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Biomedical subjects

S Murray

Publications and source records attributed to S Murray.

At least 37 records · Page 2Linked to original sources
PubMed2001

Diazinon is activated by CYP2C19 in human liver.

Phosphorothioate compounds are used throughout the world as agricultural and domestic pesticides. Here, the activation of the phosphorothioate diazinon to diazoxon in human liver is described. In an initial study using three human liver microsomal samples, K(m) for diazoxon formation varied markedly (31, 208, and 660 microM; V(max) 1125, 685, and 1028 pmol/min/mg protein, respectively), suggesting the involvement of more than one P450 enzyme. A wide variation in activity was found using 50 microM diazinon as substrate, (11-648 pmol/min/mg protein, n = 15), whereas, with 500 microM, variation was less (164-978 pmol/min/mg protein). Among eight P450-catalyzed reactions, the putative high-affinity component (50 microM diazinon) correlated with S-mephenytoin 4'-hydroxylase activity (r = 0.686, p < 0.01), suggesting the involvement of CYP2C19. The putative low-affinity component (500 microM diazinon) correlated with both S-mephenytoin 4'-hydroxylase (r = 0.714; p < 0.005) and high-affinity phenacetin O-deethylase activity (r = 0.625; p < 0.05). This activity was partially inhibited by furafylline, troleandomycin, and ketoconazole. These data suggest contributions from CYP2C19, CYP1A2, and CYP3A4. None of the inhibitors affected the high-affinity component. Of seven heterologously expressed human P450 enzymes, CYP2C19 activated diazinon (500 microM) at the fastest rate, followed by CYP3A4, CYP1A2, and CYP2C9. Both hepatic microsomal S-mephenytoin 4'-hydroxylase and high-affinity phenacetin O-deethylase activities were strongly inhibited by diazinon (IC50 < 2.5 microM), while no effect was seen on midazolam 1'-hydroxylase activity. These data indicate that CYP2C19 is the major enzyme involved in diazinon activation in human liver, while other enzymes including CYP1A2 may play a more minor role.

Aryl Hydrocarbon Hydroxylases↗
PubMed2001

Analysis of broadband x-ray spectra of highly charged krypton from a microcalorimeter detector of an electron-beam ion trap.

Spectra of highly charged Kr ions, produced in an electron-beam ion trap (EBIT), have been recorded in a broad x-ray energy band (0.3 keV to 4 keV) with a microcalorimeter detector. Most of the spectral lines have been identified as transitions of B- to Al-like Kr. The transition energies have been determined with 0.2% uncertainty. A semi-empirical EBIT plasma model has been created to calculate a synthetic spectrum of highly charged Kr and to determine a charge state distribution of Kr ions inside the EBIT.

Journal Article↗
PubMed2001

Analysis of the glutathione conjugate of paracetamol in human liver microsomal fraction by liquid chromatography mass spectrometry.

An assay based on microbore liquid chromatography-positive ion electrospray mass spectrometry with selected ion recording has been developed for the measurement of the glutathione conjugate of paracetamol (acetaminophen) in human hepatic microsomal incubations. A deuterated analogue of the glutathione conjugate was synthesized for use as an internal standard and extraction was carried out on Oasis solid phase extraction columns. The limit of quantification of the glutathione conjugate was 10 ng/incubation and the intra-assay coefficient of variation at this concentration was 6.8%.

Acetaminophen↗
PubMed2001

Using auxiliary time-dependent covariates to recover information in nonparametric testing with censored data.

Murray and Tsiatis (1996) described a weighted survival estimate that incorporates prognostic time-dependent covariate information to increase the efficiency of estimation. We propose a test statistic based on the statistic of Pepe and Fleming (1989, 1991) that incorporates these weighted survival estimates. As in Pepe and Fleming, the test is an integrated weighted difference of two estimated survival curves. This test has been shown to be effective at detecting survival differences in crossing hazards settings where the logrank test performs poorly. This method uses stratified longitudinal covariate information to get more precise estimates of the underlying survival curves when there is censored information and this leads to more powerful tests. Another important feature of the test is that it remains valid when informative censoring is captured by the incorporated covariate. In this case, the Pepe-Fleming statistic is known to be biased and should not be used. These methods could be useful in clinical trials with heavy censoring that include collection over time of covariates, such as laboratory measurements, that are prognostic of subsequent survival or capture information related to censoring.

Data Interpretation, Statistical↗
PubMed2001

Social deprivation and traumatic dental injuries among 14-year-old schoolchildren in Newham, London.

AIMS: To assess the epidemiology of dental injuries among schoolchildren in Newham, London. MATERIAL AND METHODS: This study was carried out as part of the annual Community Dental Service's School Dental Inspection (SDI) programme in Newham. All schoolchildren aged 14 years were invited to participate in the study. Dental examinations were carried out by one trained examiner (SM) and included presence of clinical evidence of dental injuries, treatment provided and needed in the upper and lower permanent incisors, size of incisal overjet and type of lip coverage. The postcode was recorded to assess the levels of social deprivation. FINDINGS: 2242 out of 2684 children were examined. The prevalence of dental injuries was 23.7%. Treatment of dental injuries was neglected. Being male, having an incisal overjet greater than 5 mm and living in an overcrowded household increased the risk of having dental injuries. CONCLUSIONS: The prevalence of dental injuries in Newham (23.7%), which is a deprived area of London, was much higher than the overall prevalence in the UK (17%). Traumatic dental injuries seem to be a serious dental public health problem among children in deprived areas. Thus, there is an urgent need to collect local data on dental injuries in order to obtain a more comprehensive picture of the dental health.

Adolescent↗
PubMed2001

Liquid meal replacements and glycemic control in obese type 2 diabetes patients.

OBJECTIVE: Although weight management is an important component in the treatment of type 2 diabetes, there has been concern about the use of liquid meal replacements (MRs) in treating obese patients with type 2 diabetes because of the sugar content of the MRs. The goal of this study was to evaluate the safety and feasibility of using MRs for weight loss in obese patients with type 2 diabetes. RESEARCH METHODS AND PROCEDURES: Seventy-five subjects with type 2 diabetes, treated only with oral agents, were recruited for this 12-week clinical study. Subjects were randomized into three groups using either a MR containing lactose, fructose, and sucrose, a MR in which fructose and sucrose were replaced with oligosaccharides (sugar-free Slim-Fast), or an exchange diet plan (EDP) using the proportion of macronutrients recommended by the American Diabetes Association. RESULTS: Fifty-seven patients (41 MR and 16 EDP) finished the study. None developed serious adverse effects, including major hypoglycemic reactions. Weight losses in the MR 1 and MR 2 groups were comparable (6.4% and 6.7%, respectively) and greater than the weight loss in the EDP group (4.9%). Fasting glucose level was significantly reduced in the MR group compared with the EDP group (p = 0.012). There was a significant reduction in the MR group in total cholesterol and low-density lipoprotein cholesterol that was not seen in the EDP group. DISCUSSION: We have shown that liquid MRs are a safe and effective weight loss tool for obese subjects with type 2 diabetes, and can result in improvements in body weight, glucose, insulin, hemoglobin A1c and lipid levels.

Blood Glucose↗
PubMed2001

Developing A&E nursing responses to people who deliberately self-harm: the provision and evaluation of a series of reflective workshops.

Accident & Emergency (A&E) departments and Medical Admission Units (MAUs) are an essential part of emergency mental health care in the UK. Deliberate self-harm and attempted suicide are particular challenges to nursing staff in such departments. Two registered mental nurses with experience of education facilitated a series of workshops with nurses from four A&E departments, two Minor Injuries Units and two MAUs. These were focused upon the assessment and management of deliberate self-harm and attempted suicide. During the workshops, participants provided systematic information on presentations of deliberate self-harm and attempted suicide, and on their professional responses to such presentations. These accounts provided invaluable information on deliberate self-harm and attempted suicide as seen by nursing staff in A&E and MAUs. Critical reflection upon nursing responses to these presentations revealed particular concerns nurses had relating to their experience with this client group which might inform future practice. Evaluation of the workshops indicated a subsequent decrease in work-related stress, which was probably a consequence of improved professional coping responses by the nurses concerned.

Adolescent↗
PubMed2001

Pre- and post-test evaluation of a project to facilitate research development in practice in a hospital setting.

BACKGROUND: This paper describes a project designed to facilitate the use of research in nursing practice in one acute hospital. A university team worked in collaboration with staff from the hospital to develop and evaluate the impact of development work designed to enhance knowledge and use of research in practice. DESIGN/METHODS: A research utilization questionnaire was administered as a pre-test (stage 1); a development phase was implemented (stage 2) and a post-test survey (stage 3) was administered to evaluate the impact of the development work. In stage 1, the total population of nursing and midwifery staff in the hospital (n=473) were targeted and 235 returned the questionnaire, giving a response rate of 50%. Data from the pre-test and focus group discussions with staff were used to plan stage 2 of the project. The development stage involved an educational strand in which open learning research materials were made available to staff, who were also offered tutorial support in their learning. A second strand supported the development of clinical research projects and funds were identified for clinical staff to apply for project development awards to enable them to develop skills in research and development activity under the supervision of a research fellow. Stage 3 involved a post-test survey of staff who had completed the questionnaire in stage 1 (n=81). FINDINGS: There were no significant differences in findings between the pre-test and post-test. Qualitative data from those involved in the clinical projects in stage 2 indicated factors impacting on the feasibility of undertaking research in practice.

Adult↗
PubMed2001

Inhibition of human CYP1A2 activity in vitro by methylxanthines: potent competitive inhibition by 8-phenyltheophylline.

1. Humans are exposed in vivo to methylxanthines by dietary ingestion, as well as from their use as therapeutic agents. The inhibitory effect of a series of these compounds on high-affinity phenacetin O-deethylase activity in the human liver microsomal fraction, a measure of CYP1A2 activity, has been evaluated. 2. Paracetamol, the product of phenacetin O-deethylase activity, was analysed by gas chromatography/negative-ion mass spectrometry using a novel bistrifluoromethylbenzoyl/ trimethylsilyl derivative, and incubation conditions for assessing high-affinity phenacetin O-deethylase activity were examined and optimized. 3. 1-Methylxanthine, caffeine, theophylline, 8-methylxanthine, pentoxyfylline and 3isobutyl-1-methylxanthine caused moderate inhibition with IC50 = 260, 140, 120, 100, 62 and 36 microM respectively. 4. 8-Phenyltheophylline was a potent competitive inhibitor of high-affinity phenacetin O-deethylase activity with an IC50 = 0.7 microM and Ki = 0.11 microM. 5. The specificity of inhibition by 8-phenyltheophylline was assessed by measuring its effect on debrisoquine 4-hydroxylase (CYP2D6), terfenadine hydroxylase (CYP3A4), chlorzoxazone 6-hydroxylase (CYP2E1) and tolbutamide 4-hydroxylase (CYP2C9) activities in human liver microsomal fraction. No inhibition of any of these activities was observed. 6. The potency and specificity of 8-phenyltheophylline as an inhibitor of human hepatic CYP1A2 indicate that the compound may be useful as a chemical inhibitor of this enzyme for further in vitro studies.

Acetaminophen↗
PubMed2001

Gamma-hydroxybutyric acid: patterns of use, effects and withdrawal.

Gamma-hydroxybutyric acid (GHB) is gaining popularity as a drug of abuse. Reports of toxicity and lethality associated with GHB use have increased. This survey study was designed to identify patterns of GHB use, its effects, and withdrawal syndrome. A survey inquiring about the effects of GHB was administered to 42 users. The results showed that GHB was used to increased feelings of euphoria, relaxation, and sexuality. Adverse effects occurred more frequently in daily users and polydrug users than in occasional GHB users. Loss of consciousness was reported by 66%, overdose by 28%, and amnesia by 13% of participants during GHB use and by 45% after GHB use. Three daily users developed a withdrawal syndrome that presented with anxiety, agitation, tremor, and delirium. Participants described GHB intoxication as having similarities to sedative-hypnotic or alcohol intoxication. Regular use has been shown to produce tolerance and dependence. Participants dependent on GHB reported using multiple daily doses around the clock. High frequency users appeared at the greatest risk for developing withdrawal delirium and psychosis after abrupt discontinuation of GHB use.

Adult↗
PubMed2001

Effect of cruciferous vegetable consumption on heterocyclic aromatic amine metabolism in man.

The consumption of cooked meat appears to predispose individuals to colonic cancer and heterocyclic aromatic amines (HA), formed during the cooking of meat, have been suggested as aetiological agents. Consumption of cruciferous vegetables is thought to protect against cancer. To study the effect of cruciferous vegetables on heterocyclic aromatic amine metabolism in man, a three-period, dietary intervention study has been carried out with 20 non-smoking Caucasian male subjects consuming cooked meat meals containing known amounts of these carcinogens. A high cruciferous vegetable diet (250 g each of Brussels sprouts and broccoli per day) was maintained during period 2 but such vegetables were excluded from periods 1 and 3. At the end of each period, subjects consumed a cooked meat meal and urinary excretion of the HA 2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) was measured. Following a 12 day period of cruciferous vegetable consumption (period 2), induction of hepatic CYP1A2 activity was apparent from changes in the kinetics of caffeine metabolism. Excretion of MeIQx and PhIP in urine at the end of this period of the study was reduced by 23 and 21%, respectively, compared with period 1. This reduction in excretion is probably due to an increase in amine metabolism that might be expected given the observed increase in CYP1A2 activity, since this enzyme has been shown to be primarily responsible for the oxidative activation of MeIQx and PhIP in man. In period 2, urinary mutagenicity was increased relative to period 1 by 52 and 64% in the absence and presence, respectively, of a human liver microsomal activation system, yet no evidence was found of PhIP adduction to lymphocyte DNA, a potential biomarker of the activation process. After another 12 days without cruciferous vegetables (period 3 of the study), the kinetics of caffeine metabolism had returned to original values but excretion of MeIQx and PhIP was still reduced by 17 and 30%, respectively, and urinary mutagenicity (with metabolic activation) was still elevated compared with period 1. This prolonged response of amine metabolism to the cruciferous vegetable diet, shown especially with PhIP, suggests that enzyme systems other than CYP1A2 are involved and affected by a cruciferous vegetable diet.

Adult↗
PubMed2001

Using weighted Kaplan-Meier statistics in nonparametric comparisons of paired censored survival outcomes.

This research introduces methods for nonparametric testing of weighted integrated survival differences in the context of paired censored survival designs. The current work extends work done by Pepe and Fleming (1989, Biometrics 45, 497-507), which considered similar test statistics directed toward independent treatment group comparisons. An asymptotic closed-form distribution of the proposed family of tests is presented, along with variance estimates constructed under null and alternative hypotheses using nonparametric maximum likelihood estimates of the closed-form quantities. The described method allows for additional information from individuals with no corresponding matched pair member to be incorporated into the test statistic in sampling scenarios where singletons are not prone to selection bias. Simulations presented over a range of potential dependence in the paired censored survival data demonstrate substantial power gains associated with taking into account the dependence structure. Consequences of ignoring the paired nature of the data include overly conservative tests in terms of power and size. In fact, simulation results using tests for independent samples in the presence of positive correlation consistently undershot both size and power targets that would have been attained in the absence of correlation. This additional worrisome effect on operating characteristics highlights the need for accounting for dependence in this popular family of tests.

Humans↗
PubMed2001

Phosphorylation of the RNA polymerase II carboxy-terminal domain by the Bur1 cyclin-dependent kinase.

BUR1, which was previously identified by a selection for mutations that have general effects on transcription in Saccharomyces cerevisiae, encodes a cyclin-dependent kinase that is essential for viability, but none of its substrates have been identified to date. Using an unbiased biochemical approach, we have identified the carboxy-terminal domain (CTD) of Rpb1, the largest subunit of RNA polymerase II, as a Bur1 substrate. Phosphorylation of Rpb1 by Bur1 is likely to be physiologically relevant, since bur1 mutations interact genetically with rpb1 CTD truncations and with mutations in other genes involved in CTD function. Several genetic interactions are presented, implying a role for Bur1 during transcriptional elongation. These results identify Bur1 as a fourth S. cerevisiae CTD kinase and provide striking functional similarities between Bur1 and metazoan P-TEFb.

Animals↗
PubMed2001

Personality profile and neuropsychological test performance in chronic cocaine-abusers.

Little is known about the association between personality disorders and neuropsychological test performance in chronic cocaine users. The aims of the present study were to (1) pinpoint the specific neuropsychological characteristics of chronic cocaine abusers, (2) analyze their personality profile, and (3) explore the association between personality traits and neuropsychological test performance. A sample of 42 drug-abusers (mean age = 34.15; SD = 6.73; mean educational level = 11.44; SD = 2.01) was selected from a state rehabilitation facility and was compared to a control group (mean age = 34.53; SD = 9.01; mean educational level = 12.29; SD = 1.31). The following information was collected for each subject: (1) A clinical history adapted from Horton (1996). (2) The Personality Assessment Inventory (PAI) (Morey, 1991). (3) A neuropsychological test battery including: Arithmetic and Digits subtests from the WAIS-R, California Verbal Learning Test, Trial Making Test, Verbal Fluency tests, Rey-Osterrieth Complex Figure, Wisconsin Card Sorting Test, Benton Visual Retention Test, Stroop Neurological Screening Test and Hooper Visual Organization. Thirty-seven of the drug-dependent subjects obtained an abnormal score in at least one PAI scale. The personality profile of the drug-dependent subjects found via the PAI pointed to a Borderline/Antisocial personality, frequently associated with mania features. In six of the drug-abusers, a normal personality profile was observed. Neuropsychological test performance scores were within the low average or borderline range. The most abnormal scores were observed in attention, memory, and executive functioning tests. The results did not show any robust association between personality profile and neuropsychological test performance.

Adult↗
PubMed2001

Food-derived heterocyclic amine mutagens: variable metabolism and significance to humans.

The cooking of meat has been found to generate compounds that possess extreme mutagenicity when examined in short term tests. This observation led to the isolation and identification of a family of mutagenic chemicals, all of which are heterocyclic amines. These amines are potent bacterial and eukaryotic cell mutagens, and all of those tested have been found to induce tumors in laboratory animals. Metabolic activation of the heterocyclic amines predominantly involves CYP1-mediated N-hydroxylation and then O-esterification by phase II enzymes. In contrast, carbon oxidation, glucuronidation, and sulfation reactions at sites other than the hydroxylamine yield detoxication metabolites. In humans, the activities of these pathways are known to vary between individuals and are likely to influence susceptibility to the genetic toxicity of the heterocyclic amines. Clearly, accurate determination of human exposure to the heterocyclic amines and identification of the key enzyme systems involved and their regulation will be required for rational assessment of the risk and will help devise strategies to reduce such risk.

Amines↗
PubMed2001

Assessment of early continence recovery after radical prostatectomy: patient reported symptoms and impairment.

PURPOSE: Patients considering radical prostatectomy often inquire as to when they can expect to regain urinary continence. However, there is a paucity of patient self-reported data regarding the recovery of continence during the initial 3 months after surgery. Our objectives were to assess urinary continence changes early in the postoperative period and determine which of 2 commonly used definitions of continence more closely relate to patient reported urinary impairment. MATERIALS AND METHODS: A prospective study of 90 men with clinically localized prostate cancer who selected radical prostatectomy as primary therapy was conducted. Repeated measures of urinary continence as defined by 1) total urinary control, 2) the use of 1 or 0 pads daily, and 3) small or no problem with urinary function were obtained with a brief survey preoperatively and postoperatively. RESULTS: At 56 days after removal of urethral catheters, the actuarial rates of urinary continence recovery based on definitions 1 to 3 were 43%, 84% and 82%, respectively. The use of definition 2 for continence resulted in a 1.9 times higher actuarial rate for continence recovery when compared to definition 1 at 56 days (p <0.001). However, strong agreement was observed between definitions 2 and 3 (kappa = 0.69). CONCLUSIONS: Urinary control is recovered in a significant proportion of men who undergo radical prostatectomy during the initial 3 months. Continence rates will vary significantly based on the use of alternative definitions. The clinical practice of asking patients how many pads daily they use may be valid, as it corresponds well to the impairment they have.

Aged↗
PubMed2000

X-ray photoelectron spectroscopy and magnetic studies on the effect of pore size, wall thickness, and wall composition on superparamagnetic cobaltocene mesoporous Nb, Ta, and Ti composites.

Recent results in our group demonstrated that mixed oxidation state mesoporous niobium oxide cobaltocene composites display superparamagnetism at certain composition ratios. This was the first report of superparamagnetism in nanoscale molecular ensembles. A series of mesoporous niobium oxide materials were synthesized in order to understand the role of pore size and thickness of the walls in the mesostructure on the magnetic properties. Mesoporous Ti oxide and Ta oxide composites were also synthesized in order to investigate the effect of changing the wall composition on the magnetic properties of this new series of materials. All samples were characterized by X-ray diffraction, nitrogen adsorption, ultraviolet spectroscopy, X-ray photoelectron spectroscopy, scanning electron microscopy, and superconducting quantum interference device magnetometry. The results of this study showed that variation of wall thickness or pore size in the Nb system had little effect on the properties and that superparamagnetism most likely arises from mixed oxidation state cobaltocene grains residing in the individual pores and not from the free electrons in the mesostructure or much larger domains. The Langevin function was applied to the isothermal magnetic data from the Nb composites and gave mean superparamagnetic particle sizes of ca. 14 nm in each system. The Co(II) to Co(III) ratios in these materials were approximately 1:1. The Ti and Ta materials showed no sign of superparamagnetism and only very low levels of neutral cobaltocene in the pores. This suggests that a critical amount of cobaltocene is required to bring about superparamagnetic behavior.

Journal Article↗