Effects of vitamin E and C supplementation on oxidative stress and viral load in HIV-infected subjects

OBJECTIVES: The HIV-infected population is known to be oxidatively stressed and deficient in antioxidant micronutrients. Since in vitro replication of HIV is increased with oxidative stress, this study assessed the effect of antioxidant vitamin supplementation on lipid peroxidation, a measure of oxidative stress, and viral load in humans. DESIGN: A randomized placebo-controlled, double-blind study. METHODS: Forty-nine HIV-positive patients were randomized to receive supplements of both DL-alpha-tocopherol acetate (800 IU daily) and vitamin C (1000 mg daily), or matched placebo, for 3 months. Plasma antioxidant micronutrient status, breath pentane output, plasma lipid peroxides, malondialdehyde and viral load were measured at baseline and at 3 months. New or recurrent infections for the 6-month period after study entry were also recorded. RESULTS: The vitamin group (n = 26) had an increase in plasma concentrations of alpha-tocopherol (P < 0.0005) and vitamin C (P < 0.005) and a reduction in lipid peroxidation measured by breath pentane (P < 0.025), plasma lipid peroxides (P < 0.01) and malondialdehyde (P < 0.0005) when compared with controls (n = 23). There was also a trend towards a reduction in viral load (mean +/- SD changes over 3 months, -0.45 +/- 0.39 versus +0.50 +/- 0.40 log10 copies/ml; P = 0.1; 95% confidence interval, -0.21 to -2.14). The number of infections reported was nine in the vitamin group and seven in the placebo group. CONCLUSION: Supplements of vitamin E and C reduce oxidative stress in HIV and produce a trend towards a reduction in viral load. This is worthy of larger clinical trials, especially in HIV-infected persons who cannot afford new combination therapies.     

Enhanced plasma level of lipid peroxidation in Iranians could be improved by antioxidants supplementation

OBJECTIVE: To study the influence of supplementation with antioxidants on factors, which might increase the risk of coronary heart disease (CHD) in Iranians. DESIGN: Twenty-one male volunteers enter the prospective, single-blind, randomized study. SETTING: The supplementation was conducted at the Cardiovascular Center, University of Tehran, the biochemical analysis were carried out in the University of Graz. SUBJECTS: Twenty-one male medical students were recruited by advertisement. Five subjects were dropped out due to lack of the compliance. METHODS: One group of Iranians received 30 mg/d beta-carotene and placebo for alpha-tocopherol; the other received beta-carotene plus 400 IU alpha-tocopherol for ten weeks. Concentrations of antioxidants in plasma and low density lipoproteins (LDL), plasma lipid profile, autoantibody against oxidized LDL (oLAb) and malondialdehyde (MDA) concentrations in plasma were measured. Oxidative resistance of LDL was estimated using conjugated diene assay. RESULTS: Iranians had a significantly lower plasma levels of total cholesterol (P < 0.002), LDL-cholesterol (P < 0.01) and high density lipoprotein-cholesterol (P < 0.002), compared to healthy Austrian subjects (n = 13). Although the baseline concentrations of alpha-tocopherol and beta-carotene were comparable with Austrians, lycopene, canthaxanthin and lutein were significantly higher in Iranians (P < 0.03-0.001). In vitro oxidative resistance of LDL, measured as lag-time, was slightly higher (P < 0.01) in Iranians comparing with Austrians. Plasma MDA and oLAb concentrations were significantly higher in Iranians (P < 0.001). Both dietary supplementations reduced plasma MDA concentrations (P < 0.001-0.001). A key finding was that a supplement combined with alpha-tocopherol caused also a significant increase of oLAb concentration (P > 0.01) as well as the significant increase of lag-time (P > 0.005). CONCLUSIONS: This study shows that high plasma MDA level of Iranians can be decreased by beta-carotene supplementation with or without alpha-tocopherol. However, alpha-tocopherol is a more powerful antioxidant, which can increase the resistance of LDL to oxidation, reduce the MDA concentrations in plasma and increase autoantibodies to oLDL.     

Long-term improvement in renal function after cyclosporine reduction in renal transplant recipients with histologically proven chronic cyclosporine nephropathy

BACKGROUND: Chronic cyclosporine (CsA) nephropathy, which has been unequivocally documented in recipients of heart, heart-lung, liver, or bone marrow transplants, as well as in nontransplant situations, usually results in a progressive deterioration of renal function. In this study, we assessed the potential reversibility of chronic CsA nephropathy in renal transplant recipients. PATIENTS AND METHODS: Twenty-three renal transplant patients with biopsy-proven CsA nephropathy associated with long-term CsA administration (27+/-4 months) were followed up for more than 2 years after CsA reduction (18/23 patients) or withdrawal (5/23 patients) and addition of azathioprine. Changes in effective renal plasma flow and glomerular filtration rate were assessed before and 2 years after CsA reduction, whereas serum creatinine, proteinuria, blood pressure, and CsA concentrations were monitored up to 5 years. RESULTS: At 2-year follow-up, glomerular filtration rate increased from 40+/-3 to 47+/-4 (P<0.05) and effective renal plasma flow from 217+/-23 to 244+/-24 ml/min/1.73 m2 (NS). Mean arterial pressure significantly decreased from 98.7+/-2.9 to 93.1+/-2.7 mmHg (P<0.05). There was no significant change in renal vascular resistance, filtration fraction, or albumin excretion. A significant decrease in serum creatinine was also observed during the whole follow-up (73+/-6.5 months). CsA reduction was followed by only one episode of acute reversible rejection; chronic rejection developed in three patients 2 years or later after CsA reduction. CONCLUSIONS: These data suggest that CsA nephropathy participates in graft dysfunction in a small group of renal transplant recipients. In addition, graft dysfunction may be reversible when CsA dosage is reduced early after diagnosis of chronic CsA nephropathy.     

Multicenter comparison of first- and second-generation IMx tacrolimus microparticle enzyme immunoassays in liver and kidney transplantation

Foetuses born to mothers with gestational diabetes are at increased risk of developing respiratory distress, foetal macrosomia, foetal anomalies and platelet hyperaggregability. High blood glucose level induces oxidative stress and decreases antioxidant defences. The present study discusses the possibility of lipid peroxidation and protein oxidation in both maternal and foetal erythrocytes as an indicator of oxygen radical activity. The level of lipid peroxidation and protein oxidation in erythrocytes was estimated in 20 mothers with gestational diabetes and their newborns. The maternal age varied between 19 and 42 y and foetal age ranged between 34 and 39 weeks. The proteolytic activities in the erythrocyte lysates obtained from mothers with gestational diabetes and their newborns were significantly greater [(mean +/- SD) 24.41 +/- 9.05 and 16.70 +/- 3.36 microM of amino groups/g haemoglobin, n = 20, respectively] than those from control group (10.18 +/- 4.84 and 14.64 +/- 6.21 microM amino groups/g haemoglobin, n = 15, respectively; p < 0.05 in both cases). Similarly erythrocyte malondialdehyde levels were significantly elevated in babies born to mothers with gestational diabetes (10.11 +/- 2.21 nM/g haemoglobin) when compared to controls (6.8 +/- 3.75 nM/g haemoglobin) (p < 0.05). In the erythrocytes of mothers with gestational diabetes, malondialdehyde levels correlated significantly with glycated haemoglobin levels (p < 0.01). The results of this study indicate that the oxidative stress induced by gestational diabetes manifests as increased lipid peroxidation and protein oxidative damage in the erythrocytes of both mothers with gestational diabetes and their newborn infants.     

NOS2 mediates opposing effects in models of acute and chronic cardiac rejection: insights from NOS2-knockout mice

To compare regulatory effects of NOS2 in acute and chronic cardiac allograft rejection, we used NOS2 knockout mice as recipients in a cardiac transplant model. To study acute and chronic rejection separately but within the same genetic strain combination, we compared allografts placed into recipients without or with immunosuppression (anti-CD4/8 for 28 days). NOS2 mRNA and protein expression were compared using 32P-RT-PCR and immunohistochemistry. In our acute rejection model, NOS2 was predominately localized to graft-infiltrating immune cells. At day 7, grafts in NOS2-deficient recipients (n = 7) showed reduced inflammatory infiltrates and myocyte damage resulting in significantly lower rejection scores (1.6 +/- 0.4) compared to wild-type controls (n = 18; 2.8 +/- 0.2, P = 0.002). In contrast, in our chronic rejection model, additional NOS2 expression was localized to graft-parenchymal cells. At day 55, grafts in NOS2-deficient recipients (n = 12) showed more parenchymal infiltration and parenchymal destruction (rejection score 3.8 +/- 0.1) than wild-type controls (n = 15; 1.6 +/- 0.2, P < 0.0001). This was associated with a significant decrease in ventricular contractility (palpation score 0.3 +/- 0.1 compared to 2.3 +/- 0.3 in wild-type, P < 0.0001). Hence, NOS2 promotes acute but prevents chronic rejection. These opposing effects during acute and chronic cardiac allograft rejection are dependent on the temporal and spatial expression pattern of NOS2 during both forms of rejection.     

Oxidative stress and advancing age: results in healthy centenarians

OBJECTIVE: Our study aims at investigating the degree of oxidative stress in centenarians DESIGN: Indices of oxidative stress (reaction products of malondialdehyde with thiobarbituric acid (TBARS) and lipid hydroperoxides (LPO)), and plasma concentrations of antioxidant defenses (plasma vitamin E and C concentrations and reduced/oxidized glutathione ratio (GSH/GSSG)) were determined. SUBJECTS: Eighty-two subjects volunteered for the study. They were divided into three groups: (1) adults (<50 years of age, n=30); (2) aged subjects (70-99 years, n=30); (3) centenarians (age > or=100 years, n=22). MEASUREMENTS: TBARS and LPO, plasma vitamin E and C concentrations, and plasma GSH/GSSG ratio were determined. Insulin action was assessed by euglycemic hyperinsulinemic glucose clamp. MAIN RESULTS: TBARS (0.44+/-0.07 vs 0.31+/-.05 nmol malondialdehyde/mL plasma, P=.020) and LPO (0.36+/-0.05 vs 0.31+/-.04 micromol/L, P=.050) were lower in centenarians than in aged subjects. In contrast, plasma GSH/GSSG ratio (0.82+/-0.09 vs 1.17+/-.06, P=.010), vitamin C (72.3+/-4.6 vs 59.4+/-3.8 micromol/L P=.010), and vitamin E (29.1+/-2.2 vs 24.4+/-2.3 micromol/L P=.050) concentrations were more elevated in centenarians than in aged subjects. Differences in daily vegetable intake, in fasting plasma glucose and free fatty acid (FFA) concentrations, and in insulin action are significant determinants of degree of oxidative stress. A specific genetic background in centenarians might also provide a possible explanation. CONCLUSIONS: The degree of oxidative stress is lower in healthy centenarians than in aged subjects.     

Reduced oxidative susceptibility of LDL from patients participating in an intensive atherosclerosis treatment program

The goal of this investigation was to determine whether participation in an atherosclerosis treatment program would reduce the oxidative susceptibility of LDL from patients with coronary artery disease. The treatment program included intensive exercise therapy, stress management, and consumption of a diet containing 10% fat. The size and antioxidant and lipid contents of LDL particles from 25 patients were analyzed at baseline and after 3 mo of therapy. The susceptibility of LDL to copper-mediated oxidation was measured by a conjugated diene assay and headspace gas chromatography (HSGC). Atherosclerosis treatment significantly reduced plasma total cholesterol and apolipoprotein B concentrations and the molar ratio of LDL cholesterol ester to apolipoprotein B (P < 0.01). The LDL content of alpha-tocopherol and beta-carotene was increased (27% and 17%, respectively, P < 0.04) and the molar ratio of LDL cholesterol ester the sum of LDL alpha-tocopherol and LDL beta-carotene decreased from 159 at baseline to 122 at 3 mo (P < 0.01). The lag phase of LDL conjugated diene formation increased 24%, whereas the maximum rate of oxidation slowed 29% (P < 0.01). As assessed by HSGC, copper-catalyzed formation of volatile lipid oxidation products was reduced 15% (P < 0.007); the reduction in volatiles was correlated with an increase in the alpha-tocopherol content of LDL (r=-0.48, P < 0.01). The principal determinants of reduced LDL oxidative susceptibility were the particle contents of alpha-tocopherol and beta-carotene. To our knowledge, this is the first report to document a reduction in LDL oxidation in coronary artery disease patients undergoing atherosclerosis-reversal therapy.     

Excess formation of lysophosphatidic acid with age inhibits myristic acid-induced superoxide anion generation in intact human neutrophils

AIM: To examine whether the elevation of endogenous NG, NG-dimethylarginine (DMA) content is related to lipid peroxidation in the high lipid-fed rabbit. METHODS: In high lipid diet-fed rabbits, concentrations of serum cholesterol, triglyceride, malondialdehyde (MDA), and DMA were measured, and endothelium-dependent relaxation to acetylcholine (ACh) was tested. RESULTS: After 6-wk on a high lipid-diet, the levels of serum total cholesterol, triglyceride, MDA, and DMA were increased vs those in control group (MDA was 2.88 +/- s 0.20 vs 1.54 +/- 0.13 nmol.L-1, P < 0.01 and DMA was 1.51 +/- 0.07 vs 0.75 +/- 0.13 mumol.L-1, P < 0.01), while the endothelium-dependent vasodilation in the isolated thoracic aorta was impaired (the maximal response to ACh was 45.59 +/- 3.10 vs 76.93 +/- 5.68%). Supplementation with vitamin E decreased MDA and DMA content and improved the endothelium-dependent vasodilation. CONCLUSIONS: An increase in serum concentration of DMA may be secondary to the elevation of lipid peroxides in the hyperlipidemic rabbit.     

Analysis of the relationship between chimerism and the allgeneic humoral response

BACKGROUND: Persistence of antigens has been suggested to play a role in two opposing immunological phenomena: tolerance and memory. Therefore, we studied the impact of chimerism on alloreactive antibody (allo-Ab) production in kidney transplant patients. METHODS: Thirty-five female renal transplant recipients of male donor organs were classified into the following groups: group 1, 13 sensitized uremic patients on dialysis; group 2, 5 nonsensitized uremic patients on dialysis; group 3, six sensitized patients experiencing graft rejection (3 acute vascular, 1 acute cellular, and 2 chronic); and group 4, 11 nonsensitized with functioning allografts (9 with good function, 1 with acute cellular rejection, and 1 with chronic rejection). Mean duration of dialysis after graft failure was similar in groups 1 (56+/-29.7 months) and 2 (41.8+/-42.4 months), as was dialysis efficiency. Chimerism was measured indirectly in the peripheral blood lymphocytes by polymerase chain reaction amplification of a specific Y chromosome DNA gene sequence with a detection sensitivity limit of 1 male cell per 1 million female cells. Allo-Ab production was measured by the PRA-STAT enzyme-linked immunosorbent assay (Sangstat) method. RESULTS: Chimerism was observed in 60% of groups 1 and 2, 83% of group 3, and 82% of group 4. Among all groups, graft existence, irrespective of its function, positively predicted chimerism in 92% with a sensitivity of 88% and a specificity of 78%. In group 3, all three patients with acute vascular rejection had chimerism and donor-specific allo-Abs. In group 4, eight of the nine patients with no rejection had chimerism. CONCLUSION: Chimerism relates to persistence of allogeneic stimulus irrespective of its function. Chimerism did not confer protection against allo-Ab production or vascular rejection, and its existence was not crucial for sustenance of allo-Ab production.     

Free radicals, oxidative stress and antioxidant vitamins

Free radicals having oxidizing properties are produced in vivo. The monoelectronic reduction of dioxygen generates the superoxide radical (.O2-) which, according to the experimental conditions, behaves as a reducing or an oxidizing agent. Its dismutation catalyzed by superoxide dismutases (SODs) produces hydrogen peroxide. The latter reacting with .O2- in the presence of "redox-active" iron produces highly aggressive prooxidant radicals, such as the hydroxyl radical (.OH). This production is prevented through intracellular enzymes (catalase and glutathione peroxidases) which destroy the hydrogen peroxide involved in the biosynthesis of .OH. An increase in SODs activity without parallel enhancement of the enzymes destroying H2O2 may lead to important cellular disturbances. Other enzymes acting with glutathione as substrate (especially glutathione S-transferases) contribute to the antioxidant defence. The same holds true for selenium and zinc which act mainly through their involvement in the structure of both antioxidant enzymes and nonenzymatic proteins. Another line of antioxidant defence is represented by substrates acting as chain-breaking antioxidants in destructive processes linked to prooxidant free radicals, such as lipid peroxidation. The main membranous antioxidant is alpha-tocopherol which is able to quench efficiently lipid peroxyl radicals. Its efficiency would be quickly exhausted if the tocopheryl radical formed during this reaction wouldn't be retransformed into alpha-tocopherol through the intervention of ascorbate and/or glutathione. Ubiquinol and dihydrolipoate also contribute to the membranous antioxidant defence, whereas carotenoids are mainly responsible for the prevention of the deleterious effects of singlet oxygen. An oxidative stress is apparent when the antioxidant defence is insufficient to cope with the prooxidant production.     

Radioimmunotherapy of orthotopically transplanted pancreatic cancer with 131I-labeled chimeric monoclonal antibody Nd2

Recent study demonstrated high susceptibility of plasma LDL to lipid peroxidative modification in patients with variant angina. Oxidized stress state, especially oxidized LDL, may induce coronary artery spasm by its impairing effect of endothelium-dependent arterial relaxation, but precise mechanisms remain unclear. Study subjects included 93 patients who underwent coronary angiographic examination: 12 patients with coronary artery spasm provoked by ergonovine without organic stenosis (group I), 11 patients who did not demonstrate coronary artery spasm or organic stenosis (group II) and 70 patients with organic coronary artery stenosis (group III). Levels of plasma HDL-cholesterol and apoA-I in group I were similar to those in III but were significantly lower than those in II, although the other plasma lipid parameters were not different among the three groups. The levels of TBARS in plasma and HDL were significantly higher in group I than in II or III (2.94+/-1.56 vs. 1.91+/-0.35 or 2.23+/-0.89 nmol MDA/ml and 1.23+/-1.00 vs. 0.54+/-0.37 or 0.70+/-0.63 nmol MDA/mg protein; P < 0.05), although the levels of TBARS in LDL were not significantly different. In the monitoring curve of diene production during copper-induced lipid peroxidation of HDL, its propagation slope was steeper and levels of maximum diene absorbance was higher in group I as compared with that in II or III, but not found in those of LDL. These results suggested that high susceptibility of HDL to lipid peroxidative modification in group I may contribute to the genesis of coronary artery spasm, and oxidized HDL rather than oxidized LDL is more likely to be related to coronary artery spasm.     

Evaluation of bosentan, pinacidil and nitroprusside on human pulmonary arteries: comparison with rat pulmonary arteries

OBJECTIVE: The general objective of the Etude du Viellissement Arterial (EVA) program is to follow vascular aging and the decline in cognitive functions at the cerebrovascular level longitudinally over a 4-year period. One of the specific objectives of this EVA study is to examine epidemiologically the relationship between the markers of oxidative stress (lipid peroxidation), the antioxidant micronutrient status (particularly of selenium, vitamin E, and the carotenoids) and the prevalence of chronic disorders occurring during the pre-aging period. METHODS: 1389 subjects aged from 59 to 71 years were studied. RESULTS: The concentration of plasma lipid peroxides was higher than in young adults (2.91 +/- 0.38, men; 2.97 +/- 0.40, women (mumol/l). On the other hand, plasma Se (1.09 +/- 0.21, men; 1.10 +/- 0.19, women (mumol/l)), erythrocyte vitamin E (5.32 +/- 1.29, men; 5.52 +/- 1.28, women (mumol/l)), and total plasma carotenoids (2.19 +/- 0.98, men; 3.07 +/- 1.33, women (mumol/l)) were comparable to values in young adults. In our cohort, 40% of subjects had unremarkable medical histories. The disorders most often encountered were lipemia (29.8% of men, 36.1% of women), and hypertension (28.9% of men, 30.4% of women). CONCLUSION: Se and vitamin E levels were raised in cases of lipemia, especially in those treated with fibrates. The mechanism of the increase is unknown. In hypertensives and diabetics, there was a decrease in total carotenoids associated with increased peroxidative risk.     

Ascorbic acid inhibits the increase in low-density lipoprotein (LDL) susceptibility to oxidation and the proportion of electronegative LDL induced by intense aerobic exercise

BACKGROUND: We have previously reported the finding of an acute increment in the susceptibility of low-density lipoprotein (LDL) to oxidation and in the proportion of electronegative LDL [LDL(-)] after intense exercise. We have now studied the effect of oral supplementation with 1 g ascorbic acid, immediately before a 4-h athletic race, on the susceptibility of LDL to oxidation, the proportion of LDL(-), and the alpha-tocopherol and lipid peroxides content in LDL, in order to inhibit such deleterious changes, and to confirm the oxidative nature of modifications of LDL induced by exercise. METHODS: We studied seven highly trained runners who received a supplement of 1 g ascorbic acid and a control group of seven who did not receive the supplement. The susceptibility of LDL to oxidation was assessed by measurement of conjugated dienes after CuSO4-induced oxidation, the proportion of LDL(-) was determined by anion exchange chromatography, alpha-tocopherol was quantified by reverse-phase high performance liquid chromatography, and lipid peroxides were measured by the thiobarbituric acid-reactive substances (TBARS) method. RESULTS: After exercise, in the control group there was an increase in both the susceptibility of LDL to oxidation (change in lag phase from 51.4 +/- 4.7 min to 47.0 +/- 4.6 min, P < 0.05) and the proportion of LDL(-) (from 11.1 +/- 1.4% to 13.0 +/- 2.2%, P < 0.05), but these did not occur in the ascorbic acid group (change in lag phase from 49.7 +/- 2.3 min to 50.4 +/- 4.2 min, and in LDL(-) from 9.7 +/- 1.7% to 10.1 +/- 1.7%). No significant changes in the absolute amount of LDL alpha-tocopherol were observed after exercise (ascorbic acid group: 6.65 +/- 0.94 mol/mol apoB before the race, 7.13 +/- 0.88 mol/mol apoB after the race; control group: 7.34 +/-0.69 mol/mol apoB before the race, 7.06 +/- 0.69 mol/mol apoB after the race), but significant differences were found when increments or decrements of alpha-tocopherol were tested (alpha-tocopherol increased 9.9 +/- 11.5% in the ascorbic acid group, and decreased 0.6 +/- 7.3% in the control group; P < 0.018). TBARS did not change after exercise. CONCLUSIONS: We conclude that 1 g ascorbic acid inhibits the increase in LDL susceptibility to oxidation after exercise, preventing this acute pro-atherogenic effect. In addition, the observation that LDL(-) enhancement is prevented by ascorbic acid supports the hypothesis that at least some of the circulating LDL(-) originates from oxidative processes.     

Streptozotocin-induced diabetic cynomolgus monkey is a model of hypertriglyceridemia with low high-density lipoprotein cholesterol

BACKGROUND: Cardiac allograft rejection is accompanied by cellular infiltration and tissue edema resulting in myocardial relaxation abnormalities. Doppler tissue imaging is capable of measuring myocardial relaxation velocities and is useful in the detection of heart rejection. However, the influence of ventricular loading conditions on myocardial relaxation velocities has not been studied. This study is performed to determine whether myocardial relaxation velocities are affected by left ventricular loading conditions. METHODS: Twenty heart transplant recipients without evidence of rejection by endomyocardial biopsy underwent preload and afterload reduction with nitroglycerin. The pulmonary wedge pressure was reduced from 18.2+/-0.9 to 12.0+/-0.9 mm Hg 9 (p=0.001) and the mean blood pressure from 130.0+/-5.6 to 116.1+/-7.0 mm Hg (p=0.001). Pulsed-wave Doppler tissue imaging was performed before and after administration of nitroglycerin, and the peak myocardial relaxation velocities of the inferior wall were measured. RESULTS: Myocardial relaxation velocities did not change with the administration of nitroglycerin; 0.188+/-0.009 to 0.178+/- 0.006 m/sec (p=0.4) in spite of a significant reduction in pulmonary capillary wedge pressure. Furthermore, there was no correlation between pulmonary capillary wedge pressure, mean arterial pressure, wall stress, and myocardial relaxation velocities. CONCLUSIONS: Loading conditions on the left ventricle have no influence on myocardial relaxation velocities. Therefore in heart transplant recipients changes in myocardial relaxation velocities by Doppler tissue imaging may be useful in the diagnosis of rejection, in spite of diverse loading conditions.     

Preservation of endogenous antioxidant activity and inhibition of lipid peroxidation as common mechanisms of antiatherosclerotic effects of vitamin E, lovastatin and amlodipine

OBJECTIVES: We sought to document the common mechanisms of the antiatherogenic effects of the cholesterol-lowering hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor lovastatin, the dihydropyridine Ca2+ blocker amlodipine and the antioxidant vitamin E. BACKGROUND: Vitamin E, HMG-CoA reductase inhibitors and Ca2+ blockers each inhibit atherosclerosis in hypercholesterolemic animals. METHODS: New Zealand White rabbits were fed regular chow (Group A), chow with 1% cholesterol (Group B), 1% cholesterol diet plus lovastatin (Group C), 1% cholesterol diet plus vitamin E (Group D) or 1% cholesterol diet plus amlodipine (Group E) for 12 weeks. The extent of aortic atherosclerosis was measured by planimetry of the sudanophilic area. Malondialdehyde (MDA) and superoxide dismutase (SOD) in blood were measured as indexes of lipid peroxidation and antioxidant activity, respectively. RESULTS: Group A rabbits showed no atherosclerosis, whereas Group B rabbits had 17.4 +/- 9.3% (mean +/- SD) of the aorta covered with atherosclerosis, and Groups C, D and E rabbits had significantly less atherosclerosis. Plasma SOD activity was lower in Group B than in Group A (6.9 +/- 1.1 vs. 12.8 +/- 1.5 U/ml, p < 0.01) and was preserved in the groups given lovastatin, vitamin E or amlodipine with a high cholesterol diet. The serum MDA level was higher in Group B rabbits than Group A rabbits (12.1 +/- 2.6 vs. 1.2 +/- 0.1 nmol/ml, p < 0.01) and increased minimally in rabbits given lovastatin, vitamin E or amlodipine with a high cholesterol diet. In in vitro experiments, both lovastatin and amlodipine preserved SOD activity and reduced the oxidizability of low density lipoproteins by rabbit leukocytes. CONCLUSIONS: This study suggests that a reduction in lipid peroxidation and preservation of SOD may be common mechanisms of antiatherosclerotic effects of lovastatin, vitamin E and amlodipine.     

Lipoproteins and lipid peroxidation abnormalities in patients with chronic renal disease

Increasing experimental and clinical evidence suggests that lipoproteins and lipid peroxidation can be important modulators in progressive kidney disease. A group of 54 patients with varying degrees of kidney impairment was studied to find the abnormalities in lipoproteins and lipid peroxidation. Lipoproteins and lipid peroxidation products, malondialdehyde (MDA) were measured in the plasma of 54 chronic renal disease patients CGN 33, nephrosclerosis 11, 7CTIN, 1PCKD, unknown 2 and compared with values obtained from 32 healthy controls. The patients were divided into 5 groups according to serum creatinine levels: Group 1 (serum creatinine of 2 mg/dl), group 2 (S. creatinine > 2-4 mg/dl), group 3 (S. creatinine > 4-8 mg/ dl), group 4 (S. creatinine > 8-12 mg/dl), group 5 (S. creatinine > 12 mg/dl). Plasma cholesterol was higher significantly than controls in patients with group 1, 2 and 3 (p < 0.01, < 0.001, < 0.05) respectively while plasma LDL-chol was statistically significantly different from controls only in group 2 patients (p < 0.001). Plasma VLDL-chol, beta-VLDL-chol, triglycerides, ratio of chol/HDL and LDL/ HDL showed high levels in all groups compared with controls but more evident in patients of group 2. Plasma HDL-chol decreased during the progression of renal failure. All groups had significantly elevated plasma malonyldialdehyde (MDA) vs controls (p < 0.001), especially highest value was found in group 2. Triglycerides, beta-VLDL chol, VLDL-chol LDL/HDL, chol/HDL correlated very closely with plasma MDA levels and also with serum creatinine. Patients with chronic renal disease showed lipoprotein abnormalities and accelerated lipid peroxidation. The evidence was more marked in patients with normal to mild renal insufficiency which suggested the role of oxidative stress early in the course of nephron injury.     

Acute intracranial complications of temporal bone trauma

BACKGROUND: A total of 110 patients, in whom kidneys from 95 living related and 15 cadaver donor, had experienced renal transplantation between February 1985 and October 1996 in our clinic. This study was conducted to evaluate the influence of the various pre-operative factors to the graft survivals and clinical course of patients in living related renal transplantation. METHODS: In 95 recipients, 17 adult patients had long term graft survivals over 5 years including 6 recurrent or denovo nephritis without chronic allografts nephropathy. Eight failed to graft loss attributed to chronic allografts nephropathy diagnosed within 5 years. Retrospective analysis were performed to elucidate the differences of these recipients. RESULTS: Donors of long graft survival recipients were younger (49.1 +/- 12.1 v.s. 58.9 +/- 10. 2) and had a better renal function evaluated by preoperative creatinine clearance in living related donors (115.5 +/- 37.0 v.s. 79.7 +/- 22.0 1/day). Graft long survival recipients had experienced less frequencies of acute rejection within 6 months (0.53 +/- 0.62: 8 patients, 9 times) compared with chronic allografts nephropathy recipients (1.00 +/- 0.53: 7 patients, 8 times). Long graft survival recipients had better responses to the antirejection therapy. Additionally acute rejection over 6 months were experienced only in chronic allografts nephropathy recipients. Higher serum creatinine level was revealed in recipients with chronic allografts nephropathy at 1 year after transplantation (1.27 +/- 0.27 v.s. 1.88 +/- 0.42 mg/dl). CONCLUSIONS: We concluded that donor age and renal function are related to the graft long survival as background factors. Long graft survival recipients had less frequency of acute rejection and good response to the antirejection therapy. In recipients with of acute rejection and good response to the antirejection therapy. In recipients with chronic allografts nephropathy, serum cretine level had already increased gradually within 1 year.     

Breakdown of blood pressure and body fluid homeostasis in heart transplant recipients

OBJECTIVES: This study was designed to investigate disturbances in arterial blood pressure and body fluid homeostasis in stable heart transplant recipients. BACKGROUND: Hypertension and fluid retention frequently complicate heart transplantation. METHODS: Blood pressure, renal and endocrine responses to acute volume expansion were compared in 10 heart transplant recipients (57 +/- 9 years old [mean +/- SD]) 20 +/- 5 months after transplantation, 6 liver transplant recipients receiving similar doses of cyclosporine (cyclosporine control group) and 7 normal volunteers (normal control subjects). After 3 days of a constant diet containing 87 mEq/24 h of sodium, 0.154 mol/liter saline was infused at 8 ml/kg per h for 4 h. Blood pressure and plasma vasopressin, angiotensin II, aldosterone, atrial natiuretic peptide and renin activity levels were determined before and at 30, 60, 120 and 240 min during the infusion. Urine was collected at 2 and 4 h. Blood pressure, fluid balance hormones and renal function were monitored for 48 h after the infusion. RESULTS: Blood pressure did not change in the two control groups but increased in the heart transplant recipients (+15 +/- 8/8 +/- 5 mm Hg) and remained elevated for 48 h (p < or = 0.05). Urine flow and urinary sodium excretion increased abruptly in the control groups sufficient to account for elimination of 86 +/- 9% of the sodium load by 48 h; the increases were blunted (p < or = 0.05) and delayed in the heart transplant recipients, resulting in elimination of only 51 +/- 13% of the sodium load. Saline infusion suppressed vasopressin, renin activity, angiotensin II and aldosterone in the two control groups (p < or = 0.05) but not in the heart transplant recipients. Heart transplant recipients had elevated atrial natriuretic peptide levels at baseline (p < or = 0.05), but relative increases during the infusion were similar to those in both control groups. CONCLUSIONS: Blood pressure in heart transplant recipients is salt sensitive. These patients have a blunted diuretic and natriuretic response to volume expansion that may be mediated by a failure to reflexly suppress fluid regulatory hormones. These defects in blood pressure and fluid homeostasis were not seen in liver transplant recipients receiving cyclosporine and therefore cannot be attributed to cyclosporine alone. Abnormal cardiorenal neuroendocrine reflexes, secondary to cardiac denervation, may contribute to salt-sensitive hypertension and fluid retention in heart transplant recipients.     

Factors affecting the ultrasonic properties of equine digital flexor tendons

Dietary treatment with three diets differing in vitamin E, Low E (15 mg of vitamin E/kg diet), Medium E (150 mg/kg), or High E (1,500 mg/kg), resulted in guinea pigs with low (but nondeficient), intermediate, or high heart alpha-tocopherol concentration. Neither the antioxidant enzymes superoxide dismutase, catalase, glutathione peroxidase, and reductase, nor the nonenzymatic antioxidants, GSH, ascorbate, and uric acid were homeostatically depressed by increases in heart alpha-tocopherol. Protection from both enzymatic (NADPH dependent) and nonenzymatic (ascorbate-Fe2+) lipid peroxidation was strongly increased by vitamin E supplementation from Low to Medium E whereas no additional gain was obtained from the Medium E to the High E group. The GSH/GSSG and GSH/total glutathione ratios increased as a function of the vitamin E dietary concentration closely resembling the shape of the dependence of heart alpha-tocopherol on dietary vitamin E. The results show the capacity of dietary vitamin E to increase the global antioxidant capacity of the heart and to improve the heart redox status in both the lipid and water-soluble compartments. This capacity occurred at levels six times higher than the minimum daily requirement of vitamin E, even in the presence of optimum dietary vitamin C concentrations and basal unstressed conditions. The need for vitamin E dietary supplementation seems specially important in this tissue due to the low constitutive levels of endogenous enzymatic and nonenzymatic antioxidants present of the mammalian heart in comparison with those of other internal organs.