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Biomedical subjects

D Holdsworth

Publications and source records attributed to D Holdsworth.

12 recordsLinked to original sources
PubMed2000

Chromosome analysis of workers occupationally exposed to radiation at the Sellafield nuclear facility.

PURPOSE: To investigate the relationship between stable chromosome aberration frequency in peripheral blood lymphocytes and occupational cumulative radiation exposure. MATERIALS AND METHODS: Cytogenetic analysis using G-banding was performed on peripheral blood lymphocyte cultures from 104 workers from the British Nuclear Fuels PLC facility at Sellafield, UK. The study group comprised 61 men with lifetime cumulative doses > 500 mSv, 39 men with minimal exposure (i.e. < 50 mSv) who formed a control group and 4 men with intermediate doses. RESULTS: The slope of the dose-response, adjusted for smoking status, for translocations and insertions was 0.55+/-0.31 x 10(-2)/cell/Sv. Consideration of chromosome breakpoints for all aberrations combined in the radiation workers revealed an excess in the C group chromosomes and a deficit in the F group chromosomes with breakpoints being concentrated in the terminal regions whereas the distribution in the control group did not deviate from expectation. CONCLUSIONS: The dose-response was not significantly different from the parallel FISH analysis (Tucker et al. 1997) and confirms that chronic radiation exposure appears to be substantially less effective at inducing stable chromosome aberrations in comparison with acute exposure.

Adult↗
PubMed1999

Assessment of maintenance therapy with reduced doses of PTH(1-34) in combination with a raloxifene analogue (LY117018) following anabolic therapy in the ovariectomized rat.

This experiment was designed to evaluate the ability of a raloxifene analogue (RA), LY117018, with or without reduced dosing of human parathyroid hormone (hPTH)(1-34) to maintain gains in bone mass after a fully anabolic treatment regimen given to aging osteopenic rats. Six-month-old rats were ovariectomized (ovx) or sham-operated (sham). After 1 month, ovx rats were treated with an anabolic regimen consisting of subcutaneous hPTH(1-34) 80 microg/kg/day and oral raloxifene 3 mg/kg/day, each given 5 days/week for 3 months. Thereafter, the treated ovx rats went on to an 8 week maintenance phase of treatment with either RA alone at the same dose, hPTH(1-34) at a reduced dosing interval (twice a week), or a combination of the two. Bone mineral density (BMD) was measured ex vivo at four skeletal sites, lumbar spine (L2-4), proximal hemipelvis, whole femur, and tibia, by dual-energy X-ray densitometry. All four sites showed a similar pattern of response. After the 3 month anabolic phase, the sham group had significantly higher BMD values than ovx rats at all skeletal sites (p < or = 0.002). The ovx rats treated with PTH + RA during the anabolic phase of the protocol had significantly higher BMD than the sham group in the femur, tibia, and spine (p < or = 0.02) and higher but not significantly different values in the pelvis. Following the 2 month maintenance phase, comparisons were made with the PTH-RA group at the end of the anabolic phase. Decrements in BMD were seen in all three maintenance therapy groups, but they were not statistically significant in the RA plus reduced PTH dose group. However, reduced hPTH(1-34) dosing and RA alone resulted in significant reductions of bone mass measurements at several skeletal sites during the maintenance phase. We conclude that the raloxifene analogue LY117018 may be useful in maintaining bone mass in aging ovx rats following anabolic therapy with hPTH(1-34) and raloxifene analogue, but that this strategy only allows for dose reduction of hPTH(1-34) rather than its discontinuation.

Absorptiometry, Photon↗
PubMed1999

The addition of a raloxifene analog (LY117018) allows for reduced PTH(1-34) dosing during reversal of osteopenia in ovariectomized rats.

To test the hypothesis that an antiresorptive agent might reduce the dosing requirement for an anabolic drug during reversal of osteopenia due to estrogen deficiency, the following experiment was conducted in 6-month-old female rats. Ovariectomy or sham surgery was performed and the following six experimental groups were studied. Untreated (SHAM) or ovariectomized (OVX) animals served as control groups. Four weeks post-OVX, osteopenic rats (now 7 months old), were treated in one of four experimental protocols: human parathyroid hormone (hPTH(1-34)), 80 microg/kg/day, given by subcutaneous injection 5 days/week; a selective estrogen receptor modulator (SERM), raloxifene analog LY117018 (RA), 3 mg/kg/day, given by gavage 5 days/week; and two combinations of LY117018 at the same dose and frequency with hPTH(1-34) (same dose, 5 times/week) and a reduced dosing interval of hPTH(1-34) (same dose, 2 times/week). After 12 weeks of treatment, the four experimental groups were sacrificed at age 10 months. SHAM and OVX controls were also studied at 7 and 10 months of age. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry at four skeletal sites: two mixed cortical/trabecular sites (femur and tibia) and two predominantly trabecular sites (lumbar spine and pelvis). The differences in BMD were consistent at all four sites. RA alone maintained BMD at all skeletal sites, but the results were not significantly improved over OVX controls, at age 10 months. hPTH(1-34) injections given 5 days/week resulted in BMD increments significantly higher than in either OVX or SHAM controls (p < 0.001). While the RA did not enhance the anabolic effects of full doses of hPTH(1-34), the addition of RA treatment to twice-weekly hPTH(1-34) dosing resulted in BMD increments at all four skeletal sites that were similar to the more intensive anabolic regimen of hPTH(1-34) therapy given 5 times/week. Therefore, an antiresorptive agent such as SERMs may potentially reduce the pharmacologic doses of PTH needed to reverse estrogen deficiency-induced osteopenia.

Animals↗
PubMed1997

Biological dosimetry of radiation workers at the Sellafield nuclear facility.

The British Nuclear Fuels plc facility at Sellafield performs a range of nuclear-related activities. The site has been in operation since 1950 and has, in general, employed a stable work force, many of whom have accumulated relatively high occupational exposures to ionizing radiation. This paper compares the physical dosimetry with two biological end points for evaluating radiation exposure: fluorescence in situ hybridization with whole-chromosome painting probes to quantify stable chromosome aberrations (translocations and insertions), and glycophorin A (GPA) analysis of variant erythrocytes. For the cytogenetic analyses, 81 workers were evaluated in five dose categories, including 23 with minimal radiation exposure (< or = 50 mSv) and 58 with exposures ranging from 173 to 1108 mSv, all but 3 being > 500 mSv. In a univariate analysis, the mean stable chromosome aberration frequencies showed a significant increase with dose category (P = 0.032), and with cumulative dose when dose is treated as a continuous variable (P = 0.015). The slope of the dose response for stable aberrations is 0.79 +/- 0.22 aberrations per 100 cells per sievert (adjusted for smoking status), which is less than that observed among atomic bomb survivors, and suggests a dose and dose-rate effectiveness factor for chronic exposure of about 6. Analyses of the data for GPA N/O and N/N variants from 36 workers revealed no correlation with dose. Neither was there a correlation between the frequencies of N/O GPA variants and stable aberrations, although a weak negative association was observed between N/N variant frequency and stable aberrations (r = -0.38, P = 0.05). These results provide clear evidence for the accumulation of stable aberrations under conditions of chronic occupational exposure to ionizing radiation and show that stable chromosome aberrations are a more sensitive indicator for chronic radiation exposure than GPA variants. In comparison with human studies of brief exposure, chronic low-dose exposures appear substantially less effective for producing somatic effects as reflected by stable chromosome aberrations.

Cells, Cultured↗
PubMed1996

Value of technetium-99m HMPAO-labelled leucocyte scintigraphy as an initial screening test in patients suspected of having inflammatory bowel disease.

OBJECTIVE: This study was designed to evaluate the role of technetium-99m (99mTc) hexamethyl propylene amine oxime (HMPAO)-labelled leucocyte imaging as an initial screening test in patients suspected of having inflammatory bowel disease (IBD). PATIENTS AND METHODS: Thirty-one patients in whom a final diagnosis of irritable bowel syndrome (IBS) was made (group 1) and another 33 patients with established Crohn's disease (group 2) were studied. All patients had 99mTc HMPAO-labelled leucocyte scan with imaging at 40 and 120 min. Scans with abnormal bowel uptake were considered positive and this uptake was quantified by visual grading and computer-based methods (scan score). Group 1 patients with positive 99mTc HMPAO scan underwent an indium-111 (111In)-labelled leucocyte scan (imaging at 180 min) followed by endoscopy and barium radiology as deemed necessary in order to verify the 99m Tc HMPAO result. RESULTS: Three scan patterns were seen: well localized and unequivocally positive scans at both 40 min and 2 h were obtained from 28 patients. All but one had established Crohn's disease. Diffuse bowel uptake was seen in 14 scans. Ten of these (false positive) were obtained from symptomatic patients with IBS and four (false negative) from patients with asymptomatic Crohn's disease. No bowel uptake at 40 min and 2 h was seen in 22 scans. All but two of these (who had quiescent Crohn's disease) were obtained from patients with IBS. Active Crohn's disease is associated with significantly higher scan score (mean +/- SEM, 82.1 +/- 13.6) than the false positive scans (12.5 +/- 3.1, P > or = 0.001). Patients with false positive 99mTc HMPAO scans had negative 111In scans, endoscopy and barium radiology. CONCLUSION: Bowel scanning using either 111In or 99mTc HMPAO is useful in excluding active IBD. Because of radiation dose, image quality and availability 99mTc may be preferred to 111In.

Adult↗
PubMed1995

Mutant frequencies in workers at the Sellafield installation.

The frequency of hypoxanthine-guanine phosphoribosyltransferase (hprt) mutations has been determined in the peripheral T-lymphocytes of 18 workers at the Sellafield nuclear reprocessing installation with cumulative recorded radiation doses of about 500 mSv or more in comparison with a matched control group of 18 workers with doses less than 50 mSv. The mean dose of the exposed group was 663 mSv (range 449.3-880.8), and of the unexposed group 10.9 mSv (range 0-46.5). During the most recent 6 y the mean doses were 40.1 mSv (range 1.9-93.9) and 2.3 mSv (range 0-8.7), respectively. The logarithmic mean mutant frequency of the exposed group (9.3 x 10(-6)) was lower than that of the unexposed group (12.4 x 10(-6)). The apparent inverse association of mutant frequency and exposure varied in statistical significance tests from borderline to p < 0.01 depending on how the analysis was performed and whether recent or total exposure was considered.

Humans↗
PubMed1984

Extended haplotypes of chromosome 6 in adult rheumatoid arthritis.

In 46 patients with rheumatoid arthritis (RA) the allele C4B*3 occurred in 6 patients, while among 350 normal controls, it occurred 6 times (P less than 0.00002). Among 9 white and 1 black families, each of which had 2 or more members with RA, there were 36 haplotypes associated with RA. An extended haplotype (specific HLA-B, DR, complotype haplotypes in significant linkage disequilibrium) containing C4B*3: HLA-B15, DR4, BF*S, C2*C, C4A*3, C4B*3, was found twice (P less than 0.001) among whites with the disease-associated chromosomes.

Adult↗
PubMed1981

Gold-induced thrombocytopenia. A clinical and immunogenetic study of twenty-three patients.

Thrombocytopenia developed in 23 patients with rheumatoid arthritis treated with gold salts over 25 years. All patients recovered, and there were no episodes of life-threatening hemorrhage; four patients eventually needed splenectomy. The clinical presentation of gold-induced thrombocytopenia and its treatment and outcome are reviewed. Because gold-induced thrombocytopenia is believed to have an immunologic basis, we sought an association between this complication and antigens of the human leukocyte antigen (HLA) region. The most significant finding was the association of the HLA-DR3 alloantigen in 12 of 15 of these patients compared with 26 of 84 in a control population (x2 12.9, p less than 0.001). This study provides further evidence that gold-induced thrombocytopenia is immunologically mediated and that genes of the major histocompatibility complex are involved.

Adult↗
PubMed1976

Pharmacological investigations of virosecurinine.

This study reports some biological studies on the alkaloid virosecurinine isolated from the plant Securinega Virosa. Virosecurinine is an isomer of the securinine group of alkaloids present in plants used in traditional medicines in many areas, including the Central District of Papua New Guinea. Virosecurinine is mildly toxic to mice with an LD50 of 73 milligrams per kilogram body weight. Death results from violent tonic convulsions and paralysis similar to those observed with strychnine poisoning. Virosecurinine had no effect on the growth of the following bacteria, E. coli, S. aureus, and B. subtilis, or the fungi, F. monoliforme, P. viridicatum, A. niger, R. solani, R. stolonifer and C. lunata.

Alkaloids↗