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Biomedical subjects

Michael Murray

Publications and source records attributed to Michael Murray.

At least 19 recordsLinked to original sources
PubMed2006

Evidence against breast self examination is not conclusive: what policymakers and health professionals need to know.

Breast cancer is a serious health concern and a disease that is not well understood. Early detection remains the best way to prevent debilitation and death. Traditionally, mammography, clinical breast examination (CBE), and breast self examination (BSE) have been accepted as legitimate breast screening modalities. Over the past 5 years, academics, health professionals, and policymakers have seriously questioned the usefulness of BSE after influential organizations such as the Canadian Task Force on Preventive Health Care downgraded their BSE recommendation citing fair evidence of no benefit and good evidence of harm. We briefly review the three large BSE trials, highlighting methodological weaknesses limiting their ability to evaluate its effectiveness, as well as critique the 2001 Canadian Task Force on Preventive Health Care report on BSE. We argue that it is premature to conclude that BSE is ineffective. Given that most women find their own breast cancer, this article cautions policymakers and health professionals that a prudent approach to BSE promotion should be taken.

Breast Self-Examination↗
PubMed2006

Effect of alcohol on cytochrome p450 arachidonic acid metabolism and blood pressure in rats and its modulation by red wine polyphenolics.

Alcohol-induced hypertension is well recognized with clear evidence for a direct pressor effect of chronic alcohol consumption provided by a number of intervention studies in humans. In experimental animals, the effect of alcohol on blood pressure is less consistent; however, in Sprague-Dawley rats, alcohol feeding consistently induces a hypertensive response. The mechanism of alcohol-induced hypertension is not clearly understood. Ethanol is known to induce certain cytochrome P450 (CYP) enzymes, particularly the 2E1 isoform, which has been shown to metabolise arachidonic acid (AA) to the 19-hydroxy metabolite (19-HETE), which could have pro-hypertensive activity; CYP4A, by comparison, is the principal AA omega-hydroxylase in the liver. Polyphenolic compounds, such as flavonoids, have been shown to inhibit some CYPs. 2. In this study, we determined the effect of alcohol administration on blood pressure and CYP-dependent AA metabolism in the rat and its possible modulation by red wine polyphenols. 3. Thirty male Sprague-Dawley rats were randomly allocated to three groups, which received water, low-dose ethanol (5% v/v) or red wine (diluted to contain 5% ethanol) for a period of 9 weeks. Bodyweight and blood pressure were measured weekly and 24h urine collected at baseline and every 2 weeks. Animals were killed at 9 weeks and blood and tissue samples were collected. The blood pressure of rats fed with alcohol increased significantly over the period of the study compared with controls (P<0.001). The blood pressure of animals fed 5% alcohol in the form of red wine was not significantly different from controls over the study period. The urinary excretion of 20-HETE did not differ significantly among the treatment groups over the study period and there was no effect of any treatment on the metabolism of AA by renal microsomes. Red wine, but not administration of the relatively low dose of alcohol alone, increased the expression of CYP2E1 protein in the liver and kidney and CYP4A in the kidney. Both red wine and alcohol decreased CYP4A protein levels in the liver compared with controls. 4. Our results suggest that constituents of red wine, possibly polyphenols, can attenuate the alcohol-induced rise in blood pressure in the Sprague-Dawley rat, although this effect does not appear to be mediated by the inhibition of CYP-derived AA metabolism.

Animals↗
PubMed2006

Health psychology and social action.

This article reviews the main epistemological approaches within health psychology. It considers the approach based on critical realism and various strategies for linking health psychology with social action. It argues that critical health psychology has a distinct contribution to make in promoting public health as part of the broader movement for social justice and health.

Behavioral Medicine↗
PubMed2006

Role of CYP pharmacogenetics and drug-drug interactions in the efficacy and safety of atypical and other antipsychotic agents.

Cytochrome P450 (CYP) drug oxidases play a pivotal role in the elimination of antipsychotic agents, and therefore influence the toxicity and efficacy of these drugs. Factors that affect CYP function and expression have a major impact on treatment outcomes with antipsychotic agents. In particular, aspects of CYP pharmacogenetics, and the processes of CYP induction and inhibition all influence in-vivo rates of drug elimination. Certain CYPs that mediate the oxidation of antipsychotic drugs exhibit genetic variants that may influence in-vivo activity. Thus, single nucleotide polymorphisms (SNPs) in CYP genes have been shown to encode enzymes that have decreased drug oxidation capacity. Additionally, psychopharmacotherapy has the potential for drug-drug inhibitory interactions involving CYPs, as well as drug-mediated CYP induction. Literature evidence supports a role for CYP1A2 in the clearance of the atypical antipsychotics clozapine and olanzapine; CYP1A2 is inducible by certain drugs and environmental chemicals. Recent studies have suggested that specific CYP1A2 variants possessing individual SNPs, and possibly also SNP combinations (haplotypes), in the 5'-regulatory regions may respond differently to inducing chemicals. CYP2D6 is an important catalyst of the oxidation of chlorpromazine, thioridazine, risperidone and haloperidol. Certain CYP2D6 allelic variants that encode enzymes with decreased drug oxidation capacity are more common in particular ethnic groups, which may lead to adverse effects with standard doses of psychoactive drugs. Thus, genotyping may be useful for dose optimization with certain psychoactive drugs that are substrates for CYP2D6. However, genotyping for inducible CYPs is unlikely to be sufficient to direct therapy with all antipsychotic agents. In-vivo CYP phenotyping with cocktails of drug substrates may assist at the commencement of therapy, but this approach could be complicated by pharmacokinetic interactions if applied when an antipsychotic drug regimen is ongoing.

Animals↗
PubMed2006

Altered CYP expression and function in response to dietary factors: potential roles in disease pathogenesis.

Increasing evidence implicates dietary factors in the progression of diseases, including certain cancers, diabetes and obesity. Diet also regulates the expression and function of CYP genes, which impacts on drug elimination and may also significantly affect disease pathogenesis. Upregulation of CYPs 2E1 and 4A occurs after feeding of experimental diets that are high in fats or carbohydrates; these diets also promote hepatic lipid infiltration, which is a component of the metabolic syndrome that characterises obesity. Increased availability of lipid substrates for CYPs can enhance free radical production and exacerbate tissue injury. Similar processes may also occur in other models of experimental disease states that exhibit a component of altered nutrient utilization. Food-derived chemicals, including constituents of cruciferous vegetables and fruits, modulate CYP expression and the expression of genes that encode cytoprotective phase II enzymes. Certain dietary indoles and flavonoids activate CYP1A expression either by direct ligand interaction with the aryl hydrocarbon receptor (AhR) or by augmenting the interaction of the AhR with xenobiotic response elements in CYP1A1 and other target genes. Other dietary chemicals, including methylenedioxyphenyl (MDP) compounds and isothiocyanates also modulate CYP gene expression. Apart from altered CYP regulation, a number of dietary agents also inhibit CYP enzyme activity, leading to pharmacokinetic interactions with coadministered drugs. A well described example is that of grapefruit juice, which contains psoralens and possibly other chemicals, that inactivate intestinal CYP3A4. Decreased presystemic oxidation by this CYP increases the systemic bioavailability of drug substrates and the likelihood of drug toxicity. Dietary interactions may complicate drug therapy but inhibition of certain CYP reactions may also protect the individual against toxic metabolites and free radicals generated by CYPs. Chemicals in teas and cruciferous vegetables may also inhibit human CYP enzymes that have been implicated in the bioactivation of chemical carcinogens. Thus, food constituents modulate CYP expression and function by a range of mechanisms, with the potential for both deleterious and beneficial outcomes.

Animals↗
PubMed2006

Evaluation of the efficacy provided by a Recombinant Canarypox-Vectored Equine West Nile Virus vaccine against an experimental West Nile Virus intrathecal challenge in horses.

Efficacy of the Recombitek Equine West Nile Virus (WNV) vaccine was evaluated against a WNV intrathecal challenge model that results in WNV-induced clinical disease. Ten vaccinated (twice at days 0 and 35) and 10 control horses were challenged 2 weeks after administration of the second vaccine with a virulent WNV by intrathecal administration. After the challenge, eight of 10 controls developed clinical signs of encephalomyelitis whereas one vaccinate exhibited muscle fasciculation only once. Nine controls and one vaccinate developed a fever. Histopathology revealed mild to moderate nonsuppurative encephalitis in eight controls and one vaccinate. None of the vaccinates and all of the controls developed WNV viremia after challenge. All vaccinated horses developed antibodies to WNV after vaccination. These and results of previous studies demonstrate efficacy of the Recombitek WNV vaccine against WNV-induced clinical disease and natural challenge with WNV-infected mosquitoes.

Animals↗
PubMed2005

Characterization of a c-Jun-responsive module in the 5'-flank of the human CYP2J2 gene that regulates transactivation.

The human cytochrome P450 2J2 (CYP2J2) generates cytoprotective epoxyeicosatrienoic acids from arachidonic acid. Expression of CYP2J2 is decreased in hypoxia, and the resultant decrease in CYP2J2-derived epoxyeicosanoids may contribute to the pathogenesis of cardiac ischaemia. Recent studies have indicated that AP-1 (activator protein-1) regulates CYP2J2 expression in normoxia and hypoxia. Down-regulation of CYP2J2 in hypoxic HepG2 cells was closely associated with the up-regulation of c-fos and transient transfection analysis demonstrated that c-Fos abolishes the activation of CYP2J2 by the AP-1 protein c-Jun. Deletion of the region between nt -122 and -50 upstream of the start codon in CYP2J2 prevented c-Jun transactivation. In this study we demonstrate that the sequence at -105/-95 is a major regulatory element that binds c-Jun and has a prominent role in CYP2J2 gene transactivation. Mutagenesis of both the -105/-95 region and the previously identified element at -56/-63 was required for complete loss of transactivation by c-Jun; separate mutagenesis of the -105/-95 element or, to a lesser extent, the -56/-63 element resulted in a partial loss of gene activation. In contrast to the behaviour of the -56/-63 element, c-Jun homodimers and c-Fos/c-Jun heterodimers bound to the -105/-95 element. These findings demonstrate that the c-Jun-responsive module between -122 and -50 in the CYP2J2 proximal promoter contains an atypical AP-1 element at -105/-95 that has a major role in c-Jun transactivation and acts in conjunction with the -56/-63 element to regulate expression.

5' Flanking Region↗
PubMed2005

Phospho-STAT5 accumulation in nuclear fractions from vitamin A-deficient rat liver.

The growth hormone (GH)-responsive cytochrome P450 (CYP) 2C11 is down-regulated in vitamin A-deficient (VAD) rat liver. This study assessed the impact of a VAD diet on the hepatic Janus kinase-Signal Transducers and Activators of Transcription (JAK-STAT) system that mediates GH signalling. Nuclear tyrosine- and serine-phosphorylated STAT5 accumulated in VAD liver, whereas nuclear JAK2 tyrosine kinase and SHP-1 phosphatase were decreased. Tyrosine-phosphorylated SHP-1 was decreased to 36+/-14% of control (P<0.01), indicating its impaired activation in VAD liver. Episodic GH pulses increased nuclear phospho-STAT5, especially in control liver, but nuclear phospho-JAK2 and phospho-SHP-1 were not restored. CYP2C11 protein and testosterone 16alpha-hydroxylation were decreased in VAD liver to 67+/-16% and 76+/-19% of control, and were further decreased by GH to 32+/-8% and 30+/-14% of control. Thus, hypo-responsiveness of JAK-STAT in VAD liver is associated with impaired nuclear phospho-STAT dephosphorylation.

Animals↗
PubMed2004

Pretranslational upregulation of microsomal CYP4A in rat liver by intake of a high-sucrose, lipid-devoid diet containing orotic acid.

In rodents, high-fat diets promote hepatic lipid accumulation in rodents, activation of peroxisome proliferator activated receptor-alpha (PPARalpha) and upregulation of cytochrome P450 (CYP) 4A gene expression. Lipid-devoid diets containing sucrose and orotic acid (S/OA-diet) also cause lipid infiltration by stimulating intrahepatic lipid synthesis and preventing lipoprotein transport through the Golgi apparatus. This study evaluated the impact of the lipid-deficient S/OA-diet on CYP4A expression and PPARalpha activation in rodent liver. CYP4A protein and laurate omega-hydroxylation activity were increased in rat liver after S/OA-feeding for 21 days. CYP4A1 and CYP4A2 mRNAs were induced to 2.1- and 2.6-fold of control, but mRNAs corresponding to CYP4A3 and the peroxisomal acyl-CoA oxidase (AOX) were unchanged. Coadministration of clofibric acid and the S/OA-diet prevented hepatic lipid accumulation and upregulated CYP4A protein to levels comparable with clofibric acid alone (five-fold of control). Clofibric acid, alone and in combination with the S/OA-diet, upregulated CYP4A1-3 and AOX mRNAs. Hepatic PPARalpha protein was decreased by the S/OA-diet but was increased to 5.7-fold of control by clofibric acid; retinoid X-receptor-alpha (RXRalpha) protein was decreased to 26-41% of control by all treatments. In further studies, administration of the S/OA-diet to control and PPARalpha-null mice promoted hepatic lipid deposition; microsomal CYP4A protein was induced in wild-type but not PPARalpha-null mice. These findings implicate PPARalpha in the induction of CYP4A in rodent liver by the lipid-devoid S/OA-diet. Decreased availability of hepatic PPARalpha and RXRalpha after intake of the diet may contribute to the selective upregulation of hepatic CYP4A1 and CYP4A2 in this model.

Animals↗
PubMed2004

Quantitative structure-activity analyses of bufokinin and other tachykinins at bufokinin (bNK1) receptors of the small intestine of the cane toad, Bufo marinus.

The toad tachykinin, bufokinin (Lys-Pro-Arg-Pro-Asp-Gln-Phe-Tyr-Gly-Leu-Met amide; BUF), acts via tachykinin NK1-like receptors to contract the intestine of the cane toad, Bufo marinus. In this structure-activity study, we used isolated segments of toad small intestine and performed binding studies with [125I] Bolton-Hunter BUF in intestinal membranes to compare the contribution of individual amino acid residues to the potencies of 18 naturally occurring tachykinins and 13 BUF analogs. Potencies were similar (r=0.94) in functional and binding studies, with BUF and ranakinin being most potent. Ranatachykinin A, physalaemin, hylambatin and cod, trout and mammalian SPs exhibited 10-60% of the potency of BUF. The Ala-substituted BUF analogs were 11-60% as potent as BUF in functional studies, with [Ala2]-BUF and [Ala4]-BUF the least efficacious, indicating the importance of both proline residues. QSAR equations were developed using 12 connectivity, shape and steric parameters for each of the 7 hypervariable amino acid residues in these peptides. For the binding data, the optimal regression equation explained 81% of the variance, and indicated the importance of the steric function at [Pro2] and simple connectivity functions at [Gln6] and [Tyr8]. The optimal functional regression equation (80% of variance) confirmed the importance of connectivity functions at [Gln6] and [Tyr8], as well as the shape of residues [Lys1] and [Pro4]. The potencies of most full-length peptides were well predicted using the leave-one-out procedure, as were the potencies of a series of model Ala-substituted BUFs, thus emphasising the potential utility of these equations in the design of new ligands interacting with tachykinin receptors.

Amino Acid Substitution↗
PubMed2004

Molecular identification and characterization of three isoforms of tachykinin NK(1)-like receptors in the cane toad Bufo marinus.

The tachykinin peptide bufokinin, isolated from the cane toad intestine, is important in intestinal and cardiovascular regulation in the toad. In this study, three tachykinin NK(1)-like receptor isoforms, bNK(1)-A, bNK(1)-B, and bNK(1)-C, encoding proteins of 309, 390, and 371 amino acids, respectively, were cloned from the toad brain and intestine. These isoforms differ only at the intracellular COOH terminus. The bNK(1)-A and bNK(1)-B isoforms are similar to the truncated and full-length forms of the mammalian NK(1) receptor, whereas bNK(1)-C is unique and does not correspond to any previously described receptor. RT-PCR studies demonstrated that three isoform transcripts are widely distributed in the toad with high expression in gut, spinal cord, brain, lung, and skeletal muscle. When expressed in COS-7 cells, bufokinin showed similar high affinity (IC(50) 0.6-0.8 nM) in competing for (125)I-labeled Bolton-Hunter bufokinin binding at all receptors, but the binding affinities of substance P (SP) and neurokinin A (NKA) were very different at each isoform. When expressed in Xenopus oocytes, the truncated isoform, bNK(1)-A, was inactive, whereas bNK(1)-B and bNK(1)-C produced changes in chloride current when stimulated by tachykinins (minimum concentrations: bufokinin, 0.1 nM; SP, 1 nM; and NKA, 10 nM). A marked desensitization of the response was seen to subsequent applications of tachykinins, as experienced by the mammalian NK(1) receptor. In summary, our study describing three isoforms of NK(1)-like receptor from the toad suggests that the alternative splicing of NK(1) receptor is a physiologically conserved mechanism and raises a fundamental question as to the physiological role of each isoform.

Amino Acid Sequence↗
PubMed2004

Assessment of mercury emissions inventories for the Great Lakes states.

Anthropogenic mercury (Hg) air emissions for the eight Great Lakes states in 1999-2000 were evaluated by analyzing three inventories. The US Environmental Protection Agency (EPA) National Emissions Inventory (NEI) had the most complete coverage for all states, and total Hg emissions ranged from 4226 lb in Minnesota to 15,828 lb in Pennsylvania. Coal-fired electric utilities accounted for 52.7% of the region's Hg emissions, varying from 20.2% of the total in New York to 67.5% in Ohio. Other important contributors to regional emissions included municipal waste combustion (5.6%), mercury-cell chlor-alkali plants and hazardous-waste incinerators (4% each), stationary internal combustion engines (ICEs) (3.5%), industrial, commercial, and institutional (ICI) boilers (3.3%), and lime manufacturing (3.0%). Although medical waste incineration accounted for just over 1% of regional emissions using the original classifications, the inclusion of health care facilities that may have been inappropriately identified with other sectors would increase the sector to 4.5% of regional emissions (and decrease the stationary ICE sector to 1.4% of the regional total). There were substantial differences for some sectors between the NEI and the Great Lakes Regional Air Toxics Emissions Inventory (GLEI), as well as unexplained differences within inventories between states (particularly for the cement, lime, and asphalt industries, and for lamp breakage). Toxics Release Inventory data for 2000 mainly covered electric utilities, and differences from the NEI were significant for several states. An independent assessment indicates the possibility of underestimated Hg emissions by about twofold for ICI boilers, although data for the sector (in particular concerning fuel oil emissions) are highly uncertain. Limited data indicate the likelihood of significant underestimates of electric arc furnace mercury emissions in the NEI and GLEI inventories. Several measures are here identified for improving the reliability of the inventories, both for modeling of atmospheric transport and deposition modeling and for tracking progress in Hg reduction initiatives.

Air Movements↗
PubMed2004

Competing values of emergency department performance: balancing multiple stakeholder perspectives.

OBJECTIVE: To describe the performance interests of multiple stakeholders associated with the management and delivery of emergency department (ED) care, and to develop a performance framework and set of indicators that reflect these interests. STUDY SETTING: Stakeholders (1,100 physicians, nurses, managers, home care providers, and prehospital care personnel) with responsibility for ED patients in hospitals in the Canadian province of Ontario. STUDY DESIGN: Sixty-two percent of stakeholders responded to a mail survey regarding the importance of 104 potential ED performance indicators. Descriptive and inferential statistics are used to explore the interests of each stakeholder group and to compare interests across the five groups. PRINCIPAL FINDINGS: Emergency department stakeholders are primarily interested in indicators that focus on their role and capacity to provide care. Key differences exist between hospital and nonhospital stakeholders. Physicians mean ratings of the importance on ED performance measures were lower than mean ratings in the other stakeholder groups. CONCLUSIONS: Emergency department performance interests are not homogeneous across stakeholder groups, and evaluating performance from the perspective of any one stakeholder group will result in unbalanced assessments. Community-based stakeholders, a group frequently excluded from commenting on ED performance, provide important insights into ED performance related to the external environment and the broader continuum of care.

Adult↗
PubMed2004

Community health psychology: promoting analysis and action for social change.

Community health psychology is concerned with the theory and method of working with communities to combat disease and to promote health. This introductory article outlines key assumptions and debates underlying this area of research and practice-in the interests of framing the papers in this special edition of the Journal of Health Psychology. Attention is given to the value of emphasizing the community level of analysis and action; the role of collective action in improving health; psycho-social mediatiors between community participation and health; and the potential role of partnerships in creating 'healthy communities'. A distinction is made between 'accommodationist' and 'critical' perspectives, and the authors consider whether or not significant social change can come from community-level action.

Community Mental Health Services↗
PubMed2004

Assumptions and values of community health psychology.

There is a need to widen the practice of health psychologists to include the theories and methods of community psychology and an awareness of contemporary issues in community health. The aim of such a community health psychology would be both to deepen our understanding of the aetiology of health and illness in society and to develop strategies that will contribute to a reduction in human suffering and an improvement in quality of life. The aim of this article is to review the background and assumptions of community health psychology and to consider some values that would underlie such an approach.

Community Mental Health Services↗