Biomedical subjects
Publications and source records attributed to J E Fleming.
Although there has been no conclusive evidence to suggest that ultrasound is dangerous in pregnancy, precautions would seem sensible. Doctors should minimize patient exposure time but a gesture by the machine manufacturers to incorporate the reduction of acoustic output into their design requirements would be admirable.
The terminal enzyme of the heme biosynthetic pathway, ferrochelatase (protoheme ferrolyase EC 4.99.1.1), has been purified to apparent homogeneity from bovine liver mitochondria using a scheme similar to that reported by Taketani and Tokunaga (Taketani, S. and Tokunaga, R. (1981) J. Biol. Chem. 256, 12748-12753) for purification of the enzyme from rat liver. The final yield was 49% with a 2000-fold purification. Ferrochelatase has an apparent molecular weight of approximately 40,000 by both sodium dodecyl sulfate-polyacrylamide gel electrophoresis and column chromatography on Sepharose CL-6B in the presence of 0.5% sodium cholate. The purified enzyme was only slightly stimulated by added lipid and was inhibited by Mn2+, Pb2+, and Hg2+. Bovine ferrochelatase utilized proto-, meso-, and deuteroporphyrin, but not disubstituted porphyrins (2,4-disulfonic and 2,4-bisglycol deuteroporphyrin). N-Methylprotoporphyrin, a toxic by-product of the metabolism of some drugs, was found to inhibit ferrochelatase in a competitive fashion with respect to porphyrin with a Ki of 7 nM and uncompetitive with respect to iron. Manganese inhibits ferrochelatase competitively with respect to iron (Ki = 15 microM) and noncompetitively with respect to the porphyrin substrate. Heme, one of the products, is a noncompetitive inhibitor with respect to iron. These findings lead to a sequential Bi Bi kinetic model for ferrochelatase with iron binding occurring prior to porphyrin binding and heme being released prior to the release of two protons.
The oxidation rates of ascorbic acid and several of its derivatives have been examined in order to delineate the role of bicyclic ring formation in the autooxidation of ascorbic acid. The compounds evaluated and their respective oxidation rates at pH 7.4 are in uM X min-1: ascorbate, 0.70; 5 methyl 3,4 dihydroxytetrone, 0.65; D-iso ascorbate, 0.73; and ascorbyl palmitate, 0.64. These data do not support the contention that bicyclic ring formation is required for the oxidation of ascorbic acid because both 5 methyl 3,4 dihydroxytetrone and ascorbyl palmitate, neither of which can form the bicyclic intermediate, have oxidation rates similar to that of ascorbate. Furthermore, evidence is presented which suggests that ionization of the oxygen on C3 of ascorbic acid is an obligatory initial step in ascorbic acid autooxidation.
Eighty-eight depressed patients who had received a dexamethasone suppression test (DST) and thyrotropin-releasing hormone (TRH) test were divided into four subgroups based on family history of psychiatric illness. Nonsuppression on the DST was found in 46% of familial pure depressive disease (FPDD) patients, 38% of sporadic depressive disease (SDD) patients, 38% of depressive spectrum disease (DSD) patients, and 50% of mixed depressive disease patients (patients with both a first degree relative with alcoholism and one with depression). A blunted thyroid-stimulating hormone response to TRH was found in 50% of FPDD patients, 56% of SDD patients, 47% of DSD patients, and 56% of mixed depressive disease patients. Neither the DST nor TRH test was found to distinguish significantly among the four familial subgroups of depression.
The respective roles of respiration rate and DNA repair in determining the life-span of Drosophila melanogaster have been investigated in three wild strains (Oregon R, Domodedov 32, & Swedish C) and two mutants (w/w & w/mei-41 D5). In agreement with the rate of living theory, there was an inverse relation between oxygen consumption and median life-span in flies having normal DNA repair. In contrast, w/mei-41 D5, showed an abnormally low life-span as compared to the controls. The median life-spans for these flies were: Oregon R, 49; Domodedov 32, 46; Swedish C, 35; w/w, 33; and w/mei-41 D5, 22. Furthermore, this mutant also showed significant deficiency in mating fitness and a depressed metabolic rate. These data suggest that the short life-span of the w/mei-41 D5 is a consequence of a specific syndrome unrelated to normal aging and is not the expression of accelerated senescence. It is proposed that DNA repair mechanisms influence adult life-span by their effect on actively dividing progenitor cells during development rather than by modulating senescence of the resulting differentiated cells of the imago during adulthood.
The autooxidation rate of ascorbic acid (AA) at 10(-5) M under aerobic conditions at pH 7.4 was found to be 1.16 mumol/min/l. A number of compounds at low concentrations were found to inhibit this oxidation rate. These were in order of effectiveness: EDTA (10(-6) M) greater than Mercaptoethanol greater than aminoethyl cysteine, oxidized glutathione greater than glycylglycylhistidine greater than glycylhistidyllysine greater than 3-methyl histidine approximately histidine greater than histamine greater than hypertensin greater than cysteic acid greater than imidazole greater than glutamine greater than hydroxyproline, and lysine. All other amino acids and peptides examined had little or no effect on the autooxidation rate of ascorbic acid. Ascorbate solutions, treated with Chelex-100 (divalent chelating resin) or containing low concentrations of EDTA (10(-7) M) did not show a significant reduction of the rate of autooxidation. Of particular interest was the finding that 3-methyl histidine had a significant inhibitory effect on ascorbic acid oxidation whereas 1-methyl histidine had no effect. These data suggest that ascorbic acid forms complexes with certain compounds and that this interaction stabilizes ascorbic acid against auto-oxidation.
Bovine serum albumin (BSA) was found to inhibit the autooxidation of ascorbic acid (AA) at physiologic pH. The spontaneous oxidation rate of AA at 1 X 10(-5) M was 0.87 mumol X L-1 min-1. In the presence of 1 microM BSA, the rate is 15% of the spontaneous rate (0.13 mumol X L-1 X min-1). The u.v. difference spectrum of the AA:BSA complex reveals a decrease in absorbance at 204 nm. These data provide evidence that AA binds to BSA and induces a conformational change in the BSA molecule.
Cardiac electromechanical intervals were measured during labour in 103 unselected human fetuses. Mean values (+/- SD) for the three intervals measured were 76.01 +/- 9.93 ms for the pre-ejection period, 41.56 +/- 8.51 ms for the isovolumetric contraction time and 156.23 +/- 16.58 ms for the left ventricular ejection time. These are consistent with previously reported data from our own and other centres. the intervals studied did not alter significantly as labour proceeded or during uterine contractions. There was no consistent correlation between them and fetal scalp blood PO2, PCO2 or pH, although the pre-ejection period was shortened considerably in three very acidaemic or hypoxic fetuses, and it was prolonged in association with tight nuchal cord entanglement and variable decelerations in fetal heart rate. These findings raise the possibility of using recorded cardiac electromechanical intervals to determine the clinical significance of different fetal heart-rate patterns that suggest the possibility of fetal distress.
Though intrinsic mitochondrial aging has been considered before as a possible cause of cellular senescence, the mechanisms of such mitochondrial aging have remained obscure. In this article we expand on our hypothesis of free-radical-induced inhibition of mitochondrial replenishment in fixed postmitotic cells. We maintain that the respiration-dependent production of superoxide and hydroxyl radicals may not be fully counteracted, leading to a continuous production of lipoperoxides and malonaldehyde in actively respiring mitochondria. These compounds, in turn, can easily react with the mitochondrial DNA which is in close spatial relationship with the inner mitochondrial membrane, producing an injury that the mitochondria may be unable to counteract because of their apparent lack of adequate repair mechanisms. Mitochondrial division may thus be inhibited leading to age-related reduction of mitochondrial numbers, a deficit in energy production with a concomitant decrease in protein synthesis, deterioration of physiological performance, and therefore, of organismic performance.
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In 80 patients, multiple measurements of the fetal biparietal diameter were made during one examination using a real-time scanner equipped with a coded cephalometer. From the sets of data, the means and standard deviations for the group of 80 patients were calculated. In 80 per cent of cases, the individual standard deviations of the results were less than or equal to the estimated standard deviation of the group as a whole. The variability of measurement related to biparietal diameter was least in the range 59 to 83 mm. Comparison of the results obtained with the coded device and others obtained 'blind' does not reveal any significant advantage for the coded device.
Rats were allowed a third of normal water intake for 20 days, and food consumption decreased. The reticulocyte count indicated a suppression of erythropoiesis. Urine osmolality increased from 2,000 mosmol/kg to 3,390 mosmol/kg. Random hemolysis and senescence of a cohort of red blood cell (RBC) previously labeled with [2-14C]glycine was monitored via the production of 14CO. Neither hemolysis nor senescence was affected. Following water restriction, the polydipsic rats generated a hypotonic urine. Urine osmolality decreased to 1,300 mosmol/kg for at least 6 days; a reticulocytosis occurred, but RBC survival was unaffected. These results contradict those previously reported, which suggest that RBC survival is influenced by the osmotic stress imposed on the RBC by extremes of urine tonicity. This discrepancy, we conclude, is due to differences in the methods employed for measuring RBC survival. The random-labeling technique employed previously assumes a steady state between RBC production and destruction. The cohort-labeling technique used here measures hemolysis and senescence independent of changes in RBC production, which is known to be depressed by fasting.
In an attempt to devise a screening method for the detection of unsuspected IUGR, a battery of ultrasonic measurements of the fetus were performed in a series of 255 patients at approximately 32, 34, and 36 weeks. The results obtained from the 16 growth-retarded and the 239 normally grown babies were evaluated. While no single measurement was found to discriminate the two groups, a simple combination of crown-rump length times area of trunk allowed us to identify an at-risk group comprising 11 per cent of the population. The false positive and false negative results were acceptable at levels of 10 and 6 per cent, approximately. It is considered that these results would justify a larger and prospectively randomized controlled trial to assess the benefits and drawbacks of applying these measurements in a screening schedule.
An electronic system for measuring area and perimeter directly on cross-sectional ultrasonic images is described. The resulting values are unaffected by the distortions common to display monitors or errors in the display scale factor. The results of accuracy tests are given, including a comparison with measurements by planimeter and map-measurer.
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