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Biomedical subjects

D P Morrison

Publications and source records attributed to D P Morrison.

At least 19 recordsLinked to original sources

Cytogenetic dose-response and adaptive response in cells of ungulate species exposed to ionizing radiation.

In the studies reported here, the micronucleus assay, a common cytogenetic technique, was used to examine the dose-responses in fibroblasts from three ungulate species (white-tailed deer, woodland caribou, and Indian muntjac) exposed to high doses of ionizing radiation (1-4 Gy of (60)Co gamma radiation). This assay was also used to examine the effects of exposure to low doses (1-100 mGy) typical of what these species experience in a year from natural and anthropogenic environmental sources. An adaptive response, defined as the induction of resistance to a stressor by a prior exposure to a small "adapting" stress, was observed after exposure to low doses. This work indicates that very small doses are protective for the endpoint examined. The same level of protection was seen at all adapting doses, including 1 radiation track per cell, the lowest possible cellular dose. These results are consistent with other studies in a wide variety of organisms that demonstrate a protective effect of low doses at both cellular and whole-organism levels. This implies that environmental regulations predicated on the idea that even the smallest dose of radiation carries a quantifiable risk of direct adverse consequences to the exposed organism require further examination. Cytogenetic assays provide affordable and feasible biological effects-based alternatives that are more biologically relevant than traditional contaminant concentration-based radioecological risk assessment.

Adaptation, Physiological↗

Low doses of radiation increase the latency of spontaneous lymphomas and spinal osteosarcomas in cancer-prone, radiation-sensitive Trp53 heterozygous mice.

Mice heterozygous for Trp53 are radiation-sensitive and cancer-prone, spontaneously developing a variety of cancer types. Osteosarcomas in the spine lead to paralysis, while lymphomas lead rapidly to death, distinct events that provide objective measures of latency. The effects of a single low-dose (10 or 100 mGy), low-dose-rate (0.5 mGy/min) (60)Co gamma irradiation on lymphoma or spinal osteosarcoma frequency and latency, defined as time of death or of onset of paralysis, respectively, were examined. Compared to spontaneous lymphomas or to spinal osteosarcomas leading to paralysis in unexposed mice, an exposure of 7-8-week-old Trp53(+/-) mice to 10 or 100 mGy had no significant effect on tumor frequency, indicating no effect on tumor initiation. All tumors are therefore assumed to be of spontaneous origin. However, a 10-mGy exposure reduced the risk of both lymphomas and spinal osteosarcomas by significantly increasing tumor latency, indicating that the main in vivo effect of a low-dose exposure is a reduction in the rate at which spontaneously initiated cells progress to malignancy. The effect of this adaptive response persisted for the entire life span of all the animals that developed these tumors. Exposure to 100 mGy delayed lymphoma latency longer than the 10-mGy exposure. However, the 100-mGy dose increased spinal osteosarcoma risk by decreasing overall latency compared to unexposed control mice. That result suggested that this higher dose was in a transition zone between reduced and increased risk, but that the dose at which the transition occurs varies with the tumor type.

Animals↗

A comparative study on potential cytogenetic fingerprints for radiation LET in human lymphocytes.

PURPOSE: To carry out a comparative study on potential cytogenetic fingerprints for radiation LET in human metaphase lymphocytes. MATERIALS AND METHOD: Human lymphocytes were irradiated in vitro with 3.0 Gy 60Co gamma-rays, 0.9 Gy 3H beta-rays or 0.2 Gy 2.7 Mev neutrons. Detailed chromosome aberrations were analysed by combined FISH with pan-telomere staining and specific whole-chromosome painting (1, 2 and 4). Total chromosome translocations and insertions were also analysed by multicolour whole-chromosome painting (chromosomes 1, 2 and 4 orange, chromosomes 3, 5 and 6 green). RESULTS: Among the six proposed radiation cytogenetic fingerprints, the ratio of total simple translocations to insertions (I-ratio), showed the largest difference between low-LET 60Co gamma-ray and high-LET neutron radiation. The ratios of complete exchanges to incomplete rejoinings [S(I)-ratio] and dicentrics to interstitial deletions (H-ratio), showed a similar significant difference between low- and high-LET radiation. The ratios of centric rings to interstitial deletion (G-ratio) showed a trend of LET-related difference, but the difference was not significant in this data set. The ratios of dicentrics to centric rings (F-ratio) and apparent complete exchanges to hidden complete exchanges [S(II)-ratio], showed no difference between low- and high-LET radiation. In the 1426 radiation-induced chromosome aberrations observed after 52 h culture, evidence for sister-chromatid fusion but not telomere addition was found. CONCLUSION: Pan-telomere staining plus specific whole chromosome painting allows simultaneous and objective detection of complete or incomplete chromosome exchanges and interstitial or terminal deletions in human peripheral lymphocytes. Of the six proposed cytogenetic ratios, the I-ratio is the most effective cytogenetic fingerprint for distinguishing low-LET from high-LET radiation in human metaphase human lymphocytes.

Beta Particles↗

Exposure temperature, but not donor age, is a confounding factor for in vitro translocation production by chronic irradiation.

PURPOSE: To assess the effects of incubation temperature during irradiation, and of donor age, on the in vitro induction of chromosomal translocations in human lymphocytes. MATERIAL AND METHODS: Lymphocytes from six human male donors were scored, using fluorescence in situ hybridization, for the presence of chromosomal translocations involving chromosomes 1 to 6 after in vitro, chronic exposure (delivered continuously over 48 h at 37 degrees C or at 20 degrees C) to tritium beta-rays or 60Co gamma-rays. RESULTS: No age-related difference in the alpha coefficients of the fitted induction curves was observed for gamma-ray-exposed lymphocytes obtained from four donors whose ages ranged from 24 to 79 years, or for tritium beta-ray-exposed lymphocytes from two donors aged 36 and 62 years. Duplicate samples from one donor, irradiated concurrently at 20 degrees C or 37 degrees C, gave significantly different alpha coefficients: 0.128+/-0.008 and 0.053+/-0.004, respectively (p<0.0001). The S-ratio (the ratio of induced complete to incomplete translocations) was found to be independent of radiation dose, donor age and exposure temperature. CONCLUSIONS: For biodosimetry in chronic irradiation situations, the use of alpha coefficients derived from the dose-response curves of cells chronically irradiated in vitro at body temperature is recommended. With respect to induction rates, donor age does not appear to be a confounding factor. The S-ratio is independent of radiation doses, exposure temperatures, or donor ages.

Adult↗

Alpha coefficient of dose-response for chromosome translocations measured by FISH in human lymphocytes exposed to chronic 60Co gamma rays at body temperature.

PURPOSE: To measure the alpha coefficient, the initial slope of the translocation dose-response curve, for 60Co gamma-rays in human lymphocytes. MATERIALS AND METHODS: Human lymphocytes were exposed to 0, 0.32, 0.62 and 0.92 Gy of chronic 60Co gamma-rays under conditions that reduce the metabolic stress to the cells. Chromosome translocation frequencies were measured using fluorescence in situ hybridization with a whole-chromosome probe cocktail specific for chromosomes 1, 2, 4 (orange) and 3, 5, 6 (green). RESULTS: A total of 72,383 metaphases were analysed (33,429 in exposed cells) in two individuals. The shape of the dose-response curves for translocations was linear, and alpha coefficient was measured as 0.024 +/- 0.002 translocations per cell per Gy for the combined data for two 24 year old male donors. CONCLUSION: The alpha coefficients measured after chronic exposure were in good agreement with that reported in the literature for acute, low-dose exposure of human lymphocytes to 60Co gamma-rays.

Adult↗

Biological dosimetry of beta-ray exposure from tritium using chromosome translocations in human lymphocytes analyzed by fluorescence in situ hybridization.

Radiation exposures from tritium make up a substantial fraction of the occupational and accidental radiation exposures associated with the nuclear power industry. Tritiated water, the most abundant form of tritium, is of particular interest because it is readily taken up by human cells and its irradiation of the cells is spread over a period of days. To approximate the prolonged exposure and the conditions that the cells of an individual would experience in vivo, we irradiated human lymphocytes with tritiated water for 48 h in a 1:1 blood:medium mix. For estimation of the tritium beta-ray dose, a cellular water content of 0.78, based on measurements of human lymphoblastoid cells in culture medium, was used. A modified dose calculation formula was developed for the radiation exposure conditions. A total of 48,014 metaphases (14,482 in irradiated samples and 33,532 in control, unirradiated samples) in human lymphocytes cultured for 72 h after exposure were analyzed for chromosome translocations using fluorescence in situ hybridization. The linear slope (alpha coefficient) of the dose-response curve was measured to be (3.93+/-0.42) x 10(-2) and (5.26+/-0.48) x 10(-2) translocations per cell per gray for complete translocations (tc) and complete translocations plus incomplete translocations [ti(Ab)], respectively, when the data were fitted to a linear model using a weighted least-squares method. The alpha coefficient for tc is significantly lower than that for conventionally measured dicentrics after tritium beta irradiation, but the alpha coefficient for tc + ti(Ab) does not differ significantly from that for dicentrics. This is in agreement with theoretical considerations. The importance of scoring criteria is stressed. The frequency of tc + ti(Ab) is proposed to be a reliable biodosimeter for tritium exposures, and its practical use in a dose reconstruction is presented.

Beta Particles↗

Heat-induced thermal tolerance and radiation resistance to apoptosis in human lymphocytes.

We have investigated heat- and radiation-induced apoptosis in human lymphocytes in vitro. We have previously shown that apoptosis was induced by radiation at doses as low as 0.05 Gy. Here we report that heat induced apoptosis in human lymphocytes in a temperature- and time-dependent manner. Temperatures at or below 42 degrees C, for up to 90 min, did not cause lymphocytes to undergo apoptosis, whereas temperatures at or above 43 degrees C, for 30 min and longer, did induce apoptosis. Lymphocytes were protected against apoptosis induced by 44 degrees C heat by a prior heat shock of 42 degrees C for 30 min. Heat-induced thermal tolerance developed immediately following the inducing heat shock, was greater after 4 h, and persisted for at least 24 h. While heat also induced radiation resistance, this change was minor and not apparent until about 24 h after the heat shock. Prior to the development of radiation resistance, heat shock sensitized lymphocytes to radiation-induced apoptosis. We have previously shown that radiation-induced apoptosis in lymphocytes varies between donors and therefore may be useful in assessing individual radiosensitivity. We report here that heat also induced variable levels of apoptosis in lymphocytes from different donors, although the range of responses was not as large as those observed with radiation-induced apoptosis. In summary, heat shock induces tolerance to heat-induced apoptosis and results first in sensitization and then protection of lymphocytes against radiation-induced apoptosis.

Apoptosis↗

Radiation-induced apoptosis in human lymphocytes: potential as a biological dosimeter.

We have tested the possibility of using apoptosis (programmed cell death) in human peripheral blood lymphocytes as a short-term biological dosimeter. Lymphocytes isolated from whole blood were irradiated in culture with 250 kVp x-rays or 60Co gamma rays. Two assays were used to measure apoptosis in lymphocytes after irradiation: in situ terminal deoxynucleotidyl transferase assay and fluorescence analysis of DNA unwinding assay. Similar qualitative and quantitative results were produced by the assays, supporting the notion that the fluorescence analysis of DNA unwinding assay measured DNA fragmentation associated with apoptosis. Induction of apoptosis in lymphocytes irradiated in vitro was proportional to dose and could be detected following exposures as low as 0.05 Gy. Lymphocytes from individual donors had reproducible dose responses. There was, however, variation between donors. X-ray and gamma-ray exposures induced similar levels of apoptosis at similar doses. The induction kinetics of apoptosis in vitro indicate a maximum is reached about 72 h after irradiation. In conclusion, the in vitro experimental evidence indicates that radiation-induced apoptosis in human lymphocytes has the kinetics, sensitivity, and reproducibility to be a potential biological dosimeter.

Adult↗

Mapping of the metalloproteinase gene matrilysin (MMP7) to human chromosome 11q21-->q22.

The matrix metalloproteinase, matrilysin, is thought to play an important role in the early steps of tumor progression. We determined the chromosome location of the matrilysin gene (MMP7) by Southern and PCR analysis of two different panels of somatic cell hybrids and in situ hybridization of metaphase chromosomes. Matrilysin maps to the region, 11q21-->q22, adding MMP7 to the cluster of matrix metalloproteinase genes that have already mapped to this region.

Base Sequence↗

A method for hyperthermic treatment of mouse skin.

The Sencar mouse skin system is a recognized model for tumour initiation, promotion and progression. The current interest in the effect of hyperthermia on this multi-stage tumorigenesis model prompted the need for a technique to accurately heat a section of dorsal skin of a large number of mice for 30 min per heat treatment. In the technique described, experimental groups of 25 female Sencar mice were treated at 7-8 weeks of age under general methoxyflurane anaesthesia. Treatment consisted of the application of initiating and/or promoting agents with or without hyperthermia. For hyperthermic skin treatments, each group of mice was placed onto a platform in a water bath so that the dorsal skin of the mice was in contact with 44 degrees C temperature controlled water.

Anesthesia, General↗

Presuicide attempt communications between parasuicides and consulted caregivers.

A high percentage of parasuicides visit professional caregivers prior to the attempted suicide. The content or outcome of these consultations is unknown. We interviewed hospitalized attempters and the professional caregivers they identified as having been consulted prior to their attempts. About half of these patients directly disclosed suicidal symptoms or intentions, especially to mental health professionals. These professionals more often inquired about suicidal ideations than did nonpsychiatric physicians. However, few caregivers noted suicidal thinking or probed suicidal symptoms. The data suggest that professional caregivers and especially nonpsychiatric physicians should be more sensitive and responsive to the signs and symptoms of suicidality.

Adolescent↗

Occupational stress in migraine--is weekend headache a myth or reality?

To determine whether or not the frequency of migraine attacks increased at weekends in employed patients and if so, whether or not this was related to the type of migraine, 35 female patients prospectively recorded the presence or absence of migraine attacks daily over a six-week period. They were also asked to estimate the frequency with which emotional factors predisposed to their migraine attacks and to provide details of their occupation. A diagnosis of common (migraine without aura) or classical migraine (migraine with aura) was made according to both the criteria of the Ad Hoc Committee on the Classification of Headache and those of the International Headache Society. Eleven percent and 6% of patients, respectively, felt that emotional factors "usually" or "always" predisposed to migraine attacks. There was no significant increase in the frequency of migraine attacks at weekends in either the total group or in the employed patients. Similarly, the type of migraine made no difference to the results. There was therefore no evidence for a delayed onset of migraine at weekends related to the weekday stress of employment.

Adult↗

Abnormal perceptual experiences in migraine.

The prevalence of abnormal perceptual experiences as symptoms of migraine attacks was determined in a consecutive series of 46 new female referrals to a migraine clinic. All patients met the diagnostic criteria of the International Headache Society for migraine with aura or migraine without aura and had no other serious physical illness. Seven patients (15%) reported abnormal perceptions (olfactory and/or gustatory hallucinations and distortions of body image) as part of most migraine attacks. A statistically significant association was found between these abnormal perceptual experiences and complaints of mood change, particularly increased depression and irritability, as part of most migraine attacks. It is suggested that spreading depression of cortical electrical activity may be responsible for the manifestations of temporal lobe and limbic system dysfunction.

Adolescent↗

Do self-report measures of affect agree? A longitudinal study.

As part of a study of the association between changes in mood and migraine attacks, daily self-report data on anxiety and depression were collected from 37 female patients attending a migraine clinic. A combination of the Irritability Depression Anxiety (IDA) Scale and two visual analogue scales (VAS) was used. The IDA and VAS measures of anxiety and depression were significantly associated in only 55 and 61 per cent of patients respectively.

Adult↗

Beta-radiation-induced resistance to MNNG initiation of papilloma but not carcinoma formation in mouse skin.

We have shown previously that the risk of tumor initiation, promotion, and progression in animals initiated with alkylating agents can be drastically altered by hyperthermia treatments. We show here that ionizing radiation can also alter the risk of tumor initiation by alkylating agents. Using a two-step skin tumorigenesis protocol in female SENCAR mice (initiation by MNNG, promotion with TPA), we exposed the dorsal skin of the mice to various doses of 90Sr/90Y beta radiation near the time of initiation. The radiation produced a dose-dependent reduction in the number of papillomas which appeared after TPA promotion, with about a 20% reduction in animals receiving 0.5 Gy surface dose just before initiation, about 50% reduction after 2.5 Gy, and greater than 80% at doses above 5 Gy. A dose of 2.5 Gy in animals initiated with DMBA produced no significant reduction. One skin hyperthermia treatment (44 degrees C, 30 min) along with radiation in MNNG-initiated animals partially blocked the protective effect of radiation and increased the papilloma frequency. Radiation (2.5 Gy) given either 6 days before or after MNNG initiation was less effective but still reduced papilloma frequency about 20%. In sharp contrast to the marked reduction in papilloma formation, these same animals showed no change in carcinoma frequency with any of the doses or schedules of beta radiation. MNNG initiation alone produced three types of initiated cells. One type, produced in low yield, was promotion-independent with a high probability of progression to a carcinoma and appeared unaffected by the radiation. A second type, produced in intermediate yield, was promotion-dependent and also had a high progression probability, but was likewise unaffected by the radiation. The third and most abundant type was promotion-dependent with a very low progression probability. Radiation exposure resulted in a decrease in the risk of an MNNG initiation event which led only to the third type of cell. The data therefore indicate that the risk of some, but not all, tumor-initiating events caused by alkylating agents can be reduced by an exposure to ionizing radiation.

Animals↗