Adriamycin and daunomycin generate reactive oxygen compounds in erythrocytes

Adriamycin and daunomycin produce dose-related cardiac toxicity that may be related to oxygen radicals. Addition of these compounds to human erythrocyte suspensions resulted in stimulation of hexose monophosphate shunt activity that was markedly impaired in the absence of oxyhemoglobin. Evidence for generation of hydrogen peroxide by these compounds was provided by oxidation of reduced glutathione, by 14C- formate oxidation, and by the catalase-aminotriazole trapping technique. These experiments indicate that Adriamycin and daunomycin interact with oxyhemoglobin to generate reactive oxygen metabolites. A similar interaction with oxymyoglobin may occur in the heart and produce oxygen radicals that injure cardiac myocytes.     

Peptide inhibition of mammalian histidine decarboxylase

The hypothesis thatN-terminal histidine peptides might act as inhibitors to histidine decarboxylase was investigated. A murine mastocytoma was utilized as enzyme source. the crude extract of this tissue exhibits high rates of decarboxylation of both histidine and DOPA and was used to establish the specificity in the effect of the compounds tested. For kinetic analyses a highly purified histidine decarboxylase fraction was used. The effect of some representative peptides on both enzyme activities were recorded.Histidine decarboxylase exclusively was inhibited byN-terminal histidine peptides. None of the other peptides investigated interfered negatively with this enzyme. This inhibition was consistent in the purified preparation and appeared to be more pronounced with increasing hydrophobicity in the second amino acid. Histidyl-phenylalanine was found to be about 100-fold as potent as the commonly used specific histidine decarboxylase inhibitor -methyl histidine.It is concluded that small peptides with histidine as theN-terminal amino acid might act as specific inhibitors for mammalian histidine decarboxylase. An analog effect of small tyrosyl or phenylalanyl peptides was not seen for the DOPA decarboxylase.Presented in part at the 11th FEBS Meeting, Copenhangen, August 1977.     

Microrheologic investigation of erythrocyte deformability in diabetes mellitus

This study was undertaken to determine whether diabetes alters the viscoelastic properties of erythrocytes. The oldest and youngest 10% fractions of circulating red cells were separated by centrifugation of freshly drawn blood obtained from ten diabetics with disease of one to 20 years' duration and from an equal number of age- and sex-matched control subjects. Cells from each fraction were suspended in phosphate- buffered saline, and their rheologic behavior was examined in a rheoscope. The elongation of cells, the percentage of cells that tank- treaded in response to shear stress, tank-treading frequency, and the rate of recovery of cell shape upon cessation of shear stress were determined in the oldest and youngest 10% of cells for diabetics as well as for controls. All four parameters were virtually identical for diabetics and controls. Additional aliquots of cells were taken for assessment of nonenzymatic glucosylation of hemoglobin and cell membrane protein. The absence of any measurable difference in rheologic behavior of cells from diabetic and control subjects, despite substantial differences in nonenzymatic glucosylation of hemoglobin and cell membrane proteins, suggests that the magnitude of glucosylation observed in these cellular constituents does not alter the viscoelastic properties of the cells. The implication of these observations is that microvascular complications of diabetes are not attributable to altered deformability of red cells.     

Analysis of steroid conversion in vitro by testicular tissue as a means of selection of infertile males for gonadotrophic substitution therapy

Testicular biopsy specimens from 11 infertile men were incubated in vitro with [3H]progesterone before and during long term gonadotrophic treatment. The main metabolites along the delta-4 metabolic pathway and 20 alpha-dihydro-progesterone were determined and the ratio between 20 alpha-dihydro-progesterone and 17 alpha-hydroxyprogesterone formed in vitro was calculated. In 5 patients with originally high ratios (indicating gonadotrophic understimulation), steroid metabolism changed significantly towards a more stimulated pattern. Three of these patients also showed a significant increase in sperm output and 2 of them fathered children. In 6 patients with an originally low ratio (indicating adequate gonadotrophic stimulation) no change in steroid metabolism in vitro or spermatogenesis was seen during therapy. Thus, this ratio between formed 20 alpha-dihydro-progesterone and 17 alpha-hydroxyprogesterone in vitro seems to be of value in predicting whether gonadotrophic treatment will be of clinical benefit.     

Estrogen effects on postural balance in postmenopausal women without vasomotor symptoms: a randomized masked trial

OBJECTIVE: To assess whether estrogen treatment given to postmenopausal women without vasomotor symptoms improves balance more than placebo. METHODS: Forty healthy postmenopausal women without vasomotor symptoms were randomized to transdermal 17beta-estradiol (E2) 50 microg/day for 14 weeks or identical transdermal placebo patches. Postural balance was measured with dynamic posturography before and after 4, 12, and 14 weeks of therapy. In this test, the visual, vestibular, and somatosensory systems were provoked with increasing difficulty and body sway was measured with a dual forceplate. A low score showed large sway and a score of 100 showed no sway at all. RESULTS: Thirty-eight women completed the study. Both groups had normal balance for their ages and near maximum scores in the three easier balance tests at baseline. In the most difficult test, both groups improved their postural balance significantly (from 13 to 32 and from 22 to 39, respectively) after 4 weeks. Thereafter, no change was seen. One problem was low statistical power, but the relative change in balance did not differ between groups. The comparison did not show even a minute advantage of E2 over placebo, so a study with higher power would probably not have shown a more pronounced effect of estrogen than placebo. The change over time did not differ between groups, which indicates a significant learning effect. CONCLUSION: In women without vasomotor symptoms, estrogen therapy did not seem to increase postural balance significantly more than placebo. However, we could not rule out that estrogens affect postural balance in women with vasomotor symptoms.