Biomedical subjects
E Lee
Publications and source records attributed to E Lee.
Critical quasielastic light scattering in KTa0.968Nb0.032O3.
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Repair and recombination of nonreplicating UV-irradiated phage DNA in E. coli III. Enhancement of excision repair in UV-treated bacteria.
The question of whether induction of the SOS response in Escherichia coli increases the efficiency of excision repair was addressed by measuring repair of UV-damaged nonreplicating lambda phage DNA in previously irradiated bacteria. Prior UV irradiation of lex+ bacteria enhanced both the rate of regeneration of infective phage DNA (about 10-fold) and the rate of cyclobutane dimer removal early in repressed infections. Indirect induction of SOS-regulated repair activities by the nonreplicating irradiated phage DNA itself seemed negligible. Prior bacterial irradiation reduced the frequency of recombination (loss of a tandem chromosomal duplication) of nonreplicating UV-irradiated DNA. In this respect UV-stimulated recombination of nonreplicating DNA differs from RecF-dependent recombination processes that are stimulated by increased SOS expression. Surprisingly, prior UV irradiation of lexA3 bacteria caused a small but reproducible increase in the regeneration of infective phage DNA.
Effect of pneumonectomy on extravascular lung water in dogs.
The effect of pneumonectomy in dogs on extravascular lung water (EVLW) was studied using a double-indicator (iced indocyanine green dye) dilution technique. The EVLW was measured in five dogs before and after a left pneumonectomy while left atrial pressure was increased in 5-mm Hg increments from 10 to 25 mm Hg by serially inflating a left atrial Foley balloon. There were no significant differences in hematocrit, total protein, or plasma oncotic pressure before or after pneumonectomy. Prepneumonectomy EVLW was adjusted to reflect right lung EVLW alone. Both before and after pneumonectomy there was a significant increase in EVLW when left atrial pressure was increased to 25 mm Hg. However, EVLW values were similar before and after pneumonectomy at each level of left atrial pressure. We conclude that pneumonectomy does not acutely increase susceptibility to EVLW formation caused by a hemodynamic challenge. This implies that following pneumonectomy, if left heart filling pressures are normal, there is no clinical benefit to excessive fluid restriction.
A possible mechanism of psoralen phototoxicity not involving direct interaction with DNA.
Psoralens in combination with ultraviolet light (UVA; 320-400 nm) are used in the photochemical treatment of a variety of skin diseases including vitiligo, a skin depigmentational disorder, and psoriasis, a disease of accelerated epidermal cell proliferation. Although it is generally assumed that the major site of action of the psoralens is DNA, we have obtained evidence that another site may be the primary target for these compounds. We have identified specific, saturable, high-affinity binding sites for 8-methoxypsoralen on HeLa cells and have detected specific binding of 8-methoxypsoralen to four other human cell lines and five mouse cell lines. In HeLa cells, specific binding is reversible and independent of the ability of the compound to intercalate into DNA. In addition, binding sites become covalently modified by the psoralen after UVA exposure. Specific binding of 8-[methoxy-3H]methoxypsoralen constitutes 79% of the label bound to the cells. Scatchard analysis indicated two classes of psoralen binding sites: high-affinity sites with a Kd of 19 X 10(-9) M (1.8 X 10(5) sites per cell) and low-affinity sites with a Kd of 4 X 10(-6) M (7.1 X 10(6) sites per cell). Four structurally related psoralen analogs block 8-methoxypsoralen binding in a manner that parallels their biological activity. Based on these findings, we hypothesize that specific binding sites for psoralens on mammalian cells mediate, at least in part, psoralen-induced phototoxicity.
Rebound hyperresponsiveness to muscarinic stimulation after chronic therapy with an inhaled muscarinic antagonist.
In 9 young subjects with mild asthma, we investigated the possibility that chronic daily administration of an inhaled muscarinic antagonist (ipratropium bromide) might increase the response of muscarinic receptors in airway smooth muscle to agonist stimulation caused by receptor upregulation. Subjects inhaled 60 micrograms of ipratropium 4 times daily for 3 wk. Methacholine bronchoprovocation (with or without acute pretreatment with ipratropium) was performed before (control period) and during 3 wk of daily ipratropium therapy (medication period). At the end of the medication period, subjects returned at 12, 24, 48, and 72 h after the last dose of ipratropium (withdrawal period) to determine the provocative concentration of methacholine producing a 20% decrease in FEV1 (PC20). During the medication period, there was no significant diminution of the acute bronchodilator response to ipratropium or of the protective effect of ipratropium against methacholine-induced bronchospasm when compared with the control period. During the withdrawal period, mean in PC20 was significantly less (increased airway responsiveness) at 24 h than during the control period (p less than 0.01) and returned to the control period value within 48 to 72 h. We conclude that daily administration of ipratropium to mildly asthmatic subjects for 3 wk does not produce tolerance to either the bronchodilator effect of ipratropium or to its inhibition of methacholine-induced bronchospasm but does induce transient supersensitivity of airway cholinergic receptors to muscarinic stimulation.
An evaluation of the significance of microscopic colitis in patients with chronic diarrhea.
Some patients with chronic idiopathic diarrhea have an apparent nonspecific inflammation of colonic mucosa, even though their colons appear normal by barium enema and colonoscopy. This has been referred to as microscopic colitis. However, the significance of this finding is unclear, because the ability of pathologists to accurately distinguish mild degrees of abnormality has not been established. Furthermore, even if the mucosa of these patients is nonspecifically inflamed, it is not known whether this is associated with deranged colonic function that could contribute to the development of chronic diarrhea. To assess these questions, we first examined colonic biopsy specimens in a blinded fashion, comparing biopsy results from patients with microscopic colitis with biopsy specimens from subjects in two control groups. This analysis revealed that colonic mucosa from six patients with microscopic colitis was in fact abnormal. For example, their mucosa contained an excess of both neutrophiles and round cells in the lamina propria, cryptitis, and reactive changes. These and other differences were statistically significant. Second, colonic absorption, measured by the steady state nonabsorbable marker perfusion method, was severely depressed in the patients. For example, mean water absorption rate was 159 ml/h in normal subjects and was reduced to only 26 ml/h in six patients with microscopic colitis. Results of net and unidirectional electrolyte fluxes and of electrical potential difference suggested that colonic fluid absorption was abnormal because of reduced active and passive sodium and chloride absorption and because of reduced Cl/HCO3 exchange. Small intestinal fluid and electrolyte absorption was abnormally reduced in two of the six patients, suggesting the possibility of coexistent small intestinal involvement in some of these patients. We conclude that nonspecific inflammation of colonic mucosa is associated with a severe reduction of colonic fluid absorption, and that the latter probably contributes to the development of chronic diarrhea.
Importance of drug enantiomers in clinical pharmacology.
The ordered asymmetry of biological macromolecules allows them to differentiate between the optical isomers of monomeric substrates. Optical isomers of drugs often have greatly different affinities at receptor sites, are metabolised at different rates, and have different affinities for tissue and protein binding sites. Despite this knowledge, many drugs are administered as their racemates. Manipulation of the enantiomeric ratio or the use of only one enantiomer of a drug may allow separation of toxicity and efficacy, and this may lead to a significant increase in therapeutic ratio and a more rational approach to therapeutics.
Zinc levels of hospitalized elderly.
Zinc status was evaluated in 99 consecutive elderly patients admitted to a geriatric assessment unit. The assessment of zinc status was based on measurement of plasma, erythrocyte, and urinary zinc levels by atomic absorption spectrophotometry; serum lactic dehydrogenase and alkaline phosphatase by standard laboratory methods; and dietary intake by the food frequency questionnaire method. Mean (+/- standard deviation) plasma zinc concentration was 72 +/- 16 micrograms/100 ml (N = 91). Although 67% of the group had plasma zinc levels in the deficient range, only three patients had values below the normal range for erythrocyte zinc and none fell below the reference range for urinary zinc per 24 hours (N = 15) or the urinary zinc:creatinine ratio. Mean values for the other parameters of zinc status were 1.27 +/- 0.26 micrograms/10(9) RBC for erythrocyte zinc, 285 +/- 217 micrograms/24 hours for urinary zinc, and 588 +/- 309 micrograms/gm for the urinary zinc:creatinine ratio. Serum alkaline phosphatase and lactic dehydrogenase were not specific indicators of zinc status. Forty-six percent had adequate and 54% inadequate dietary intakes (N = 46). Twenty percent were receiving an inadequate intake of meat products, suggesting that the majority (80%) were ingesting an adequate supply of zinc-rich foods. Zinc status appeared to be adequate in this population.
The pattern of arteriosclerotic changes in the peripheral arteries and the role of physical exercise.
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Selective induction of cytochrome b5 and NADH cytochrome b5 reductase by propylthiouracil.
Both the cytochrome b5 level and NADH cytochrome b5 reductase activity in rat liver microsomes were increased 2-fold by repeated i.p. administration of 1.5 mmol/kg propylthiouracil (PTU) for 2 weeks, but neither the cytochrome P-450 level nor NADPH cytochrome P-450 reductase activity were affected by the treatment. Liver microsomes from PTU-treated rats showed a significant decrease in aminopyrine N-demethylation, but not in benzphetamine N-demethylation, aniline hydroxylation or 7-ethoxycoumarin O-deethylation. A single administration of the compound had no effect on any components of the system. In vitro, drug hydroxylation activities were not affected by PTU up to 1.0 mM. From the above evidence, repeated administration of PTU selectively induced cytochrome b5 and NADH cytochrome b5 reductase in rat liver microsomes.
A new calcium current underlying the plateau of the cardiac action potential.
A small and very slow inward calcium current has been identified in isolated single ventricular cells using TTX and Cd2+ to block the sodium and fast calcium currents. Activation requires about 300 ms at the threshold potential of -60 mV, decreasing to 80 ms at the peak current voltage of -30 mV. Inactivation is five to ten times longer. Half steady-state activation and inactivation are at -50 and -45 mV respectively. The current is distinctively different in both its kinetics and pharmacology from the conventional calcium current described in single heart cells. It is proposed that it contributes significant current to help maintain a major portion of the long ventricular action potential.
Beta-bend conformation of CH3CO-Pro-Pro-Gly-Pro-NHCH3: implications for posttranslational proline hydroxylation in collagen.
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The nucleotide sequence at the recombination/integration sites of the hybrid viruses Ad2+ND3 and Ad2+ND5.
The nucleotide sequence at the recombination/integration sites of the adenovirus 2-simian virus 40 hybrid viruses, Ad2+ND3 and Ad2+ND5, is reported. These viruses were obtained by passages through human cells and fail to express the SV40-related proteins. The lack of expression of SV40-related proteins has been explained on the basis of the nucleotide sequence at the recombination sites. Ad2+ND3 has the entire reading frame for the SV40 T antigen removed up to the translation termination codon. The recombination event in Ad2+ND5 was found to occur in the leader region 11 nucleotides upstream from the splice junction, thus totally eliminating the naturally occurring splice site, which might have lead to defective processing of the mRNA. Alternatively, because of the large deletion, this virus is incapable of making similar hybrid proteins as in Ad2+ND1, Ad2+ND2, and Ad2+ND4, which share the N-terminal sequence of the 16-kDa glycoprotein of the wild-type virus. Thus, either one or both of these events may explain the lack of synthesis of the SV40 T antigen specific protein. Ad2+ND3 and Ad2+ND5 share the sequences at the right junction which suggests their origin from a common precursor. Also, the recombination was found to result in the disruption of the poly (A) addition signal of the adenovirus 2 early region III transcripts. All of the junction sequences were found to be rich in A:T base pairs.
RecF and RecBC function during recombination of nonreplicating, UV-irradiated phage lambda DNA and during other recombination processes.
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Relationship between leukopenia and bone marrow myeloperoxidase in the rat treated with propylthiouracil.
The relationship between the toxic effect of propylthiouracil (PTU) and myeloperoxidase activity of rat bone marrow was examined. The administration of PTU for 1 or 2 weeks caused a decrease in leukocyte count with the concomitant inhibition of the activity of myeloperoxidase in the bone marrow. The decreases in both leukocyte counts and myeloperoxidase activity were restored to control levels at 2 weeks after the discontinuation of the administration. PTU treatment did not affect the affinity of H2O2 for the enzyme; however, an increase in the Km value for guaiacol was seen. PTU, incubated with bone marrow peroxidase in vitro increased the Km value of the enzyme for guaiacol, but had no effect on the Km value for H2O2. The results suggest that the mechanism of inhibition of myeloperoxidase activity by PTU given in vivo or incubated with the enzyme in vitro may be the same. The activity of bone marrow glutathione peroxidase was not influenced by PTU treatment.
Enhancement of glutathione S-transferase activity in rat liver by repeated administration of propylthiouracil.
Treatment of rats with propylthiouracil for one to two weeks caused an increase in glutathione S-transferase (GST) activity of the liver cytosol, but not of the particulate fraction. Increased GST activity was reversed two weeks after discontinuing PTU administration. Activation of the enzyme was inversely proportional to the decrease in leukocytes. Repeated administration of PTU increased the Vmax of the enzyme without affecting the Km value for the substrate 1-chloro-2,4-dinitrobenzene, whereas both the Km and Vmax for glutathione (GSH) were increased by PTU treatment. GSH content and GSH peroxidase activity were not affected by PTU, but this resulted in an increase in glucose 6-phosphate dehydrogenase activity. PTU treatment caused increase in GST activity using 1-chloro-2,4-dinitrobenzene, 1,2-dichloro-4-nitrobenzene, p-nitrobenzyl chloride, and benzalacetone as substrates; enzyme activity towards chlorodinitrobenzene was the highest.
Anti-rheumatic drug interactions.
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