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E Munro

Publications and source records attributed to E Munro.

At least 19 recordsLinked to original sources
PubMed2001

Inter-individual differences in repair of DNA base oxidation, measured in vitro with the comet assay.

There is a need for a reliable, robust and sensitive assay for DNA repair, suitable for use with human lymphocyte samples in molecular epidemiological investigations. The comet assay (single cell alkaline gel electrophoresis) has been modified to measure the ability of a simple subcellular extract of lymphocytes to carry out the initial step of repair, i.e. incision, on a DNA substrate carrying specific lesions--namely, oxidized bases introduced by visible light in the presence of photosensitizer. The cell extract is free of non-specific nuclease activity, incising DNA only if the DNA has been treated with photosensitizer and light. The activity varies between individuals, but consistency is seen between samples from each individual taken on occasions several months apart. The lack of activity of extract from Ogg1(-) mouse cells (deficient in the glycosylase that excises 8-oxoguanine) in this assay confirms that the activity measured is predominantly excision repair of oxidized bases. This new DNA repair assay is simple, rapid and requires only small quantities of lymphocyte extract (obtainable from 10 ml blood).

Animals↗
PubMed2000

Resolution of skin lesions and long-term survival in a dog with superficial necrolytic dermatitis and liver cirrhosis.

A nine-year-old, neutered female Shetland sheepdog was presented with crusted, ulcerative skin lesions affecting the footpads, commissures of the lips and the lateral canthi of the eyes. Histopathological examination of skin biopsies revealed changes consistent with superficial necrolytic dermatitis and biochemical analysis demonstrated elevated liver enzymes. Abdominal radiography revealed a small liver which, on ultrasonography, appeared diffusely mottled and showed changes suggestive of periportal fibrosis. On exploratory laparotomy, the pancreas appeared normal, but the liver was small and had multiple nodules throughout the parenchyma. This appearance was confirmed as cirrhosis on histopathological examination. The dog was placed on a hepatic support diet and treated with colchicine, essential fatty acid supplementation and raw egg yolks. After four weeks, the skin lesions had resolved and the dog remained free of clinical signs over a 22-month follow-up period.

Animals↗
PubMed2000

Role of risk assessment in reducing homicides by people with mental illness.

BACKGROUND: Improved risk assessment has been stressed as the way to reduce homicides by people with mental illness. The feasibility of predicting rare events needs examining. AIMS: To examine the findings of public inquiries into homicides by people with mental illness to see if they support the claim that better risk assessment would have averted the tragedy. METHOD: Analysis was made of the findings of the public inquiries between 1988 and 1997 in relation to the predictability and preventability of the homicides. RESULTS: Of the homicides considered by the inquiry panels, 27.5% were judged to have been predictable, 65% preventable and 60% of the patients had a long-term history containing violence or substantial risk factors for violence. CONCLUSIONS: Improved risk assessment has only a limited role in reducing homicides. More deaths could be prevented by improved mental health care irrespective of the risk of violence. If services become biased towards those assessed as high risk, then ethical concerns arise about the care of both violent and non-violent patients.

Community Mental Health Services↗
PubMed1999

Modularity in animal development and evolution: elements of a conceptual framework for EvoDevo.

For at least a century biologists have been talking, mostly in a black-box sense, about developmental mechanisms. Only recently have biologists succeeded broadly in fishing out the contents of these black boxes. Unfortunately the view from inside the black box is almost as obscure as that from without, and developmental biologists increasingly confront the need to synthesize known facts about developmental phenomena into mechanistic descriptions of complex systems. To evolutionary biologists, the emerging understanding of developmental mechanisms is an opportunity to understand the origins of variation not just in the selective milieu but also in the variability of the developmental process, the substrate for morphological change. Ultimately, evolutionary developmental biology (EvoDevo) expects to articulate how the diversity of organic form results from adaptive variation in development. This ambition demands a shift in the way biologists describe causality, and the central problem of EvoDevo is to understand how the architecture of development confers evolvability. We argue in this essay that it makes little sense to think of this question in terms of individual gene function or isolated morphometrics, but rather in terms of higher-order modules such as gene networks and homologous characters. We outline the conceptual challenges raised by this shift in perspective, then present a selection of case studies we believe to be paradigmatic for how biologists think about modularity in development and evolution. J. Exp. Zool. (Mol. Dev. Evol.) 285:307-325, 1999.

Animals↗
PubMed1999

Common errors of reasoning in child protection work.

OBJECTIVE: Repeated public inquiries into child abuse tragedies in Britain demonstrate the level of public concern about the services designed to protect children. These inquiries identify faults in professionals' practice but the similarities in their findings indicate that they are having insufficient impact on improving practice. This study is based on the hypothesis that the recurrent errors may be explicable as examples of the typical errors of human reasoning identified by psychological research. METHODS: The sample comprised all child abuse inquiry reports published in Britain between 1973 and 1994 (45 in total). Using a content analysis and a framework derived from psychological research on reasoning, a study was made of the reasoning of the professionals involved and the findings of the inquiries. RESULTS: It was found that professionals based assessments of risk on a narrow range of evidence. It was biased towards the information readily available to them, overlooking significant data known to other professionals. The range was also biased towards the more memorable data, that is, towards evidence that was vivid, concrete, arousing emotion and either the first or last information received. The evidence was also often faulty, due, in the main, to biased or dishonest reporting or errors in communication. A critical attitude to evidence was found to correlate with whether or not the new information supported the existing view of the family. A major problem was that professionals were slow to revise their judgements despite a mounting body of evidence against them. CONCLUSIONS: Errors in professional reasoning in child protection work are not random but predictable on the basis of research on how people intuitively simplify reasoning processes in making complex judgements. These errors can be reduced if people are aware of them and strive consciously to avoid them. Aids to reasoning need to be developed that recognize the central role of intuitive reasoning but offer methods for checking intuitive judgements more rigorously and systematically.

Child↗
PubMed1998

Vein graft stenosis and the heparin responsiveness of human vascular smooth muscle cells.

BACKGROUND: Vascular smooth muscle cell (VMSC) proliferation is an essential component of myointimal hyperplasia, which is implicated in the failure of 30% to 50% of vascular interventions, such as coronary angioplasty and peripheral vein grafting. We have shown that cells derived from stenotic lesions in infrainguinal vein grafts were significantly more resistant than controls to growth inhibition by heparin. METHODS AND RESULTS: In a prospective study, we correlated antiproliferative responses to heparin in vitro with graft patency after 1 year. Sixty-two patients with infrainguinal vein grafts were entered into a graft surveillance program for > or = 1 year. At operation, saphenous vein segments were explanted for VSMC culture. Cell proliferation in response to fetal calf serum was later determined in the presence and absence of heparin. In 35 cell cultures, including 13 from the above-mentioned patients, [3H]heparin binding was also estimated. VSMCs from patients with patent grafts were significantly more sensitive to growth inhibition by heparin than cells from patients with stenoses (median, 54% versus 20.9%, P<0.001), and [3H]heparin binding was strongly correlated with inhibition of proliferation (r=0.81). CONCLUSIONS: Responsiveness to heparin in cultured VSMCs is a strong predictor of outcome for infrainguinal vein grafts, and reduced sensitivity to heparin is correlated with decreased heparin binding. Relative resistance to the antiproliferative action of heparin may be a marker for aberrant regulation of VSMC growth.

Adult↗
PubMed1998

Depolarization and cAMP elevation rapidly recruit TrkB to the plasma membrane of CNS neurons.

Here, we describe a novel mechanism for the rapid regulation of surface levels of the neurotrophin receptor TrkB. Unlike nodose ganglion neurons, both retinal ganglion cells (RGCs) and spinal motor neurons (SMNs) in culture display only low levels of surface TrkB, though high levels are present intracellularly. Within minutes of depolarization or cAMP elevation, surface TrkB levels increase by nearly 4-fold, and this increase is not blocked by cycloheximide. These findings suggest that activity and cAMP elevation rapidly recruit TrkB to the plasma membrane by translocation from intracellular stores. We propose that a fundamental difference between peripheral nervous system (PNS) and central nervous system (CNS) neurons is the activity dependence of CNS neurons for responsiveness to their peptide trophic factors and that differences in membrane compartmentalization of the receptors underlie this difference.

Animals↗
PubMed1998

Carotid surgery.

Explore the source record for details and available documents.

Anesthesia, Conduction↗
PubMed1998

Changing the response of professionals to child abuse.

Britain has developed a child protection system that relies on good interprofessional communication. However, some doctors are questioning the benefits to the child of triggering a child abuse referral. The system has become disproportionately skewed towards investigation and risk assessment, leaving few resources for meeting the needs of children, or helping parents provide better care. The Department of Health (DoH) is proposing a policy to redress the balance; creating a more cooperative and less adversarial relationship with parents, and paying more attention to assessing family needs and long-term family functioning. This paper examines the history of the current system and argues that, while the proposed changes are desirable, it needs to be acknowledged that they may reduce the accuracy of risk assessments. Professionals, therefore, need the backing of the general public to implement such a fundamental shift in emphasis.

Child↗
PubMed1994

Consistent responses of the human vascular smooth muscle cell in culture: implications for restenosis.

PURPOSE: The mechanisms whereby restenoses occur at discrete sites within the vasculature remain uncertain. We have recently reported that vascular smooth muscle cells (VSMC) derived from patients with graft stenoses are resistant to growth inhibition by heparin. In this study, we have examined whether VSMC proliferation rates and responses to inhibition by heparin vary according to the individual or the anatomic site of origin. METHODS: Long saphenous veins from seven patients were divided into proximal, middle, and distal portions, and VSMC were cultured separately from each. VSMC proliferation in response to 15% fetal calf serum +/- 100 micrograms/ml heparin was measured by counting triplicate samples at 0, 3, 7, 10, and 14 days. This experiment was repeated from the second to the sixth passage (n = 6) and for artery and vein pairs derived from four additional patients. RESULTS: Differences between vein segment cultures of individual veins were found not to differ significantly from experimental error for either proliferation or heparin inhibition and were not altered by repeated passage (ANOVA). There were, however, significant differences in sensitivity to heparin inhibition between patients (p = 0.02) (ANOVA). There were no significant differences between paired samples of artery and vein for either proliferation or heparin inhibition (Mann-Whitney test). CONCLUSIONS: VSMC growth characteristics reflect the individual patient and are maintained in cell culture.

Analysis of Variance↗
PubMed1994

Growth inhibition of human vascular smooth muscle cells by fenofibrate: a possible therapy for restenosis.

OBJECTIVE: The aim was to assess the growth inhibitory effect of fibrates on human vascular smooth muscle cells. Restenosis is the most important factor limiting the long term success of invasive vascular interventions and there is as yet no effective preventive treatment. Platelet derived growth factor (PDGF) is considered to be an important growth promoting agent for vascular smooth muscle cells (VSMC) and fenofibric acid (a hypolipidaemic drug) has been reported to be a PDGF antagonist. METHODS: The effect of the fibrate drugs fenofibrate, clofibrate, bezafibrate, and gemfibrozil were examined on the proliferation of cultured human vascular smooth muscle cells derived from saphenous vein (n = 20) and graft stenoses (n = 7). RESULTS: Fenofibrate (100 microM) produced potent inhibition (48%) of VSMC proliferation at a concentration equivalent to that of its circulating metabolite fenofibric acid, but none of the other drugs produced any significant effect on growth. VSMC derived from graft stenoses were equally sensitive to inhibition as saphenous vein derived controls, in contrast to our previous work which reported that graft stenosis derived VSMC were resistant to growth inhibition by the physiological inhibitor heparin. The antiproliferative effect of fenofibrate was independent of inhibition of cellular cholesterol synthesis or toxicity. Fenofibrate inhibited VSMC growth induced by 15% fetal calf serum, PDGF, and basic fibroblast growth factor to a similar degree, indicating that it is not a specific PDGF antagonist. CONCLUSIONS: Fenofibrate is not a specific PDGF antagonist. Fenofibric acid, one of the principal metabolites of fenofibrate, did not produce any inhibition of growth, suggesting that oral administration of fenofibrate would not be efficacious. Fenofibrate is the first potent inhibitor to be described for VSMC derived from human myo-intimal hyperplastic lesions.

Bezafibrate↗
PubMed1994

Effect of calcium channel blockers on the growth of human vascular smooth muscle cells derived from saphenous vein and vascular graft stenoses.

Vascular restenosis after invasive interventions is an important clinical problem for which no preventive pharmacologic therapy exists. Calcium channel blockers have been shown to inhibit myointimal hyperplasia in animal models of restenosis and in some small and flawed clinical coronary restenosis trials. We examined the inhibitory effect of amlodipine, verapamil, and diltiazem on the growth of cultured human vascular smooth muscle cells (VSMC) derived from saphenous vein (n = 20) and graft stenoses (n = 7), in 14-day proliferation assays and [methyl 3H]thymidine uptake studies. Amlodipine and verapamil produced significant inhibition (30%) of VSMC proliferation and DNA synthesis at 10 microM but not at 500 nM-1 microM. To our knowledge, this is the first study to examine the antiproliferative effect of calcium channel blockers in VSMC derived from human graft stenoses. Growth inhibition of VSMC from graft stenoses was not significantly different from that of control saphenous vein-derived cells. We conclude, therefore, that calcium channel blockers inhibit human VSMC proliferation in vitro, regardless of whether the cells were grown from graft stenoses or saphenous vein. However, the concentrations at which these calcium channel blockers elicit antiproliferative effects may not be attainable during therapeutic dosing in humans.

Amlodipine↗
PubMed1994

Inhibition of human vascular smooth muscle cell proliferation by lovastatin: the role of isoprenoid intermediates of cholesterol synthesis.

Restenosis remains the largest single obstacle to the long-term success of invasive vascular interventions. Lovastatin, an HMG-CoA reductase inhibitor, has been shown to reduce myointimal hyperplasia in animal models of restenosis and in one clinical coronary restenosis trial. We have assessed the effect of lovastatin on the growth of cultured human vascular smooth muscle cells derived from saphenous vein and vascular graft stenoses. Lovastatin (2 microM) inhibited proliferation over 14 days in saphenous vein (and graft stenoses) derived vascular smooth muscle cells by 42% and 32% respectively: this was not significantly different. Lovastatin (10 microM) reduced [methyl 3H]-thymidine uptake by 51% in saphenous vein-derived cells. These concentrations were significantly higher than those achieved in plasma during therapeutic dosage. Lovastatin-induced inhibition of vascular smooth muscle cell proliferation and [methyl 3H]-thymidine uptake was completely reversed by adding mevalonate (100 microM) but cholesterol (10-40 micrograms ml-1) had no effect. Isopentenyl adenine (25-50 microM) did not affect the inhibition of [methyl 3H]-thymidine uptake by lovastatin (10 microM), but farnesol (20 microM), another isoprenoid precursor of cholesterol synthesis, reversed the antiproliferative effect.

Adenine↗
PubMed1993

Abnormal growth regulation of vascular smooth muscle cells by heparin in patients with restenosis.

Proliferation of vascular smooth muscle cells (VSMC) underlies myointimal hyperplasia, which can lead to restenosis after angioplasty and vascular surgery. We propose that some individuals have an intrinsic capacity for this exaggerated response to vascular injury, partly through decreased sensitivity to the physiological growth inhibitor heparin. We investigated the effect of heparin on VSMC from restenotic lesions and from apparently normal vessels of the same patients, and VSMC from control patients undergoing primary bypass procedures. Cells from patients with restenosis (both restenotic lesion and undiseased vein) showed much lower sensitivity to growth inhibition by heparin than the controls (median inhibition 8 [95% Cl -2 to 25] vs 22 [15-44]%, p < 0.001); this finding suggests aberrant growth regulation in these cells.

Arterial Occlusive Diseases↗
PubMed1993

Cellular biology of human intimal hyperplastic stenosis.

Restenosis after angioplasty and vascular surgery remains a major unsolved clinical problem. Vascular smooth muscle cell (VSMC) hyperplasia is an invariable response, but in 20-50% of cases proceeds to compromise the vessel lumen. We sought to identify cellular characteristics of human VSMC which are associated with restenosis. Human VSMC were grown from 135 samples of vascular tissue derived from patients undergoing primary cardiovascular surgery and revision surgery for restenosis. Cells derived from normal vein and artery, atherosclerotic plaques and from stenotic lesions were studied for successful proliferation in cell culture. Furthermore, growth rates were measured in response to 15% foetal calf serum +/- inhibition with heparin (100 micrograms/ml). Significantly fewer cells from atherosclerotic plaques progress to the third passage in cell culture than those derived from stenoses and controls (p < 0.001, Chi square) and growth rates after the third passage could not be studied in these cells. Of cells that progress to this stage, growth rates do not differ between stenosis-derived and normal cells under standard conditions. VSMC from mature atherosclerotic plaques may have undergone senescent changes. Stenosis-derived cells do not grow more rapidly than normal cells, but are significantly less sensitive to heparin (p < 0.001, Mann-Witney test), which is a major physiological inhibitor of VSMC growth. Differences in biological characteristics of human VSMC, observed in cell culture, may provide important insights into human vascular disease.

Actins↗
PubMed1991

The construction of human somatic cell hybrids containing portions of the mouse X chromosome and their use to generate DNA probes via interspersed repetitive sequence polymerase chain reaction.

Interspersed repetitive sequence polymerase chain reaction (IRS-PCR) has become a powerful tool for the rapid generation of DNA probes from human chromosomes present in rodent somatic cell hybrids. We have constructed a somatic cell hybrid containing a major portion of the mouse X chromosome in a human background (clone 8.0). IRS-PCR was developed for the specific amplification of mouse DNA using either of two primers from the rodent-specific portion of the murine B1 repeat. Amplification was subsequently performed with clone 8.0 and a subclone, 8.1/1, which retains a small murine X-chromosomal fragment including Hprt and the Gdx locus. A total of 15-20 discrete PCR products ranging in size from less than 500 to greater than 3000 bp were obtained from clone 8.0 with each primer. In clone 8.1/1, a subset of these bands plus some additional bands were observed. Nine bands amplified from clone 8.1/1 have been excised from gels and used as probes on Southern blots. All of the fragments behaved as single-copy probes and detected domesticus/spretus variation. They have been regionally mapped using an interspecific backcross. The probe locations are compatible with those of markers known to be present in clone 8.1/1. These results demonstrate the feasibility of this method as applied to the mouse genome and the high likelihood of generating useful DNA probes from a targeted region.

Animals↗