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Biomedical subjects

J B Cologne

Publications and source records attributed to J B Cologne.

At least 19 recordsLinked to original sources
PubMed1998

Lifespan of human memory T-cells in the absence of T-cell receptor expression.

To evaluate the intrinsic lifespan of human memory T-cells in the absence of T-cell receptor signaling, we used radiation-induced mutant CD4+ T-cells lacking surface expression of TCR/CD3 complex as an in vivo cell marker. We analyzed the long-term kinetics of TCR/CD3 - mutant T-cells among CD4+ CD45RA+ naive and CD4+ CD45RA- memory T-cell fractions in peripheral blood of gynecological cancer patients receiving radiotherapy. Both the proportion and number of these mutant T-cells decayed exponentially with time following radiotherapy. The estimated half-life of mutant memory T-cells was 2 to 3 years and did not differ from that of mutant naive T-cells. These results indicate that the lifespan of mature CD4+ T-cells is limited regardless of their memory or naive phenotype in the absence of TCR/CD3 expression. This finding may suggest that continued T-cell receptor signaling is required for lifetime maintenance of human memory T-cells.

Adult↗
PubMed1998

Statistical issues in biological radiation dosimetry for risk assessment using stable chromosome aberrations.

Biological dosimeters are useful for epidemiologic risk assessment in populations exposed to catastrophic nuclear events and as a means of validating physical dosimetry in radiation workers. Application requires knowledge of the magnitude of uncertainty in the biological dose estimates and an understanding of potential statistical pitfalls arising from their use. This paper describes the statistical aspects of biological dosimetry in general and presents a detailed analysis in the specific case of dosimetry for risk assessment using stable chromosome aberration frequency. Biological dose estimates may be obtained from a dose-response curve, but negative estimates can result and adjustment must be made for regression bias due to imprecise estimation when the estimates are used in regression analyses. Posterior-mean estimates, derived as the mean of the distribution of true doses compatible with a given value of the biological endpoint, have several desirable properties: they are nonnegative, less sensitive to extreme skewness in the true dose distribution, and implicitly adjusted to avoid regression bias. The methods necessitate approximating the true-dose distribution in the population in which biological dosimetry is being applied, which calls for careful consideration of this distribution through other information. An important question addressed here is to what extent the methods are robust to misspecification of this distribution, because in many applications of biological dosimetry it cannot be characterized well. The findings suggest that dosimetry based solely on stable chromosome aberration frequency may be useful for population-based risk assessment.

Calibration↗
PubMed1996

Monitoring exposure to atomic bomb radiation by somatic mutation.

Atomic bomb survivors are a population suitable for studying the relationship between somatic mutation and cancer risk because their exposure doses are relatively well known and their dose responses in terms of cancer risk have also been thoroughly studied. An analysis has been made of erythrocyte glycophorin A (GPA) gene mutations in 1,226 atomic bomb survivors in Hiroshima and Nagasaki. The GPA mutation frequency (Mf) increased slightly but significantly with age at the time of measurement and with the number of cigarettes smoked. After adjustment for the effect of smoking, the Mf was significantly higher in males than in females and higher in Hiroshima than in Nagasaki. All of these characteristics of the background GPA Mf were in accord with those of solid tumor incidence obtained from an earlier epidemiological study of A-bomb survivors. Analysis of the dose effect on Mf revealed the doubling dose to be about 1.20 Sv and the minimum dose for detection of a significant increase to be about 0.24 Sv. No significant dose effect for difference in sex, city, or age at the time of bombing was observed. Interestingly, the doubling dose for the GPA Mf approximated that for solid cancer incidence (1.59 Sv). And the minimum dose for detection was not inconsistent with the data for solid cancer incidence. The dose effect was significantly higher in those diagnosed with cancer before or after measurement than in those without a history of cancer. These findings are consistent with the hypothesis that somatic mutations are the main cause of excess cancer risk from radiation exposure.

Adult↗
PubMed1996

Somatic cell mutations at the glycophorin A locus in erythrocytes of atomic bomb survivors: implications for radiation carcinogenesis.

To clarify the relationship between somatic cell mutations and radiation exposure, the frequency of hemizygous mutant erythrocytes at the glycophorin A (GPA) locus was measured by flow cytometry for 1,226 heterozygous atomic bomb (A-bomb) survivors in Hiroshima and Nagasaki. For statistical analysis, both GPA mutant frequency and radiation dose were log-transformed to normalize skewed distributions of these variables. The GPA mutant frequency increased slightly but significantly with age at testing and with the number of cigarettes smoked. Also, mutant frequency was significantly higher in males than in females even with adjustment for smoking and was higher in Hiroshima than in Nagasaki. These characteristics of background GPA mutant frequency are qualitatively similar to those of background solid cancer incidence or mortality obtained from previous epidemiological studies of survivors. An analysis of the mutant frequency dose response using a descriptive model showed that the doubling dose is about 1.20 Sv [95% confidence interval (CI): 0.95-1.56], whereas the minimum dose for detecting a significant increase in mutant frequency is about 0.24 Sv (95% CI: 0.041-0.51). No significant effects of sex, city or age at the time of exposure on the dose response were detected. Interestingly, the doubling dose of the GPA mutant frequency was similar to that of solid cancer incidence in A-bomb survivors. This observation is in line with the hypothesis that radiation-induced somatic cell mutations are the major cause of excess cancer risk after radiation exposure. Furthermore, the dose response was significantly higher in persons previously or subsequently diagnosed with cancer than in cancer-free individuals. This may suggest an earlier onset of cancer due to elevated mutant frequency or a higher radiation sensitivity in the cancer group, although the possibility of dosimetry errors should be considered. The findings obtained in the present study suggest that the GPA mutant frequency may reflect the cancer risk among people exposed to radiation.

Adult↗
PubMed1995

Effect of radiation and cigarette smoking on expression of FUdR-inducible common fragile sites in human peripheral lymphocytes.

In vitro X-irradiation of human peripheral blood lymphocytes increased the frequencies of fluorodeoxyuridine-induced fragile sites in a dose-related manner. However, the cells from 30 atomic bomb survivors exposed to either high or low radiation doses 47 years earlier showed no demonstrable difference in fragile site expression, indicating that fragile site induction was ephemeral in nature. When fragile sites were analyzed on the basis of tobacco smoking habits, an elevated number was observed in the smokers. The results confirm that fragile sites can be affected by recent exposure to exogenous agents, but the effect is probably of limited duration, based on the atomic bomb survivor experience.

Aged↗
PubMed1995

Optimal case-control matching in practice.

We illustrate modern matching techniques and discuss practical issues in defining the closeness of matching for retrospective case-control designs (in which the pool of subjects already exists when the study commences). We empirically compare matching on a balancing score, analogous to the propensity score for treated/control matching, with matching on a weighted distance measure. Although both methods in principle produce balance between cases and controls in the marginal distributions of the matching covariates, the weighted distance measure provides better balance in practice because the balancing score can be poorly estimated. We emphasize the use of optimal matching based on efficient network algorithms. An illustration is based on the design of a case-control study of hepatitis B virus infection as a possible confounder and/or effect modifier of radiation-related primary liver cancer in atomic bomb survivors.

Adult↗
PubMed1994

Nonparametric regression analysis of data from the Ames mutagenicity assay.

The Ames assay has received widespread attention from statisticians because of its popularity and importance to risk assessment. However, investigators have yet to routinely apply modern regression methods that have been available for more than a decade. We study yet another approach, the application of nonparametric regression techniques, not as the ultimate solution but rather as a framework within which to address some of the shortcomings of other methods. But nonparametric regression is itself prone to difficulties when applied to Ames assay data, as we show through the use of two examples and some simulation studies. We argue that there remains a great need for further development of statistical methods suitable to the Ames assay. It is hoped that such work can be stimulated and guided by greater collaboration between statisticians and laboratory investigators.

Bias↗
PubMed1993

Application of generalized estimating equations to a study of in vitro radiation sensitivity.

We describe an application of the generalized estimating equation (GEE) method (Liang and Zeger, 1986, Biometrika 73, 13-22) for regression analysis of correlated Poisson data from a split-plot design with a small number of experimental units. As an alternative to the use of an arbitrarily chosen working correlation matrix, we demonstrate the use of GEE with a reasonable model for the true covariance structure among repeated observations within individuals. We show that, under such a split-plot design with large clusters, the asymptotic relative efficiency of GEE with simple (independence or exchangeable) working correlation matrices is rather low. We conclude by summarizing issues and needs for further work concerning efficiency of the GEE parameter estimates in practice.

Biometry↗
PubMed1993

Study of the titers of anti-Epstein-Barr virus antibodies in the sera of atomic bomb survivors.

Antibody titers to Epstein-Barr virus antigens were determined in the sera of 372 atomic bomb survivors to evaluate the effect of the previous radiation exposure on immune competence against the latent infection of the virus. The proportion of persons with high titers (> or = 1:40) of IgG antibodies to the early antigen was significantly elevated in the exposed survivors. Furthermore, the distribution of IgM titers against the viral capsid antigen was significantly affected by radiation dose with an increased occurrence of titers of 1:5 and 1:10 in the exposed persons, although the dose effect was only marginally suggestive when persons with rheumatoid factor were eliminated from the analysis. These results suggest that reactivation of Epstein-Barr virus in the latent stage occurs more frequently in the survivors, even though this might not be affected by the radiation dose. Otherwise, there was neither an increased trend in the prevalence of high titers (> or = 1:640) of IgG antibodies to the viral capsid antigen among the exposed people nor a correlation between the radiation exposure and distributions of titers of IgA antibodies to the viral capsid antigen or antibodies to the anti-Epstein-Barr virus-associated nuclear antigen.

Adult↗
PubMed1993

Radiosensitivity of atomic bomb survivors as determined with a micronucleus assay.

If A-bomb survivors include a disproportionately large number of either radioresistant or radiosensitive persons, the surviving population would provide a biased estimate of the true risk of radiogenic cancer. To test this hypothesis, the in vitro X-ray sensitivities of peripheral blood lymphocytes obtained from 937 A-bomb survivors were measured with a cytokinesis-blocking micronucleus assay. Background frequencies (no irradiation in vitro) of micronuclei show a wide distribution. Frequencies in both males and females tend to increase with increasing donor age. Frequencies in females are significantly higher than those in males. Donor age decreases the sensitivity of lymphocytes to in vitro X-ray exposure at a rate of about 0.001 micronuclei per cell per year per gray. There is no effect of donors' sex on in vitro radiation sensitivity. Atomic bomb radiation and cigarette smoking had no significant effect on background and X-ray-induced micronuclei frequencies. Thus there is no difference in radiosensitivity of peripheral blood lymphocytes between proximally and distally exposed survivors.

Age Factors↗
PubMed1992

Development of a flow-cytometric HLA-A locus mutation assay for human peripheral blood lymphocytes.

A flow-cytometric technique was developed to measure the frequency of variant lymphocytes lacking expression of HLA-A2 or A24 allele products among donors heterozygous for HLA-A2 or A24. It was found that the variant frequency of lymphocytes in peripheral blood was of the order of 10(-4) and increased with donor age. Molecular analyses of mutant clones revealed that about one-third were derived from somatic recombinations and that the remaining two-thirds did not show any alterations after Southern blotting analysis. In contrast, mutants obtained after in vitro X-ray mutagenesis study were found to be mostly derived from large chromosomal deletions. A small-scale study on atomic bomb survivors did not show a significant dose effect.

Adult↗
PubMed1992

X-ray induction of micronuclei in human lymphocyte subpopulations differentiated by immunoperoxidase staining.

In this study we sought to confirm the radiosensitivity of human peripheral blood lymphocyte subpopulations using a micronucleus assay. Mononucleated cells isolated from peripheral blood were irradiated with X rays. After being cultured for 3 days, cells were fixed and stained using the immunoperoxidase staining technique. Lymphocyte subpopulations were characterized by means of the monoclonal antibodies Leu4 (CD3), Leu2a (CD8) and Leu19 (CD56). Dose-response curves were obtained by scoring the number of micronuclei in binucleated cells that reacted with a specific antibody and were then stained. The dose response of CD8+ (suppressor/cytotoxic) cells was quite similar to that of CD3+ (pan T) cells. In comparison, CD56+ (natural killer) cells were significantly less sensitive, although scorable binucleated CD56+ cells made up less than 4% of the total number of binucleated cells.

Adult↗
PubMed1991

Flow cytometric measurements of somatic cell mutations in Thorotrast patients.

Exposure to ionizing radiation has long been well-recognized as a risk factor for cancer development. Since ionizing radiation can induce mutations, an accurate way of measuring somatic mutation frequencies could be a useful tool for evaluating cancer risks. In the present study, we have examined in vivo somatic mutation frequencies at the erythrocyte glycophorin A (GPA) and T-cell receptor (TCR) loci in 18 Thorotrast patients who have been continuously irradiated with alpha-particles emitted from the internal deposition of thorium dioxide and who thus have increased risks of certain malignant tumors. When compared with controls, the results showed a significantly higher frequency of mutants at the lymphocyte TCR loci but not at the erythrocyte GPA loci in the Thorotrast patients. The discrepancy between the results of the two assays is discussed.

Aged↗
PubMed1991

Gamma-ray- and fission neutron-induced micronuclei in PHA stimulated and unstimulated human lymphocytes.

Two groups of normal human blood cells, one stimulated with phytohaemagglutinin (PHA) for 24 hr (G1-S phase of the cell cycle) and one unstimulated (G0 phase), were irradiated with 60Co gamma rays or 252Cf radiation. A comparison of radiation-induced micronucleus frequencies showed that the high-dose-rate gamma rays were more effective in inducing micronuclei than low-dose-rate gamma rays. In the cells exposed to low-dose-rate irradiation, there was little difference between the frequency of micronuclei in the G0 phase and the G1-S phase. However, cells in the G1-S phase were more sensitive than G0-phase cells to high-dose-rate gamma rays. The relative biological effectiveness of 252Cf neutron irradiation measured in micronucleus assays was consistent with the value obtained for the lethal effect of 252Cf on cultured cells.

Adult↗
PubMed1989

Statistical comparison of ligand-binding kinetics.

We describe the application of generalized linear model methodology to the problem of testing differences among ligand-receptor interactions, and show that the method is analogous to weighted least squares regression methodology and F tests familiar to many investigators. The method accommodates incomplete block designs so that one can obtain kinetic parameter estimates directly comparable among samples analysed on incompletely overlapping sets of experimental runs. We demonstrate the method with data that compare saturation kinetics for a single penicillin-binding protein in isogenic ampicillin susceptible and resistant bacteria.

Ampicillin Resistance↗
PubMed1986

Comparison of isotonic and hypertonic fluids in resuscitation from hypovolemic shock.

Hypertonic electrolyte solutions provide effective fluids for resuscitation of burn patients and concurrent replacement of hemorrhage. Infusion of mannitol has also been advocated as a means of increasing cardiac output in acutely ill patients. Pigs which were bled to one-third of their blood volume were used in this random study of resuscitation with Ringer's lactate solution (RL), hypertonic saline solution (HSL) and RL with mannitol added (HMR) to give the same osmolality as HSL. Smaller volumes of the hyposmolar solution than of RL restored blood pressure and cardiac output. RL and HSL restored and maintained cardiac output more effectively than HMR. At 24 hours, HSL maintained blood pressure most effectively.

Animals↗