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PubMed1984

Glycogenosis type VIII.

Glycogenosis Type VIII, characterized ultrastructurally by an accumulation of rosettes (alpha-particles) of glycogen in the central nervous system, is an extremely rare condition; only two sporadic cases are on record. The first complete autopsy on a patient with cerebral alpha-particle glycogenosis, a 20-year-old American-Indian female, is the subject of this report. The case was clinically unique because of long survival and presumable familial incidence. The gross pathology was characterized by severe brain atrophy but preserved thickness of the cortical mantle. Vacuolation of the neuropil was the main histological abnormality and was most extensive in the striatum and less so in the cerebral cortex and some brain stem nuclei. Biochemical analysis showed glycogen levels elevated fiftyfold in the striatum and eightfold in the cerebral cortex in comparison with control tissue. Ultrastructural observations and evidence obtained from the Golgi method suggest that the distal axon was the principal site of storage. Two prominent additional abnormalities, spheroids, not previously observed in this disease, and massive accumulation of lipofuscin, were probably both related to the prolonged course of illness. The viscera, including the liver were morphologically free of storage.

Adult↗

PubMed2001

Microdosimetric calculation of absorption fraction and the resulting dose conversion factor for radon progeny.

It is an established fact that radon progeny can induce lung cancers. However, there is a well-known discrepancy between the epidemiologically derived dose conversion factor for radon progeny (4 mSv/WLM) and the dosimetrically derived value (15 mSv/WLM) (mSv is a unit of the dose while WLM is a unit of exposure to radon progeny). Up to now there is no satisfactory explanation to this. In the present study we propose that microdosimetry will help reduce the discrepancy significantly. The ICRP Human Respiratory Tract Model (HRTM) has been applied to calculate the effective dose conversion factor. All parameters have been kept at their best estimates. Modifications were made in the calculation of the absorbed fractions of alpha particles. In contrast to the ICRP approach where the energy has been considered to be deposited in the layer containing the sensitive cells, we used a microdosimetric approach in which the alpha particles deposit their energy only in the nuclei of sensitive cells. This modification alone has lowered the dose conversion factor by about one-third (from 15 mSv/WLM down to approximately 10 mSv/WLM).

Cell Nucleus↗

PubMed1999

Lung carcinogenesis in rats after inhalation exposure to (237)NpO2.

The results of several studies of experimental carcinogenesis suggest that, after inhalation of alpha-particle emitters, lung tumor incidence varies depending on the exposure rate and dose distribution in the tissue. In the case of transuranics, the main influencing factor would be the specific alpha-particle activity of the inhaled actinide. To confirm these results, long-term studies were performed using male Sprague-Dawley rats exposed to (237)NpO(2) by inhalation. The initial lung burdens of the animals ranged from 0. 1 to about 7 kBq. The rats were followed during their life span and weighed regularly, and their lung burdens were determined in vivo and at death to estimate the lung dose. At death, the incidence of lung tumors and their malignancy and histological types were analyzed. The analysis revealed a typically linear-quadratic dose response for incidence of malignant lung neoplasm and a differential dose response for various types of tumors. Although these results confirm the influence of the activity of the inhaled actinide oxide, further experiments are needed to be able to compare a more homogeneous population of animals.

Administration, Inhalation↗

PubMed1999

p53 mutations in tumor and non-tumor tissues of thorotrast recipients: a model for cellular selection during radiation carcinogenesis in the liver.

Concerns over cancer development from exposure to environmental sources of densely ionizing, high linear energy transfer (LET) radiation, such as alpha-particles from radon, is a current public health issue. The study of tumors attributable to high LET irradiation would greatly augment our insights into the biological mechanisms of carcinogenesis. Chronic low-dose-rate internal exposure to alpha-radiation from thorium dioxide deposits following intravascular administration of the radiographic contrast agent Thorotrast is known to markedly increase the risk of cancer development, especially that of hepatic angiosarcomas and cholangiocarcinomas. Although the mechanism is hypothesized to be via cellular damage, DNA being a major target, wrought by the high LET alpha-particles, the specific genes and the actual sequence of events involved in the process of transforming a normal cell into a malignant one are largely unknown. To shed some light on the molecular mechanisms of cancer development during a lifetime exposure to alpha-radiation, we analyzed the most commonly affected tumor suppressor gene in humans, p53, in 20 Thorotrast recipients who developed cancer, mostly of hepatic bile duct and blood vessel origin. Of the 20 cases, 19 were found to harbor p53 point mutations. Moreover, the accompanying non-tumor tissues from these patients also had p53 mutations, albeit at lower frequency. The distribution pattern of the point mutations was significantly different between the non-tumor and tumor tissues, with most mutations in malignant tissues located in the highly conserved domains of the p53 gene. Our results support the idea that p53 mutations are important in the genesis of Thorotrast-induced tumors but that these point mutations are a secondary outcome of genomic instability induced by the irradiation. Additionally, non-tumor cells harboring p53 mutations may gain some survival advantage in situ but mutations in the domains responsible for the formation of structural elements critical in binding DNA may be necessary for a cell to reach full malignancy.

Aged↗

PubMed2005

(3)He-particle-induced reactions on (nat)Sb for production of (124)I.

Excitation functions of the reactions (nat)Sb((3)He,xn)(124,123,121)I were measured from their respective thresholds up to 35 MeV, with particular emphasis on data for the production of the medically important radionuclide (124)I. The conventional stacked-foil technique was used. From the experimental data the theoretical yields of the three investigated radionuclides were calculated. The yield of (124)I over the energy range E9(30He) = 35 --> 13 MeV amounts to 0.95 MBq/microA h. The radionuclidic impurities are discussed. A comparison of (3)He- and alpha-particle-induced reactions on antimony for production of (124)I is given. The alpha-particle-induced reaction on enriched (121)Sb and the (3)He-particle-induced reaction on enriched (123)Sb would lead to comparable (124)I yields, but the level of impurities in the latter case would be somewhat higher.

Journal Article↗

PubMed1999

The study on related genes in the neoplastic transformation of immortalized human fetal tracheal fibroblast cells induced by irradiation.

In this study, we investigated the genes related to the transformation of immortalized human fetal tracheal fibroblast cell line induced by alpha particles by means of differential display mRNA method. The result revealed that there were 23 DNA fragments that were expressed intensively in alphaSHTF cells (SHTF cells forming clone on agar after irradiated by alpha particles emitted by 238Pu) only and not in SHTF (SV40-immortalized human fetal tracheal fibroblast) cells. Northern dot confirmed two fragments, C17-5, C23-1 which showed intensive mRNA expression in alphaSHTF cells, but not in SHTF cells. The length of the C17-5 fragment was 310bp. Searching in BLAST database revealed that the C17-5 fragment might be an unknown sequence.

Base Sequence↗

PubMed2001

Short-lived alpha sources of energies 6.0 MeV and 7.69 MeV for calibration purposes.

An approach for preparation of short-lived alpha sources of energy 6.0 MeV and 7.69 MeV is proposed. The sources are prepared by taking a sample of 222Rn progeny on an alpha spectrometric filter. The activities (or related parameters) of 218Po, 214Pb and 214Bi at the end of sampling are precisely determined by a reference measurement with an alpha spectrometer. Further they are used as input values to calculate with a sufficient precision the number of emitted alpha particles of any energy and at any time interval of interest. Theoretical modelling and experimental results demonstrated that such sources could be prepared with a sufficient purity. There is a potential for the number of alpha particles emitted in a given time interval to be certified with an accuracy of 1-2%.

Calibration↗

PubMed2002

Intrachromosomal exchange aberrations predicted on the basis of the globular interphase chromosome model.

One of the key questions in understanding mechanisms of chromosome aberration production is how does interphase chromosome structure affect aberration formation. To explore this a modelling approach is presented which combines Monte Carlo simulation of both alpha particle track and interphase chromosome structure. The structural state of interphase chromosome influences a dose-effect relationship for intrachromosomal exchange aberrations (intrachanges). It is shown that intrachanges are induced frequently by both X rays and alpha particles if the chromosome is in the condensed globular but not in the decondensed coiled state. Truly simple intra-arm intrachanges induced by X rays are dose squared in coiled chromosomes, but exhibit linear dose dependence in globular chromosomes. Experimental data on interarm intrachanges obtained by dual arm chromosome painting are analysed by means of the technique presented. Results of analysis support the conclusion about the arms proximity of chromosome 1 in human lymphocytes.

Chromatids↗

PubMed1985

239Plutonium-induced heritable translocations in male mice.

This study was conducted to estimate the frequency of transmitted reciprocal translocations per rad of exposure to alpha particles from [239Pu]citrate. Data indicate that the rate of induction of heritable translocations is related linearly to the duration of spermatogonia stem cell exposure. The estimated increase in heritable translocations per rad of exposure of the stem cell to alpha particles is in the range of 1.45-2.91 X 10(-5)/gamete.

Animals↗

PubMed2001

Low-dose hypersensitivity of V79 cells under exposure to gamma-rays and 4He ions of different energies: survival and chromosome aberrations.

PURPOSE: To examine the low-dose sensitivity of V79 cells under exposure to gamma-rays and 4He ions of different energies. MATERIALS AND METHODS: Cell survival and cytogenetic analysis using the Giemsa technique were studied following irradiation to doses of 0-3 Gy at the INFN-LNL facilities. RESULTS: Low-dose hyper-radiosensitivity (HRS) of V79 was demonstrated after irradiation with gamma-rays and alpha-particles of various linear energy transfers (LET) (58.9, 79.3 and 101.7 keV microm(-1)). Cytogenetic analysis showed an LET dependence of aberrations at a dose of 1Gy; the frequency of chromatid fragments appeared to vary with the number of alpha-particles traversing the cell nucleus. The results of both studies fit together to give a better understanding of so-called 'induced radioresistance' phenomenon. CONCLUSIONS: The mechanism of induced cellular radioresistance appears to be initiated after a certain amount of energy is deposited in the cell nucleus. This amount depends on both radiation quality and the number of particles traversing the cell.

Animals↗

PubMed1995

Radon-exposed underground miners and inverse dose-rate (protraction enhancement) effects.

Recent models for radon-induced lung cancer assume that at high levels of cumulative exposure, as experienced historically by many underground miners of uranium and other ores, the risk of lung cancer follows an inverse dose-rate (protraction enhancement) pattern. That is, for equal total dose, a greater risk is incurred by those whose total dose is accumulated at a lower rate over a longer duration than at a higher rate over a shorter duration. This inverse dose-rate effect is hypothesized to be the consequence of multiple traversals of the nucleus of a target cell by alpha particles. It has recently been concluded, however, that for low total doses, as in most residential settings, the inverse dose-rate effect should diminish and perhaps even disappear, since at very low doses the probability that more than one alpha particle would traverse a cell is small and there would be no possibility for interactions from multiple hits. Pooling original data from 11 cohort studies of underground miners, including nearly 1.2 million person-y of observation and 2,701 lung cancer deaths, we evaluate the presence of an inverse dose-rate effect and its modification by total dose. An inverse dose-rate effect was confirmed in each cohort, except one, and overall in the pooled data. There also appears to be a diminution of the inverse dose-rate effect below 50 Working Level Months (WLM), although analyses were necessarily hampered by a limited range of exposure rates at low total WLM. These data support both the presence of an inverse dose-rate effect, as well as its diminution at low total dose. As a consequence, assessment of risks of radon progeny exposure in homes (on average 15-20 WLM for a lifetime) using miner-based models should not assume an ever-increasing risk per unit dose. Rather, it is more appropriate to apply risk models that take into account protraction enhancement and its diminution.

Humans↗

PubMed2000

Evidence for and implications of self-background of radon dosimeters with glass-fiber filters.

The first national radon survey in The Netherlands was conducted in 1984 with passive radon dosimeters that contain glass-fiber diffusion filters. During the last few years, measurements of outdoor-radon concentrations and information in the literature suggested to us that these dosimeters may give falsely elevated readings. A systematic contribution would be present due to alpha particles from natural radionuclides in the glass-fiber filter producing tracks on the track-etch foil. In the framework of the quality assurance of our laboratories, the origin of this offset was systematically assessed by means of measurements of alpha and gamma radiation from the glass-fiber filters and by intercomparisons between different types of detectors at low radon concentrations. It was found that alpha particles from the decay of 214Po in the glass-fiber filter are the main cause of the extra tracks (only 12% originates from decay of 212Po), leading, for this type of filter, to an offset in concentration of approximately 8 Bq m(-3). The implications of this offset are discussed.

Air Pollutants, Radioactive↗

PubMed2004

Inflammatory time course after quartz instillation: role of tumor necrosis factor-alpha and particle surface.

Inflammation has been suggested as the key factor in the development of quartz-induced fibrosis and carcinogenesis, and particle surface properties are argued as an important characteristic responsible for these pathologic alterations. To evaluate the effect of surface modification on acute and subchronic inflammation, female Wistar rats were intratracheally instilled with 2 mg native quartz, or quartz coated either with polyvinyl-pyridine-N-oxide or with aluminium lactate. Various markers of lung toxicity, inflammation, and oxidative stress were found to be enhanced at 3, 7, 21, and 90 d after instillation of native quartz. Quartz-treated animals also showed enhanced immunostaining of nuclear factor-kappaB (NF-kappaB) in alveolar macrophages and lung epithelium, as well as reduced IkappaBalpha levels in whole lung homogenate. Both surface modifications were found to inhibit most of the effects as observed with native quartz. NF-kappaB activation was also observed in vitro in rat lung epithelial cells following treatment with lavage fluid from quartz-treated animals, as well as with conditioned medium of quartz-treated macrophages, and these effects appeared to be at least partly tumor necrosis factor-alpha-independent. In conclusion, the persistent subchronic inflammatory lung response after quartz exposure appears to be particle surface-driven and is associated with NF-kappaB activation in both alveolar macrophages and the lung epithelium.

Animals↗

PubMed2004

Clusters of ionisation in nanometre targets for propane-experiments with a Jet Counter.

Further evidence on the reliability of the device called the Jet Counter (JC) for studying the formation of ionisation clusters at the nanometre level are presented. The new experimental data on the distributions of ionisation cluster size originating from a 2-10 nm size target in propane irradiated by 3.8 MeV alpha particles are described. The JC consists of a pulse-operated valve that injects an expanding jet of propane into an interaction chamber, where a sensitive volume in the form of a cylinder is created. The sensitive volume was irradiated by 3.8 MeV alpha particles. The resulting distribution of ion clusters, ranging from 2 to 10 nm in unit density gas, has been measured. A method of determining the efficiency of registration of single propane ions using an ion detector is described. A method of deconvolution of the measured to true cluster size distributions is also given. Finally, the measured cluster size distributions are compared with modelled distributions based on Monte Carlo calculations. The results for propane together with previous ones for nitrogen indicate the JC to be an efficient tool for the investigation of radiation quality at the nanometre level.

Algorithms↗

PubMed1988

Thorotrast-induced oro- and hypopharyngeal fibrosis with recurrent bleeding.

Thorium dioxide, widely used as a contrast material, is a producer of alpha particle radiation. This is well demonstrated by autoradiography. The case described illustrates that life-threatening, thorium dioxide-induced pharyngeal haemorrhage may occur even with an occluded carotid artery. The radiation exposure caused an intense foreign body reaction with a marked cell-deficient fibrosis. The alpha particles are well demonstrated by autoradiography. In addition, we were able to show a defect in the wall of the carotid artery due to the Thorotrast injection, which was closed by cell-depleted connective tissue. As the radioactivity of the nuclides of thorium dioxide peaks 30-40 years after its first application, the morbidity will increase and the disease has to be taken into careful consideration in head and neck tumour lesions.

Aneurysm↗

PubMed1991

In vitro exposure of mammalian cells to radon: dosimetric considerations.

We have developed a model to calculate the dose to the cell nucleus in cells exposed in suspension to radon and/or radon progeny. The model addresses the influence of (1) different radiation qualities and energies in the irradiation milieu; (2) the contribution to dose from radioactivity in the medium surrounding the cell after exposure to the radon gas as well as that from excess radon progeny associated with the cell; (3) the geometry of the cell and of the radiosensitive target, the cell nucleus; (4) the intracellular localization of the radionuclides; (5) attenuation of the alpha particles by the cytoplasm; (6) the radionuclide concentrations in the medium; and (7) the length of exposure. Investigation of the influence of these various parameters was made using an irradiation system in which cells were exposed to 212Bi, which decays to stability with the emission of an alpha particle (either 6.05 or 8.78 MeV). The information from these studies was then used to develop the system further for more complex systems in which 222Rn and its progeny are present. The model takes into account the contribution of dose from different radiation sources using scintillation counts of the medium and the cells, and it is useful for calculations of dose in situations where cells are exposed in suspension culture.

Animals↗

PubMed1994

Estimation of the dose of radon progeny to the peripheral lung and the effect of exposure to radon progeny on the alveolar macrophage.

Groups of rats were exposed to radon progeny attached to a vector aerosol of cigarette smoke particles in a closed-loop exposure system. The total exposures ranged from 70 to 1020 WLM over a 3-5-h period. Alveolar macrophages were lavaged from exposed and control rats (exposed to the vector aerosol alone). There were no differences between phagocytic capabilities of the macrophages lavaged from the controls and any group of exposed rats. The increases in the numbers of binucleated/multinucleated and micronucleated macrophages were enumerated using cytological preparations of lavaged alveolar macrophages after exposure compared to the numbers in the control rats. The peak response in numbers of binucleated/multinucleated and micronucleated macrophages occurred at 21 days after exposure, beyond which the numbers decreased. This peak response showed a significant exposure-dependent relationship. The number of micronuclei provided a sensitive indicator of exposure. The lowest exposure level used (70 WLM) resulted in a significant difference in the number of micronucleated macrophages between control and exposed rats. The alpha-particle dose to the peripheral lung was estimated by comparing formation of micronuclei in cultured macrophages exposed to alpha particles from 238Pu (where the dose was known) to micronuclei in lavaged macrophages from animals exposed to radon progeny (where the exposure concentration was known, but the dose was not known). The dose estimated in this way for the peripheral lung was 9.8 +/- 1.2 mGy/WLM. This value is three to five times higher than predicted from mathematical models currently available.

Animals↗

PubMed1993

Mechanisms involved in rejoining DNA double-strand breaks induced by ionizing radiation and restriction enzymes.

DNA double-strand breaks are considered to be the most deleterious lesion induced by ionizing radiation. However, the mechanism of rejoining of these lesions has not been extensively studied at the molecular level. We have used a shuttle vector, pHAZE, to analyze the mechanism of rejoining of DNA double-strand breaks in human cells. The advantage of this vector system is that, unlike many previously described shuttle vectors, it has a large target gene for the detection of deletions and it is maintained as a freely replicating episome with chromatin conformation in the nucleus of human cells. In this study we compare data obtained on the spectrum of mutations induced in pHAZE by ionizing radiation (alpha-particles) and restriction enzymes (PvuII, ClaI, and PvuI). Unlike ionizing radiation, restriction enzymes induce double-strand breaks in DNA with known end structures at defined locations and therefore provide a model system for analyzing cellular responses to DNA double-strand breaks. Exposure of human cells containing the vector to alpha-particle irradiation produced both point mutations and large deletions in pHAZE. When the junction regions of the deletions were sequenced it was found that 65% were rejoined with up to 6 bp of homology at the junction region. Analysis of restriction-enzyme-induced mutations suggests that double-strand break ends are modified to facilitate rejoining and that the type of modification is characteristic for different end structures. Double-strand breaks with cohesive ends appear to have fewer modifications introduced at the break points before rejoining than breaks with blunt ends. When considered in relation to the data obtained with ionizing radiation this suggests that the presence of cohesive sequences either at, or in proximity to, the ends enhances rejoining of DNA double-strand breaks.

Base Sequence↗