scholarly journals Stage specificity, dose response, and doubling dose for mouse minisatellite germ-line mutation induced by acute radiation

1998 ◽  
Vol 95 (11) ◽  
pp. 6251-6255 ◽  
Author(s):  
Y. E. Dubrova ◽  
M. Plumb ◽  
J. Brown ◽  
J. Fennelly ◽  
P. Bois ◽  
...  
Keyword(s):  
Dose Response ◽  
Germ Line ◽  
Acute Radiation ◽  
Doubling Dose ◽  
Stage Specificity ◽  
Germ Line Mutation

Improved 125I radioimmunoassay for cotinine by selective removal of bridge antibodies.

1985 ◽  
Vol 31 (1) ◽  
pp. 118-121 ◽  
Author(s):  
G J Knight ◽  
P Wylie ◽  
M S Holman ◽  
J E Haddow
Keyword(s):  
Chemical Bond ◽  
Dose Response ◽  
Response Curve ◽  
Selective Removal ◽  
Major Metabolite ◽  
Dose Response Curve ◽  
Carrier Protein ◽  
Doubling Dose

Abstract We describe an 125I-based RIA for cotinine, the major metabolite of nicotine. The slope of the dose-response curve was quite shallow (6-8% change in binding per doubling dose), resulting in between-assay CVs of 15 to 20%. This effect occurred because the radioligand formed by linking a cotinine derivative to tyramine manifested greater affinity for the anti-cotinine antibodies than did cotinine itself. We absorbed the serum with a derivative of nicotine coupled to the carrier protein via a chemical bridge similar to that used to form the cotinine/carrier protein immunogen. An RIA in which we used such absorbed serum showed a significantly increased slope of the dose-response curve (11-13% change in binding per doubling dose), and between-assay CVS were only 6 to 8%. We suggest that this improvement results because absorption removes anti-bridge antibodies directed against the chemical-bond common to the cotinine/carrier-protein immunogen and to the cotinine/tyramine radioligand.

Effect of Sodium-Transport Inhibitors on Bronchial Reactivity in Vivo

1990 ◽  
Vol 79 (4) ◽  
pp. 325-330 ◽  
Author(s):  
Alan J. Knox ◽  
John R. Britton ◽  
Anne E. Tattersfield
Keyword(s):  
Confidence Intervals ◽  
Sodium Transport ◽  
Geometric Mean ◽  
Normal Subjects ◽  
Bronchial Reactivity ◽  
Mean Values ◽  
Doubling Dose ◽  
The Difference

1. We have recently shown that ouabain, an inhibitor of Na+/K+-adenosine triphosphatase, causes contraction of bovine and human airways in vitro, and that amiloride causes relaxation and inhibits receptor-operated contraction in bovine trachealis. 2. To determine whether such drugs alter bronchial reactivity in vivo, we have studied the effect of oral digoxin (an inhibitor of Na+/K+-adenosine triphosphatase) and oral and inhaled amiloride on bronchial reactivity to histamine in three double-blind, placebo-controlled studies. 3. Histamine reactivity was measured as the provocative dose causing a 20% reduction in the forced expiratory volume in 1 s (PD20FEV1) or, when normal subjects were included, the provocative dose causing a 35% reduction in the specific airways conductance (PD35sGaw); the results are given as geometric mean values. 4. In study 1, 13 atopic asthmatic subjects were given 20 mg of oral amiloride or placebo on separate days. Two hours after the drug, the geometric mean PD20FEV1 for histamine was 0.43 μmol after amiloride and 0.54 μmol after placebo (95% confidence intervals for the difference: 0.9 to −0.2 doubling doses of histamine; P = 0.2). 5. In study 2, six normal and 24 atopic asthmatic men inhaled 10 ml of 10−2 mol/l amiloride or diluent control in a crossover study. The mean values of PD35sGaw for histamine immediately after inhalation of amiloride and placebo were 3.0 μmol and 4.3 μmol, respectively, in the normal subjects (95% confidence intervals for the difference: −0.53 to 1.52 doubling doses, P = 0.2), and 0.33 μmol and 0.29 μmol in the asthmatic subjects (95% confidence intervals for the difference: −0.95 to 0.57 doubling doses; P = 0.6). 6. In study 3, 24 atopic asthmatic men were treated for 7 days with placebo or oral digoxin (1.5 mg loading dose plus 0.25 mg twice daily for 6 days). The PD20FEV1 for histamine was measured before, 12 h after the loading dose and on day 7 of treatment. The change in PD20FEV1 did not differ significantly after digoxin and placebo, after either 1 day's treatment [mean (95% confidence intervals) difference: 0.56 doubling dose (−0.37 to 1.5 doubling dose)] or 7 day's treatment [mean (95% confidence intervals) difference: 0.3 doubling dose (−1.23 to 1.8 doubling doses)]. 7. Although our work in vitro has suggested that membrane sodium transport may play an important role in determining airway smooth muscle contractility, we have been unable to demonstrate any effect of the sodium-transport inhibitors amiloride and digoxin on histamine reactivity in these studies.

The rate of spontaneous sex-linked mutations and the doubling dose in man

1960 ◽  
Vol 24 (4) ◽  
pp. 367-374 ◽  
Author(s):  
O. FROTA-PESSOA ◽  
P. H. SALDANHA
Keyword(s):  
Doubling Dose

Implications of the Hiroshima–Nagasaki genetic studies for the estimation of the human "doubling dose" of radiation

Genome ◽  
1989 ◽  
Vol 31 (2) ◽  
pp. 853-859 ◽  
Author(s):  
J. V. Neel ◽  
W. J. Schull ◽  
A. A. Awa ◽  
C. Satoh ◽  
M. Otake ◽  
...  
Keyword(s):  
Chromosomal Abnormalities ◽  
Chromosomal Rearrangements ◽  
Genetic Effect ◽  
Genetic Effects ◽  
Physical Growth ◽  
Genetic Studies ◽  
Doubling Dose ◽  
The Difference ◽  
Effects Of Radiation ◽  
Dose Radiation

Since 1946 a continuous effort to evaluate the potential genetic effects of the atomic bombs has been sustained. Observations on children born in Hiroshima and Nagasaki include sex ratio, congenital malformations, stillbirths, survival of liveborn infants, chromosomal abnormalities (sex chromosomal abnormalities and balanced chromosomal rearrangements), mutations altering protein structure or activity, and physical growth and development. There are no statistically significant differences between the children of parents who received increased amounts of radiation at the time of the bombings and those whose parents did not. However, the difference between the two sets of children is consistent with the hypothesis of a genetic effect of the exposure, but its magnitude suggests humans are not as sensitive to the genetic effects of radiation as projected from the mouse paradigm.Key words: Hiroshima–Nagasaki, genetic doubling dose, radiation.

Possible interaction between exposure to environmental tobacco smoke and therapy in children with asthma

1998 ◽  
Vol 95 (2) ◽  
pp. 143-149 ◽  
Author(s):  
Jean-Christophe DUBUS ◽  
Christiane ODDOZE ◽  
Monique BADIER ◽  
Chantal GUILLOT ◽  
Bernard BRUGUEROLLE
Keyword(s):  
Environmental Tobacco Smoke ◽  
Tobacco Smoke ◽  
Fold Increase ◽  
Bronchial Reactivity ◽  
Urinary Cotinine ◽  
Bronchodilator Response ◽  
Doubling Dose ◽  
Children With Asthma ◽  
Anti Inflammatory ◽  
The Difference

1.The aim of the study was to determine the carbachol and albuterol responsiveness in treated and untreated asthmatic and allergic children exposed to environmental tobacco smoke assessed by urinary cotinine measurements. 2.Forty-six asthmatic and allergic children with normal spirometric values were recruited. The doubling dose, concentration of carbachol producing a 2-fold increase in specific airway resistance (SRaw) was determined and 200 ;μg of albuterol were administered via a Volumatic® spacer. The percentage of bronchodilatation was defined as the difference between the largest obtained SRaw and the post-β2 SRaw divided by the largest SRaw. Data were compared by a Mann–Whitney U-test. 3.The 23 children with a high urinary cotinine, compared with the 23 children without urinary cotinine, had a decreased doubling dose (108.2±14.7 ;μg versus 160.9±19.5 ;μg; P = 0.04) and an increased percentage of bronchodilatation (74.8±1.4% versus 68.8±1.8%; P = 0.03). A prophylactic anti-inflammatory treatment induced a weaker bronchial reactivity to carbachol and a slightly greater bronchodilatation in children exposed to environmental tobacco smoke. 4.Environmental tobacco smoke increases bronchial reactivity in asthmatic and allergic children. This effect might be reduced by anti-inflammatory therapy. The bronchodilator response may be enhanced in exposed children and may be caused by one or several direct interactions between tobacco smoke compounds and albuterol.

Risk estimation based on germ-cell mutations in animals

Genome ◽  
1989 ◽  
Vol 31 (2) ◽  
pp. 844-852 ◽  
Author(s):  
Jack Favor
Keyword(s):  
Enzyme Activity ◽  
Germ Cell ◽  
Gene Product ◽  
Mutation Rate ◽  
Genetic Risk ◽  
Mutation Rates ◽  
Protein Charge ◽  
Doubling Dose ◽  
Dna Alterations ◽  
Specific Locus

The set of mouse germ cell mutation rate results following spermatogonial exposure to high dose rate irradiation have been presented as the most relevant experimental results upon which to extrapolate the expected genetic risk of offspring of the survivors of the Hiroshima and Nagasaki atomic bombings. Results include mutation rates to recessive specific-locus, dominant cataract, protein-charge, and enzyme-activity alleles. The mutability as determined by the various genetic end points differed: the mutation rates to recessive specific-locus alleles and enzyme-activity alleles were similar and greater than the mutation rates to dominant cataract and protein-charge alleles. It is argued that the type of mutation event scored by a particular test will determine the mutability of the genetic end point screened. When the loss of functional gene product can be scored in a particular mutation test, as in the recessive specific-locus and enzyme-activity tests, a wide spectrum of DNA alterations may result in a loss and a higher mutation rate is observed. When an altered gene product is scored, as in the dominant cataract and protein-charge tests, a narrower spectrum of DNA alterations is screened and a lower mutation rate is observed. The radiation doubling dose, defined as the dose that induces as many mutations as occur spontaneously per generation, was shown to be four times higher in the dominant cataract test than the specific-locus test. These results indicate that to extrapolate to genetic risks in humans using the doubling-dose method, the extrapolation must be based on experimental mutation rate results for the same genetic end point. Alternatively, the extrapolation could employ the direct-approach procedures. Finally, a direct comparison of the irradiation-induced mutation rate to enzyme-activity alleles in mouse and man indicates no species differences.Key words: ethylnitrosourea, irradiation, mammalian mutagenesis, mouse, dominant cataract mutations, specific-locus mutations, protein-charge mutations, enzyme-activity mutations, doubling dose, human genetic risk.

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