Steroid hormone measurements from different types of assays in relation to body mass index and breast cancer risk in postmenopausal women: Reanalysis of eighteen prospective studies.

Epidemiological studies have examined breast cancer risk in relation to sex hormone concentrations measured by different methods: "extraction" immunoassays (with prior purification by organic solvent extraction, with or without column chromatography), "direct" immunoassays (no prior extraction or column chromatography), and more recently with mass spectrometry-based assays. We describe the associations of estradiol, estrone and testosterone with both body mass index and breast cancer risk in postmenopausal women according to assay method, using data from a collaborative pooled analysis of 18 prospective studies. In general, hormone concentrations were highest in studies that used direct assays and lowest in studies that used mass spectrometry-based assays. Estradiol and estrone were strongly positively associated with body mass index, regardless of the assay method; testosterone was positively associated with body mass index for direct assays, but less clearly for extraction assays, and there were few data for mass spectrometry assays. The correlations of estradiol with body mass index, estrone and testosterone were lower for direct assays than for extraction and mass spectrometry assays, suggesting that the estimates from the direct assays were less precise. For breast cancer risk, all three hormones were strongly positively associated with risk regardless of assay method (except for testosterone by mass spectrometry where there were few data), with no statistically significant differences in the trends, but differences may emerge as new data accumulate. Future epidemiological and clinical research studies should continue to use the most accurate assays that are feasible within the design characteristics of each study.

Fasting glucose and treatment outcome in breast and colorectal cancer patients treated with targeted agents: results from a historic cohort.

BACKGROUND: We investigated pretreatment fasting glucose as a predictor of patients' important outcomes in breast and colorectal cancers undergoing targeted therapies. PATIENTS AND METHODS: In a historic cohort of 202 breast and 218 colorectal cancers treated with targeted agents from 1998 to 2009, we used the Kaplan-Meier method and the log-rank test to estimate survival through tertiles of fasting glucose and the Cox proportional hazards model for multivariate analysis stratified by primary site of cancer and including gender, age and body mass index. RESULTS: The median follow-up was 20 months (1-128). At 60 months, 65% of patients in the lowest tertile of fasting glucose did not experiment disease progression compared with 34% in the highest tertile (P=0.001). Seventy-six percent of females in the lowest tertile showed no progression compared with 49% in the top tertiles (P=0.015). In multivariate analysis, fasting glucose was a significant predictor of time to disease progression only in breast cancer patients in the first tertile compared with the third (P=0.017). CONCLUSIONS: We found evidence of a predictive role of pretreatment fasting glucose in the development of resistance in breast cancer patients treated with targeted agents. Prospective studies are warranted to confirm our findings.

A new approach to measuring estrogen exposure and metabolism in epidemiologic studies.

Endogenous estrogen plays an integral role in the etiology of breast and endometrial cancer, and conceivably ovarian cancer. However, the underlying mechanisms and the importance of patterns of estrogen metabolism and specific estrogen metabolites have not been adequately explored. Long-standing hypotheses, derived from laboratory experiments, have not been tested in epidemiologic research because of the lack of robust, rapid, accurate measurement techniques appropriate for large-scale studies. We have developed a stable isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS(2)) method that can measure concurrently all 15 estrogens and estrogen metabolites (EM) in urine and serum with high sensitivity (level of detection=2.5-3.0fmol EM/mL serum), specificity, accuracy, and precision [laboratory coefficients of variation (CV's) < or =5% for nearly all EM]. The assay requires only extraction, a single chemical derivatization, and less than 0.5mL of serum or urine. By incorporating enzymatic hydrolysis, the assay measures total (glucuronidated+sulfated+unconjugated) EM. If the hydrolysis step is omitted, the assay measures unconjugated EM. Interindividual differences in urinary EM concentrations (pg/mL creatinine), which reflect total EM production, were consistently large, with a range of 10-100-fold for nearly all EM in premenopausal and postmenopausal women and men. Correlational analyses indicated that urinary estrone and estradiol, the most commonly measured EM, do not accurately represent levels of total urinary EM or of the other EM. In serum, all 15 EM were detected as conjugates, but only 5 were detected in unconjugated form. When we compared our assay methods with indirect radioimmunoassays for estrone, estradiol, and estriol and enzyme-linked immunosorbent assays for 2-hydroxyestrone and 16alpha-hydroxyestrone, ranking of individuals agreed well for premenopausal women [Spearman r (r(s))=0.8-0.9], but only moderately for postmenopausal women (r(s)=0.4-0.8). Our absolute readings were consistently lower, especially at the low concentrations characteristic of postmenopausal women, possibly because of improved specificity. We are currently applying our EM measurement techniques in several epidemiologic studies of premenopausal and postmenopausal breast cancer.

Coffee intake and risk of incident diabetes in Puerto Rican men: results from the Puerto Rico Heart Health Program.

OBJECTIVE: To study prospectively the association of coffee intake with incident diabetes in the Puerto Rico Heart Health Program cohort, comprising 9824 middle-aged men (aged 35-79 years). METHODS: Of 9824 men, 3869 did not provide a fasting blood sample at baseline, 1095 had prevalent diabetes and 131 were not given fasting glucose tests at any subsequent study visit. Thus, the present analysis includes 4685 participants. Diabetes was ascertained at baseline and at two study visits between 1968 and 1975 using fasting glucose tests and self-reports of physician-diagnosed diabetes or use of insulin or hypoglycaemic medication. Logistic regression analysis was used to assess the association of coffee intake with risk of incident diabetes while adjusting for covariates (age, BMI, physical activity, smoking, education, alcohol intake, family history of diabetes, intakes of milk and sugar). RESULTS: Five hundred and nineteen participants met the criteria for incident diabetes. Compared with those reporting intake of 1-2 servings of coffee/d, coffee abstainers were at reduced risk (OR = 0.64; 95 % CI 0.43, 0.94). Among coffee drinkers, there was a significant trend of decreasing risk by intake (P = 0.02); intake of >/=4 servings/d was associated with an odds ratio of 0.75 (95 % CI 0.58, 0.97). CONCLUSIONS: Study findings support a protective effect of coffee intake on diabetes risk, while also suggesting that abstainers may be at reduced risk.

Reliability of urinary 6-sulfatoxymelatonin as a biomarker in breast cancer.

The objective of this study is to evaluate the effect of cryopreservation at different storage temperatures on urinary 6-sulfatoxymelatonin (aMT6s) concentration. Overnight urine from 28 postmenopausal women participating in the ORDET cohort study was filtered and separated into 6 mL aliquots. Urine samples were stored at -80 degrees C and at -30 degrees C for an average of 14 years. Urinary aMT6s concentration was assessed using a competitive immunoassay. Mean aMT6s values of samples stored at -30 degrees C were systematically lower than those of samples stored at -80 degrees C (10.7 ng/mL versus 15.8 ng/mL, p<0.001). Bland Altman plots showed disagreement between determinations at different storage temperatures at the highest levels of the metabolite concentration. The degree of agreement evaluated in terms of intraclass correlation coefficient was 0.68 (95% CI 0.41-0.84, p<0.0001). Pearson's correlation coefficient between aMT6s values of the two differently stored samples was 0.93 (p<0.001), while the Kendal tau coefficient for rank distribution was 0.73 (p<0.001). Our data suggest that storage temperatures might affect degradation of aMT6s during storage. However, individual characterization by melatonin levels does not seem to be affected by cryopreservation conditions.

Dietary antioxidants and paraoxonases against LDL oxidation and atherosclerosis development.

Oxidative modification of low-density lipoprotein (LDL) in the arterial wall plays a key role in the pathogenesis of atherosclerosis. Under oxidative stress LDL is exposed to oxidative modifications by arterial wall cells including macrophages. Oxidative stress also induces cellular-lipid peroxidation, resulting in the formation of 'oxidized macrophages', which demonstrate increased capacity to oxidize LDL and increased uptake of oxidized LDL. Macrophage-mediated oxidation of LDL depends on the balance between pro-oxidants and antioxidants in the lipoprotein and in the cells. LDL is protected from oxidation by antioxidants, as well as by a second line of defense--paraoxonase 1 (PON1), which is a high-density lipoprotein-associated esterase that can hydrolyze and reduce lipid peroxides in lipoproteins and in arterial cells. Cellular paraoxonases (PON2 and PON3) may also play an important protective role against oxidative stress at the cellular level. Many epidemiological studies have indicated a protective role for a diet rich in fruits and vegetables against the development and progression of cardiovascular disease. A large number of studies provide data suggesting that consumption of dietary antioxidants is associated with reduced risk for cardiovascular diseases. Basic research provides plausible mechanisms by which dietary antioxidants might reduce the development of atherosclerosis. These mechanisms include inhibition of LDL oxidation, inhibition of cellular lipid peroxidation and consequently attenuation of cell-mediated oxidation of LDL. An additional possible mechanism is preservation/increment of paraoxonases activity by dietary antioxidants. This review chapter presents recent data on the anti-atherosclerotic effects and mechanism of action of three major groups of dietary antioxidants-vitamin E, carotenoids and polyphenolic flavonoids.

The antioxidative effect of the bacteria Dienococcus radiophilus against LDL lipid peroxidation.

BACKGROUND: Lipid peroxidation is an important process in the development of atherosclerosis. Thus agents with antioxidant properties may play an important role in the inhibition of atherosclerosis. OBJECTIVES: In this study we aimed to show that the lipid extract of the bacteria Deinococcus radiophilus (leDR) has antioxidant properties against LDL oxidation. RESULTS: This antioxidant effect was shown in both transition metal ion and free radical generating systems. We also showed that leDR can protect LDL from UV light-induced oxidative damage. The antioxidative capacity of leDR is partly due to copper ion chelation. CONCLUSION: We conclude that some specific bacteria constituent has the ability to inhibit LDL oxidation and, thus, to attenuate atherogenesis.

Pomegranate juice flavonoids inhibit low-density lipoprotein oxidation and cardiovascular diseases: studies in atherosclerotic mice and in humans.

The beneficial health effects attributed to the consumption of fruit and vegetables are related, at least in part, to their antioxidant activity. Of special interest is the inverse relationship between the intake of dietary nutrients rich in polyphenols and cardiovascular diseases. This effect is attributed to polyphenols' ability to inhibit low-density lipoprotein (LDL) oxidation, macrophage foam cell formation and atherosclerosis. Pomegranate polyphenols can protect LDL against cell-mediated oxidation via two pathways, including either direct interaction of the polyphenols with the lipoprotein and/or an indirect effect through accumulation of polyphenols in arterial macrophages. Pomegranate polyphenols were shown to reduce the capacity of macrophages to oxidatively modify LDL, due to their interaction with LDL to inhibit its oxidation by scavenging reactive oxygen species and reactive nitrogen species and also due to accumulation of polyphenols in arterial macrophages; hence, the inhibition of macrophage lipid peroxidation and the formation of lipid peroxide-rich macrophages. Furthermore, pomegranate polyphenols increase serum paraoxonase activity, resulting in the hydrolysis of lipid peroxides in oxidized lipoproteins and in atherosclerotic lesions. These antioxidative and antiatherogenic effects of pomegranate polyphenols were demonstrated in vitro, as well as in vivo in humans and in atherosclerotic apolipoprotein E deficient mice. Dietary supplementation of polyphenol-rich pomegranate juice to atherosclerotic mice significantly inhibited the development of atherosclerotic lesions and this may be attributed to the protection of LDL against oxidation.

Comparison of lung protective ventilation strategies in a rabbit model of acute lung injury.

OBJECTIVE: To determine the impact of different protective and nonprotective mechanical ventilation strategies on the degree of pulmonary inflammation, oxidative damage, and hemodynamic stability in a saline lavage model of acute lung injury. DESIGN: A prospective, randomized, controlled, in vivo animal laboratory study. SETTING: Animal research facility of a health sciences university. SUBJECTS: Forty-six New Zealand White rabbits. INTERVENTIONS: Mature rabbits were instrumented with a tracheostomy and vascular catheters. Lavage-injured rabbits were randomized to receive conventional ventilation with either a) low peak end-expiratory pressure (PEEP; tidal volume of 10 mL/kg, PEEP of 2 cm H2O); b) high PEEP (tidal volume of 10 mL/kg, PEEP of 10 cm H2O); c) low tidal volume with PEEP above Pflex (open lung strategy, tidal volume of 6 mL/kg, PEEP set 2 cm H2O > Pflex); or d) high-frequency oscillatory ventilation. Animals were ventilated for 4 hrs. Lung lavage fluid and tissue samples were obtained immediately after animals were killed. Lung lavage fluid was assayed for measurements of total protein, elastase activity, tumor necrosis factor-alpha, and malondialdehyde. Lung tissue homogenates were assayed for measurements of myeloperoxidase activity and malondialdehyde. The need for inotropic support was recorded. MEASUREMENTS AND MAIN RESULTS: Animals that received a lung protective strategy (open lung or high-frequency oscillatory ventilation) exhibited more favorable oxygenation and lung mechanics compared with the low PEEP and high PEEP groups. Animals ventilated by a lung protective strategy also showed attenuation of inflammation (reduced tracheal fluid protein, tracheal fluid elastase, tracheal fluid tumor necrosis factor-alpha, and pulmonary leukostasis). Animals treated with high-frequency oscillatory ventilation had attenuated oxidative injury to the lung and greater hemodynamic stability compared with the other experimental groups. CONCLUSIONS: Both lung protective strategies were associated with improved oxygenation, attenuated inflammation, and decreased lung damage. However, in this small-animal model of acute lung injury, an open lung strategy with deliberate hypercapnia was associated with significant hemodynamic instability.

White wine with red wine-like properties: increased extraction of grape skin polyphenols improves the antioxidant capacity of the derived white wine.

Lower antioxidant activity in white wines in comparison to red wines lies in the low grape-skin-derived polyphenol content. This paper reports the analysis of the antioxidant capacities of white wine samples obtained along two different processing procedures directed to enrich the wine with polyphenols. White wine samples derived from whole squeezed grapes stored for increasing periods of time (up to 18 h) contained increasing concentrations of polyphenols (from 0.35 to 0.55 mmol/L) and, in parallel, exhibited increased capacity to scavenge free radicals and to inhibit copper ion-induced low-density lipoprotein (LDL) oxidation. However, addition of increasing concentrations of alcohol (up to 18%) to the whole squeezed grapes remarkably augmented the extraction of grape skin polyphenols into the wine up to 1.25 mmol/L, resulting in an increased capacity of the wine to scavenge free radicals and to inhibit LDL oxidation, to an extent similar to that of red wine. The extent of LDL oxidation inhibition was directly related to the wine polyphenolic content (r = 0.986). It is concluded that processing white wine by imposing a short period of grape skin contact in the presence of alcohol leads to extraction of grape skin polyphenols and produces polyphenol-rich white wine with antioxidant characteristics similar to those of red wine.

Flavonoids protect LDL from oxidation and attenuate atherosclerosis.

Consumption of some plant-derived flavonoids results in their absorption and appearance in plasma and tissues. The inverse relationship between dietary flavonoids consumption and cardiovascular diseases may be associated with the ability of flavonoids to attenuate LDL oxidation, macrophage foam cell formation and atherosclerosis. The effect of flavonoids on arterial cell-mediated oxidation of LDL is determined by their accumulation in the lipoprotein and in arterial cells, such as macrophages. Flavonoids can reduce LDL lipid peroxidation by scavenging reactive oxygen/nitrogen species, chelation of transition metal ions and sparing of LDL-associated antioxidants. They can also reduce macrophage oxidative stress by inhibition of cellular oxygenases [such as nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase] or by activating cellular antioxidants (such as the glutathione system). Thus, plant flavonoids, as potent natural antioxidants that protect against lipid peroxidation in arterial cells and lipoproteins, significantly attenuate the development of atherosclerosis.

Anti-atherogenicity of nutritional antioxidants.

Epidemiological studies have indicated that fruit- and vegetable-rich diets play a protective role against cardiovascular disease. An explanation for this protection lies in the presence of antioxidant vitamins in fruits and vegetables. A large number of studies have provided data suggesting that consumption of dietary antioxidants is associated with reduced risk for cardiovascular disease. Plausible mechanisms by which these antioxidants may reduce the development of atherosclerosis include inhibition of low-density lipoprotein (LDL) oxidation, cellular lipid peroxidation and cell-mediated oxidation of LDL, and reduction in blood cholesterol levels. This review reports on the recent data of the anti-atherosclerotic effects and mechanistical aspects of three major groups of dietary antioxidants: vitamin E, carotenoids and flavonoids.

Pomegranate juice consumption reduces oxidative stress, atherogenic modifications to LDL, and platelet aggregation: studies in humans and in atherosclerotic apolipoprotein E-deficient mice.

BACKGROUND: Dietary supplementation with nutrients rich in antioxidants is associated with inhibition of atherogenic modifications to LDL, macrophage foam cell formation, and atherosclerosis. Pomegranates are a source of polyphenols and other antioxidants. OBJECTIVE: We analyzed, in healthy male volunteers and in atherosclerotic apolipoprotein E-deficient (E(0)) mice, the effect of pomegranate juice consumption on lipoprotein oxidation, aggregation, and retention; macrophage atherogenicity; platelet aggregation; and atherosclerosis. DESIGN: Potent antioxidative effects of pomegranate juice against lipid peroxidation in whole plasma and in isolated lipoproteins (HDL and LDL) were assessed in humans and in E(0) mice after pomegranate juice consumption for

Ginger extract consumption reduces plasma cholesterol, inhibits LDL oxidation and attenuates development of atherosclerosis in atherosclerotic, apolipoprotein E-deficient mice.

Oxidative modification of LDL is thought to play a key role in the pathogenesis of atherosclerosis. Consumption of nutrients rich in phenolic antioxidants has been shown to be associated with attenuation of development of atherosclerosis. This study was undertaken to investigate the ex vivo effect of standardized ginger extract on the development of atherosclerosis in apolipoprotein E-deficient (E(0)) mice, in relation to plasma cholesterol levels and the resistance of their LDL to oxidation and aggregation. E(0) mice (n = 60; 6-wk-old) were divided into three groups of 20 and fed for 10 wk via their drinking water with the following: group i) placebo (control group), 1.1% alcohol and water (11 mL of alcohol in 1 L of water); group ii) 25 microg of ginger extract/d in 1.1% alcohol and water and group iii) 250 microg of ginger extract/day in 1.1% alcohol and water. Aortic atherosclerotic lesion areas were reduced 44% (P<0.01) in mice that consumed 250 microg of ginger extract/day. Consumption of 250 microg of ginger extract/day resulted in reductions (P<0.01) in plasma triglycerides and cholesterol (by 27 and 29%, respectively), in VLDL (by 36 and 53%, respectively) and in LDL (by 58 and 33%, respectively). These results were associated with a 76% reduction in cellular cholesterol biosynthesis rate in peritoneal macrophages derived from the E(0) mice that consumed the high dose of ginger extract for 10 wk (P<0.01). Furthermore, peritoneal macrophages harvested from E(0) mice after consumption of 25 or 250 microg of ginger extract/day had a lower (P<0.01) capacity to oxidize LDL (by 45 and by 60%, respectively), and to take up and degrade oxidized LDL (by 43 and 47%, respectively). Consumption of 250 microg of ginger extract/day also reduced (P<0.01) the basal level of LDL-associated lipid peroxides by 62%. In parallel, a 33% inhibition (P<0.01) in LDL aggregation (induced by vortexing) was obtained in mice fed ginger extract. We conclude that dietary consumption of ginger extract by E(0) mice significantly attenuates the development of atherosclerotic lesions. This antiatherogenic effect is associated with a significant reduction in plasma and LDL cholesterol levels and a significant reduction in the LDL basal oxidative state, as well as their susceptibility to oxidation and aggregation.

Partial liquid ventilation with perflubron attenuates in vivo oxidative damage to proteins and lipids.

OBJECTIVE: To determine the impact of partial liquid ventilation on the degree of pulmonary damage by reactive oxygen species in a model of acute lung injury caused by systemic endotoxemia. DESIGN: A prospective, controlled, in vivo, animal laboratory study. SETTING: Animal research facility of a health sciences university. SUBJECTS: Forty New Zealand White rabbits. INTERVENTIONS: Mature rabbits were anesthetized and instrumented with a tracheostomy and vascular catheters. Animals were assigned to receive either partial liquid ventilation (n = 16) with perflubron (18 mL/kg via endotracheal tube) or conventional mechanical ventilation (n = 16). Both groups were ventilated using similar strategies, with an Fio2 of 1.0 and tidal volume as required to obtain a normal Paco2. Animals were then given 0.9 mg/kg Escherichia coli endotoxin intravenously over 30 mins. Eight uninjured instrumented and mechanically ventilated animals served as controls. Partial liquid ventilation or conventional ventilation was continued for 4 hrs before the animals were killed. Lung homogenates were analyzed for malondialdehyde (MDA) and 4-hydroxy-2(E)-nonenal (4-HNE) concentrations using a colorimetric assay. To assess protein oxidative damage, carbonyl groups in protein side chains were derivatized with 2,4-dinitrophenylhydrazine followed by Western blotting with a dinitrophenylated-specific primary antibody. MEASUREMENTS AND MAIN RESULTS: MDA (713.42+/-662 vs. 1601.4+/-1156 nmol/g protein; p = .023) and MDA plus 4-HNE (1480.24+/-788 vs. 2675.2+/-1628 nmol/g protein; p = .038) concentrations were lower in animals treated with partial liquid ventilation compared with conventionally ventilated animals, respectively. Animals treated with partial liquid ventilation exhibited attenuation of dinitrophenylated-derivatized protein bands by Western blotting, indicating a reduction in protein oxidative damage. The presence of perfluorocarbon did not interfere with the MDA assay when assessed by independent analysis in vitro. Perflubron did not serve as a sink for peroxyl radicals produced in the aqueous phase during separate in vitro oxidation experiments. CONCLUSIONS: Partial liquid ventilation attenuates oxidative damage to lipids and proteins during experimental acute lung injury. This finding is not caused by binding of lipid peroxidation products to perflubron or by the peroxyl radical scavenging properties of perflubron.

Lycopene synergistically inhibits LDL oxidation in combination with vitamin E, glabridin, rosmarinic acid, carnosic acid, or garlic.

Several lines of evidence suggest that oxidatively modified low-density lipoprotein (LDL) is atherogenic, and that atherosclerosis can be attenuated by natural antioxidants, which inhibit LDL oxidation. This study was conducted to determine the effect of tomato lycopene alone, or in combination with other natural antioxidants, on LDL oxidation. LDL (100 microg of protein/ml) was incubated with increasing concentrations of lycopene or of tomato oleoresin (lipid extract of tomatoes containing 6% lycopene, 0.1% beta-carotene, 1% vitamin E, and polyphenols), after which it was oxidized by the addition of 5 micromol/liter of CuSO4. Tomato oleoresin exhibited superior capacity to inhibit LDL oxidation in comparison to pure lycopene, by up to five-fold [97% vs. 22% inhibition of thiobarbituric acid reactive substances (TBARS) formation, and 93% vs. 27% inhibition of lipid peroxides formation, respectively]. Because tomato oleoresin also contains, in addition to lycopene, vitamin E, flavonoids, and phenolics, a possible cooperative interaction between lycopene and such natural antioxidants was studied. A combination of lycopene (5 micromol/liter) with vitamin E (alpha-tocopherol) in the concentration range of 1-10 micromol/liter resulted in an inhibition of copper ion-induced LDL oxidation that was significantly greater than the expected additive individual inhibitions. The synergistic antioxidative effect of lycopene with vitamin E was not shared by gamma-to-cotrienol. The polyphenols glabridin (derived from licorice), rosmarinic acid or carnosic acid (derived from rosemary), as well as garlic (which contains a mixture of natural antioxidants) inhibited LDL oxidation in a dose-dependent manner. When lycopene (5 micromol/liter) was added to LDL in combination with glabridin, rosmarinic acid, carnosic acid, or garlic, synergistic antioxidative effects were obtained against LDL oxidation induced either by copper ions or by the radical generator AAPH. Similar interactive effects seen with lycopene were also observed with beta-carotene, but, however, to a lesser extent of synergism. Because natural antioxidants exist in nature in combination, the in vivo relevance of lycopene in combination with other natural antioxidants was studied. Four healthy subjects were administered a fatty meal containing 30 mg of lycopene in the form of tomato oleoresin. The lycopene concentration in postprandial plasma was elevated by 70% in comparison to plasma obtained before meal consumption. Postprandial LDL isolated 5 hr after meal consumption exhibited a significant (p < 0.01) reduced susceptibility to oxidation by 21%. We conclude that lycopene acts synergistically, as an effective antioxidant against LDL oxidation, with several natural antioxidants such as vitamin E, the flavonoid glabridin, the phenolics rosmarinic acid and carnosic acid, and garlic. These observations suggest a superior antiatherogenic characteristic to a combination of different natural antioxidants over that of an individual one.

Pathophysiology of cardiac extracorporeal membrane oxygenation.

The treatment of cardiogenic shock using inotropic agents and vascular volume expansion places an added burden on the heart. The resultant increase in cardiac work may cause myocardial ischemia and lead to cardiac arrest. Extracorporeal membrane oxygenation (ECMO) may be used to treat cardiogenic shock. It supports systemic circulation, assures diastolic perfusion of the myocardium, and reduces cardiac workload. The rise in blood pressure associated with restoring systemic circulation afterloads the heart and can cause left atrial hypertension and pulmonary edema. ECMO does not automatically reduce cardiac work, especially in the presence of residual shunts. Left atrial drainage or decompression may be essential in certain patients both to avert pulmonary edema and to reduce cardiac work.

Partial liquid ventilation influences pulmonary histopathology in an animal model of acute lung injury.

PURPOSE: The aim of this study was to assess the effect of partial liquid ventilation (PLV) and conventional mechanical ventilation (CMV) in the pattern of distribution of lung injury in a rabbit model of acute lung injury. MATERIALS AND METHODS: Animals (1.5 to 3.5 kg) were assigned to receive CMV (tidal volume of 10 mL/kg and a PEEP of 5 cm H2O) or PLV with 18 mL/kg of intratracheal perflubron (tidal volume of 10 mL/kg and a PEEP of 5 cm H2O). Lung injury was elicited by intravenous administration of Escherichia coliendotoxin. Uninjured animals ventilated as the CMV group served as controls. After 4 hours of mechanical ventilation, the lungs were removed and tissue injury was assessed by light microscopy using a scoring system. RESULTS: Animals in the CMV group had higher lung injury scores in comparison to the PLV group (10+/-4.5 vs. 5+/-3.3, respectively, P < .05). The injury scores were similar for nondependent lung regions (CMV: 8+/-4.3, PLV: 6+/-2.9) but significantly different for the dependent regions (CMV: 12+/-4.6, PLV: 5+/-3.8, P< .05). CONCLUSIONS: PLV is associated with significant attenuation of lung injury, in comparison to CMV. This effect is predominantly due to attenuation of injury in the dependent region of the lung.

Liquid ventilation attenuates pulmonary oxidative damage.

PURPOSE: Liquid perfluorochemicals reduce the production of reaction oxygen species by alveolar macrophages. We sought to determine whether the use of liquid perfluorochemicals in vivo during liquid ventilation would attenuate oxidative damage to the lung. MATERIALS AND METHODS: Healthy infant piglets (n = 16) were instrumented for mechanical ventilation and received intravenous oleic acid to create an acute lung injury. The animals were assigned to a nontreatment group receiving conventional mechanical ventilation or a treatment group receiving partial liquid ventilation with a liquid perfluorochemical. Following sacrifice, the bronchoalveolar lavage and lung parenchyma were analyzed for evidence of oxidative damage to lipids and proteins by determination of TBARS and carbonylated protein residues, respectively. RESULTS: Mortality in the control group was 50% at the completion of the study compared with no deaths in the partial liquid ventilation group (P = .025). The alveolar-arterial oxygen difference was more favorable following injury in the partial liquid ventilation group. The liquid ventilation group demonstrated a 32% reduction in TBARS (P = .043) and a 14% reduction in carbonylated protein residues (P = .061). CONCLUSION: These data suggest that partial liquid ventilation supports gas exchange and reduces mortality in association with a reduction in the production of reactive oxygen species and the concomitant attenuation of tissue damage during the early phase of acute lung injury.