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Biomedical subjects

D Murray

Publications and source records attributed to D Murray.

At least 73 records · Page 4Linked to original sources
PubMed2000

Protection of human tumor cells of differing radiosensitivity by WR-1065.

We examined the ability of WR-1065, the biologically active aminothiol form of the clinically used drug amifostine (WR-2721, Ethyol), to protect cultures of two human glioblastoma cell lines of greatly differing radiosensitivity from the cytotoxic effects of gamma radiation. M059J cells are extremely radiosensitive compared to M059K cells (which were derived from the same tumor) and are defective in the DNA-dependent protein kinase (DNAPK)-mediated pathway for the repair of DSBs. In spite of their marked phenotypic differences, the two glioblastoma lines were protected equivalently ( approximately 1.8-fold) after a 30-min preirradiation treatment with 4 mM WR-1065. These findings are in agreement with earlier studies that showed no relationship between the ability of another aminothiol, cysteamine, to protect human tumor cells with differing abilities to repair DSBs and/or radiosensitivity. Thus it appears that differences in intrinsic radiosensitivity and ability to repair DSBs are not important general factors in the modulation of the radiosensitivity of human cells by aminothiols. Because of a previous report that the radiosensitive mutant rodent xrs5 cell line (which, like M059J, is defective in the DNAPK-mediated pathway for repairing DSBs) is unusually refractory to the radioprotective effects of WR-1065, we re-examined the ability of WR-1065 to protect these cells. In contrast to the earlier studies, both the wild-type and mutant rodent lines were protected extensively by WR-1065. This discrepancy might be related to some unknown factor, such as differences in chromatin organization among xrs5 subclones that arise during their karyotypic evolution, possibly leading to altered DNA-drug associations.

Animals↗
PubMed2000

The North Staffordshire Maternity Hospital prospective study of pregnancy-associated depression.

The objective of the study was to establish the frequency of depression during pregnancy and the puerperium, and its relationship to marital disharmony and sociodemographic variables. A prospective longitudinal study was carried out in a district general hospital in the West Midlands, UK. The cohort consisted of 417 women booked for confinement at the hospital. Depression was measured as a proportion of high scores (> 14) on the Edinburgh Postnatal Depression Scale (EPDS) and marital disharmony was determined by the Spanier Dyadic Adjustment Scale. Using recommended cut-offs, 41/417 (9.8%) of the women were depressed during pregnancy and 31/417 (7.4%) were depressed at 3 months postpartum. There was a significant association between antenatal and postnatal depression, seven of the 31 women who were depressed postpartum had also been depressed in the antenatal period. Only five of the 41 women with antenatal depression and eight of the 31 women with postnatal depression were identified by their general practitioners as depressed. Marital disharmony was sequentially associated with depression before and after delivery. We conclude that antenatal depression is more common than generally thought, and that both antenatal and postnatal depression are frequently missed during routine consultation. Pregnancy-associated depression is more common where marital disharmony exists. More widespread use of the EPDS during pregnancy may help to highlight these often unidentified mental health problems.

Adolescent↗
PubMed2000

Establishing a mobile coronary care service in a rural setting.

A mobile coronary care unit (MCCU) service was introduced at Sligo General Hospital in 1992. Initially, a medical registrar and CCU staff nurse drove a fully equipped MCCU car to the patient location (Phase 1). When the patient was medically stabilised and had received thrombolysis, if appropriate, the doctor and nurse travelled with him in the conventional ambulance to the hospital. Subsequently, on a pilot basis, the doctor, nurse and equipment were transported by taxi to the patient (Phase 2). Since 1995, the MCCU service has been provided routinely by Sligo General Hospital (Phase 3). During each Phase the proportion of patients with acute myocardial infarction (AMI) was as follows: Phase 1--16 of 35 (46%), Phase 2--7 of 19 (36%), Phase 3--53 of 154 (34%). The incidence of unstable angina (UA) was 25%, 32% and 26% during each of the three Phases. Five patients had successful out of hospital (OOH) defibrillation and 56(74%) of the 76 AMI patients had OOH thrombolysis. The MCCU reduced the median "Call to needle" time by 64 minutes in Phase 1 and 102 minutes in Phase 2 compared to the conventional service. Median delay to MCCU treatment was 46, 40 and 80 minutes during each of the three Phases. In an Irish setting, a MCCU service provided rapid safe and effective care, including thrombolysis and defibrillation for patients with suspected AMI.

Coronary Care Units↗
PubMed1999

The flattened face of type II beta phosphatidylinositol phosphate kinase binds acidic phospholipid membranes.

Type II beta phosphatidylinositol phosphate kinase is a representative phosphatidylinositol phosphate kinase that is active against membrane-bound substrates. The structure of the enzyme contains a flattened basic face that spans the crystallographic dimer interface and is adjacent to the active site. Analytical ultracentrifugation shows that phosphatidylinositol phosphate kinase is a dimer in solution. Modeling suggested that the flattened face binds to acidic phospholipids by electrostatic interactions. The enzyme binds to acidic vesicles containing phosphatidylserine, phosphatidic acid, or phosphoinositides mixed with phosphatidylcholine, but not to neutral phosphatidylcholine vesicles. Binding to acidic vesicles is abolished in the presence of 1.0 M NaCl, consistent with an essential electrostatic contribution to the free energy of binding. The +14 charge on the flattened face of the dimer was reduced to +2 in the triple mutant Lys72Glu/Lys76Glu/Lys78Glu. The mutation has no effect on dimerization, but reduces the apparent KA for 25% phosphatidylserine/75% phosphatidylcholine mixed vesicles by 16-fold. The reduction in the level of binding can be ascribed to a loss of electrostatic interactions based on the finite difference solution to the Poisson-Boltzmann equation. The mutant reduces catalytic activity toward phosphatidylinositol 5-phosphate by approximately 50-fold. The wild-type enzyme binds half-maximally to phosphatidylinositol 4,5-bisphosphate-containing vesicles at a mole fraction of 0.3% in a phosphatidylcholine background, as compared to a 22% mole fraction in phosphatidylserine. The binding to phosphatidylinositol 4,5-bisphosphate-containing membranes is less sensitive to salt and to the triple mutation than binding to phosphatidylserine-containing membranes, suggesting that at least part of phosphatidylinositol 4,5-bisphosphate's interaction with the enzyme is independent of the flattened face. It is concluded that the flattened face of type II beta phosphatidylinositol phosphate kinase binds to membranes through nonspecific interactions, and that this interaction is essential for efficient catalysis.

1-Phosphatidylinositol 4-Kinase↗
PubMed1999

Subclinical health effects of environmental pesticide contamination in a developing country: cholinesterase depression in children.

The effect of exposure to pesticides among children in a Nicaraguan community in the path of rain water runoff from a large crop-dusting airport was evaluated by measuring plasma cholinesterase. Mean cholinesterase activity in 17 children in the path of runoff was 2.4 international units/ml blood/min, lower than the 2.9 IU/ml/min measured in a group of 43 children from an unexposed community (difference=0.49 IU/ml/min; 95% C.I. 0.24, 0.76). Six (35%) of the 17 exposed children had abnormally low cholinesterase levels. A possible explanation for this physiological effect of exposure to pesticides is the dermal absorption which may have occurred among children playing barefoot in puddles grossly contaminated by runoff from the airport. Drinking water from a well in the exposed community demonstrated low level residues of cholinesterase-inhibiting pesticides, although contamination with toxaphene (not a cholinesterase inhibitor) exceeded by over 8-fold the United States Environmental Protection Agency maximum permissible concentration in drinking water. The difficulty in measuring health effects resulting from environmental pesticide contamination, and in controlling exposure resulting from the rapidly increasing use of pesticides, is a growing problem for developing countries like Nicaragua.

Child↗
PubMed1999

Electrostatic properties of membranes containing acidic lipids and adsorbed basic peptides: theory and experiment.

The interaction of heptalysine with vesicles formed from mixtures of the acidic lipid phosphatidylserine (PS) and the zwitterionic lipid phosphatidylcholine (PC) was examined experimentally and theoretically. Three types of experiments showed that smeared charge theories (e.g., Gouy-Chapman-Stern) underestimate the membrane association when the peptide concentration is high. First, the zeta potential of PC/PS vesicles in 100 mM KCl solution increased more rapidly with heptalysine concentration (14.5 mV per decade) than predicted by a smeared charge theory (6.0 mV per decade). Second, changing the net surface charge density of vesicles by the same amount in two distinct ways produced dramatically different effects: the molar partition coefficient decreased 1000-fold when the mole percentage of PS was decreased from 17% to 4%, but decreased only 10-fold when the peptide concentration was increased to 1 microM. Third, high concentrations of basic peptides reversed the charge on PS and PC/PS vesicles. Calculations based on finite difference solutions to the Poisson-Boltzmann equation applied to atomic models of heptalysine and PC/PS membranes provide a molecular explanation for the observations: a peptide adsorbing to the membrane in the presence of other surface-adsorbed peptides senses a local potential more negative than the average potential. The biological implications of these "discreteness-of-charge" effects are discussed.

2-Naphthylamine↗
PubMed1999

Effects of the protein kinase inhibitors wortmannin and KN62 on cellular radiosensitivity and radiation-activated S phase and G1/S checkpoints in normal human fibroblasts.

Wortmannin is a potent inhibitor of phosphatidylinositol (PI) 3-kinase and PI 3-kinase-related proteins (e.g. ATM), but it does not inhibit the activity of purified calmodulin-dependent protein kinase II (CaMKII). In the present study, we compared the effects of wortmannin and the CaMKII inhibitor KN62 on the response of normal human dermal fibroblast cultures to gamma radiation. We demonstrate that wortmannin confers a phenotype on normal fibroblasts remarkably similar to that characteristic of cells homozygous for the ATM mutation. Thus wortmannin-treated normal fibroblasts exhibit increased sensitivity to radiation-induced cell killing, lack of temporary block in transition from G1 to S phase following irradiation (i.e. impaired G1/S checkpoint), and radioresistant DNA synthesis (i.e. impaired S phase checkpoint). Wortmannin-treated cultures display a diminished capacity for radiation-induced up-regulation of p53 protein and expression of p21WAF1, a p53-regulated gene involved in cell cycle arrest at the G1/S border; the treated cultures also exhibit decreased capacity for enhancement of CaMKII activity post-irradiation, known to be necessary for triggering the S phase checkpoint. We further demonstrate that KN62 confers a radioresistant DNA synthesis phenotype on normal fibroblasts and moderately potentiates their sensitivity to killing by gamma rays, without modulating G1/S checkpoint, p53 up-regulation and p21WAF1 expression following radiation exposure. We conclude that CaMKII is involved in the radiation responsive signalling pathway mediating S phase checkpoint but not in the p53-dependent pathway controlling G1/S checkpoint, and that a wortmannin-sensitive kinase functions upstream in both pathways.

Androstadienes↗
PubMed1999

Is dieting good for you?: Prevalence, duration and associated weight and behaviour changes for specific weight loss strategies over four years in US adults.

OBJECTIVES: This present study describes weight control strategies used by a heterogeneous sample of US adults and their associations with weight and behaviour change over time. DESIGN: A prospective cohort study. PARTICIPANTS: Participants for this study were 1120 US adults recruited from the community who enrolled in a three-year intervention study to examine methods for preventing age-related weight gain. MEASURES: Measured body weight and self-reported behaviours related to body weight (dieting practices, dietary intake and physical activity) were completed annually for four years. RESULTS: Over 70% reported using each of the following dieting strategies at least once in four years: increase exercise (82.2%); decrease fat intake (78.7%); reduce food amount (78.2%); and reduce calories (73.2%). Cumulative duration of use of these behaviours was brief (for example, even the most common behaviours were used only 20% of the time). Global reports of dieting were not predictive of weight change over time. However, a dose-response relationship was observed between reported duration of use of several specific weight loss strategies over the four years and change in behaviours and weight gain. CONCLUSIONS: These findings suggest that public health recommendations for weight control may need to place greater emphasis on persistence of weight control behaviours.

Adult↗
PubMed1999

Variability of prothrombin time and activated partial thromboplastin time in the diagnosis of increased surgical bleeding.

BACKGROUND: Prothrombin time (PT) and activated partial thromboplastin time (APTT) are used to diagnose causes of increased surgical bleeding and to guide treatment of acquired coagulation factor deficiency. This study compared the sensitivity of various commercial PT and APTT tests in patients with dilutional coagulopathy. STUDY DESIGN AND METHODS: A prospective study was used to identify patients who experienced increased surgical bleeding during elective extensive (>10 spinal segments) spinal fusion and instrumentation. In patients with clinical signs of increased bleeding, blood was obtained to compare the sensitivity of various commercial PT and APTT tests. PT, PT ratio, the International Normalized Ratio (INR), APTT, and APTT ratio were compared for their sensitivity in the diagnosis of a dilutional coagulopathy. RESULTS: Sixteen patients experienced increased bleeding during surgery. Mean estimated blood volume lost exceeded 1 blood volume (1.14 +/- 0.28). PT and APTT test results varied markedly. In the most sensitive PT and APTT tests, the results were 1.5 times the mean reference range values in all but on of the patients. The least sensitive combination of tests had results that were 1.5 times the mean reference range values in only 2 of 16 patients. Variability among tests was not reduced by the use of the PT or the APTT ratio, by the use of INR, or by incorporation of a measure of PT or APTT test sensitivity to factor-deficient serum. CONCLUSION: In surgical patients with dilutional coagulopathy, diagnostic and treatment decisions could depend on which PT and APTT test was used to determine the etiology of increased bleeding. This study indicates that the relationship between increased bleeding and an increased PT and APTT may be more difficult to define than is suggested by current practice guidelines. Each laboratory must establish guidelines based on reagent and instrument sensitivity to coagulation factor dilution.

Blood Coagulation Disorders↗
PubMed1999

Inverse correlation between p53 protein levels and DNA repair efficiency in human fibroblast strains treated with 4-nitroquinoline 1-oxide: evidence that lesions other than DNA strand breaks trigger the p53 response.

Ionizing radiation-induced stabilization and the resultant transient accumulation of the p53 tumor suppressor protein is impaired in cells from ataxia telangiectasia (AT) patients, indicating a key role for ATM, the gene mutated in AT, upstream in the radiation-responsive p53 signaling pathway. Activation of this pathway is generally assumed to be triggered by DNA strand breaks produced directly following genotoxic stress or indirectly during excision repair of DNA lesions. The aim of this study was to identify the triggering signal for induction of p53 in diploid human dermal fibroblasts treated with 4-nitroquinoline 1-oxide (4NQO), a model environmental carcinogen that produces both DNA strand breaks (like ionizing radiation) and alkali-stable bulky DNA lesions (like UV light). 4NQO treatment of fibroblasts cultured from normal and AT donors and those from patients with the UV-hypersensitivity disorder xeroderma pigmentosum (XP, complementation groups A, E and G) resulted in up-regulation of p53 protein. In normal fibroblasts, there was no temporal relationship between the incidence of DNA strand breaks and levels of p53 protein; >90% of strand breaks and alkali-labile sites were repaired over 2 h following treatment with 1 microM 4NQO, whereas approximately 3 h of post-treatment incubation was required to demonstrate a significant rise in p53 protein. In contrast, exposure of normal fibroblasts to gamma-rays resulted in a rapid up-regulation of p53 and the level peaked at 2 h post-irradiation. XP cells with a severe deficiency in the nucleotide excision repair pathway showed abnormally high levels of p53 protein in response to 4NQO treatment, indicating that lesions other than incision-associated DNA strand breaks trigger p53 up-regulation. We observed a consistent, inverse correlation between the ability of the various fibroblast cultures to induce p53 following 4NQO treatment and their DNA repair efficiencies. Treatment with 0.12 microM 4NQO, for example, caused a >2-fold up-regulation of p53 in excision repair-deficient (AT, XPA and XPG) strains without eliciting any effect on p53 levels in repair-proficient (normal and XPE) strains. We conclude that up-regulation of p53 by 4NQO is mediated solely by an ATM-independent mechanism and that the p53 response is primarily triggered by persistent alkali-stable 4NQO-DNA adducts.

4-Nitroquinoline-1-oxide↗
PubMed1999

Chloramine-induced haemolysis presenting as erythropoietin resistance.

BACKGROUND: In December 1996 we identified an outbreak of erythropoietin (rHuEpo) resistance requiring a substantial increase in rHuEpo dosage in one of our four haemodialysis (HD) units. The dialysate chloramine levels in this unit had risen from <0.1 p.p.m. in 1996 to 0.25-0.3 p.p.m. in 1997. In the other three HD units levels remained <0.1 p.p.m. Other parameters of water quality were within accepted standards. METHODS: Monthly records of haemoglobin level and rHuEpo dose were available for 148 patients between January 1996 and May 1998. Seventy-two patients, with no recognized cause of rHuEpo resistance, were analysed in detail (August 1997 to April 1998). A subgroup of 15 patients was examined for evidence of haemolysis during HD (methaemoglobin and haptoglobin levels, reticulocyte counts and Heinz bodies). Larger carbon columns were installed in December 1997 to effect chloramine removal. RESULTS: There was an increase in mean methaemoglobinaemia of 23% (P<0.01) and a 21% fall in mean haptoglobin (P<0.01) across HD, although no patient had a reticulocytosis and only one patient with G6PD deficiency had Heinz bodies. Following installation of larger carbon columns there was an 18.6% rise (P<0.001) in mean haemoglobin level and a subsequent 25.0% reduction (P<0.001) in mean rHuEpo dose. Intradialytic changes in methaemoglobin and haptoglobin were abolished. The dialysate chloramine levels fell to < 0.1 p.p.m. Water company records subsequently revealed a sustained twofold increase in mains water chloramine from November 1996. CONCLUSIONS: This is the first report linking chloramine exposure and rHuEpo resistance, with only subtle signs of haemolysis. Unheralded changes in mains water constituents can directly affect dialysate water quality and clinical outcomes.

Adult↗
PubMed1999

Incomplete cement mantles in the sagittal femoral plane: an anatomical explanation.

The influence of operative technique on the formation of incomplete cement mantles in the sagittal plane has been rarely considered in the literature. In this article, we discuss the influence of the anatomy of the proximal femur on the formation of incomplete cement mantles and discuss how their incidence can be reduced by correct component positioning.

Cementation↗
PubMed1999

Decreased host-cell reactivation of UV-irradiated adenovirus in human colon tumor cell lines that have normal post-UV survival.

An ongoing study in our laboratories is to examine the relationship of DNA repair defects to human cancer. Our underlying hypothesis has been that human tumors may arise that lack interesting DNA repair pathways if these pathways are important in preventing cancer. In this study, we found that the UV-irradiated adenoviruses showed hypersensitivity when assayed on monolayers of certain human colon tumor cell lines, including three that are reported to have defects in long patch DNA mismatch repair genes and one with no reported defect in mismatch repair. The survival curves showed two components. The first sensitive component was characteristic of 77-95% of the infections depending upon the cell line and the experiment and had an average slope indicating 4.8-fold hypersensitivity to UV. The average of the second-component slopes indicated that the remainder of the infections was accompanied by near-normal repair. Although the value of the first component indicated that the colon tumor lines supported the growth of UV-damaged adenoviruses poorly, the cell lines themselves showed the same post-UV colony-forming ability as did normal human fibroblasts, and their ability to support the growth of N-methyl-N'-nitro-N-nitrosoguanidine-damaged adenoviruses was normal, i.e. it parallelled their ability to repair O6-methylguanine in vitro. We previously observed two-component survival curves when assaying UV-irradiated adenovirus on monolayers of all of seven strains of fibroblasts from Cockayne's syndrome patients. By contrast, single-component curves have been obtained using 21 strains of normal human fibroblasts and seven other tumor lines. We interpret the two-component survival curves in terms of the defective transcription-coupled repair of UV-induced DNA damage that is characteristic both of Cockayne's and certain colon tumor cell lines. In addition, four mismatch repair-deficient colon tumor lines were resistant to killing by elevated levels of dG.

Adenoviruses, Human↗
PubMed1999

Mechanisms of resistance to the toxicity of cyclophosphamide.

Resistance to cyclophosphamide therapy continues to be a major reason for treatment failure. This chapter covers some of the mechanisms implicated in resistance to the toxic and mutagenic effects of cyclophosphamide therapy in the laboratory and clinic. Since resistance is likely to be the result of a number of interrelating factors, this chapter evaluates the contribution of both glutathione and DNA repair processes to cyclophosphamide resistance. Glutathione appears to be involved directly in the detoxification of cyclophosphamide and metabolites and may play a more indirect role in other processes. The ability of the cell to repair cyclophosphamide-induced DNA lesions, possibly through nucleotide excision repair or other processes, may be a key contributor to drug resistance. Interestingly, the presence of the repair enzyme, O6-alkylguanine-DNA alkyltransferase, long thought to be involved with resistance to methylating and chloroethylating agents, may also contribute to resistance to the cytotoxic and mutagenic effects of cyclophosphamide.

Animals↗