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R Stocker

Publications and source records attributed to R Stocker.

At least 37 records · Page 2Linked to original sources
PubMed2001

Is ischemia involved in the pathogenesis of murine cerebral malaria?

Sequestration of parasitized erythrocytes in the central nervous system microcirculation and increased cerebrospinal fluid lactate are prominent features of cerebral malaria (CM), suggesting that sequestration causes mechanical obstruction and ischemia. To examine the potential role of ischemia in the pathogenesis of CM, Plasmodium berghei ANKA (PbA) infection in CBA mice was compared to infection with P. berghei K173 (PbK) which does not cause CM (the non-CM model, NCM). Cerebral metabolite pools were measured by (1)H nuclear magnetic resonance spectroscopy during PbA and PbK infections. Lactate and alanine concentrations increased significantly at the terminal stage of CM, but not in NCM mice at any stage. These changes did not correlate with parasitemia. Brain NAD/NADH ratio was unchanged in CM and NCM mice at any time studied, but the total NAD pool size decreased significantly in the CM mice on day 7 after inoculation. Brain levels of glutamine and several essential amino acids were increased significantly in CM mice. There was a significant linear correlation between the time elapsed after infection and small, progressive decreases in the cell density/cell viability markers glycerophosphocholine and N-acetylaspartate in CM, indicative of gradual loss of cell viability. The metabolite changes followed a different pattern, with a sudden significant alteration in the levels of lactate, alanine, and glutamine at the time of terminal CM. In NCM, there were significant decreases with time of glutamate, the osmolyte myo-inositol, and glycerophosphocholine. These results are consistent with an ischemic change in the metabolic pattern of the brain in CM mice, whereas in NCM mice the changes were more consistent with hypoxia without vascular obstruction. Mild obstructive ischemia is a likely cause of the metabolic changes during CM, but a role for immune cell effector molecules cannot be ruled out.

Adenosine Triphosphate↗
PubMed2001

Oxidants and antioxidants in atherosclerosis.

The oxidative theory suggests that LDL oxidation contributes to atherogenesis, implying that attenuation of this process by antioxidants should decrease atherosclerosis. However, a causative link between LDL oxidation and atherogenesis is not firmly established. It requires the identification of the oxidants that are responsible for the initiation of LDL oxidation, and an understanding of the modified moieties that are responsible for the proatherogenic activities of oxidized LDL. The present review summarizes recent data on potential biological oxidants for LDL in the vessel wall, and discusses the antiatherogenic role(s) of selected antioxidants.

Antioxidants↗
PubMed2001

Limiting light-induced lipid peroxidation and vitamin loss in infant parenteral nutrition by adding multivitamin preparations to Intralipid.

UNLABELLED: Parenteral lipids are susceptible to light-induced peroxidation, particularly under phototherapy. Ascorbic acid is protective. The aim of this study was to investigate whether dark delivery tubing and/or coadministration of multivitamin preparations could prevent peroxidation of Intralipid without undue vitamin loss. In experiments carried out on the benchtop, lipid peroxidation occurred in ambient light and was more extensive under phototherapy. Dark tubing decreased peroxide formation, but only by about 65%. In simulated clinical conditions in which solutions were pumped through standard clear or dark minibore plastic tubing. Intralipid accumulated lipid peroxides as measured by the FOX assay (280 microM) or as triglyceride hydroperoxides (52 microM). Multivitamin preparations (MVIP or Soluvit/Vitlipid) inhibited peroxide formation almost completely, and were fully protective when used with dark tubing. There was loss of riboflavin (65% from Soluvit and 35% from MVIP) in clear tubing but this was decreased to 18% and 11%, respectively, in dark tubing. Ascorbate loss was 20% (MVIP) and 50% (Soluvit) and only slightly less in dark tubing. Ascorbate loss was also seen in the absence of Intralipid and is due to riboflavin-induced photo-oxidation. CONCLUSION: Multivitamin preparations protect Intralipid against light-induced formation of lipid hydroperoxides, and administering multivitamins with Intralipid via dark delivery tubing provides a practical way of preventing peroxidation of the lipid while limiting vitamin loss. This procedure should be considered for routine use as well as with phototherapy.

Ascorbic Acid↗
PubMed2001

Dietary cosupplementation with vitamin E and coenzyme Q(10) inhibits atherosclerosis in apolipoprotein E gene knockout mice.

Intimal oxidation of LDL is considered an important early event in atherogenesis, and certain antioxidants are antiatherogenic. Dietary coenrichment with vitamin E (VitE) plus ubiquinone-10 (CoQ(10), which is reduced during intestinal uptake to the antioxidant ubiquinol-10, CoQ(10)H(2)) protects, whereas enrichment with VitE alone can increase oxidizability of LDL lipid against ex vivo oxidation. In the present study, we tested whether VitE plus CoQ(10) cosupplementation is more antiatherogenic than either antioxidant alone, by use of apolipoprotein E-deficient (apoE-/-) mice fed a high-fat diet without (control) or with 0.2% (wt/wt) VitE, 0.5% CoQ(10), or 0.2% VitE plus 0.5% CoQ(10) (VitE+CoQ(10)) for 24 weeks. None of the supplements affected plasma cholesterol concentrations, whereas in the VitE and CoQ(10) groups, plasma level of the respective supplement increased. Compared with control, plasma from CoQ(10) or VitE+CoQ(10) but not VitE-supplemented animals was more resistant to ex vivo lipid peroxidation induced by peroxyl radicals. VitE supplementation increased VitE levels in aorta, heart, brain, and skeletal muscle, whereas CoQ(10) supplementation increased CoQ(10) only in plasma and aorta and lowered tissue VITE: All treatments significantly lowered aortic cholesterol compared with control, but only VitE+CoQ(10) supplementation significantly decreased tissue lipid hydroperoxides when expressed per parent lipid. In contrast, none of the treatments affected aortic ratios of 7-ketocholesterol to cholesterol. Compared with controls, VitE+CoQ(10) supplementation decreased atherosclerosis at the aortic root and arch and descending thoracic aorta to an extent that increased with increasing distance from the aortic root. CoQ(10) significantly inhibited atherosclerosis at aortic root and arch, whereas VitE decreased disease at aortic root only. Thus, in apoE-/- mice, VitE+CoQ(10) supplements are more antiatherogenic than CoQ(10) or VitE supplements alone and disease inhibition is associated with a decrease in aortic lipid hydroperoxides but not 7-ketocholesterol.

Animals↗
PubMed2001

Oxidation of LDL by rabbit and human 15-lipoxygenase: prevalence of nonenzymatic reactions.

15-Lipoxygenase (15-LO)-induced oxidation of lipids in human LDL may be pro-atherogenic. However, the extent to which 15-LO promotes enzymatic oxidation of esterified (i.e., major) lipids in LDL may depend on various factors. Here, we show that overall, LDL lipid oxidation was favored with high activity of human 15-LO, that phospholipids were the preferred esterified substrate, and that low temperature maintained a higher proportion of enzymatic product. However, under all conditions, 15-LO induced alpha-tocopherol consumption and the accumulation of nonenzymatic products that predominated with increasing time of incubation and inactivation of the enzyme. Lysates prepared from cells overexpressing human 15-LO oxidized linoleic acid readily and in an almost exclusive enzymatic manner. In sharp contrast, such lysates failed to oxidize LDL lipids unless linoleic acid was added, in which case nonenzymatic oxidation of LDL lipids occurred. We conclude that although purified 15-LO can oxidize isolated LDL lipids in vitro, such oxygenation always includes nonenzymatic reactions that likely play a major role in the more extensive oxidation of LDL by cell-derived 15-LO.

Animals↗
PubMed2000

Myeloperoxidase binds to low-density lipoprotein: potential implications for atherosclerosis.

Myeloperoxidase (MPO), an abundant heme enzyme released by activated phagocytes, catalyzes the formation of a number of reactive species that can modify low-density lipoprotein (LDL) to a form that converts macrophages into lipid-laden or 'foam' cells, the hallmark of atherosclerotic lesions. Since MPO has been shown to bind to a number of different cell types, we investigated binding of MPO to LDL. Using the precipitation reagents phosphotungstate or isopropanol, MPO co-precipitated with LDL, retaining its catalytic activity. The association of MPO with LDL was confirmed using native gel electrophoresis. MPO was also found to co-precipitate with apolipoprotein B-100-containing lipoproteins in whole plasma. No precipitation of MPO was observed in lipoprotein-deficient plasma, and there was a dose-dependent increase in precipitation following addition of LDL to lipoprotein-deficient plasma. Binding of MPO to LDL could potentially enhance site-directed oxidation of the lipoprotein and limit scavenging of reactive oxygen species by antioxidants.

Arteriosclerosis↗
PubMed2000

Seroprevalence of diphtheria immunity among injured adults in Austria.

Over a period of 1 year a seroepidemiological study was conducted at the outpatient clinic of a trauma department. Immunity to diphtheria was determined in serum samples from 558 injured patients (205 women and 353 men, age from 18 to 70). Diphtheria-antitoxin concentrations were measured with an enzyme immunoassay and a tissue culture toxin-neutralization assay. Sero-immunity was classified as susceptibility (<0.01 IU/ml), basic protection (0.01-<0.1 IU/ml) and full protection (>/=0.1 IU/ml) against the toxic manifestations of the disease. A total of 27.1% of the subjects were susceptible to diphtheria, 26.5% had basic protection, and 46.4% were fully protected. The median antitoxin concentration reached 0.08 IU/ml (0. 0-0.29; quartiles Q25-Q75). A non linear trend toward decreasing immunity with increasing age was observed (P<0.001) and females proved less protected than males (P=0.006). The country of original immunization (Austria, Western European countries, Eastern European countries and Non European countries) had no influence on sero-immunity (P=0.49). Multiple linear regression analysis revealed that age (P<0.001) and gender (P=0.004) had a significant independent influence on diphtheria immunity level, whereas the country of original immunization was not significant (P=0.72).

Adolescent↗
PubMed2000

[Clinical management of acute head injury].

Patients after acute head injury are susceptible to secondary insults and therefore to secondary brain injury. A comprehensive approach, starting at the site of the accident, followed by emergency diagnosis and treatment in the appropriate emergency department of the trauma centre, intensive care and specific neurorehabilitation is the only way to minimise sequelae of primary brain lesions, prevent secondary brain damage and establish optimum frame conditions with respect to recovery from non-definite brain damage.

Accidents↗
PubMed2000

Oxidation of methionine residues to methionine sulfoxides does not decrease potential antiatherogenic properties of apolipoprotein A-I.

The initial stage of oxidation of high density lipoproteins (HDL) is accompanied by the lipid hydroperoxide-dependent, selective oxidation of two of the three Met residues of apolipoprotein A-I (apoA-I) to Met sulfoxides (Met(O)). Formation of such selectively oxidized apoA-I (i.e. apoA-I(+32)) may affect the antiatherogenic properties of HDL, because it has been suggested that Met(86) and Met(112) are important for cholesterol efflux and Met(148) is involved in the activation of lecithin:cholesterol acyl transferase (LCAT). We therefore determined which Met residues were oxidized in apoA-I(+32) and how such oxidation of apoA-I affects its secondary structure, the affinity for lipids, and its ability to remove lipids from human macrophages. We also assessed the capacity of discoidal reconstituted HDL containing apoA-I(+32) to act as substrate for LCAT, and the dissociation of apoA-I and apoA-I(+32) from reconstituted HDL. Met(86) and Met(112) were present as Met(O), as determined by amino acid sequencing and mass spectrometry of isolated peptides derived from apoA-I(+32). Selective oxidation did not alter the alpha-helicity of lipid-free and lipid-associated apoA-I as assessed by circular dichroism, and the affinity for LCAT was comparable for reconstituted HDL containing apoA-I or apoA-I(+32). Cholesteryl ester transfer protein mediated the dissociation of apoA-I more readily from reconstituted HDL containing apoA-I(+32) than unoxidized apoA-I. Also, compared with native apoA-I, apoA-I(+32) had a 2- to 3-fold greater affinity for lipid (as determined by the rate of clearance of multilamellar phospholipid vesicles) and its ability to cause efflux of [(3)H]cholesterol, [(3)H]phospholipid, and [(14)C]alpha-tocopherol from lipid-laden human monocyte-derived macrophages was significantly enhanced. By contrast, no difference was observed for cholesterol and alpha-tocopherol efflux to lipid-associated apolipoproteins. Together, these results suggest that selective oxidation of Met residues enhances rather than diminishes known antiatherogenic activities of apoA-I, consistent with the overall hypothesis that detoxification of lipid hydroperoxides by HDL is potentially antiatherogenic.

Apolipoprotein A-I↗
PubMed2000

Molecular action of vitamin E in lipoprotein oxidation: implications for atherosclerosis.

The oxidation theory of atherosclerosis proposes that the oxidative modification of low-density lipoproteins (LDL) plays a central role in the disease. Although a direct causative role of LDL oxidation for atherogenesis has not been established, oxidized lipoproteins are detected in atherosclerotic lesions, and in vitro oxidized LDL exhibits putative pro-atherogenic activities. alpha-Tocopherol (alpha-TOH; vitamin E), the major lipid-soluble antioxidant present in lipoproteins, is thought to be antiatherogenic. However, results of vitamin E interventions on atherosclerosis in experimental animals and cardiovascular disease in humans have been inconclusive. Also, recent mechanistic studies demonstrate that the role of alpha-TOH during the early stages of lipoprotein lipid peroxidation is complex and that the vitamin does not act as a chain-breaking antioxidant. In the absence of co-antioxidants, compounds capable of reducing the alpha-TOH radical and exporting the radical from the lipoprotein particle, alpha-TOH exhibits anti- or pro-oxidant activity for lipoprotein lipids depending on the degree of radical flux and reactivity of the oxidant. The model of tocopherol-mediated peroxidation (TMP) explains the complex molecular action of alpha-TOH during lipoprotein lipid peroxidation and antioxidation. This article outlines the salient features of TMP, comments on whether TMP is relevant for in vivo lipoprotein lipid oxidation, and discusses how co-antioxidants may be required to attenuate lipoprotein lipid oxidation in vivo and perhaps atherosclerosis.

Animals↗
PubMed2000

[Intensive care treatment concepts after traumatic spinal cord injury].

Spinal injuries are caused by strong traumatic impacts, followed not only by a local spinal reaction but also systemic involvement. The main problems in the early posttraumatic period are haemodynamic instability, pulmonary insufficiency and SIRS. In this period multiple risks of secondary injuries to the spinal cord or other organs exist and may develop towards life-threatening sepsis, ARDS and multi-organ failure. Optimum therapy for spinal injury patients is demanding and requires an experienced team for diagnosis as well as primary and secondary care. Close cooperation between intensive care and surgery is also important.

Critical Care↗
PubMed2000

Coenzyme Q improves LDL resistance to ex vivo oxidation but does not enhance endothelial function in hypercholesterolemic young adults.

Oxidative modification of low-density lipoprotein (LDL) may cause arterial endothelial dysfunction in hyperlipidemic subjects. Antioxidants can protect LDL from oxidation and therefore improve endothelial function. Dietary supplementation with coenzyme Q (CoQ(10)) raises its level within LDL, which may subsequently become more resistant to oxidation. Therefore, the aim of this study was to assess whether oral supplementation of CoQ(10) (50 mg three times daily) is effective in reducing ex vivo LDL oxidizability and in improving vascular endothelial function. Twelve nonsmoking healthy adults with hypercholesterolemia (age 34+/-10 years, nine women and three men, total cholesterol 7.4+/-1.1 mmol/l) and endothelial dysfunction (below population mean) at baseline were randomized to receive CoQ(10) or matching placebo in a double-blind crossover study (active/placebo phase 4 weeks, washout 4 weeks). Flow-mediated (FMD, endothelium-dependent) and nitrate-mediated (NMD, smooth muscle-dependent) arterial dilatation were measured by high-resolution ultrasound. CoQ(10) treatment increased plasma CoQ(10) levels from 1.1 +/-0.5 to 5.0+/-2.8 micromol/l (p =.009) but had no significant effect on FMD (4.3+/-2.4 to 5.1+/-3.6 %, p =.99), NMD (21.6+/-6.1 to 20.7+/-7.8 %, p = .38) or serum LDL-cholesterol levels (p = .51). Four subjects were selected randomly for detailed analysis of LDL oxidizability using aqueous peroxyl radicals as the oxidant. In this subgroup, CoQ(10) supplementation significantly increased the time for CoQ(10)H(2) depletion upon oxidant exposure of LDL by 41+/-19 min (p = .04) and decreased the extent of lipid hydroperoxide accumulation after 2 hours by 50+/-37 micromol/l (p =.04). We conclude that dietary supplementation with CoQ(10) decreases ex-vivo LDL oxidizability but has no significant effect on arterial endothelial function in patients with moderate hypercholesterolemia.

Adolescent↗
PubMed2000

Effect on diphtheria immunity of combined tetanus and diphtheria booster vaccination in adults.

The effect of a single booster injection of an adult formulation of a combined diphtheria-tetanus vaccine (Td) on diphtheria-specific immunity was evaluated. The booster injection, containing 2 IU diphtheria toxoid per dose, was given as part of the surgical wound management for adults with open soft tissue injuries. Diphtheria antitoxin concentrations were determined in serum samples from 534 patients (199 women and 335 men, aged 18-70 years) using an enzyme immunoassay and a tissue culture toxin neutralization assay. Seroimmunity against diphtheria toxin was classified at three levels: susceptibility, basic protection, and full protection against the toxic manifestations of the disease. Before vaccination, 27.1% of the subjects were susceptible to diphtheria, 26.5% had basic protection, and 46.4% were fully protected. Six weeks (minimum 25 days, maximum 98 days) after a single booster injection, 89.7% of the subjects achieved full protection against diphtheria, and only 3.9% had antitoxin levels below the protective level. The median increase from the prevaccination to postvaccination antitoxin concentration was found to be 14-fold (4.4-47; quartiles Q25 to Q75). The change in antitoxin levels after revaccination was higher in older age groups (P< 0.001), whereas neither sex (P = 0.86) nor the country of previous immunization with a different national immunization schedule (P=0.61) had a significant influence on the revaccination effect. Systemic adverse reactions were rare, and local reactions of clinical significance were reported in only 1.9% of subjects.

Adolescent↗
PubMed2000

Oral vitamin C and endothelial function in smokers: short-term improvement, but no sustained beneficial effect.

OBJECTIVES: To test the hypothesis that antioxidant therapy would improve endothelial function in smokers. BACKGROUND: Several studies have documented a beneficial effect of short-term oral or parenteral vitamin C on endothelial physiology in subjects with early arterial dysfunction. Possible long-term effects of vitamin C on endothelial function, however, are not known. METHODS: We studied the effects of short- and long-term oral vitamin C therapy on endothelial function in 20 healthy young adult smokers (age 36 +/- 6 years, 8 male subjects, 21 +/- 10 pack-years). Each subject was studied at baseline, 2 h after a single dose of 2 g vitamin C and 8 weeks after taking 1 g vitamin C daily, and after placebo, in a randomized double-blind crossover study. Blood samples were analyzed for plasma ascorbate levels and endothelial function was measured as flow-mediated dilation of the brachial artery, using high resolution ultrasound. Nitroglycerin-mediated dilation (endothelium-independent) was also measured at each visit. RESULTS: At baseline, plasma ascorbate level was low in the smokers (42 +/- 21 micromol/liter; normal range, 50 to 150 micromol/liter), increased with vitamin C therapy after 2 h to 120 +/- 54 micromol/liter (p < 0.001) and remained elevated after eight weeks of supplementation at 92 +/- 32 micromol/liter (p < 0.001, compared with placebo). Flow-mediated dilation, however, increased at 2 h (from 2.8 +/- 2.0% to 6.3 +/- 2.8%, p < 0.001), but there was no sustained beneficial effect after eight weeks (3.9 +/- 3.2%, p = 0.26). Nitroglycerin-mediated dilation was unchanged throughout. CONCLUSION: Oral vitamin C therapy improves endothelial dysfunction in the short term in healthy young smokers, but it has no beneficial long-term effect, despite sustained elevation of plasma ascorbate levels.

Administration, Oral↗
PubMed2000

Anti-atherogenic effect of coenzyme Q10 in apolipoprotein E gene knockout mice.

Oxidation of low-density lipoprotein (LDL) lipid is implicated in atherogenesis and certain antioxidants inhibit atherosclerosis. Ubiquinol-10 (CoQ10H2) inhibits LDL lipid peroxidation in vitro although it is not known whether such activity occurs in vivo, and, if so, whether this is anti-atherogenic. We therefore tested the effect of ubiquinone-10 (CoQ10) supplemented at 1% (w/w) on aortic lipoprotein lipid peroxidation and atherosclerosis in apolipoprotein E-deficient (apoE-/-) mice fed a high-fat diet. Hydroperoxides of cholesteryl esters and triacylglycerols (together referred to as LOOH) and their corresponding alcohols were used as the marker for lipoprotein lipid oxidation. Atherosclerosis was assessed by morphometry at the aortic root, proximal and distal arch, and the descending thoracic and abdominal aorta. Compared to controls, CoQ10-treatment increased plasma coenzyme Q, ascorbate, and the CoQ10H2:CoQ10 + CoQ10H2 ratio, decreased plasma alpha-tocopherol (alpha-TOH), and had no effect on cholesterol and cholesterylester alcohols (CE-OH). Plasma from CoQ10-supplemented mice was more resistant to ex vivo lipid peroxidation. CoQ10 treatment increased aortic coenzyme Q and alpha-TOH and decreased the absolute concentration of LOOH, whereas tissue cholesterol, cholesteryl esters, CE-OH, and LOOH expressed per bisallylic hydrogen-containing lipids were not significantly different. CoQ10-treatment significantly decreased lesion size in the aortic root and the ascending and the descending aorta. Together these data show that CoQ10 decreases the absolute concentration of aortic LOOH and atherosclerosis in apoE-/- mice.

Animals↗