on macrophage cholesterol esterification was maximal within 24 h of incubation, and it was not significantly affected by inhibition of cholesterol synthesis. The platelet-modified LDL was taken up by the macrophages in a saturable fashion and its uptake was competitively inhibited by LDL, but not by acetylated LDL. We conclude that platelet-modified LDL interacts with the LDL receptor and induces macrophage cholesterol accumulation. Since the modified lipoprotein induces in vitro foam cell formation and platelet activation, platelet-modified LDL could be considered to be pro-atherogenic.

Animals↗
PubMed1989

[Intralipid infusion in familial hypercholesterolemia].

Intralipid, used for intravenous alimentation and containing triglyceride emulsion particles and phospholipid liposomes, has been shown to induce regression of atherosclerosis in experimental animals. Intravenous infusions of Intralipid were given to 2 patients with severe familial hypercholesterolemia refractory to conventional therapy, and to control subjects. Intracellular cholesterol esterification was inhibited in macrophages incubated with serum taken during infusions as compared to the preinfusion state, with maximal effect after 6 h of infusion. A significant decrease in platelet aggregation was also demonstrated in both groups, which persisted for 18 h after infusion. We conclude that infusion of Intralipid may have anti-atherogenic effects and plan to use it in patients with severe atherosclerosis.

Cholesterol↗
PubMed1989

Arterial blood derived low density lipoprotein increases platelet aggregation and macrophage cholesterol content in comparison to lipoprotein derived from veinous blood.

We studied the biochemical and biological properties of plasma lipoproteins taken from blood derived from either the aorta or femoral vein of patients with normal coronary arteriography. There were no significant differences in concentrations of cholesterol, triglycerides, apoprotein A-1 and apoprotein B derived from either source. The cholesterol content of very low density lipoprotein (VLDL) and high density lipoprotein (HDL) was similar in both aortic and venous blood. The low density lipoprotein (LDL) concentration, however, was significantly higher in the aortic blood sample. Arterial LDL significantly enhanced in vitro platelet aggregation when compared to venous LDL. (p less than 0.02). When incubated with mouse peritoneal macrophages (MPM) arterial LDL and VLDL caused an increased cholesterol accumulation and enhanced cholesterol esterification within these macrophages. The venous lipoproteins had little effect. The differences noted in the arterial lipoproteins in composition and biological function when compared to venous lipoproteins might be related to the much higher incidence of atherosclerosis found in the arterial tree.

Adult↗
PubMed1989

[Platelet-modified LDL: uptake and metabolism in macrophages].

Mouse peritoneal macrophages accumulate large amounts of cholesterol ester when incubated with chemically or biologically modified lipoproteins. Incubation of LDL with platelet secretory products for 2 hours at 37 degrees C decreases its protein and cholesterol content. Subsequently this modified LDL, named PCM-LDL, enhances in-vitro platelet aggregation. When it is incubated with cultures of macrophages, cholesterol accumulates in the cells and esterification is increased. PCM-LDL is taken up by macrophages via a receptor-mediated mechanism, independent of the scavenger receptor for acetyl-LDL. Its degradation in lysosomes is required for stimulation of cholesterol ester synthesis.

Animals↗
PubMed1989

High density lipoprotein stimulates sterol translocation between intracellular and plasma membrane pools in human monocyte-derived macrophages.

Binding of high density lipoprotein (HDL) to its receptor on cultured fibroblasts and aortic endothelial cells was previously shown to facilitate sterol efflux by initiation of translocation of intracellular sterol to the plasma membrane. After cholesterol-loaded human monocyte-derived macrophages were incubated with either [3H]mevalonolactone or lipoprotein-associated [3H]cholesteryl ester to radiolabel intracellular pools of sterol, incubation with HDL3 led to stimulation of 3H-labeled sterol translocation from intracellular sites to the cell surface which preceeded maximum 3H-labeled sterol efflux. A similar pattern was demonstrated for macrophages that were preloaded with cholesterol derived from either low density lipoprotein (LDL), acetyl-LDL, or phospholipase C-modified LDL. However, in macrophages that were not loaded with cholesterol, HDL3 stimulated net movement of 3H-labeled sterol from the plasma membrane into intracellular compartments, the opposite direction from that seen for cholesterol-loaded cells. A similar influx pattern was found in nonloaded macrophages and fibroblasts that were labeled with trace amounts of exogenous [3H]cholesterol. Cholesterol translocation from intracellular pools to the cell surface of cholesterol-loaded macrophages appeared to be stimulated by receptor binding of HDL, since chemical modification of HDL with tetranitromethane (TNM), which abolishes its receptor binding, reduced its ability to stimulate 3H-labeled sterol translocation and efflux. In nonloaded cells, however, the ability of HDL3 to stimulate sterol efflux and movement of sterol from the plasma membrane into intracellular pools was unaffected by TNM modification. Thus, binding of HDL to its receptor on cholesterol-loaded macrophages appears to promote translocation of intracellular cholesterol to the plasma membrane followed by cholesterol efflux into the medium. However, in nonloaded macrophages, HDL stimulates sterol movement from the plasma membrane into intracellular pools by a receptor-independent process.

Body Fluids↗
PubMed1988

The influence of the triglyceride content of low density lipoprotein on the interaction of apolipoprotein B-100 with cells.

To study the effect of triglyceride content of low density lipoprotein (LDL) on its physicochemical and biological properties, we have depleted the triglyceride by incubation with hepatic lipase (HL-LDL) and raised the triglyceride by incubation of HL-LDL with very low density lipoprotein and lipoprotein-deficient serum. HL-LDL was taken up by human monocyte-derived macrophages and by human skin fibroblasts at an increased rate compared to untreated LDL. Incubation of the various LDL preparations revealed that cellular LDL degradation as well as LDL-mediated cholesterol esterification were inversely related to the triglyceride content of the LDL preparation. Modification of the triglyceride content of LDL also was associated with changes in the free fatty acid content, but the interaction of the LDL with cells was unaffected by the level of this component. The triglyceride content of LDL was found to be reciprocally related to the number of free lysine amino groups of LDL apolipoprotein B (apoB) which could be labeled with trinitrobenzenesulfonic acid. 13C-Nuclear magnetic resonance (NMR) spectra of native LDL and HL-LDL samples containing [13CH3]2 lysine residues formed by reductive methylation (11-13% modification) showed that the arrangement of apoB lysines is perturbed by the exposure to hepatic lipase. The ratio of labeled lysines with pK 8.9 to those with pK 10.5 exposed on the surface of LDL particles was decreased by about 40% by lipase treatment. These effects are apparently due to changes in local apoB conformation because circular dichroism spectra revealed that the average secondary structure of the entire apoB molecule is the same in native LDL and HL-LDL. The triglyceride content of LDL reciprocally affected its binding to a monoclonal antibody which recognizes epitopes around the LDL receptor binding domain of apoB. The above evidence indicates that modulation of the core triglyceride and possibly also surface phospholipid content of LDL can alter the conformation of apoB on the surface of the particle, thereby influencing the interaction with cell surface LDL receptors.

Apolipoprotein B-100↗