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Biomedical subjects

M Otten

Publications and source records attributed to M Otten.

14 recordsLinked to original sources
PubMed1995

Alginate regulatory and biosynthetic gene homologs in Pseudomonas putida WCS358: correlation with the siderophore regulatory gene pfrA.

A previous study [Venturi et al., Mol. Microbiol. 10 (1993) 63-73] demonstrated that the siderophore regulatory gene pfrA of Pseudomonas putida (Pp) WCS358 is highly similar and interchangeable with the alginate regulatory gene algQ (algR2) of P. aeruginosa (Pa). The algQ gene is physically linked to two other alginate regulators in the Pa chromosome, namely algR (algR1), a response regulator, and algP (algR3), a histone-like gene. In this study, we have identified the same genes and a similar genetic organization in the Pp chromosome. The two genes linked to pfrA, designated pprA and pprB, are similar to algR and algP, respectively. Chromosomal mutants of pprA and pprB were constructed showing that unlike pfrA, the two newly identified regulators are not involved in siderophore regulation. The pprA gene complemented a Pa algR mutant phenotype, suggesting that it could be involved in alginate gene regulation. The WCS358 strain is not producing alginate, but we demonstrated by Southern analysis that it also possesses, in addition to pprA and pprB, algD and algU (algT) gene homologs, two genes essential for alginate biosynthesis. Using an algD-xylE transcriptional fusion, we observed that the algD promoter is active in strain WCS358 and absolutely requires pfrA. The possibility that all five genes of Pp WCS358 are involved in alginate biosynthesis is discussed.

Alginates↗
PubMed1984

Influence of thyroid function on theophylline kinetics.

Theophylline kinetics were examined in five patients with hyperthyroidism before and after treatment with carbimazole. Theophylline clearance fell after carbimazole, but the apparent volume of distribution did not change. There was a correlation between reduction in theophylline clearance and decreased thyroxine serum concentration. Data suggest that maximum induction is reached at a specific level of thyroxine beyond which no further increase in drug metabolizing activity takes place. In 15 subjects treated with aminophylline for acute bronchial obstruction, there was a positive correlation between thyroxine concentration and total body theophylline clearance (r = 0.72 for nonsmokers; r = 0.44 for smokers and nonsmokers).

Adult↗
PubMed1983

Increased mortality with cardiotoxic doses of Adriamycin after verapamil pretreatment despite prevention of myocardial calcium accumulation.

The purpose of this investigation was to determine whether the calcium blocking agent, verapamil, could modify Adriamycin cardiotoxicity, and if so, whether or not such modification is mediated by a mechanism involving myocardial electrolyte distribution. The mean survival time of female New Zealand white rabbits administered Adriamycin was reduced by pretreatment with verapamil. Myocardial cellular calcium concentration, [Ca]i, in animals pretreated with verapamil before receiving Adriamycin was lower than in animals receiving Adriamycin alone (1.49 +/- 0.11 vs. 2.22 +/- 0.35 mmol/kg cell water, respectively; P = 0.05). Myocardial [Ca]i in control animals was 1.68 +/- 0.10 mmol/kg cell water. Myocardial [Mg]i in animals receiving Adriamycin alone was lower than that for animals receiving verapamil alone (15.6 +/- 1.4 vs. 19.2 +/- 0.8 mmol/kg cell water, respectively). When these drugs were combined, [Mg]i approached the control value of 17.3 +/- 0.06 mmol/kg cell water. Cellular concentrations of the monovalent electrolytes were little affected by these drugs, except for a reduction of [Cl]i by verapamil. Neither myocardial water distribution nor plasma concentrations of these electrolytes were altered by either drug. The data indicate that verapamil pretreatment increases the mortality associated with Adriamycin in rabbits despite the continued efficacy of verapamil as a Ca-blocking agent after injection of Adriamycin. Particular caution must be exercised if clinical combination of Ca-blocking agents and anthracyclines is contemplated.

Animals↗
PubMed1979

Raised total thyroxine and free thyroxine index but normal free thyroxine. A serum abnormality due to inherited increased affinity of iodothyronines for serum binding protein.

2 people from different families had high levels of serum-thyroxine (T4) and a high free T4 (FT4) index but a normal serum triiodothyronine (T3) and serum-reverse-T3 (rT3). The abnormal serum thyroid hormone profile appeared to be inherited in an autosomal dominant manner. Serum-FT4 in affected relatives was normal. The increases in serum-T4 and FT4 index are explained on the basis of an observed increase in affinity of T4 for thyroxine-binding globulin, thyroxine-binding prealbumin, and albumin. The FT4 index did not reflect the true concentration of circulating free T4 in these cases. Thyroid function in the propositi was normal and the results of T4, T3, and rT3 kinetic studies accorded with increased binding of T4 by serum proteins and normal binding of the other iodo-thyronines. This "euthyroid high total T4, normal T3 syndrome" should be kept in mind during diagnostic evaluation of thyroid function.

Female↗
PubMed1979

Evaluation of ribonucleoside and deoxyribonucleoside triphosphate pools in cultured leukemia cells during exposure to methotrexate or methotrexate plus thymidine.

Continuous exposure to inhibitory concentrations of methotrexate produces distinct rates of steady-state growth of murine leukemia L1210 and human leukemia CCRF-CEM cells in culture. Addition of thymidine to the medium produces reversal (6 to 40%) of this steady-state growth rate inhibition. This study utilized combinations of methotrexate and thymidine for an evaluation of the accompanying relationship between steady-state growth rate and changes in the ribo- and deoxyribonucleoside triphosphate pools. In L1210 cells exposed to methotrexate alone, the deoxythymidine 5'-phosphate (dTTP) pools decreased, whereas deoxyadenosine 5'-triphosphate, deoxyguanosine 5'-triphosphate, and deoxycytidine 5'-triphosphate (dCTP) remained relatively constant up to 70% inhibition of growth rate, with dCTP at a constant 112% of controls. The corresponding ribonucleoside triphosphates decreased only slightly. With the combination of methotrexate and thymidine resulting in up to 40% inhibition of growth rate, there was also a decrease in the dTTP pool while the other deoxyribonucleoside triphosphates remained relatively constant, and the corresponding ribonucleoside triphosphates again decreased only slightly. The dCTP pool was reduced to a constant 42% of control comparable to that produced by thymidine alone. With greater than 40% (with thymidine) or 70% (without thymidine) inhibition of growth rate, all pools decreased, but only dTTP was substantially reduced in proportion to the growth rate inhibition caused by methotrexate. The dTTP pool became depleted in spite of the presence of exogenous thymidine. Evaluation of CCRF-CEM cells indicated that inhibition of growth rate and nucleotide pool perturbations by methotrexate were similar to those observed in L1210 cells. However, in the presence of thymidine, inhibition of growth rate appeared related to decreased pools of dCTP, deoxyadenosine 5'-triphosphate, and deoxyguanosine 5'-triphosphate, rather than dTTP as was observed for L1210 cells. Hence, mammalian cells were capable of responding in a differential fashion to pharmacological perturbations, and this capacity may play a role in determining therapeutic selectivity. Since the ribonucleoside triphosphate decreases were slight and relatively uniform during methotrexate-induced perturbations, the deoxyribonucleoside triphosphate pools appear to be more directly related to inhibition of growth rate. The results are consistent with the concept that slight imbalances in the deoxyribonucleoside triphosphate pools dramatically inhibit DNA synthesis, as mediated through their interaction with DNA polymerase.

Animals↗
PubMed1979

Isolation of a DNA polymerase alpha-associated regulatory protein from calf thymus.

A regulatory protein for DNA polymerase alpha, responsive to noncomplementary deoxyribonucleoside triphosphates, has been isolated from calf thymus. The regulatory protein was separated from DNA polymerase alpha using Affi-Gel Blue and gel filtration. The regulatory protein had a molecular weight of approximately 70,000 as determined by gel filtration, and its activity was nondialyzable, heat labile, and abolished by pronase treatment. In the presence of regulatory protein, DNA polymerase alpha activity, measured by using polydeoxyadenylate-oligodeoxythymidylate as template primer, was inhibited by 2'-deoxyguanosine 5'-triphosphate in a parabolic-competitive fashion [Ki = 15 +/- 1 (S.E.) microM] and by 2'-deoxycytidine 5'-triphosphate in a linear-competitive manner (Ki = 162 +/- 23 microM). Neither the four natural ribonucleoside triphosphates nor 2'-deoxyadenosine 5'-triphosphate inhibited the DNA polymerase-regulatory protein system to any significant extent. The regulatory protein by itself had no effect on either DNA polymerase alpha activity or the Km for template primer. These results indicate that deoxyribonucleoside triphosphate pools may be involved in the regulation of cellular DNA synthesis through a direct effect on DNA polymerization.

Animals↗
PubMed1975

The effect of dieldrin-contaminated feed on rat hepatic microsomal epoxide hydrase and aryl hydrocarbon hydroxylase.

Adult male rats were exposed to dieldrin-contaminated rations. The hydroxylation of benzpyrene (AHH) and hydration of styrene oxide (EH) by the hepatic microsomal fraction were followed. At dieldrin levels of 5 to 25 ppm for one week, the EH activity increased from 19% to 115% above control levels respectively. Animals exposed to 25 ppm developed elevated EH activities after a few days, with a maximum increase of 2.5 times control levels after two weeks. AHH activity was not elevated over control levels at any dose or time studied. Slight but significant increases in levels of cytochrome P-450 were observed. Pentobartibal sleeping time was decreased to 61% of control levels after exposure to 20 ppm dieldrin-contaminated food for 7 days. Two days of intraperitoneal administration of technical grade dieldrin, analytical grade dieldrin and analytical grade aldrin gave similar increases in EH activity within this group. Again, no changes in AHH activity were seen.

Aldrin↗
PubMedDate not supplied

Induction of hepatic aryl hydrocarbon hydroxylase and epoxide hydrase in Wistar rats pretreated with oral methadone hydrochloride.

Methadone-HCl added to the drinking water of adult female Wistar rats for 4 weeks produced an increase in the aryl hydrocarbon hydroxylase activity of the hepatic microsomal fraction to 222% of control levels. No change was seen in epoxide hydrase activity. In contrast, when male rats were treated similarly, there was an increase in epoxide hydrase activity to 212% of controls with no change in aryl hydrocarbon hydroxylase activity. No such changes were observed when the subcutaneous route of administration or chronic, low-dose, intraperitoneal injections were used. There were no differences in hepatic cytochrome P-450 or protein concentrations in treated animals as compared to their respective control groups. Control studies were carried out with quinine sulfate in the drinking water to decrease water intake to the level of the methadone-treated group. No elevation in either enzyme activity occurred in this control group. Similarly, paired-feeding studies showed the elevation of enzyme activity to be due to the methadone, not food deprivation. The effects of concurrent therapy of methadone with phenobarbital sodium or 3-methylcholanthrene were compared.

Administration, Oral↗