Oxidative damage accumulation in macromolecules has been considered as a cause of cellular damage and pathology. Rarely, the oxidative stress parameters in healthy humans related to the individual age have been reported. The purpose of this study was to examine the redox status in plasma and erythrocytes of healthy individuals and determine correlations between these parameters and the aging process. The following parameters were used: malondialdehyde (MDA), protein carbonyls (PCO), 4-hydroxy-2,3-trans-nonenal (HNE), reduced glutathione (GSH), glutathione disulfide (GSSG) and uric acid (UA) in blood and plasma samples of 194 healthy women and men of ages ranging from 18 to 84 years. The results indicate that the balance of oxidant and antioxidant systems in plasma shifts in favor of accelerated oxidation during ageing. That is demonstrated by increases of MDA, HNE, GSSG and by the slight decrease of erythrocytic GSH with age. As the content of UA is more determined by metabolic and nutritional influences than by the balance between prooxidants and antioxidants there was no significant age-related change observed. For plasma concentrations of HNE the first time age-dependent reference values for healthy humans are presented.
Abstract. Recent concern has arisen about the development of neutralizing anti-erythropoietin (EPO) antibodies during the course of treatment with recombinant EPO. The underlying mechanisms are poorly understood. A patient was observed who developed wheals at the sites of subcutaneous injections of epoetin-␣ before the manifestation of pure red cell aplasia (PRCA). Intravenous application of different epoetins evoked skin reactions at the sites of former subcutaneous injections, indicating local persistence of sensitized cells, and eventually a systemic anaphylactoid response. Anti-EPO antibodies crossreactive with epoetin- and darbepoetin-␣ were demonstrated in patient serum. PRCA gradually improved after treatment with prednisolone.Since recombinant human erythropoietin (EPO) became available in 1986, millions of patients have received the hormone for correction of renal and nonrenal anemias. EPO therapy is associated with few side effects, usually related to an increase in hemoglobin (Hgb) levels and the associated rise in blood viscosity. The extremely favorable risk/benefit relationship has in part been attributed to the close similarity between the endogenous and the recombinant hormone. The protein backbone of 165 amino acids is predicted by the human gene. The carbohydrate moiety consisting of three N-linked and one O-linked side chain closely resembles human urinary EPO, although slight differences exist between endogenous and recombinant EPO as well as between recombinant EPO preparations produced by different manufacturers (epoetin-␣ and epoetin-) (1,2). Two additional sites for N-linked glycosylation have recently been introduced into the EPO gene to generate a recombinant epoetin molecule with increased stability, allowing less frequent applications (darbepoetin-␣) (3).All preparations of recombinant EPO have so far proven to be poorly immunogenic. During one decade, clinically relevant anti-EPO antibodies were observed in single cases only (4 -7). In the last few years, however, there appears to be an increase in the number of patients developing neutralizing anti-EPO antibodies during the course of therapy (8,9). These patients develop aplastic pure red cell anemia, which responds poorly to immunosuppressive therapy and results in prolonged transfusion dependence. Although the total number of fewer than 100 cases reported so far is small in relation to the number of patients treated, this development raises some concern, because the true incidence is unknown and the underlying mechanisms remain unclear. Interestingly, all 13 cases of patients with anti-EPO antibodies for which details have recently been published (8) have received epoetin therapy via the subcutaneous route. We report a patient with anti-EPO antibodies in whom intravenous injection of epoetins has evoked skin reactions at sites of former subcutaneous injections, suggesting that immune reactions in the subcutis play an important role in antibody generation.
This study investigated the influence of temperature or glutamate antagonism on the immediate outcome of perinatal asphyxia. Perinatal asphyxia was produced by water immersion of fetus-containing uterus horns removed by cesarean section from ready to deliver rats. The uterus horns were kept in a water bath for different time periods, before the pups were delivered and stimulated to breathe. After delivery, the pups were assessed for behavior and for systemic glutamate, aspartate, lactate and pyruvate levels measured with in vivo microdialysis, or ex vivo for energy-rich phosphates, including adenosine triphosphate (ATP), in brain, heart and kidney. In a series of experiments, asphyxia was initiated in a water bath at 37 degrees C, before the pup-containing uterus horns were moved for different time intervals to a 15 degrees C bath. In another series of experiments, the mothers were treated with N-methyl-D-aspartate (NMDA) antagonist, dizocilpine (MK-801), or alpha-amino-3-hydroxy-methylisoxazole-4-propionic acid (AMPA) antagonist,2,3-dihydroxy-6-nitro-7-sulfamoyl benzo(f) quinoxalin NBQX) 1 h before hysterectomy and asphyxia at 37 degrees C. The rate of survival rapidly decreased following exposure to more than 16 min of asphyxia, and no survival could be observed after 22 min of asphyxia. An LD50 was estimated to occur at approximately 19 min of asphyxia. The outcome was paralleled by a decrease in ATP in kidney, followed by a decrease in heart and brain. A maximal decrease in ATP was observed after 20 min of asphyxia in all tissues. Systemic microdialysis revealed that glutamate, aspartate and pyruvate levels were increased with a peak after 5 min of asphyxia. In contrast, lactate levels increased along with the length of the insult. Survival was increased when the pup-containing uterus horns were moved from a 37 degrees C to a 15 degrees C bath, at 15 min of asphyxia (the LD50 was thus increased to 30 min). If the shift occurred at 10 or 5 min of asphyxia, the LD50 increased to 80 or 110 min, respectively. The effect of glutamate antagonism was minor compared to hypothermia; the best effect (an increase in the LD50 to approximately 22 min) was observed after combining AMPA and NMDA antagonists.
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