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Biomedical subjects

M Murray

Publications and source records attributed to M Murray.

At least 19 recordsLinked to original sources
PubMed2006

Tumor-selective drug activation: a GDEPT approach utilizing cytochrome P450 1A1 and AQ4N.

Drug metabolizing transgene products, which activate bioreductive cytotoxins, can be used to target treatment-resistant hypoxic tumors. The prodrug AQ4N is bioreduced in hypoxic cells by cytochrome P450s (CYPs) to the cytotoxin AQ4. Previously we have shown that intra-tumoral injection of CYP3A4 and CYP2B6 transgenes with AQ4N and radiation inhibits tumor growth. Here we examine the ability of other CYPs, in particular CYP1A1, to metabolize AQ4N, and to enhance radiosensitization. Metabolism of AQ4N was assessed using microsomes prepared from baculovirus-infected cells transfected with various CYP isoforms. AQ4N metabolism was most efficient with CYP1A1 (66.7 nmol/min/pmol) and 2B6 (34.4 nmol/min/pmol). Transient transfection of human CYP1A1+/-CYP reductase (CYPRED) was investigated in hypoxic RIF-1 mouse cells in vitro using the alkaline comet assay. There was a significant increase in DNA damage following transient transfection of CYP1A1 compared to non-transfected cells; inclusion of CYPRED provided no additional effect. In vivo, a single intra-tumoral injection of a CYP1A1 construct in combination with AQ4N (100 mg/kg i.p.) and 20 Gy X-rays caused a 16-day delay in tumor regrowth compared to tumors receiving AQ4N plus radiation and empty vector (P=0.0344). The results show the efficacy of a CYP1A1-mediated GDEPT strategy for bioreduction of AQ4N.

Animals↗
PubMed2006

Neuropsychological dysfunction following repeat concussions in jockeys.

BACKGROUND: Single and repeat concussions have a high prevalence in sport. However, there is limited research into longterm risks associated with single and repeat concussions. OBJECTIVES: To determine the effects of single and repeat historical concussions on the neuropsychological functioning and neurological reports of licensed jockeys. METHODS: Six hundred and ninety eight licensed jockeys in the UK were assessed for neurological and neuropsychological symptoms of concussion at least three months after potential episodes. RESULTS: Jockeys reporting multiple historical injuries versus a single injury showed reliable decrements on a measure of response inhibition and, to a less robust degree, on divided attention. Younger adults showed greater vulnerability. CONCLUSIONS: Repeated concussion is associated with reliable decrements in cognitive performance--even after a three month window for recent recovery.

Adolescent↗
PubMed2006

An outbreak of drug-resistant tuberculosis caused by a Beijing strain in the western Cape, South Africa.

During October 2005, four children in a school in Cape Town were identified with multidrug-resistant tuberculosis (MDR-TB). Genetic analysis confirmed that these isolates belonged to a single cluster (Beijing cluster 220) and that all harboured a -15 inhA(C-T) promoter mutation demonstrating transmission. Genetic analysis of isolates cultured from patients from the Boland-Overberg-South Cape-Karoo and Cape Town regions showed that 28% (58/209) of patients infected with a Beijing strain had the cluster 220 genotypes and that all harboured the same -15 inhA(C-T) promoter mutation. The presence of these transmissible MDR-TB strains may pose a threat to the community, and rigorous infection control measures are needed to ensure the safety of those exposed.

Bacterial Proteins↗
PubMed2005

Charged meson rapidity distributions in central Au+Au collisions at square root(sNN) = 200 GeV.

We have measured rapidity densities dN/dy of pi+/- and K+/- over a broad rapidity range (-0.1 < y < 3.5) for central Au + Au collisions at square root(sNN) = 200 GeV. These data have significant implications for the chemistry and dynamics of the dense system that is initially created in the collisions. The full phase-space yields are 1660 +/- 15 +/- 133 (pi+), 1683 +/- 16 +/- 135 (pi-), 286 +/- 5 +/- 23 (K+), and 242 +/- 4 +/- 19 (K-). The systematics of the strange to nonstrange meson ratios are found to track the variation of the baryochemical potential with rapidity and energy. Landau-Carruthers hydrodynamics is found to describe the bulk transport of the pions in the longitudinal direction.

Journal Article↗
PubMed2005

Centrality dependence of charged-particle pseudorapidity distributions from d + Au collisions at sqrt[sNN] = 200 GeV.

Charged-particle pseudorapidity densities are presented for the d + Au reaction at sqrt[s(NN)] = 200 GeV with -4.2 < or = eta < or = 4.2. The results, from the BRAHMS experiment at BNL Relativistic Heavy-Ion Collider, are shown for minimum-bias events and 0%-30%, 30%-60%, and 60%-80% centrality classes. Models incorporating both soft physics and hard, perturbative QCD-based scattering physics agree well with the experimental results. The data do not support predictions based on strong-coupling, semiclassical QCD. In the deuteron-fragmentation region the central 200 GeV data show behavior similar to full-overlap d+Au results at sqrt[s(NN)] = 19.4 GeV.

Journal Article↗
PubMed2005

The number of dyskaryotic cells on an initial ThinPrep cervical sample showing mild dyskaryosis has predictive value.

OBJECTIVES: Recent National Health Service Cervical Screening Programme (NHSCSP) guidelines suggest referral for colposcopy following an initial result of mild dyskaryosis. The aim of this study was to investigate if the number of dyskaryotic cells counted on an initial ThinPrep cervical sample showing mild dyskaryosis has predictive value. METHODS: Cases of mild dyskaryosis on ThinPrep cervical samples from 2002 were retrieved from the cytology department records of St Luke's Hospital. A total of 123 sequential cases with a first-time result of mild dyskaryosis on ThinPrep slides with follow-up cytology available in the same institution were identified. While blinded to outcome, the number of dyskaryotic cells was counted in each case. Follow-up colposcopy/histology information was retrieved where indicated. The number of dyskaryotic cells counted on each slide was collated with outcome data. RESULTS: Of the 123 cases, six women were lost to follow-up. Seventy-three had a negative outcome, 27 had a low-grade outcome and 17 had a high-grade outcome. Only one of 17 high-grade outcome cases had < or = 15 dyskaryotic cells on the initial slide. The distribution of women with a negative/low-grade outcome and those with a high-grade outcome with >15 and < or = 15 dyskaryotic cells on the initial slide was tested using a chi-square test (P = 0.008). The negative predictive value for a high-grade outcome when < or = 15 dyskaryotic cells were present on the initial slide was 97.7%. CONCLUSION: The number of dyskaryotic cells on ThinPrep slides showing mild cervical dyskaryosis has predictive value. The number of dyskaryotic cells may be used to select women suitable for cytological rather than colposcopic follow-up.

Cell Nucleus↗
PubMed2005

Does a hospital formulary influence prescribing practice in an acute medical admissions unit?

AIM: To assess the extent to which prescribing of cardiovascular medications in a busy medical unit deviates from the local joint primary and secondary care drug formulary guidelines. METHOD: A retrospective audit of the case notes, prescription charts and discharge summaries of 150 randomly selected emergency medical admissions over a 4 month period. RESULTS: No patient receiving a non-formulary cardiovascular drug on admission had the choice reviewed in line with formulary recommendations. One third of new cardiovascular medications commenced in hospital were not compliant with formulary recommendations. Decisions about drug therapy were rarely justfied in the written hospital record. CONCLUSIONS: Our results demonstrate that in a busy acute medical admissions' unit there is a clear failure to amend or query non-formulary prescribing at the time of admission and a tendency to exacerbate it during the inpatient period. This potentially undermines the purpose of a joint drug formulary as a guideline for safe, evidence-based and cost-effective prescribing.

Acute Disease↗
PubMed2005

Combined effects of neurotrophin secreting transplants, exercise, and serotonergic drug challenge improve function in spinal rats.

OBJECTIVES: To determine the effects of neurotrophin-secreting transplants combined with exercise and serotonergic drug challenges on recovery of hindlimb function in rats with midthoracic spinal cord transection injuries. METHODS: Spinalized animals received transplants of fibroblasts genetically modified to express brain-derived neurotrophic factor and neurotrophin-3 and daily cycling exercise. Hindlimb movement in an open-field test (BBB) was scored weekly. Serotonin agonists were used monthly to further stimulate motor function. Axonal growth was quantified in the transplant and at L5 using immunocytochemical markers. Weights of hindlimb muscles were used to assess muscle atrophy. RESULTS: Neurotrophin-secreting transplants stimulated axonal growth, and cycling prevented muscle atrophy, but individual treatments did not improve motor scores. Combined treatments resulted in improvements in motor function. Serotonergic agonists further improved function in all groups, and transplant groups with exercise achieved weight-supporting levels following drug treatment. CONCLUSION: Combined treatments, but not individual treatments, improved hindlimb function.

Animals↗
PubMed2005

Screening for haemoglobinopathy--a comparison of two methods in an Irish maternity unit.

Two-pronged retrospective and prospective studies were carried out to compare opportunistic versus systematic screening for carriers of haemoglobinopathy in an Irish maternity unit. Identification was either performed opportunistically on the basis of ethnicity or systematically on the basis of a low mean corpuscular haemoglobin. A comparison was made between the numbers that were tested for haemoglobinopathy and subsequent detection rates. In the prospective study women were identified again on the basis of either ethnicity or a low MCH and all women identified were tested for haemoglobin variants. A comparison was made between the numbers tested and subsequent detection rates. In both studies systematic screening identified similar rates as opportunistic screening. However, opportunistic screening identified a greater absolute number of carriers. Our retrospective study showed a disappointing uptake of testing of those identified, regardless of the method of screening. Better identification of carriers requires that all those identified as at-risk of haemoglobinopathy carriage should be tested, irrespective of the method of screening.

Female↗
PubMed2004

Evolution of the nuclear modification factors with rapidity and centrality in d + Au collisions at (sqrt)[N(S)N]=200 GeV.

We report on a study of the transverse momentum dependence of nuclear modification factors R(dAu) for charged hadrons produced in deuteron + gold collisions at sqrt[s(NN)]=200 GeV, as a function of collision centrality and of the pseudorapidity (eta=0, 1, 2.2, 3.2) of the produced hadrons. We find a significant and systematic decrease of R(dAu) with increasing rapidity. The midrapidity enhancement and the forward rapidity suppression are more pronounced in central collisions relative to peripheral collisions. These results are relevant to the study of the possible onset of gluon saturation at energies reached at BNL RHIC.

Journal Article↗
PubMed2004

Nuclear stopping in Au+Au collisions at square root of S(NN)=200 GeV.

Transverse momentum spectra and rapidity densities, dN/dy, of protons, antiprotons, and net protons (p-p) from central (0%-5%) Au+Au collisions at square root of S(NN)=200 GeV were measured with the BRAHMS experiment within the rapidity range 0</=y</=3. The proton and antiproton dN/dy decrease from midrapidity to y=3. The net-proton yield is roughly constant for y<1 at dN/dy approximately 7, and increases to dN/dy approximately 12 at y approximately 3. The data show that collisions at this energy exhibit a high degree of transparency and that the linear scaling of rapidity loss with rapidity observed at lower energies is broken. The energy loss per participant nucleon is estimated to be 73+/-6 GeV.

Journal Article↗
PubMed2004

Comparative inhibition of inducible and constitutive CYPs in rat hepatic microsomes by parathion.

1. In microsomal fractions, the phosphorothioate pesticide parathion inhibits cytochrome P450 (CYP) enzymes by reversible and irreversible mechanisms resulting in the long-term suppression of drug oxidation. The present study evaluated the relative susceptibilities of constitutive and inducible CYP2 and CYP3 steroid hydroxylases to inhibition by the pesticide. 2. Enzyme kinetic analysis indicated that constitutive and dexamethasone (DEX)-induced androst-4-ene-3,17-dione (AD) 6beta-hydroxylations were similarly susceptible to inhibition by parathion (Km/Ki ratios 1.5-1.6). However, preincubation of parathion with NADPH-fortified microsomes intensified the extent of inhibition of CYP3A-dependent 6beta-hydroxylation. Comparison of Km/Ki ratios indicated that 6beta-hydroxylation activity in fractions from DEX-pretreated rats was about twice as susceptible as the control activity to inactivation by parathion metabolites (Km/Ki ratio of 8.0 versus 4.0). 3. The time-dependent loss of AD 6beta-hydroxylation by parathion occurred more efficiently in fractions from DEX-induced liver than in control. Thus, half-times of 1.3 and 6.1 min, respectively, were determined for the inactivation of DEX-inducible and constitutive activities. Parathion concentrations required for half-maximal inactivation were 32 and 67 microM in microsomes from DEX-induced and control rats. 4. In phenobarbital (PB)-induced fractions CYP2B1-mediated AD 16beta-hydroxylation was inhibited potently in a reversible fashion by parathion (Ki = 0.37 microM; Km/Ki ratio about 73). Inhibition was not enhanced at parathion concentrations near the Ki by a preincubation step with NADPH. 5. In control microsomes parathion elicited a type I binding interaction with oxidized CYP (Ks=7.7 microM, deltaAmax=2.2 x 10(-2) a.u.nmol CYP-1; deltaAmax/Ks 2.86 x 10(3) a.u. nmol CYP(-1)/mM). Ligand binding was 13- and 1.6-fold more efficient in PB and DEX microsomes, respectively. 6. These findings indicate that pretreatment of rats with enzyme-inducing drugs like DEX and PB alters the profile of CYPs and their susceptibility to inhibition by parathion. Potent reversible inhibition of CYP2B1 occurred in PB-induced fractions and DEX-inducible CYPs 3A were more susceptible to mechanism-based inactivation than the corresponding constitutive CYPs from the same subfamily.

Androstenedione↗
PubMed2004

Clinicopathological significance of Borderline Nuclear Change - High Grade Dyskaryosis Not Excluded.

During a recent discussion on classification of cervical cytology, the introduction of a 'Borderline Nuclear Change - High Grade Dyskaryosis Not Excluded' (BNCH) category was proposed. BNCH cases diagnosed prospectively were retrieved from laboratory records. Questionnaires were sent to referring practitioners regarding clinicopathological outcome. Cytopathological features resulting in the BNCH classification were recorded on slide review. A total of 103 reports on conventional cervical smears diagnosed as BNCH from 1999 to 2002 were retrieved, comprising 0.096% of 107 634 smears. Of 86/103 cases with clinical follow-up, CIN2 or worse was present in 30 (35%); 15 (17%) showed a borderline/low-grade abnormality and 41 (48%) were negative. No individual cytopathological feature was predictive of high-grade disease on follow-up. The yield of high-grade abnormalities on follow-up of BNCH supports the introduction of this terminology.

Artifacts↗
PubMed2004

Right atrial thrombi complicating use of central venous catheters in hemodialysis.

BACKGROUND: There has been an increase in the use of central venous catheters for temporary hemodialysis access. In this report, we describe a case series of 12 patients on hemodialysis who developed intracardiac clots associated with the use of central venous catheters, their outcomes and review the literature on this syndrome. METHODS: Retrospective, single-center case series of 12 patients with right atrial thrombi associated with central venous catheter use for dialysis vascular access. These patients were treated between June 1, 2001 and June 30th 2002 at the three University of Rochester affiliated dialysis clinics. The medical records of these patients were reviewed to obtain information concerning demographics, dialysis history, dates of catheter insertion, catheter complications, identification and dimensions of intracardiac thrombi, echocardiographic data, and outcome of anticoagulant therapy. RESULTS: Right heart thrombi were identified in 12 patients in our hemodialysis population over the study interval. Anticoagulation for 6 months led to clot resolution in more than 50% of our patients. Bacteremia recurred in 6 patients (50%), in spite of catheter replacement. There was zero mortality related to presence of clots in the short term. One patient with non-bacteremic right atrial thrombus suffered sudden cardiac arrest, but was successfully resuscitated. CONCLUSION: Right atrial thrombi may occur in hemodialysis patients who use central venous catheters for dialysis access. These clots are frequently found in the right atrium or right atrial-superior vena caval junction. Ten of 12 patients (83%), had catheter-associated bacteremia, but the precise relationship between bacteremia and intracardiac clots is unclear. Chronic anticoagulation for 6 months lead to resolution of these clots in more than 50% of patients in our series.

Adult↗
PubMed2004

Osteochondral defects of the talus treated with autologous bone grafting.

We reviewed, retrospectively, 13 patients who had undergone open anterograde autologous bone grafting of the talus for symptomatic osteochondral defects of the dome of the talus. The mean age of the seven men and six women was 38.4 years. The defects included the full thickness of articular cartilage, extended through the subchondral plate and were associated with subchondral cysts. Six patients (46%) were clinical failures requiring further surgery. Of the remaining seven, functional outcome results were obtained at a mean of 51.9 months after surgery. The mean outcome scores for the Musculoskeletal Outcomes Data Evaluation and Management System foot and ankle questionnaire and the American Orthopaedic Foot and Ankle Society ankle-hindfoot scale were 87.0 and 84.3, respectively. There was an overall 46.2% patient satisfaction rate. We believe that the technique of autologous bone grafting presented should be used with extreme caution, when considered as the primary treatment for the adult patient with a symptomatic advanced osteochondral defect of the talus.

Adult↗
PubMed2003

Transverse-momentum spectra in Au+Au and d+Au collisions at sqrt[s(NN)]=200 GeV and the pseudorapidity dependence of high-p(T) suppression.

We present spectra of charged hadrons from Au+Au and d+Au collisions at sqrt[s(NN)]=200 GeV measured with the BRAHMS experiment at RHIC. The spectra for different collision centralities are compared to spectra from p+(-)p collisions at the same energy scaled by the number of binary collisions. The resulting ratios (nuclear modification factors) for central Au+Au collisions at eta=0 and eta=2.2 evidence a strong suppression in the high p(T) region (>2 GeV/c). In contrast, the d+Au nuclear modification factor (at eta=0) exhibits an enhancement of the high p(T) yields. These measurements indicate a high energy loss of the high p(T) particles in the medium created in the central Au+Au collisions. The lack of suppression in d+Au collisions makes it unlikely that initial state effects can explain the suppression in the central Au+Au collisions.

Journal Article↗
PubMed2003

Rapidity dependence of charged antihadron to hadron ratios in Au+Au collisions at sqrt[s(NN)]=200 GeV.

We present ratios of the numbers of charged antihadrons to hadrons (pions, kaons, and protons) in Au+Au collisions at sqrt[s(NN)]=200 GeV as a function of rapidity in the range y=0-3. While the ratios at midrapidity are approaching unity, the K(-)/K(+) and p;/p ratios decrease significantly at forward rapidities. An interpretation of the results within the statistical model indicates a reduction of the baryon chemical potential from mu(B) approximately 130 MeV at y=3 to mu(B) approximately 25 MeV at y=0.

Journal Article↗