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Biomedical subjects

L Price

Publications and source records attributed to L Price.

At least 19 recordsLinked to original sources
PubMed2007

A study to determine the minimum volume of blood necessary to be discarded from a central venous catheter before a valid sample is obtained in children with cancer.

BACKGROUND: The objective of this study was to determine the minimum volume of blood that should be discarded from a range of different types of central venous catheter (CVC), such that the subsequent blood sample was not diluted or contaminated by the residual intra-luminal fluid. PROCEDURE: Seventy children aged 1-19 years with central venous access inserted as part of their standard clinical treatment were recruited to this prospective study. Statistical comparison of the extent of variation in biochemical and haematological parameters observed between two blood samples taken following routine 5 ml discard blood volumes, as compared to the extent of variation between samples drawn following a 5 ml discard volume and <5 ml volumes, was carried out. RESULTS: Data indicate that the measurement error in a clinical sample obtained following a 3 ml discard volume is no different to the measurement error obtained when using a standard 5 ml discard volume. Comparable results were obtained from patients with various different types of CVC or portacath access. CONCLUSIONS: The withdrawal of a 3 ml discard volume is sufficient to ensure that the subsequent blood sample is not diluted or contaminated by residual intra-luminal fluid. This may have a significant clinical impact in paediatric oncology, where patients frequently require blood transfusions due to the haematological toxicities associated with chemotherapy. It is hoped that these results will impact on hospital policies concerning specified discard volumes taken from CVCs prior to the withdrawal of blood samples for research purposes and routine clinical analysis.

Adolescent↗
PubMed2006

Treating the clock and not the patient: ambulance response times and risk.

BACKGROUND: In a qualitative study of paramedics' attitudes to pre-hospital thrombolysis (PHT), the government target that emergency calls should receive a response within 8 minutes emerged as a key factor influencing attitudes to staff morale and attitudes to the job as a whole. A study was undertaken to examine paramedics' accounts of the effects on patient care and on their own health and safety of attempts to meet the 8 minute target. METHODS: In-depth semi-structured interviews were conducted with a purposive sample of 20 experienced paramedics (16 men) mostly aged 30-50 years with a mean length of service of 19 years. The paramedics were encouraged to raise issues which they themselves considered salient. The interviews were tape recorded, transcribed, and analysed according to the constant comparative method. RESULTS: The paramedics argued that response time targets are inadequate as a performance indicator. They dominate ambulance service culture and practice at the expense of other quality indicators and are vulnerable to "fiddling". The targets can conflict with other quality indicators such as timely administration of PHT and rapid transport of patients to hospital. The strategies introduced to meet the targets can be detrimental to patient care and also have adverse effects on the health, safety, wellbeing, and morale of paramedics. CONCLUSIONS: The results of this study suggest that the 8 minute response time is not evidence based and is putting patients and ambulance crews at risk. There is a need for less simplistic quality indicators which recognise that there are many stages between a patient's call for help and safe arrival in hospital.

Adult↗
PubMed2005

Pharmacokinetics and metabolism of ifosfamide in relation to DNA damage assessed by the COMET assay in children with cancer.

The degree of damage to DNA following ifosfamide (IFO) treatment may be linked to the therapeutic efficacy. The pharmacokinetics and metabolism of IFO were studied in 19 paediatric patients, mostly with rhabdomyosarcoma or Ewings sarcoma. Ifosfamide was dosed either as a continuous infusion or as fractionated doses over 2 or 3 days. Samples of peripheral blood lymphocytes were obtained during and up to 96 h after treatment, and again prior to the next cycle of chemotherapy. DNA damage was measured using the alkaline COMET assay, and quantified as the percentage of highly damaged cells per sample. Samples were also taken for the determination of IFO and metabolites. Pharmacokinetics and metabolism of IFO were comparable with previous studies. Elevations in DNA damage could be determined in all patients after IFO administration. The degree of damage increased to a peak at 72 h, but had returned to pretreatment values prior to the next dose of chemotherapy. There was a good correlation between area under the curve of IFO and the cumulative percentage of cells with DNA damage (r2=0.554, P=0.004), but only in those patients receiving fractionated dosing. The latter patients had more DNA damage (mean+/-s.d., 2736+/-597) than those patients in whom IFO was administered by continuous infusion (1453+/-730). The COMET assay can be used to quantify DNA damage following IFO therapy. Fractionated dosing causes a greater degree of DNA damage, which may suggest a greater degree of efficacy, with a good correlation between pharmacokinetic and pharmacodynamic data.

Adult↗
PubMed2005

A qualitative study of paramedics' attitudes to providing prehospital thrombolysis.

OBJECTIVES: To explore paramedics' attitudes to administering prehospital thrombolysis (PHT). METHOD: In-depth interviews with 20 paramedics were recorded and transcribed and analysed for emergent themes using the constant comparative method. RESULTS: Although there was a will to provide PHT because of its benefits to patients, its associated risks, aspects of pay and working conditions, and certain organisational factors undermined the willingness of some paramedics to administer thrombolysis. The eight minute response time standard is a competing imperative which can delay thrombolysis. CONCLUSIONS: A minority of paramedics are likely to be unwilling to deliver PHT unless countervailing imperatives are addressed.

Attitude of Health Personnel↗
PubMed2004

Estimation of glomerular filtration rate in paediatric cancer patients using 51CR-EDTA population pharmacokinetics.

Estimation of glomerular filtration rate (GFR) using the clearance of chromium 51 EDTA ((51)Cr-EDTA) (or other radiolabelled isotopes) is reliable, but invasive and not always practicable. Mathematical models have been devised for estimating GFR using readily obtainable patient characteristics. Unfortunately, these models were developed using various patient populations and may not provide the optimal prediction of GFR in children with cancer. The current study uses population pharmacokinetics to determine the relationship between (51)Cr-EDTA clearance, and patient covariates in 50 paediatric cancer patients. These models were validated using a separate group of 43 children and were compared with previously published models of renal function. Body size was the major determinant of (51)Cr-EDTA clearance and inclusion of weight or surface area reduced the residual variability between individuals (coefficient of variation) from 61 to 32%. Serum creatinine was the only other parameter that significantly improved the model. Mean percentage error values of -5.0 and -1.1% were observed for models including weight alone or weight and creatinine, respectively, with precision estimates of 21.7 and 20.0%. These simple additive models provide a more rationale approach than the use of complex formulae, involving additional parameters, to predict renal function.

Adolescent↗
PubMed2003

Diurnal variation in p42/44 mitogen-activated protein kinase in the rat pineal gland.

In this study, we investigated whether there was a diurnal difference in mitogen-activated protein kinase (p42/44(MAPK)) phosphorylation in the rat pineal gland. Under a lighting regimen with 12h of darkness, there was a two- to four-fold increase in phosphorylated levels of MAPK kinase 1/2 (MEK1/2) and p42/44(MAPK) 2h after onset of darkness, an increase that was sustained for 8h. The increases in phosphorylated levels of MEK1/2 and p42/44(MAPK) occurred without increases in MEK1/2 and p42/44(MAPK) proteins. When rats were treated with propranolol 1h before onset of darkness or subjected to continuous light exposure during the dark phase, the nocturnal increase in MEK1/2 and p42/44(MAPK) phosphorylation was reduced. Acute light exposure during darkness caused a decline in MEK1/2 and p42/44(MAPK) phosphorylation within 30 min of light exposure. These results indicate the presence of a diurnal difference in MEK1/2 and p42/44(MAPK) phosphorylation in the rat pineal gland that is under adrenergic control.

Animals↗
PubMed2002

Nephrotoxicity in survivors of Wilms' tumours in the North of England.

One aspect of concern for survivors of Wilms' tumour has been the late outcome in terms of renal function. Previous studies have documented low glomerular filtration rate and high blood pressure in some patients. Furthermore, disorders in tubular function (especially urinary concentration defects) have been suggested but not confirmed in small studies. The aim of this study was to determine the prevalence and nature of subclinical and overt glomerular, proximal and distal renal tubular toxicity in a population based cohort of survivors of Wilms' tumour. Forty patients (24 female) with a median age of 4.3 years (3 months-11.8 years) at diagnosis were studied. Median follow-up was 8.8 (range 0.06-27.5) years. Glomerular filtration rate was measured by (51)Cr-EDTA plasma clearance, proximal tubular function by electrolyte fractional excretions, urine excretion of low molecular weight proteins (retinol-binding protein) and renal tubular enzymes (alanine aminopeptidase; N-acetylglucosaminidase) and distal tubular function by the osmolality of the first two urines of the day on 3 consecutive days. Renal size (ultrasound) and blood pressure were also measured. Mean (range) glomerular filtration rate was 100 (61-150) ml min(-1) 1.73 m(-2). Nine were below the reference range for healthy individuals with two kidneys. Most serum electrolyte concentrations (sodium, potassium, chloride, calcium, magnesium and phosphate) fell within the normal range for age, as did the fractional excretions. The values that fell outside the normal range were only marginally abnormal. Subclinical measures of tubular toxicity (retinal-binding protein, alanine aminopeptidase, N-acetylglucosaminidase) were abnormal in only four patients. Thirty-seven patients achieved maximal urine osmolalities > or =800 mOsm kg(-1), but three failed to achieve this value even after DDAVP administration. Two patients had evidence of increased urinary albumin excretion. Compensatory renal hypertrophy was seen in all but two patients, but blood pressure was within normal limits in all patients. Current and past treatment for Wilms' tumour does not have any clinically important nephrotoxic effect in the majority of patients. This finding will enable paediatric oncologists to reassure patients and parents that treatment for Wilms' tumour rarely causes long-term renal impairment.

Age Factors↗
PubMed2002

Somatic and psychological problems in a cohort of sexually abused boys: a six year follow up case-control study.

AIMS: To obtain information about the health and well being of 108 boys six years after their involvement with the same paedophile. METHODS: Case-control study of the health records of 93 male victims of a major episode of school based child sexual abuse and 93 matched controls. Interviews with a sample of their general practitioners. RESULTS: The number and frequency of reported health problems were similar in both cases and controls. However, abused boys were more likely than controls to present with symptoms that persisted for more than a year (31 cases compared with 10 controls). CONCLUSIONS: Boys who have previously suffered sexual abuse at school did not utilise primary health care services more than a group of age matched controls. They did not present with psychological or somatic problems different from those presented by non-abused boys. However, abused boys were more likely to complain of persistent somatic or psychological problems lasting more than a year. This pattern appeared to persist after the abuse had stopped and the perpetrator imprisoned.

Case-Control Studies↗
PubMed2001

Potentiation of cyclic AMP and cyclic GMP accumulation by p38 mitogen-activated protein kinase (p38MAPK) inhibitors in rat pinealocytes.

The effects of p38 mitogen-activated protein kinase (p38MAPK) inhibitors on the adrenergic-stimulated cyclic nucleotide production in rat pinealocytes were investigated. Treatment with SB202190 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)IH-imidazole] and SB203580 [4-(4-fluoropheny)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)IH-imidazole] (1-100 microM), two pyridinyl imidazole compounds that inhibit p38MAPK, as well as SB202474 [4-(ethyl)-2-(4-methoxyphenyl)-5-(4-pyridyl)IH-imidazole], an inactive analog, was effective in potentiating norepinephrine- and isoproterenol-stimulated cyclic AMP (cAMP) and cyclic GMP (cGMP) accumulation in a concentration-dependent manner. All three compounds caused a greater increase in the cGMP than the cAMP response, with SB202474 being substantially more potent than the two active analogs. At 100 microM, SB202474 potentiated the isoproterenol-stimulated cAMP and cGMP accumulation by 65 and 500%, respectively. Pharmacological studies indicated that the potentiating effect of SB202474 was independent of protein kinase C activation, intracellular calcium elevation, or serine/threonine phosphatase inhibition, three pathways known to potentiate the beta-adrenergic-stimulated cyclic nucleotide responses in rat pinealocytes. In contrast, the potentiating effect of SB202474 was abolished in the presence of a phosphodiesterase inhibitor, isobutylmethylxanthine. At 100 microM, all three compounds inhibited cAMP- and cGMP-phosphodiesterase activities by 50 and 80%, respectively. These results suggest that the commonly used p38MAPK inhibitors can modulate cyclic nucleotide responses through phosphodiesterase inhibition, a mechanism that appears to be independent of p38MAPK inhibition.

Anacardic Acids↗
PubMed2001

An essential role for ARF6-regulated membrane traffic in adherens junction turnover and epithelial cell migration.

We describe a novel role for the ARF6 GTPase in the regulation of adherens junction (AJ) turnover in MDCK epithelial cells. Expression of a GTPase-defective ARF6 mutant, ARF6(Q67L), led to a loss of AJs and ruffling of the lateral plasma membrane via mechanisms that were mutually exclusive. ARF6-GTP-induced AJ disassembly did not require actin remodeling, but was dependent on the internalization of E-cadherin into the cytoplasm via vesicle transport. ARF6 activation was accompanied by increased migratory potential, and treatment of cells with hepatocyte growth factor (HGF) induced the activation of endogenous ARF6. The effect of ARF6(Q67L) on AJs was specific since ARF6 activation did not perturb tight junction assembly or cell polarity. In contrast, dominant-negative ARF6, ARF6(T27N), localized to AJs and its expression blocked cell migration and HGF-induced internalization of cadherin-based junctional components into the cytoplasm. Finally, we show that ARF6 exerts its role downstream of v-Src activation during the disassembly of AJs. These findings document an essential role for ARF6- regulated membrane traffic in AJ disassembly and epithelial cell migration.

ADP-Ribosylation Factor 6↗
PubMed2001

A phase I study of nolatrexed dihydrochloride in children with advanced cancer. A United Kingdom Children's Cancer Study Group Investigation.

A phase I study of nolatrexed, administered as a continuous 5 day intravenous infusion every 28 days, has been undertaken for children with advanced malignancy. 16 patients were treated at 3 dose levels; 420, 640 and 768 mg/m(2)24 h(-1). 8 patients were evaluable for toxicity. In the 6 patients treated at 768 mg/m(2)24 h(-1), dose-limiting oral mucositis and myelosuppression were observed. Plasma nolatrexed concentrations and systemic exposure, measured in 14 patients, were dose related, with mean AUC values of 36 mg(-1)ml(-1)min(-1), 50 mg ml(-1)min(-1)and 80 mg ml(-1)min(-1)at the 3 dose levels studied. Whereas no toxicity was encountered if the nolatrexed AUC was <45 mg ml(-1)min(-1), Grade 3 or 4 toxicity was observed with AUC values of >60 mg ml(-1)min(-1). Elevated plasma deoxyuridine levels, measured as a surrogate marker of thymidylate synthase inhibition, were seen at all of the dose levels studied. One patient with a spinal primitive neuroectodermal tumour had stable disease for 11 cycles of therapy, and in two patients with acute lymphoblastic leukaemia a short-lived 50% reduction in peripheral lymphoblast counts was observed. Nolatrexed can be safely administered to children with cancer, and there is evidence of therapeutic activity as well as antiproliferative toxicity. Phase II studies of nolatrexed in children at the maximum tolerated dose of 640 mg/m(2)24 h(-1)are warranted.

Acute Disease↗
PubMed2001

Cyclophosphamide metabolism in children following a 1-h and a 24-h infusion.

PURPOSE: The pharmacokinetics and metabolism of cyclophosphamide (CPA) when given as a 1-h and a 24-h infusion to children were compared. METHODS: Thirteen children with a variety of different malignancies received an identical dose of cyclophosphamide as a 1- and 24-h infusion. In each case the concentration of CPA and its principal metabolites were measured by a thin-layer-chromatography-photographic-densitometry technique. RESULTS: Cyclophosphamide clearance was greater during the 24-h infusion, following time-dependent increases in the metabolism of the drug (autoinduction) (median 5.1 vs 3.1 l/h/m2: P = 0.037). Autoinduction was seen in five children (38%), producing a median end of infusion concentration of 49% (range 28-89%) of the maximum and was not accompanied by an increase in the production of the principal inactive metabolites carboxyphosphamide and dechloroethylcyclophosphamide. CONCLUSIONS: These results suggest potential benefits of prolonging the infusion of CPA in clinical practice.

Adolescent↗
PubMed2001

Early initiation of growth hormone treatment allows age-appropriate estrogen use in Turner's syndrome.

Because estrogen (E) accelerates skeletal maturation it can decrease final height attainable with GH therapy in girls with Turner's syndrome (TS). Nonetheless, as age-appropriate E administration does have psychobehavioral benefits for such patients, we asked whether E treatment in TS could occur without adverse impact on final adult height if GH therapy were started at an earlier age. Near adult height (NAH) was assessed in 344 girls with TS, who had received both GH and E and were followed in the National Cooperative Growth Study database. The groups were divided into quartiles based on age at initiation of GH (2-10, 10-12, 12-14, and 14-18 yr). The longest total and E-free period of GH treatment occurred in the girls who had started treatment in the youngest quartile (mean age, 8.2 +/- 1.5 (SD) yr); they were also exposed to E at the youngest age (12.7 +/- 1.6 yr). Although the girls in the youngest group received E at an earlier age, they had a significantly greater increase (1.8 +/- 0.8) in Lyon height SD score at NAH over Lyon predicted adult height than those in the oldest GH-treated group (0.8 +/- 0.6), which first received E at 15.9 +/- 1.3 yr. Multiple linear regression equations for gain in Lyon height SD score and in height (cm) showed greater increments with a longer period of E-free GH therapy. All four GH age groups had the same NAH, but the youngest quartile was youngest at NAH and likely still having more growth potential. Comparable data were found in 127 TS girls with spontaneous puberty. In conclusion, girls with TS starting GH at an early age have a greater gain in Lyon SD score at NAH compared with those starting later, even though they received E at a younger age. If GH therapy were started early, E treatment could be initiated at a younger, more age-appropriate time without compromising adult height.

Adolescent↗
PubMed2001

Reconstruction of ligand-dependent transactivation of Choristoneura fumiferana ecdysone receptor in yeast.

Ecdysteroids play an important role in regulating development and reproduction in insects. Interaction of 20-hydroxyecdysone (20E) with ecdysone receptor (EcR) as a heterodimer with ultraspiracle (USP) protein triggers the activation of 20E-responsive genes. In this paper we describe a ligand-mediated transactivation system in yeast using the spruce budworm Choristoneura fumiferana ecdysone receptor (CfEcR). Coexpression of C. fumiferana USP (CfUSP) with CfEcR in yeast led to constitutive transcription of the reporter gene. However, deletion of the A/B domain of CfUSP abolished constitutive activity observed for the CfUSP:CfEcR complex. Replacement of USP with its mammalian homolog retinoid X receptors (RXRs) abolished the constitutive activity of the heterodimer but it did not restore EcR ligand-mediated transactivation. These data suggest that USP and its A/B domain play a role in the constitutive function of CfEcR:USP in yeast. A ligand-mediated transactivation was observed when GRIP1, a mouse coactivator gene, was added to EcR:RXR or EcR:DeltaA/BUSP complexes. Deletion of the A/B domain of EcR in the context of DeltaA/BEcR:RXR:GRIP1 or DeltaA/BEcR:DeltaA/BUSP:GRIP1 dramatically improved the ligand-dependent transactivation. This is the first example of highly efficient ligand-dependent transactivation of insect EcR in yeast. Analysis of transactivation activity of different ecdysteroidal compounds showed that the yeast system remarkably mimics the response observed in insect tissue culture cells and whole insect systems. The results open the way to develop assays that can be used to screen novel species-specific ecdysone agonist/antagonist insecticides.

Animals↗
PubMed2001

Telepathology.

The development of a Queensland-wide videoconferencing network provided an opportunity to develop telepathology. In 1999, weekly videoconferences began with remote laboratories and clinical staff in four peripheral hospitals and the Royal Brisbane Hospital and in 2000 biweekly videoconference pathology grand rounds started across Queensland with up to six sites, from Cairns to the Gold Coast, joining in or presenting. The average number of sites connected was 3.0 in 1998, 3.5 in 1999, 4.4 in 2000 and 4.5 in 2001. Problems included the complexity of the system, timing and need for bookings, coordination of presenters and presentations, and the time needed to organize sessions, set up linkages, advertise sessions and attend the telepathology conference. Successful meetings have been associated with well prepared cases, time for discussion, attendance by all sites, timeliness of cases and responses, and the presence of experts to respond to questions, as well as effective linkages and trouble-free hardware. Future needs include better infrastructure and trained staff to coordinate the linkages and presentations. Telepathology has an important part to play in the provision of cost-effective medical care in Queensland.

Computer Terminals↗
PubMed2001

Influence of cellular factors and pharmacokinetics on the formation of platinum-DNA adducts in leukocytes of children receiving cisplatin therapy.

The formation of platinum (Pt)-DNA adducts is thought to be crucial to the antitumor activity of cisplatin, and relationships between adduct formation in peripheral blood leukocytes (PBLs) and response to cisplatin therapy have been reported. The current study directly tests, for the first time, whether pharmacokinetic or other factors predominantly determine the drug-target interaction of cisplatin in a pediatric patient population. Cisplatin pharmacokinetics and Pt-DNA adduct formation in PBLs were determined in 10 children in parallel with measurement of adduct levels after incubation of pretreatment blood samples with cisplatin in vitro. Total and unbound plasma Pt concentrations were determined by atomic absorption spectrophotometry and adduct measurements performed by competitive ELISA. Pt-DNA adduct levels determined after cisplatin treatment showed considerable interindividual variation (peak levels at 24 h ranged from 0.15 to 1.31 nmol/g DNA) and correlated strongly with adduct levels determined after incubation of pretreatment whole blood with cisplatin (r = 0.92; P = 0.0002). No significant correlation was observed between in vivo adduct formation and either unbound or total cisplatin plasma concentrations (r = 0.14 and 0.18, respectively). A correlation was also observed between the degree of myelosuppression, as determined by WBC nadirs measured over a 14-day period after cisplatin treatment, and the extent of adduct formation, with greater WBC toxicity observed in patients with higher levels of Pt-DNA adducts (P = 0.010). These preliminary results provide evidence that interpatient variation in formation of Pt-DNA adducts in PBLs of children is determined by host-specific factors other than cisplatin pharmacokinetics. These results imply that analysis of adducts in PBLs after incubation of pretreatment blood samples with cisplatin may be used to predict in vivo adduct levels, leukopenia, and, potentially, response to cisplatin therapy.

Adolescent↗