Biomedical subjects
Publications and source records attributed to J Kiefer.
After a short historical survey on the foundation of the scientific association of Erfurt at 1754 some famous gynaecologists and obstetricians as members of this academy are being described. In this way the development of obstetrics and gynaecology and the relations between historical base, medical specialization and personalities are illustrated, too.
For a quantitative interpretation of biological heavy ion action the following parameters have to be taken into account: variations of energy depositions in microscopical sites, the dependence of primary lesion formation on local energy density and changes in reparability. They can be studied in objects of different size and with different sensitivities. Results on survival and mutation induction in yeast and in mammalian cells will be compared with theoretical predictions. It is shown that shouldered survival curves of diploid yeast can be adequately described if the final slope is adjusted according to the varying production of primary lesions. This is not the case for mammalian cells where the experiments show a rapid loss of the shoulder with LET, contrary to theoretical expectations. This behaviour is interpreted to mean that the reparability of heavy ion lesions is different in the two systems. Mutation induction is theoretically expected to decrease with higher LET. This is found in yeast but not in mammalian cells where it actually increases. These results suggest a higher rate of misrepair in mammalian cells.
The energy deposition in ion tracks as a function of radial distance is calculated on the basis of classical collision dynamics and using empirical range-energy relationships for electrons. The calculations show that the energy density (i.e. energy deposited per unit mass) varies according to an inverse-square function with distance from the track centre. The maximum extension, the 'penumbra radius', is a power function of the ion's kinetic energy divided by its mass. Comparison with experimental data demonstrates the applicability of the model for ion specific energies greater than 1 MeVu-1.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
The inhibition of recovery from potentially lethal damage and the influence of mutation induction by lactate, pyruvate, novobiocin, and nalidixic acid was studied in the stationary phase of Chinese hamster V79 A cells. Lactate and pyruvate were selected to elucidate their possible involvement in the inhibition of recovery from PLD since high levels of lactate and pyruvate accumulate due to increased aerobic and anaerobic glycolysis in tumours. Effects of novobiocin and nalidixic acid were also studied to elucidate the possible role of an enzyme similar to DNA gyrase in the potentially lethal damage recovery of V79 cells. The inhibition of recovery depends on drug concentration and is complete with 20 mM of lactate and pyruvate and 20 microM of nalidixic acid and novobiocin. The chemicals seem to interfere with an early step in the recovery process. Incubation with novobiocin in a post-irradiation period does not change the mutation frequency significantly whereas lactate and pyruvate demonstrate a slight increase. Cells incubated with nalidixic acid showed a significant increase in mutation frequency at 24 h post-irradiation recovery time.
X-ray induced potentially lethal damage and its inhibition by the aromatic amide 3-aminobenzamide have been investigated in Chinese hamster V79 cells. 3-Aminobenzamide (3-AB) is a known inhibitor of polyadenosine diphosphoribose synthetase. With increasing concentrations of 3-AB an increasing inhibition of PLD repair was observed. Little inhibition of PLD repair was seen when 3-AB was added 3 h following irradiation. Utilizing the 6-thioguanine mutation assay, the effect of poly(ADP-R) synthetase inhibition under conditions of PLD repair upon mutation frequency were also studied. A large increase in mutation frequency following 24 h post-irradiation recovery in the presence of 3-AB was seen. These results favour a possible role of 3-AB in preventing repair by facilitating early damage fixation before repair can occur, simultaneously reducing G2-arrest.
The biological effects of irradiation with ions of masses larger than 40 and energies up to 20 MeV per atomic mass unit are reviewed. The objects are viruses, bacterial spores, yeast and mammalian cells. Experimental parameters include loss of colony forming ability, induction of mutants, chromosomal aberrations, cell cycle progression, inhibition of biochemical activities and the formation of strand breaks. Some of the pertinent physical questions--e.g. track structure--are also discussed. It is shown that with very heavy ions the biological effectiveness is no longer unambiguously related to a single parameter like l.e.t. or Z*2/beta 2 but depends strongly on ion energy. This points to the importance of far-reaching delta-electrons. The analysis indicates also that even with very high l.e.t., cells are not killed by the passage of a single particle through their nucleus. Possible implications of the findings for fundamental radiation biology are outlined.
No oxygen effect is found if X-ray-induced inhibition of ribosomal RNA synthesis in yeast is assessed immediately after exposure. A 20-h liquid holding period, however, leads to a differential recovery in diploid cells which is markedly greater after irradiation in nitrogen. Haploid yeast exhibits a much smaller recovery and does not show any significant difference between exposures in air or nitrogen.
Explore the source record for details and available documents.
Cell cycle parameters in different radiation-sensitive strains of diploid yeast were determined by flow cytofluorometry. The cell generation time was increased in homozygous rad2 and rad51 mutants but was not significantly different from the wild type in rad9 and rad6 mutants. All mutants had a longer G1-phase than the wild type. A lengthened S-phase was found in rad2 cells. Rad51 mutants displayed a considerably longer duration of G2.
Current analyses of heavy ion action assume that the survival probability of a cell hit by a heavy ion depends only on the energy absorbed in its critical site. It is known, however, that the efficiency to produce a biological effect depends also on the spatial pattern of energy deposition. This has to be included in the quantitative evaluation of heavy ion action. Based on recent models of lesion formation by ionizing radiation (Goodhead and Brenner, Phys. Med. Biol. 28, 485, 1983) data with lighter ions (LET < 500 keV/micrometer) were re-analysed. It is shown that the behaviour of various cell systems can be described by a common curve which can be used to estimate the contribution of "non-linear" components (i.e. where the distribution of energy deposition plays a role) with heavy ions. It is concluded that even with Uranium ions the regions of non-linear effects does not extend beyond 50 nm from the trade core. These data will be used to assess quantitatively survival curves obtained with very heavy ion exposure.
Survival of a diploid and a haploid wild type and a radiation-sensitive rad52-mutant was investigated after exposure to accelerated ions in the presence or absence of oxygen. Ar, Kr, Xe, Sm, Pb and U ions were used with specific energies between 0.3 and 12 MeV/u. The results demonstrate that the oxygen enhancement ratios (o.e.r.) do not only depend on LET or Z*2/beta 2 but even more so on ion specific energy. The o.e.r.s are always higher with greater E/m values pointing to the importance of delta-electron action.
The effects of ionizing radiations on transcriptional activity were studied in the diploid yeast Saccharomyces cerevisiae. As experimental indicator the synthesis of ribosomal RNA (r-RNA) was measured for 1 h after exposure of cells to gamma-rays, X-rays or alpha-particles. gamma- or X-ray induced transcription inhibition was always found to decrease exponentially with dose. D0 values of 2150 or 1950 Gy were determined in wild-type cells, corresponding to a mean energy of about 60 eV per r-RNA gene. The finding of differential sensitivities of the two high molecular-weight r-RNA species which are cotranscribed from r-DNA is compatible with the existence of a transcription terminating mechanism. Cells from a mutant strain (rad-9), radiation sensitive with respect to colony forming ability, show an approximately equal sensitivity for transcription inhibition compared to the wild-type (D0 (2095) = 2400 Gy). Inactivation of r-RNA synthesis in cells exposed to alpha-particles at room-temperature showed a decreased sensitivity with higher particle fluences ('resistant tail'). This phenomenon, however, was drastically reduced if the temperature during irradiation was lowered to 4 degrees C, and was completely abolished when dried cells were used. The results may be explained by the presence of recovery processes in vegetative cells during prolonged exposures to alpha-particles at room temperature. An inactivation cross-section for alpha-particle induced transcription inhibition of about 0.02 micron 2 can be derived from the experimental data. When comparing this value with the estimated target volume, it appears that no single genes but the whole cluster of about 120 r-RNA genes on each of the chromosomes XII in the diploid cell may be inactivated by a single alpha-particle.
Explore the source record for details and available documents.
In many cellular systems the shape of survival curves is changed from a sigmoidal to a purely exponential type if the LET of the radiation is increased. This is often explained by the hypothesis that repair mechanisms are less effective or non-functional with lesions generated by densely ionizing radiation. The absence of split-dose sparing and/or recovery from potentially lethal damage is then taken as further support. A careful consideration has to take into account, however, that with particle exposure the pattern of energy deposition varies considerably within a cell population and that the actual distribution depends also on cell geometry. If one accepts the view that with low-LET radiations repair may be saturated at high dose, the survival curve shape characteristic of high LET may be explained by the assumption that in this case saturation may occur due to the energy deposited by one or few heavy charged particles. The absence of recovery would then be due to microdosimetric parameters rather than to the nature or pattern of the primary molecular lesions. This alternative can be tested quantitatively by comparative analysis of the survival behaviour of different cellular systems exposed to radiations of varying LET. Our experiments with yeast strains of different sensitivities show that recovery from potentially lethal damage can be demonstrated even after exposure to uranium ions. Quantitative analysis leads to the conclusion that the apparent reduction in the extent of recovery is mostly due to saturation at the cellular level rather than to non-reparability of the primary lesions or to destruction of the repair system.
Repair process operating on radiation damaged DNA may be investigated by studying its functional integrity, e.g. its ability to serve as template for transcription. We measured the synthesis of ribosomal RNA and of the inducible enzyme arginase in yeast cells and followed their recovery after X-ray, alpha-particle and heavy ion exposure. Transcription inhibiting lesions formed upon X-irradiation in yeast cells are repaired during post-exposure incubation ("liquid-holding"). The inactivation curves are strictly exponential immediately after irradiation. After the "liquid holding" treatment the inactivation curves are still exponential but with a progressive decrease of the slopes as a function of incubation time. This indicates that a constant fraction of the lesions is repaired per time interval. But even after long incubation times (24 h) there is still a sizeable unrepaired fraction. Comparing different yeast strains and different irradiation temperatures recovery can also be demonstrated in cells exposed to alpha-particles. In addition, recovery is detected by the arginase assay after irradiation of yeast with very heavy charged particles, e.g. titanium ions.