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Biomedical subjects

R Stocker

Publications and source records attributed to R Stocker.

At least 109 records · Page 6Linked to original sources
PubMed1997

[Neurochemical changes and current pharmacological approaches in craniocerebral trauma].

In recent years, our knowledge concerning pathophysiological changes in brain metabolism after traumatic brain injury (TBI) has greatly expanded. This, in turn, has enabled the development of specific pharmacological strategies for the supplementary treatment of brain-injured patients with the aim of reducing secondary brain damage. The present article focuses on the pathophysiology of TBI and the possibilities for pharmacological intervention. While some of the substances reviewed and presently used in the treatment of TBI, others are under experimental and clinical evaluation at different stages.

Animals↗
PubMed1997

Breathing pattern and additional work of breathing in spontaneously breathing patients with different ventilatory demands during inspiratory pressure support and automatic tube compensation.

OBJECTIVE: We designed a new ventilatory mode to support spontaneously breathing, intubated patients and to improve weaning from mechanical ventilation. This mode, named Automatic Tube Compensation (ATC), compensates for the flow-dependent pressure drop across the endotracheal tube (ETT) and controls tracheal pressure to a constant value. In this study, we compared ATC with conventional patient-triggered inspiratory pressure support (IPS). DESIGN: A prospective, interventional study. SETTING: A medical intensive care unit (ICU) and an ICU for heart and thoracic surgery in a university hospital. PATIENTS: We investigated two groups of intubated, spontaneously breathing patients: ten postoperative patients without lung injury, who had a normal minute ventilation (VE) of 7.6 +/- 1.7 l/min, and six critically ill patients who showed increased ventilatory demand (VE = 16.8 +/- 3.0 l/ min). INTERVENTIONS: We measured the breathing pattern [VE, tidal volume (VT), and respiratory rate (RR)] and additional work of breathing (WOBadd) due to ETT resistance and demand valve resistance. Measurements were performed under IPS of 5, 10, and 15 mbar and under ATC. RESULTS: The response of VT, RR, and WOBadd to different ventilatory modes was different in both patient groups, whereas VE remained unchanged. In postoperative patients, ATC, IPS of 10 mbar, and IPS of 15 mbar were sufficient to compensate for WOBadd. In contrast, WOBadd under IPS was greatly increased in patients with increased ventilatory demand, and only ATC was able to compensate for WOBadd. CONCLUSIONS: The breathing pattern response to IPS and ATC is different in patients with differing ventilatory demand. ATC, in contrast to IPS, is a suitable mode to compensate for WOBadd in patients with increased ventilatory demand. When WOBadd was avoided using ATC, the patients did not need additional pressure support.

Adult↗
PubMed1997

Inhibition of LDL oxidation by ubiquinol-10. A protective mechanism for coenzyme Q in atherogenesis?

The oxidation of low density lipoprotein (LDL) is now commonly regarded as an important early event in atherogenesis. As such there is considerable interest in the ability of antioxidant supplementation to attenuate LDL oxidation and hence atherosclerosis. A majority of studies on LDL antioxidation have focused on alpha-tocopherol (alpha-TOH), biologically and chemically the most active form of vitamin E and quantitatively the major lipid-soluble antioxidant in extracts prepared from human LDL. In addition to alpha-TOH, circulating LDL also contains low levels of ubiquinol-10 (CoQ10H2; the reduced form of coenzyme Q). Recent studies have shown that in intact, isolated LDL, alpha-TOH can act as either an anti- or prooxidant for the lipoprotein's lipids. This article reviews the molecular action of alpha-TOH in LDL undergoing radical-initiated oxidation, and how the presence of CoQ10H2 suppresses the pro-oxidant or complements the antioxidant activity of the vitamin. We also comment on the plasma and intimal levels of alpha-TOH and CoQ10H2 in patients suffering from coronary artery disease and discuss the potential implications of these results for atherogenesis.

Antioxidants↗
PubMed1997

Detectable concentrations of Fas ligand in cerebrospinal fluid after severe head injury.

When the cell surface molecule Fas is triggered by its agonist Fas ligand the result is apoptosis of these cells and tissue destruction. To elucidate the pathophysiological relevance of Fas ligand in patients with cerebral oedema caused by trauma, we examined its concentrations in cerebrospinal fluid in 18 patients using specific ELISA. Serum and cerebrospinal fluid from healthy people and injured patients without head trauma did not contain detectable Fas ligand. In contrast, cerebrospinal fluid from patients with severe brain injury contained high concentrations of Fas ligand without detectable concentrations in serum. Soluble Fas ligand concentrations in cerebrospinal fluid correlated significantly with severity of brain injury. The Fas-Fas ligand-system may have a pivotal role in causing oedema and local tissue destruction in the brain after severe head injury.

Adult↗
PubMed1997

Requirement for, promotion, or inhibition by alpha-tocopherol of radical-induced initiation of plasma lipoprotein lipid peroxidation.

alpha-Tocopherol (alpha-TOH), generally regarded as the most important lipid-soluble, chain-breaking antioxidant in human plasma, can also be a pro-oxidant in isolated low-density lipoprotein (LDL) (Bowry V. W.; Stocker R. J. Am. Chem. Soc. 115:6029-6044; 1993). Here we examined whether this pro-oxidant activity of alpha-TOH is of more general relevance. We compared the oxidizability of lipid hydroperoxide-free, in vivo or in vitro alpha-TOH-depleted LDL and high-density lipoprotein (HDL), as well as plasma reconstituted with alpha-TOH-depleted lipoproteins, with that of the corresponding native and alpha-TOH-supplemented samples, using water- and lipid-soluble peroxyl radicals (ROO.), hydroxyl radicals (.OH), Cu2+, the transition metal-containing Ham's F-10 medium, soybean 15-lipoxygenase, and horseradish peroxidase as oxidants. Lipoprotein and plasma oxidizability was assessed by the loss of cholesteryl esters and alpha-TOH and the accumulation of hydroperoxides of cholesteryl esters and phospholipids. Compared to native LDL, HDL, and plasma, the in vivo and in vitro alpha-TOH-depleted counterparts were highly resistant to peroxidation initiation by all oxidants when used at mild radical flux conditions. Wherever tested, the oxidizability of isolated LDL decreased proportionally with decreasing alpha-TOH content. Initiation of LDL lipid oxidation by lipoxygenase and Cu2+ (even up to Cu2+:LDL ratio of 20:1) had an absolute requirement for alpha-TOH. Oxidation of reconstituted plasma with ROO. showed that in the absence of the vitamin, plasma lipids were largely resistant to oxidation, whereas bilirubin and urate oxidized more rapidly. Replenishing the in vitro depleted LDL with alpha-TOH, but not with alpha-tocopherol acetate, fully restored its original content of vitamin E and its oxidizability. Similarly, dietary supplementation with alpha-TOH restored the vitamin content and oxidizability of the in vivo alpha-TOH-depleted lipoproteins and plasma obtained from a patient with familial isolated vitamin E deficiency. Under high fluxes of ROO. and .OH, the activity of alpha-TOH in LDL switched from pro- to anti-oxidant, with the switching point for .OH observed at a lower radical flux than that for ROO.. Together, our results show that alpha-TOH generally makes lipoproteins more reactive towards radical oxidants; this can result in a pro-oxidant activity depending on the specific oxidation conditions.

Free Radicals↗
PubMed1997

Unexpected dose response of copper concentration on lipoprotein oxidation in serum: discovery of a unique peroxidase-like activity of urate/albumin in the presence of high copper concentrations.

Oxidative modification of low-density lipoprotein (LDL) may be an important factor in atherogenesis. The susceptibility of LDL to oxidation is usually determined in isolation by exposing LDL to oxidative stress induced by Cu ions or a free radical initiator. In these cases oxidation is carried out in the absence of water-soluble vitamins or serum proteins that may be present at the site of oxidation in vivo. We have examined the Cu2+-induced oxidation of lipoproteins in diluted serum. When oxidizing isolated LDL, there is a decrease in lag time with increasing concentration of Cu2+ until a minimum "lag time" is reached at a Cu:LDL ratio of about 50:1. In serum, we have shown an initial decrease in "lag time" with increasing Cu concentration up to 12.5 microM. However, with higher Cu concentrations "lag time" to oxidation increases, contrary to expectation, until a maximum is reached at about 50 microM Cu. This dose response observed for Cu oxidation of diluted serum was highly reproducible in a number of individual subjects. When serum was gel-filtered to remove low molecular weight compounds, the resulting filtrate behaved the same as isolated LDL. Uric acid was found to be an important component of the low molecular weight fraction responsible for the paradoxical effect of Cu concentration on serum oxidation. The same paradoxical effect was found when isolated LDL was incubated with uric acid in the presence of human serum albumin (HSA) and Cu. The incubation of HSA with reducing agents such as uric acid or bilirubin in the presence of high Cu concentrations, produces a "peroxidase-like" activity, capable of breaking down hydrogen peroxide as well as lipid hydroperoxides. The decomposition of lipid peroxides is a likely explanation for the longer serum oxidation lag times seen at higher Cu concentrations. Our study highlights the possible importance of interactions between uric acid and serum proteins in the presence of high metal ion concentrations.

Copper Sulfate↗
PubMed1997

Production of cytokines following brain injury: beneficial and deleterious for the damaged tissue.

A profound inflammatory response is initiated immediately following traumatic brain injury (TBI) and is characterized by the release of several cytokines with pro- and anti-inflammatory functions. In order to elucidate which cytokines are released in the human brain in response to injury as well as in the peripheral compartment, IL-1, IL-6, IL-8, IL-10, TNF-alpha and TGF-beta were monitored in CSF and serum of severely brain-injured patients. Furthermore, we investigated the possible modulation of systemic reactions by IL-6 and the ability of IL-6 and IL-8 to promote the synthesis of nerve growth factor.

Animals↗
PubMed1997

Noninvasive monitoring of cardiac output in critically ill patients with thoracocardiography.

Thoracocardiography noninvasively estimates changes in cardiac output by recording ventricular volume curves from an inductive plethysmographic transducer placed around the chest near the xiphoid process. We evaluated performance of thoracocardiography for estimation of cardiac output in 21 critically ill patients in comparison to thermodilution. A total of 201 paired cardiac output measurements were obtained over periods of 35 to 254 min. Since thoracocardiography tracks relative changes in cardiac output but does not provide absolute values, the first cardiac output by thermodilution in each patient was used to calibrate thoracocardiography for comparisons of subsequent cardiac output estimates to thermodilution. The mean difference (bias) of cardiac output (thoracocardiography - thermodilution) was 0.0 L/min, the limits of agreement (bias +/- 2 SD) included a range from -1.5 to +1.6 L/min. For estimations of relative changes in cardiac output by thoracocardiography and thermodilution the bias was 0%, and the limits of agreement -21 and +22%. We conclude that thoracocardiography is a promising noninvasive technique for monitoring cardiac output in critically ill patients.

Adult↗
PubMed1997

Inhalation of the nitric oxide synthase cofactor tetrahydrobiopterin in healthy volunteers.

Pulmonary endothelial dysfunction is the hallmark of acute lung injury. Impaired pulmonary endothelial nitric oxide (NO) production in this event has been described. Tetrahydrobiopterin (BH4) is an essential cofactor for NO synthase and modulator of its activity. At high local concentrations, BH4 provokes local vasodilation in vivo in healthy individuals. At lower concentrations, BH4 selectively and locally restores disturbed NO-dependent vasodilation in patients with endothelial dysfunction. In this preliminary study, we therefore investigated the feasibility of BH4 inhalation in five healthy human volunteers. Inhalation of buffered, aqueous BH4-dihydrochloride solution was well tolerated; despite the buffer, BH4 stability was completely preserved. Resorption of inhaled BH4 was demonstrated by significantly increased BH4 levels in plasma and urine. Inhaled BH4 did not alter pulmonary function and had no effect on systemic hemodynamic values. Our data demonstrate that inhalation is a novel method for local BH4 administration, offering a basic therapeutic tool for investigation of restoration of impaired NO-dependent vasodilation due to pulmonary endothelial dysfunction.

Administration, Inhalation↗
PubMed1997

Prone postioning and low-volume pressure-limited ventilation improve survival in patients with severe ARDS.

STUDY OBJECTIVES: Investigating the effect of low-volume pressure-limited ventilation and repeated prone positioning on the short-term course and outcome in patients with severe ARDS. SETTING: Level 1 trauma center of a university hospital. PATIENTS: Twenty-five patients suffering from ARDS with a lung injury score (LIS) > or = 2.5 admitted consecutively to our ICU from January 1992 to December 1994. METHODS: Mechanical ventilation with peak inspiratory pressure limitation to 35 mbar, irrespective of hypercapnia and prone positioning to achieve adequate oxygenation. SCORING AND MEASUREMENTS: Patient assessment with LIS, APACHE (acute physiology and chronic health evaluation) II score, injury severity score, and multiple organ failure score. Blood gas analyses and estimation of static compliance were repeated at least every 4 h during the treatment period. PaO2/FIO2 (fraction of inspired oxygen) ratio, alveolo-arterial oxygen difference, and intrapulmonary shunt were calculated according to standard equations. The best values taken from each 4-h period during the investigation were used to evaluate the best possible performance of the lung within this interval and to investigate the entire course. RESULTS: Mean predicted mortality based on the APACHE II score was 35.4+/-15.2%. Three of the 25 patients (12%) died. However, none was related to respiratory failure. No pneumothorax occurred. Sixteen patients, lacking any contraindication for prone positioning, responded positively to this change in position, each to a different individual degree. CONCLUSION: We assume that our low mortality in patients with severe ARDS might be due mainly to low-volume pressure-limited ventilation and prone positioning. This simple strategy seems to allow successful treatment for patients with severe ARDS.

APACHE↗
PubMed1997

Separation and characterization of cholesteryl oxo- and hydroxy-linoleate isolated from human atherosclerotic plaque.

In previous work we demonstrated that up to 30% of cholesteryl linoleate in homogenates of advanced human plaque samples is present in oxidized forms. Here we show that the material from plaque hexane extracts which co-elutes with cholesteryl hydroxy-linoleate on reversed phase HPLC (Anal Biochem 1993;213:79), is composed of several isomers of cholesteryl hydroxy- and cholesteryl oxo-octadecadienoate. Enzymatic hydrolysis and measurement of liberated cholesterol and disappearance of the esters revealed that almost all of the material consisted of unoxidized cholesterol esterified to oxidized derivatives of octadecadienoate. Semi-preparative reversed-phase HPLC was used to obtain sufficient quantities of this co-eluting material to undertake normal phase HPLC separation of these components. The nature of such separated and isolated compounds was identified, by co-chromatography with authentic standards, UV spectroscopy and chemical ionization and electron impact mass spectrometry, as cholesteryl hydroxy- and cholesteryl oxo-octadecadienoate. These oxidized fatty acids have been observed previously in plaque, in agreement with our new unambiguous demonstration of their presence as cholesteryl esters. The application of the methods described for the separation of the various forms of oxidized cholesteryl octadecadienoate may aid mechanistic studies of in vitro and in vivo lipoprotein lipid oxidation.

Arteriosclerosis↗
PubMed1997

Plasma and LDL levels of major lipophilic antioxidants are similar in patients with advanced atherosclerosis and age-matched controls.

Oxidative modification of low-density lipoprotein (LDL), regarded an early event in atherogenesis, is associated with the depletion of the lipoprotein's antioxidants. We tested whether the levels of major lipophilic antioxidants in the blood of patients with advanced atherosclerosis are different to those in age-matched controls. On average, plasma ubiquinol-10, total coenzyme Q and coenzyme Q redox status were slightly lower whereas the levels of alpha-tocopherol were slightly higher in patients (63 +/- 11 years, n = 32) than controls (64 +/- 10 years, n = 24). However, these differences were not statistically significant (p > 0.05). The levels of antioxidants in LDL isolated from a subset of patients (n = 20) and controls (n = 15) were also indifferent, and hydroperoxides of cholesteryl esters were undetectable (detection limit 10 nM) in plasma of patients (n = 11) and controls (n = 10). The data suggests that plasma and LDL levels of lipophilic antioxidants are not depleted in patients suffering from severe atherosclerosis, and that neither parameter serves as a useful diagnostic indicator for this disease.

Aged↗
PubMed1996

3-Hydroxyanthranilic acid is an efficient, cell-derived co-antioxidant for alpha-tocopherol, inhibiting human low density lipoprotein and plasma lipid peroxidation.

alpha-Tocopherol (alpha-TOH) can promote lipid peroxidation in human low density lipoprotein (LDL) unless co-antioxidants are present that eliminate the chain-carrying alpha-tocopheroxyl radical (alpha-TO.) (Bowry, V. W., Mohr, D., Cleary, J., and Stocker, R. (1995) J. Biol. Chem. 270, 5756-5763). Interferon-gamma inhibits human monocyte/macrophage-facilitated LDL lipid peroxidation via induction of cellular tryptophan degradation and production and release of 3-hydroxyanthranilic acid (3HAA) (Christen, S., Thomas, S. R., Garner, B., and Stocker, R. (1994) J. Clin. Invest. 93, 2149-2158). We now report on the mechanism of antioxidant action of 3HAA. 3HAA directly reduced alpha-TO. in UV-exposed micellar dispersions of alpha-TOH or in LDL incubated with soybean 15-lipoxygenase (SLO), as assessed by electron paramagnetic resonance spectroscopy. 3HAA did not inhibit SLO enzyme activity. Anthranilic acid, which lacks the phenoxyl group, was incapable of reducing alpha-TO.. 3HAA dose-dependently inhibited the peroxidation of surface phospholipids and core cholesteryl esters in LDL exposed to SLO, peroxyl radicals (ROO.), or Cu2+; oxidants that convert alpha-TOH to alpha-TO.. In all cases, sparing of LDL's alpha-TOH, but not ubiquinol-10 (CoQ10H2), was observed until the majority of 3HAA was consumed. Addition of 3HAA or ascorbate prevented further consumption of alpha-TOH and accumulation of lipid hydroperoxides when added to aqueous or lipophilic ROO.-oxidizing LDL after complete and partial consumption of CoQ10H2 and alpha-TOH, respectively. In contrast, addition of urate, an efficient ROO. scavenger incapable of scavenging alpha-TO., did not efficiently inhibit ongoing lipid peroxidation. Oxidation of 3HAA-supplemented human plasma by aqueous ROO. resulted in the successive consumption of ascorbate, CoQ10H2, 3HAA, bilirubin, alpha-TOH, and urate. Lipid peroxidation was prevented as long as ascorbate, CoQ10H2, and 3HAA were present, but subsequently proceeded as a free-radical chain reaction concomitant with alpha-TOH, bilirubin, and urate consumption. Addition of 3HAA to aqueous ROO.-oxidizing plasma, after complete consumption of ascorbate and CoQ10H2, strongly inhibited ongoing lipid peroxidation and consumption of alpha-TOH, bilirubin, and urate immediately and as efficiently as did ascorbate. These findings demonstrate that 3HAA is a highly efficient co-antioxidant for plasma lipid peroxidation by virtue of its ability to interact with alpha-TO. in lipoproteins. Since interferon-gamma is the principal inducer of tryptophan degradation and release of 3HAA by monocytes/macrophages, this may represent a localized extracellular antioxidant defense against LDL oxidation in inflammation.

3-Hydroxyanthranilic Acid↗
PubMed1996

Inhibition of copper- and peroxyl radical-induced LDL lipid oxidation by ebselen: antioxidant actions in addition to hydroperoxide-reducing activity.

The effects of ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) on human LDL lipid oxidation induced by different fluxes of aqueous peroxyl radicals and cupric ion (at a Cu2+:LDL ratio of 17:1) were investigated. Addition of ebselen to LDL oxidised with Cu2+ prolonged the duration of the lag-phase typical for this oxidising condition, with the increase being proportional to the square of the ebselen concentration. Ebselen also prevented the formation of lipid hydroperoxides and inhibited the consumption of endogenous antioxidants during the early period of Cu(2+)-induced oxidation, during which time the drug was converted stoichiometrically into ebselen oxide (2-phenyl-1,2-benzisoselenazol-3(2H)-one-Se-oxide). Ebselen oxide itself was antioxidant inactive. Ebselen also inhibited formation of lipid-hydroperoxides and spared alpha-tocopherol during the initial stages of LDL oxidation mediated by low-flux of aqueous peroxyl radicals, where a lag-phase was not observed. When a higher flux of aqueous peroxyl radicals was used, ebselen increased the observed inhibited phase of peroxidation in a dose-dependent manner, though less pronounced than its prolongating effect on the lag-phase of Cu(2+)-induced LDL lipid oxidation. Ebselen was also able to directly interact with Cu1+, alkyl peroxyl radicals and alpha-tocopheroxyl radicals, demonstrating that the drug has a number of potential antioxidant activities in addition to its well-known hydroperoxide-reducing activity. We conclude that the antioxidant activities of ebselen are complex and that their relative importance likely vary depending on the experimental system used.

Adult↗
PubMed1996

Rapid reduction and removal of HDL- but not LDL-associated cholesteryl ester hydroperoxides by rat liver perfused in situ.

To test whether high-density lipoproteins (HDL) could aid in the removal in vivo of potentially atherogenic oxidized lipids, we perfused rat liver in situ with buffer supplemented with isolated human HDL containing small amounts of cholesteryl linoleate hydro(pero)xides [CH18:2-O(O)H]. Perfusion resulted in the rapid removal of Ch18:2-O(O)H from HDL with a half-life (t1/2)of 11.4 min., faster than that of unoxidized cholesteryl linoleate, and dependent of the presence of the liver. In addition, the liver enhanced the reduction of Ch18:2-OOH associated with HDL remaining in the perfusate buffer. Perfusion resulted in the release of a hepatic activity that enhanced the reduction of HDL-associated CH18:2-OOH and was resistant to heat treatment. In contrast with the situation with HDL, low-density lipoprotein (LDL)-associated CH18:2-O(O)H were neither removed nor reduced by perfused rat liver within the time course studied, in support of a possible role for HDL in the detoxification of circulating lipid hydroperoxides in vivo.

Adult↗
PubMed1996

Presence of hypochlorite-modified proteins in human atherosclerotic lesions.

Oxidation of LDL may contribute to atherogenesis, though the nature of the in vivo oxidant(s) remains obscure. Myeloperoxidase, the enzyme responsible for hypochlorous acid/hypochlorite (HOCl) production in vivo, is present in active form in human atherosclerotic lesions, and HOCl aggregates and transforms LDL into a high-uptake form for macrophages in vitro. Here we demonstrate HOCl-modified proteins in human lesions using an mAb raised against HOCl-modified LDL that recognizes HOCl-oxidized proteins but does not cross-react with Cu2+-, malondialdehyde-, or 4-hydroxynonenal-modified LDL. This antibody detected significantly more material in advanced atherosclerotic lesions than normal arteries, even though azide and methionine were included during sample work-up to inhibit myeloperoxidase and to scavenge HOCl. The epitope(s) recognized was predominantly cell associated and present in monocyte/macrophages, smooth muscle, and endothelial cells. The intima and cholesterol clefts stained more heavily than the center of the thickened vessels; adventitial staining was apparent in some cases. Immunostaining was also detected in a very early lesion from an accident victim, beside healthy areas that were unreactive. LDL oxidized by HOCl in vitro, but not native LDL, effectively competed with the epitopes in lesions for antibody binding. Density centrifugation of plaque homogenates and Western blot analysis showed that, in the apo B-containing lipoprotein fraction, the mAb recognized protein(s) of molecular mass greater than apo B, similar to those produced during oxidation of LDL with HOCl in vitro. Three major proteins were recognized by the anti-HOCl-modified protein antibody but not by an anti-apo B antibody in the apo B-free fraction. Together, these results demonstrate HOCl-oxidized proteins in human atherosclerotic lesions, implicating this oxidant in LDL modification in vivo.

Arteriosclerosis↗