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M Aviram

Publications and source records attributed to M Aviram.

At least 91 records · Page 5Linked to original sources
PubMed1997

Reduced progression of atherosclerosis in apolipoprotein E-deficient mice following consumption of red wine, or its polyphenols quercetin or catechin, is associated with reduced susceptibility of LDL to oxidation and aggregation.

The effect of consuming red wine, or its major polyphenol constituents catechin or quercetin, on the development of atherosclerotic lesions, in relation to the susceptibility of plasma LDL to oxidation and to aggregation, was studied in atherosclerotic apolipoprotein E deficient (E degree) mice. Forty E degree mice at the age of 4 weeks were divided into four groups, 10 mice in each group, and were supplemented for up to 6 weeks in their drinking water with placebo (1.1% alcohol); catechin or quercetin (50 micrograms/d per mouse), or red wine (0.5 mL/d per mouse). Consumption of catechin, quercetin, or red wine had no effect on plasma LDL or HDL cholesterol levels. The atherosclerotic lesion area was smaller in the treated mice by 39%, 46%, and 48%, respectively, in comparison with E degree mice that were treated with placebo. In accordance with these findings, cellular uptake of LDL derived after catechin, quercetin, or red wine consumption was found to be reduced by 31%, 40%, and 52%, respectively. These results were associated with reduced susceptibility to oxidation (induced by different modes such as copper ions, free radical generator, or macrophages) of LDL isolated after red wine or quercetin and, to a lesser extent after catechin consumption, in comparison with LDL isolated from the placebo group. Similar results were obtained when LDL was preincubated in vitro with red wine or with the polyphenols prior to its oxidation. Even in the basal oxidative state (not induced oxidation), LDL isolated from E degree mice that consumed catechin, quercetin, or red wine for 2 weeks was found to be less oxidized in comparison with LDL isolated from E degree mice that received placebo, as evidenced by 39%, 48%, and 49% reduced content of LDL-associated lipid peroxides, respectively. This effect could be related to enhanced serum paraoxonase activity in the polyphenol-treated mice. LDL oxidation was previously shown to lead to its aggregation. The present study demonstrated that the susceptibility of LDL to aggregation was reduced in comparison with placebo-treated mice, by 63%, 48%, or 50% by catechin, quercetin, and red wine consumption, respectively, and this effect could be shown also in vitro. The inhibition of LDL oxidation by polyphenols could be related, at least in part, to a direct effect of the polyphenols on the LDL, since both quercetin and catechin were found to bind to the LDL particle via the formation of an ether bond. We thus conclude that dietary consumption by E degree mice of red wine or its polyphenolic flavonoids quercetin and, to a lesser extent, catechin leads to attenuation in the development of the atherosclerotic lesion, and this effect is associated with reduced susceptibility of their LDL to oxidation and aggregation.

Animals↗
PubMed1997

Plasma LDL oxidation leads to its aggregation in the atherosclerotic apolipoprotein E-deficient mice.

Two major modifications of low density lipoprotein (LDL) that can lead to macrophage cholesterol accumulation and foam cell formation include its oxidation and aggregation. To find out whether these modifications can already occur in vivo in plasma and whether they are related to each other, the oxidation and aggregation states of plasma LDL were analyzed in the apolipoprotein E-deficient (E degree) transgenic mice during their aging (and the development of atherosclerosis), in comparison to plasma LDL from control mice. Plasma LDL from the E degree mice was already minimally oxidized at 1 month of age in comparison to control mice LDL, and it further oxidized with age in the E degree mice but not in the control mice. At 6 months of age, the contents of the E degree mice LDL-associated cholesteryl ester hydroperoxides, thiobarbituric acid reactive substances, and conjugated dienes were higher by two, three, and twofold, respectively, in comparison to LDL from the young, 1-month-old E degree mice. We also investigated the LDL aggregation state in E degree mice. In the young E degree mice, LDL oxidation was shown in comparison to control mice, but in both groups of young mice their LDL was not aggregated. In the E degree mice, however, the LDL aggregation state substantially increased with age, by as much as 125% at 6 months of age compared to the 1-month-old mice, whereas no significant aggregation could be detected in plasma LDL from control mice at the same age. To question the possible effect of LDL oxidation on its subsequent aggregation, LDL oxidation was induced by either copper ions, or by the free radical generator 2,2-azobis-2-amidinopropane hydrochloride, or by hypochlorite. All these oxidative systems led to LDL oxidation (to different degrees) and resulted in a similar, substantial LDL aggregation. These oxidation systems also enhanced the susceptibility of LDL to aggregation (induced by vortexing) by 23%, 28%, or 40%, respectively. To further analyze the relationships between the lipoprotein oxidation and its aggregation, LDL (0.1 mg of protein/mL) was incubated with 5 mumol/L CuSO4 at 37 degrees C in the absence or presence of the antioxidant, vitamin E (25 mumol/L). In the absence of vitamin E, a time-dependent increment in LDL oxidation was noted, which reached a plateau after 2 hours of incubation. LDL aggregation, however, only started at this time point and reached a plateau after only 5 hours of incubation. In the presence of vitamin E, both LDL oxidation and its aggregation were reduced at all time points studied. We extended the vitamin E study to the in vivo situation, and the effect of vitamin E supplementation to the E degree mice (50 mg.kg-1.d-1 for a 3-month period) on their plasma LDL oxidation and aggregation states was studied. Vitamin E supplementation to these mice resulted in a 35% reduction in the LDL oxidation state and in parallel, the LDL aggregation state was also reduced by 23%. These reductions in LDL oxidation and aggregation states were accompanied by a 33% reduction in the aortic lesion area, in comparison to nontreated E degree mice. We conclude that in E degree mice, LDL oxidation, which already took place in the plasma, can lead to the lipoprotein aggregation. These modified forms of LDL were shown to be taken up by macrophages at an enhanced rate, leading to foam cell formation. Thus, the use of an appropriate antioxidant can inhibit the formation of both atherogenic forms of LDL.

Amidines↗
PubMed1997

A cystic fibrosis transmembrane conductance regulator splice variant with partial penetrance associated with variable cystic fibrosis presentations.

Some patients express various features of cystic fibrosis (CF) even though essential characteristics of the disease might be absent. Such patients may suffer from respiratory disease without pancreatic insufficiency and normal sweat chloride levels. Others may present as male infertility because of congenital bilateral aplasia of the vas deferens (CBAVD) with no other signs of CF. The 5T allele, a DNA variant in a noncoding region of the cystic fibrosis transmembrane conductance regulator (CFTR) gene that reduces the level of the normal CFTR transcripts, was found in increased frequency among male patients with CBAVD. The purpose of this study was to investigate the possibility that the 5T allele is associated with dysfunction of organs other than the male reproductive system, leading to CF or atypical CF. Analysis of the 5T allele was performed on 148 subjects (29 with CF, 61 with atypical CF, and 58 with CBAVD) carrying 232 chromosomes with unidentified CFTR mutations, and on 142 non-CF chromosomes from healthy subjects of Ashkenazi origin. The frequency of the 5T allele among chromosomes from patients of Jewish Ashkenazi origin with CF and atypical CF (six of 33; 18%) was significantly higher than the frequency in the normal Ashkenazi population (eight of 142; 6%; p = 0.03). Analysis of the clinical presentation of the five patients with CF and the 12 patients with atypical CF carrying the 5T allele indicated that most patients suffered from respiratory disease presenting as asthma like symptoms, nasal polyposis, chronic sinusitis, chronic bronchitis, or bronchiectasis. Six patients had pancreatic insufficiency, two with meconium ileus. Sweat Cl- levels ranged from normal to elevated. Of the six male patients with respiratory disease who were old enough to be evaluated for fertility status, five were fertile and one had pancreatic insufficiency. Among male patients with CBAVD, 41% suffered from respiratory symptoms. Thus, the 5T allele is a variant with partial penetrance causing disease with an extreme variability of clinical presentation: from normal healthy fertile subjects or male patients with CBAVD to those with atypical or typical clinical phenotype of CF.

Adolescent↗
PubMed1996

Deposition pattern of radiolabeled salbutamol inhaled from a metered-dose inhaler by means of a spacer with mask in young children with airway obstruction.

BACKGROUND: The exact amount of drug deposited in the respiratory and gastrointestinal tract in children with airway obstruction, when delivered from a metered-dose inhaler (MDI) via a spacer with mask, and its distribution in children with airway obstruction, are unknown. METHODS: We studied 15 children, using salbutamol labeled with technetium 99m. Each patient was imaged with a gamma-camera immediately after one puff of labeled salbutamol was administered via a spacer with mask. Drug deposition was then analyzed to measure the distribution of the labeled spray in the oropharynx, the lungs, the stomach, and the spacer with mask (Aerochamber) itself. RESULTS: Fifteen infants and children (mean age, 21 months (range, 3 months to 5 years); mean weight, 9.3 kg (range, 3.2 to 15 kg)) were studied. Mean aerosol deposition was 1.97% +/- 1.4% in the lungs, 1.28% +/- 0.77% in the oropharynx, and 1.11% +/- 2.4% in the stomach. The remainder was trapped in the spacer. Lung imaging after inhalation from an MDI via a spacer showed widespread deposition of the drug in central and peripheral intrapulmonary airways. In two adult volunteers the deposition after one puff of the same radiolabeled drug, inhaled from an MDI via a spacer with a mouthpiece, was 19% in the lungs and 2% in the stomach. CONCLUSIONS: Infants and toddlers with obstructive lung disease can be reliably and safely treated with inhaled medication administered with an MDI via a spacer with mask. The doses of a drug given from an MDI to infants and toddlers when a spacer with mask is used are not yet well defined but should be higher than the currently recommended doses, perhaps as much as an adult dose.

Administration, Inhalation↗
PubMed1996

Activation of NADPH oxidase required for macrophage-mediated oxidation of low-density lipoprotein.

Low-density lipoprotein (LDL) oxidation by arterial wall cells, a key event during early atherogenesis, was suggested to involve the activation of 15-lipoxygenase and/or nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. We sought to analyze the role of these oxygenases in macrophage-mediated oxidation of LDL under oxidative stress. Upon incubation of LDL with the J-774 A.1 macrophage-like cell line or with human monocyte-derived macrophages (HMDM) in the presence of 1 micromol/L CuSO4, the release of superoxide anions to the medium was demonstrated. Under these conditions, the cytosolic protein components of the NADPH oxidase complex, P-47 and P-67, translocated to the plasma membrane, indicating LDL-mediated activation of the NADPH oxidase complex. Under the above-mentioned experimental conditions, the macrophage 15-lipoxygenase was also activated, as determined by the release of 15-hydroxy-5,8,11,13-eicosatetraenoic acid (15-HETE) and 13-hydroxyoctadecadienoic acid (13-HODE) to the medium. Inhibition of the macrophage NADPH oxidase with apocynin or dismutation of superoxide anions, the product of NADPH oxidase activation, with superoxide dismutase (SOD) significantly inhibited macrophage-mediated oxidation of LDL (by 61% to 89%) under these conditions. Phorbol myristate acetate (PMA), which causes NADPH oxidase activation in J-774 A.1 macrophages, had no significant effect on 15-lipoxygenase activity, but still resulted in cell-mediated oxidation of LDL. Finally, HMDM from two patients with chronic granulomatous disease (CGD) that were shown to lack active NADPH oxidase, but to possess almost normal 15-lipoxygenase activity failed to oxidize LDL. We thus conclude that LDL-induced NADPH oxidase activation (under oxidative stress) is required for macrophage-mediated oxidation of LDL, whereas activation of 15-lipoxygenase may not be sufficient for LDL oxidation under these conditions.

Adolescent↗
PubMed1996

Fosinopril reduces ADP-induced platelet aggregation in hypertensive patients.

Platelets are intimately involved in atherosclerosis, and hypertension is a known risk factor for coronary artery disease. The angiotensin-converting enzyme (ACE) inhibitors were demonstrated to reduce hypertension and attenuate atherosclerosis. Because increased platelet aggregation was shown in hypertensive patients, the effect of a new ACE inhibitor, fosinopril, on platelet aggregation was studied. Fosinopril therapy (10 mg/day for 4 weeks) in 18 male hypertensive patients showed > or = 31% reduction in ADP-induced platelet aggregation. In vitro studies showed that fosinopril had similar inhibitory effect on ADP-induced platelet aggregation. No inhibitory effect could be detected with collagen as the aggregating agent. Finally, inhibition of platelet aggregation by fosinopril was less effective in platelets derived from hypertensive patients as compared with platelets derived from normal subjects. We conclude that fosinopril possesses a significant inhibitory activity on ADP-induced platelet aggregation both in vitro and in vivo.

Adenosine Diphosphate↗
PubMed1996

Effect of deoxycholic acid and ursodeoxycholic acid on lipid peroxidation in cultured macrophages.

BACKGROUND: Kupffer cells are essential for normal hepatic homeostasis and when stimulated, they secrete reactive oxygen species, nitric oxide, eicosanoids, and cytokines. Some of these products are cytotoxic and attack nucleic acids, thiol proteins, or membrane lipids causing lipid peroxidation. Hydrophobic bile acids, such as deoxycholic acid (DCA), can damage hepatocytes by solubilising membranes and impairing mitochondrial function, as well as increasing the generation of reactive oxygen species. OBJECTIVES: The hypothesis that hydrophobic bile acids could stimulate Kupffer cells to increase their capacity to generate reactive oxygen species by measuring cellular lipid peroxidation was tested. Because the hydrophilic bile acid, ursodeoxycholic acid (UDCA) can block hydrophobic bile acid induced cellular phenomena, it was also hypothesised that UDCA could antagonise macrophage activation by hydrophobic bile acids to blunt their capacity to generate reactive oxygen species. METHODS: J-774A.1 murine macrophages were incubated for 24 hours with either 10(-5) M and 10(-4) M (final concentration) DCA alone, or 10(-4) M UDCA alone, or a mixture of 10(-4) M 1:1 molar ratio of DCA and UDCA. At the end of the incubation period, the culture medium was collected for determination of cellular lipid peroxidation by measuring the malondialdehyde (MDA) content in the medium with the thiobarbituric acid reactive substances assay. RESULTS: 10(-5) M and 10(-4) M DCA increased MDA generation by cultured macrophages. 10(-4) M UDCA alone did not increase MDA generation but blocked the peroxidative actions of DCA. CONCLUSIONS: Hydrophobic bile acids, after their hepatic retention, can oxidatively activate Kupffer cells to generate reactive oxygen species. Because UDCA can block this action, the beneficial effect of UDCA is, in part, related to its ability to act as an antioxidant.

Animals↗
PubMed1996

Consumption of eggs with meals increases the susceptibility of human plasma and low-density lipoprotein to lipid peroxidation.

Consumption of eggs for a long period was shown to result in hypercholesterolemia and is generally restricted for this reason. In the present study we analyzed the effect of eggs consumption for 3 weeks on lipoprotein atherogenicity. Consumption of 2 eggs per day with the meals, for 3 weeks resulted in a minor elevation in plasma glucose and urea concentrations. Plasma cholesterol concentration increased by 11% (p < 0.05) as a result of increased plasma low-density lipoprotein (LDL) cholesterol levels. Plasma triglycerides decreased by 13% (p < 0.01), but there were no significant alterations in plasma apolipoproteins A-I or B-100 concentrations. Plasma high-density lipoprotein (HDL) cholesterol decreased by 11% (p < 0.05). There was a 13% reduction, though not significant, in the cholesterol efflux from J-774 A.1 macrophages by HDL that was derived after eggs consumption in comparison to HDL that was obtained at baseline. The susceptibility of plasma [using 100 mM of 2,2' azobis 2-amidinopropane (AAPH)] as well as that of LDL (using 10 microM of copper ions) to lipid peroxidation was increased by 42% and 34%, respectively, as measured by the thiobarbituric acid reactive substance (TBARS) assay (p < 0.01). Kinetic analysis of LDL oxidation by copper ions revealed a 37% reduction in the lag time required for the initiation of LDL oxidation after 3 weeks of eggs consumption. The total plasma fatty acids concentration increased from 2.2 +/- 0.5 to 3.2 +/- 0.6 mg/ml. The plasma antioxidants, vitamin E and carotenoids were not significantly affected by eggs consumption. We conclude that eggs consumption, in addition to its hypercholesterolemic effect, increases plasma and LDL oxidizability, a phenomenon which was shown to enhance the progression of atherosclerosis. The atherogenic properties may contribute to the accelerated atherosclerosis prevalent in populations with high cholesterol intake.

Adult↗
PubMed1996

Angiotensin II-modified LDL is taken up by macrophages via the scavenger receptor, leading to cellular cholesterol accumulation.

The incidence of myocardial infarction is significantly higher in hypertensive patients with increased plasma concentration of angiotensin (Ang) II. Ang II was shown to bind to LDL in vitro, and in the present study we showed its binding to LDL in vivo. Ang II (10(-7) mol/L) was incubated with LDL for 3 hours at 37 degrees C, followed by reseparation of the modified lipoprotein (Ang II-LDL) and its incubation with J-774 A.1 macrophages. Binding of Ang II to LDL significantly increased the lipoprotein protein degradation (by 25%) and its cell association (by 75%) compared with nontreated LDL. Unlike Ang II-LDL, both Ang I-LDL and Ang III-LDL were taken up by macrophages similar to native LDL. The lipid composition and size of Ang II-LDL were similar to those of native LDL, and it was not aggregated. Ang II-LDL was not oxidized, as the contents of malondialdehyde and peroxides were not different from those found in native LDL. On heparin-Sepharose column chromatography, Ang II-LDL was eluted in the void volume, like acetylated LDL (Ac-LDL) and unlike native LDL, which binds to heparin. The cellular degradation of Ang II-125I-labeled LDL by J-774 A.1 macrophages of Ang II-125I-labeled LDL by J-774 A.1 macrophages was studied in the presence of a 50-fold excess of nonlabeled native LDL, Ang II-LDL, Ac-LDL, or oxidized LDL (Ox-LDL). Whereas native LDL had no effect on the degradation of Ang II-125I-LDL by the macrophages, Ac-LDL, Ox-LDL, and Ang II-LDL reduced the cellular uptake of the lipoprotein by 77%, 82%, and 87%, respectively. Similarly, fucoidin but not free Ang II reduced macrophage degradation of the labeled Ang II-LDL. We conclude that Ang II can modify LDL to a form that is not oxidized or aggregated but is still taken up at an enhanced rate by macrophages via the scavenger receptor.

Angiotensin II↗
PubMed1996

Normolipidemic xanthelasma palpebrarum: lipid composition, cholesterol metabolism in monocyte-derived macrophages, and plasma lipid peroxidation.

The lipid compositions of 8 normolipidemic xanthelasma palpebrarum (XP) lesions were analyzed using thin-layer chromatography, with the adjacent uninvolved skin used as control. The lesions were found to be composed predominantly of cholesterol, mostly cholesteryl ester, whereas in the control specimens phospholipids predominated. The degradation rates of 125I-low-density lipoprotein (LDL), oxidized LDL, and acetyl LDL, and the rates of intracellular cholesterol synthesis from 1,2-(14)C-acetate, in blood monocyte-derived macrophages (MDM) from 3 normolipidemic patients, were similar to those of MDM from 3 normal control subjects. The mean levels of lipid peroxides and conjugated dienes under basal conditions, as well as following the addition of a free radical-generating compound (2,2-azobis-2-amidinopropane hydrochloride) to the plasma of 14 normolipidemic XP patients were significantly higher than those of 14 age- and sex-matched normal controls. We conclude that the predominant lipid accumulated in normolipidemic XP lesions is cholesteryl ester, but there is no evidence for intrinsic cellular cholesterol metabolism derangement in blood MDM from patients which could account for this. Since macrophage cholesterol accumulation can also result from enhanced uptake of increased levels of oxidized LDL, the increased plasma lipid peroxidation (derived from oxidized LDL) might lead to accumulation of cholesterol in macrophages and formation of foam cells via this mechanism.

Adult↗
PubMed1996

Effect of dietary supplementation of beta-carotene on human monocyte-macrophage-mediated oxidation of low density lipoprotein.

Oxidative modification of low density lipoprotein (LDL), a key step in early atherosclerosis, is protected by the lipoprotein-associated antioxidants. The present study analyzes the effect of beta-carotene in plasma, in LDL and in monocyte-macrophages, on macrophage-mediated oxidation of LDL. We investigated the effect of dietary supplementation of beta-carotene on plasma lipid peroxidation [induced by AAPH (2,2-Azobis-2-amidinopropane hydrochloride)] and on cell-free and cell-mediated oxidation of LDL by human monocyte-derived macrophages (HMDM) in the presence of CuSO4. Significant enrichment with beta-carotene was noted in plasma (twofold), in LDL (2.6-fold) and in HMDM (1.6-fold) 2 weeks after dietary supplementation with 180 mg/day of beta-carotene. Plasma lipid peroxidation analyzed by conjugated dienes generation decreased by 22% (P < 0.01) and LDL susceptibility to oxidation analyzed by malondialdehyde generation decreased by 40% (P < 0.01). After beta-carotene supplementation, beta-carotene-enrichment of HMDM capacity to oxidize native LDL, whereas beta-carotene enrichment of LDL significantly reduced LDL oxidation. In conclusion, then, our results suggest that beta-carotene content of LDL, but not that of the macrophages, is responsible for the inhibition of oxidation of LDL.

Administration, Oral↗
PubMed1996

Macrophage activation with phorbol myristate acetate is associated with cellular lipid peroxidation.

The present study analyzed the association between two major processes that occur during atherogenesis: macrophage activation and peroxidation of the cellular lipids. Macrophage activation was achieved by cell incubation with phorbol myristate acetate (PMA) for 24 h at 37 degrees C, and was determined as: a) PMA concentration-dependent increment in the release of beta-glucuronidase, b) decrement in the procoagulant activity, and c) increment in the release of superoxides from the cells. PMA-induced macrophage activation was accompanied by cellular lipid peroxidation, as measured by increased formation of lipid peroxides (by 435%), thiobarbituric acid-reactive substances (TBARS) (by 26%), and conjugated dienes (by 77%) in comparison with control nonactivated cells. The maximal effect of PMA on lipid peroxidation in macrophages was achieved within 1 h of cell incubation with PMA. This effect was demonstrated in J-774 A.1 macrophages, as well as in mouse peritoneal, macrophages, U-937 and P-338 macrophage cell lines. Upon incubation of macrophages with 4 alpha phorbol 12, 13 didecanoate, an analogue of PMA (which, unlike PMA, does not activate protein kinase C), macrophage lipid peroxidation was lower compared with PMA, suggesting a role for protein kinase C in cellular lipid peroxidation. Analysis of cellular antioxidants under PMA-induced macrophage activation revealed a decrease of 50% in total glutathione, and in catalase levels following treatment with 100 nM PMA compared with control cells. In summary, our study demonstrates that PMA-activated macrophages undergo significant lipid peroxidation, which is associated with reduced activity of the cellular antioxidative system.

Animals↗
PubMed1996

Phospholipase A2 and phospholipase D are involved in macrophage NADPH oxidase-mediated oxidation of low density lipoprotein.

Macrophage-mediated oxidation of low density lipoprotein (LDL) under oxidative stress induces activation of reduced nicotinamide adenine dinuleotide phosphate (NADPH) oxidase. Using J-774 A.1 macrophages, the present study demonstrates that phospholipase A2 (PLase A2) as well as phospholipase D (PLase D) are involved in macrophage NADPH oxidase-mediated oxidation of LDL. Furthermore, the products of these phospholipases, arachidonic acid and phosphatidic acid, can induce NADPH oxidase activation, followed by cell-mediated oxidation of LDL. This LDL oxidation was shown to be dependent on extracellular calcium ions. We conclude that PLase A2 and PLase D can induce macrophage NADPH oxidase-dependent oxidation of LDL and thus can contribute to the formation of atherogenic oxidized lipoprotein.

Arachidonic Acid↗
PubMed1996

Interaction of oxidized low density lipoprotein with macrophages in atherosclerosis, and the antiatherogenicity of antioxidants.

Macrophage cholesterol accumulation and foam cell formation, the hallmark of early atherosclerosis, is the result of enhanced cellular uptake of plasma low density lipoprotein (LDL). Native LDL, has to undergo oxidative modifications in order to be taken up at an enhanced rate by macrophages, leading to foam cell formation. Macrophage uptake of oxidized LDL involves its binding to scavanger receptors (including cellular proteoglycans) and this is followed by an impaired cellular cholesterol metabolism. Cells of the arterial wall including macrophages can oxidize LDL in a process that involves activation of cellular oxygenases, such as NADPH oxidase and 15-lipoxygenase. This process, however, also depends on the macrophage antioxidant environment, where glutathione peroxidase and reduced glutathione play an important protective role against cell-mediated oxidation of LDL. Macrophage phospholipids peroxidation under oxidative stress can also contribute to macrophage-mediated oxidation of LDL. Evidence for the occurrence of oxidized LDL in vivo is as follows: 1) In the atherosclerotic lesion [in humans, as well as in the transgenic, apolipoprotein E-deficient mice], LDL is oxidized (and as a result, it is also aggregated), in comparison to plasma LDL which is normally not oxidized. 2) Plasma LDL from patients at high risk for atherosclerosis (such as hypercholesterolaemic, hypertensive, diabetic and renal failure patients), as well as from the apolipoprotein E-deficient mice, demonstrates increased susceptibility to oxidation in comparison to normal LDL. In some groups of these patients LDL is minimally oxidized already in plasma. 3) Supplementation of nutritional antioxidants, which are rich in polyphenols (red wine, licorice, olive oil), or of selenium to humans or to the apolipoprotein E-deficient mice, as well as therapy with beta-hydroxy-beta-methyl-glutaryl-CoA reductase inhibitors (so-called "statins") in hyperocholesterolaemic patients, were shown to reduce the susceptibility of LDL to oxidation. This effect could be associated with a reduction in the size of the atherosclerotic lesion and may thus contribute to attenuation of the atherosclerotic process.

Animals↗
PubMed1996

The 3849 + 10 kB C-->T mutation in a 21-year-old patient with cystic fibrosis.

Cystic fibrosis (CF) is the most common lethal inherited disease in the white population. It is characterized by exocrine gland epithelia dysfunction, which leads to pulmonary and pancreatic insufficiency. Since the cloning of the CF gene in 1989 and the identification of the most common CF mutation (delta F508), more than 400 different mutations have been described. These mutations appear to contribute to the heterogeneity of the CF phenotype and several reports have speculated on the relationship between the most common CF mutations and the patient's clinical status. We report the case of a 21-year-old woman with longstanding chronic pansinusitis, nasal polyposis, chronic cough and severe nasal crusting. During a period of five years she had been followed by her otolaryngologist and pediatric pulmonologist. Sweat tests performed at the age of 17 and 18 were within normal limits and she underwent repeated conventional sinonasal procedures, with no improvement in her clinical status. On her present admission, sweat tests showed a 70 meq/l chloride concentration. The diagnosis of CF was then confirmed by DNA analysis and the patient was found to carry the 3849 + 10 kB C-->T mutation. The early detection of this newly recognized form of CF in adults as well as in children presenting with sinonasal symptoms is critical for life expectancy and quality.

Adult↗
PubMed1996

The effects of time interval after venipuncture and of anticoagulation on platelet adhesion and aggregation.

Abnormal platelet function plays an important role in atherosclerosis and thrombotic disorders. Simple in vitro testing of platelet function is preferable to other techniques, and adhesion measurement is especially important because it reflects an immediate platelet response. The time lapse after venipuncture and the anticoagulant may affect platelet function in an as yet unknown way. A method for determining platelet adhesion under controlled whole blood flow conditions and an aggregation study were used. Platelet adhesion and aggregation changed significantly with time elapsed since venipuncture, peaking after 60 min (P < 0.05): a plateau was reached only after more than 120 min. Platelet adhesion was directly suppressed by the use of sodium citrate as an anticoagulant, and surface density decreased from 14.2 to 8.8 (P < 0.001). To prevent the effect of time after venipuncture on platelet function, testing should be performed at the plateau phase.

Adenosine Diphosphate↗
PubMed1995

Lesioned low density lipoprotein in atherosclerotic apolipoprotein E-deficient transgenic mice and in humans is oxidized and aggregated.

We analyzed lesioned LDL in both atherosclerotic humans and in the apo E deficient (E degree) mice and compared its characteristics to plasma LDL. Lesioned LDL, in comparison to plasma LDL, was minimally oxidized and aggregated. Upon incubation of E degree-aortic lesions with 125[I]-labeled LDL, a time-dependent oxidation of the lipoprotein occurred as evident by a rapid and substantial elevation in LDL-associated TBARS from 0.2 to 10.3 and 14.5 nmoles of MDA equivalents/mg LDL protein after 2 and 24 hours of incubation, respectively. Only minimal LDL aggregates could be detected after 2 hours of incubation. Extensive LDL aggregation (15%), however, occurred after 24 h of incubation. Similar results were obtained on using human lesioned aortas. We conclude that both oxidation and aggregation of lesioned LDL could be the result of aortic lesioned-induced modification of the lipoprotein, and both of these modified forms of LDL can further contribute to the acceleration of the atherosclerotic process.

Animals↗