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M J Davies

Publications and source records attributed to M J Davies.

At least 19 recordsLinked to original sources
PubMed1992

Detection of radicals produced by reaction of hydroperoxides with rat liver microsomal fractions.

EPR spin trapping using the spin traps 5,5-dimethyl-1-pyrroline N-oxide (DMPO) and 3,5-dibromo-4-nitrosobenzene sulphonic acid (DBNBS) has been employed to examine the generation of radicals produced on reaction of a number of primary, secondary and lipid hydroperoxides with rat liver microsomal fractions in both the presence and absence of reducing equivalents. Two major mechanisms of radical generation have been elucidated. In the absence of NADPH or NADH, oxidative degradation of the hydroperoxide occurs to give initially a peroxyl radical which in the majority of cases can be detected as a spin adduct to DMPO; these radicals can undergo further reactions which result in the generation of alkoxyl and carbon-centered radicals. In the presence of NADPH (and to a lesser extent NADH) alkoxyl radicals are generated directly via reductive cleavage of the hydroperoxide. These alkoxyl radicals undergo further fragmentation and rearrangement reactions to give carbon-centered species which can be identified by trapping with DBNBS. The type of transformation that occurs is highly dependent on the structure of the alkoxyl radical with species arising from beta-scission, 1,2-hydrogen shifts and ring closure reactions being identified; these processes are in accord with previous chemical studies and are characteristic of alkoxyl radicals present in free solution. Studies using specific enzyme inhibitors and metal-ion chelators suggest that most of the radical generation occurs via a catalytic process involving haem proteins and in particular cytochrome P-450. An unusual species (an acyl radical) is observed with lipid hydroperoxides; this is believed to arise via a cage reaction after beta-scission of an initial alkoxyl radical.

Animals↗
PubMed1992

Direct detection of a globin-derived radical in leghaemoglobin treated with peroxides.

The root nodules of leguminous plants contain an oxygen-carrying protein which is somewhat similar to myoglobin. Reaction of the Fe3+ form of this protein (metleghaemoglobin; MetLb) with H2O2 is known to generate a ferryl [iron(IV)-oxo] species. This intermediate, which is analogous to Compound II of peroxidases and ferryl myoglobin, is one oxidizing equivalent above the initial level. In the present study it is shown that the second oxidizing equivalent from the peroxide is rapidly transferred into the surrounding protein, generating a protein radical which has been detected by e.p.r. spectroscopy; this reaction is analogous to that observed with metmyoglobin. An identical protein-derived species is observed with all three forms of MetLb tested (a, c1, c3) and with a number of other hydroperoxides and two-electron oxidants. This latter result, the observation that the concentration of this species is not affected by certain hydroxyl-radical scavengers, and the loss of the radical when the oxy or deoxy forms are used, demonstrate that this species is formed by electron transfer within the protein rather than by the generation and subsequent reaction of hydroxyl radicals (and related species from the other hydroperoxides). The e.p.r. signal of this species, which decays rapidly with a half-life of approx. 40 s, is consistent with the formation of a sterically constrained tyrosine-derived phenoxyl radical; protein-iodination experiments lend support to this assignment. Reaction between the radical and a number of other compounds has been observed, demonstrating that it is at least partially exposed on the surface of the protein. Analysis of the protein structure suggest that the radical may be centred on a tyrosine residue present at position 132 in the protein; this residue is close to the haem prosthetic group, which would facilitate rapid electron transfer.

Electron Spin Resonance Spectroscopy↗
PubMed1992

Assessment of rejection in orthotopic human heart transplantation using proliferating cell nuclear antigen (PCNA) as an index of cell proliferation.

Myocardial biopsies taken during the management of cardiac transplantation were stained for proliferating cell nuclear antigen (PCNA). Counts of PCNA-positive interstitial cells were compared, in retrospect, with the reported histological grade of rejection. Biopsies without rejection had negligible numbers of PCNA-positive cells. Ascending grades of rejection were paralleled by an increase in the number of PCNA-positive cells [grade 1, 13 +/- 35 (mean +/- SD); grade 2a, 38 +/- 40; grade 2b, 91 +/- 75; grade 3, 170 +/- 78]. While highly significant, in statistical terms, the overlap in the counts between different grades means that prediction of rejection from the PCNA count alone is not feasible. Biopsies graded as 0 or 1 and which immediately preceded more severe rejection episodes showed no increase in PCNA-positive cells. The majority of PCNA-positive cells are fibroblasts, although in grade 2b and 3 rejection a small population of PCNA-positive T lymphocytes occurs. PCNA staining is also seen in cardiac myocytes immediately after transplantation, during rejection episodes, and late after transplantation in the absence of rejection. The positive PCNA staining of cardiac myocytes probably reflects DNA synthesis that occurs with the shift toward polyploidy in hypertrophy.

Autoantigens↗
PubMed1992

Collagen types I and III, collagen content, GAGs and mechanical strength of human atherosclerotic plaque caps: span-wise variations.

Measurements of total collagen, of the ratio of collagen types III/(I+III) and of sulphated glycosaminoglycans (GAGs) were compared with mechanical strength for individual ulcerated and non-ulcerated human aortic plaque caps and with intima adjacent to the plaques. The distributions of the collagen type ratio were similar for both ulcerated and non-ulcerated plaque caps but different from that of the adjacent intima. The proportions of different collagen types were not related to fracture stress and are thus unlikely to affect the potential to ulcerate. The distributions of the sulphated GAGs showed lower amounts for the plaque caps compared with the nearby intima, with the centres of ulcerated plaque caps having the lowest values. Total collagen had higher values in the peripheries of plaque caps compared with the nearby intima, but was distinctly lower in the centres of ulcerated plaque caps. Plaque caps appeared to require a higher collagen content than adjacent intima to support a given level of mechanical strength, suggesting that while collagen production had occurred in the plaque caps it was not as efficiently organized to resist fracture as a similar amount of collagen in the adjacent intima. Ulcerated plaque caps are notable for much larger transverse (centre vs. periphery) gradients of connective tissue constituents than for non-ulcerated plaque caps. The development of these transverse gradients may be a critical aspect in determining the propensity of a plaque to ulcerate.

Aortic Diseases↗
PubMed1992

Thioguanine-resistant mutant frequency in T-lymphocytes from a healthy human population.

Resistance to 6-thioguanine in T-lymphocytes was used to study in vivo somatic mutations in normal healthy adults. Donor age had a significant effect on mutant frequency at the hprt locus, showing an increase of 0.09/10(6) cells per year of age. No significant increase was associated with sex of donor, smoking habits, alcohol or coffee/tea intake, or X-ray exposure. The lower mutant frequency seen with contraceptive pill usage was probably due to the age difference between the groups of users and non-users.

Adult↗
PubMed1992

The antioxidant potential of propofol (2,6-diisopropylphenol).

We have examined in vitro the antioxidant properties of 2,6-diisopropylphenol. In studies using electron spin resonance spectroscopy we have demonstrated that 2,6-diisopropylphenol acts as an antioxidant by reacting with free radicals to form a phenoxyl radical--a property common to all phenol-based free radical scavengers. In additional experiments, the antioxidant properties of the clinical formulation of 2,6-diisopropylphenol (propofol) have been measured using an assay of antioxidant potential. In these experiments, propofol, but not Intralipid, was found to exhibit significant antioxidant activity, such that in the range of propofol concentrations examined (10(-6)-10(-5) mol litre-1), each molecule of 2,6-diisopropylphenol was able to scavenge two radical species. We conclude that the free radical scavenging properties of 2,6-diisopropylphenol resemble those of the endogenous antioxidant alpha-tocopherol (vitamin E).

Antioxidants↗
PubMed1992

Atrial myxoma: a tumour in search of its origins.

OBJECTIVE: To determine whether atrial myxomas express antigens suggesting a neural origin. DESIGN: A retrospective analysis based on immunohistochemical examination of myxoma tissue. SETTING: Atrial myxomas excised by two tertiary referral cardiothoracic surgical units. SUBJECTS: 24 excised atrial myxomas. Three were from known cases of familial myxoma syndrome. METHODS: Immunohistochemical identifications of three neuroendocrine markers (protein gene product (PGP) 9.5, neurone specific enolase (NSE), synaptophysin) and S100 antigen; CD34 and von Willebrand factor; and chi smooth muscle actin to identify possible Schwann cell differentiation, endothelial cells, and smooth muscle cells respectively. RESULTS: The myxoma cells were PGP 9.5 positive in 18, S100 positive in 16, and NSE positive in 12. Of the 12 NSE positive myxomas seven were synaptophysin positive. All tumours that were NSE positive were also S100 and PGP 9.5 positive. The tumour surface was partially covered by myxoma cells, partly by endothelial cells. CONCLUSION: The histological appearances of myxomas with stellate cells embedded within a loose connective tissue stroma, abundant basophil cell infiltration, and the presence of pericellular type IV collagen are similar to nerve sheath tumours (neurofibromas) at other sites. A significant proportion of myxomas also express Schwann cell and neuroendocrine differentiation markers. These features cannot prove the origin of myxomas because tumours may develop aberrant phenotype expression but they do accord with the view that myxomas originate from endocardial sensory nerve tissue.

Antigens, Neoplasm↗
PubMed1992

Similar prevalence of enteroviral genome within the myocardium from patients with idiopathic dilated cardiomyopathy and controls by the polymerase chain reaction.

OBJECTIVE: To assess the prevalence and significance of enteroviral genome within myocardial biopsy specimens taken from patients with idiopathic dilated cardiomyopathy and from controls. DESIGN: Prospective evaluation of myocardial tissue for the presence of an enteroviral genome by the polymerase chain reaction. SETTING: A tertiary referral centre for patients with idiopathic dilated cardiomyopathy. PATIENTS: Tissue for the study came from 50 consecutive patients with dilated cardiomyopathy, 41 with other forms of heart disease and 34 from coroners' necropsy cases. RESULTS: Enteroviral genome was detected in 6/50 (12%) patients with dilated cardiomyopathy and 13/75 (17%) of the controls (not significant). No differences were seen between dilated cardiomyopathy patients with or without myocardial enteroviral genome in respect of age; duration of symptoms; proportion of patients with a premorbid acute viral illness, excess alcohol consumption, or hypertension; New York Heart Association functional class; measures of left ventricular function; or endomyocardial histology. Within the control group enteroviral genome was detected in 3/15 (20%) patients with ischaemic heart disease, 2/19 (10.5%) with valvar heart disease, 1/5 (20%) with specific heart muscle disease, 0/2 (0%) with congenital heart disease, and 7/34 (20.6%) cases of sudden death. During 2-52 month follow up (mean 22) 15/44 (34%) patients without myocardial enteroviral genome and 2/6 (33%) with myocardial enteroviral genome died suddenly or required orthotopic heart transplantation for progressive heart failure. CONCLUSIONS: These findings do not support the hypothesis that persistent enteroviral infection is of pathogenic or prognostic importance in dilated cardiomyopathy but they are consistent with enterovirus being a common environmental pathogen.

Adolescent↗
PubMed1992

Intravascular ultrasound imaging of the coronary arteries: an in vitro evaluation of measurement of area of the lumen and atheroma characterisation.

OBJECTIVE: To assess the accuracy of measurement of area of the lumen, and sensitivity, and specificity of detection of atheroma in coronary arteries in vitro with a commercially available 20 MHz intravascular ultrasound system. SETTING: A teaching hospital department of cardiology with the support of the department of cardiovascular pathology. PROCEDURE: 10 segments of coronary artery were removed from cadaver hearts. Intravascular ultrasound imaging was performed at fixed levels and the vessels were then sectioned and photographed before histological preparation. An independent blinded observer measured luminal area and assessed the presence of atheroma on the intravascular ultrasound images of 76 vessel sections (304 quadrants). The sensitivity and specificity of detection of atheroma was assessed in comparison with the histologically prepared sections. Luminal areas from intravascular ultrasound, photographs of cross sections of the vessels and histological sections were compared with the technique of limits of agreement. RESULTS: Overall 36% of the 304 quadrants studied histologically had identifiable atheroma. Intravascular ultrasound sensitivity for atheroma was 0.593 and the specificity was 0.839. The positive predictive value was 0.674, and the relative risk 3.139. Values for area of the vessel lumen were on average 9.4 mm2 (confidence interval (CI) 8.6-10.2 mm2) larger than those measured from photographs and 10.7 (CI 9.8-11.6 mm2) larger than those measured from the histological sections. CONCLUSIONS: The intravascular ultrasound system assessed in this study significantly overestimated coronary vessel luminal area and had low sensitivity and specificity for detection of atheroma. Improvements in image resolution are required before this system can provide useful information on coronary artery size and morphology.

Coronary Artery Disease↗
PubMed1992

Prevention of tachycardia with atenolol pretreatment for carotid endarterectomy under cervical plexus blockade.

A double-blind, randomised, controlled trial of forty patients was carried out to determine if oral atenolol pretreatment would reduce the incidence of tachycardia during carotid endarterectomy performed under cervical plexus block. Twenty patients received a placebo and twenty patients 50 mg of atenolol two hours prior to surgery. The superficial and deep cervical blocks were performed with 1.5% lignocaine containing 1:200,000 adrenaline. The patients were monitored with the V5 lead of the electrocardiogram and intra-arterial blood pressure. These measurements were recorded on a correctly calibrated paper recorder. Tachycardia (heart rate greater than 90 beats per minute for more than three minutes) occurred in thirteen patients in the placebo group and two patients in the atenolol group (P less than 0.01). There was no difference in the occurrence of bradycardia, hypotension or hypertension between the two groups. It is concluded that atenolol pretreatment is an effective method of reducing the incidence of tachycardia during carotid endarterectomy performed under cervical plexus blockade.

Aged↗
PubMed1992

Plaque fissure: the link between atherosclerosis and thrombosis.

The immediate cause of arterial, predominantly coronary thrombosis is almost always cracking or fissuring of the cap of an atheromatous plaque. This exposes collagen and lipids to the flowing blood and thereby initiates thrombotic platelet aggregation, almost immediately followed by coagulation. The thrombi tend to extend into the arterial lumen, causing obstruction to blood flow and clinical symptoms and signs. Evidence for this sequence of events comes, inter alia, from angiograms of patients with unstable angina and developing myocardial infarction. Direct angioscopy in life is also visualising mural thrombi over fissured plaques in atheromatous coronary arteries. We are investigating the initial development of atheromatous plaques liable to fissuring. The cap over such plaques covers a "lipid pool". We have discovered that one factor promoting the uptake of lipid, in the form of plasma low-density lipoprotein, is the concentration of circulating catecholamines (Cardona-Sanclemente LE, Gorog P, Born GVR (1992) J Physiol London, in press). We are also investigating the immediate cause(s) of plaque fissure. We have evidence for a complex interaction of different determinants, including the concentration of macrophages, presumably as foam cells, in the plaque caps (Lendon CL, Davies MJ, Born BVR, Richardson PD (1991) Atherosclerosis 87: 87).

Angina, Unstable↗
PubMed1992

Anatomic features in victims of sudden coronary death. Coronary artery pathology.

Study of the detailed pathology of the myocardium and coronary arteries in ambulatory subjects dying suddenly of coronary heart disease shows that they can be divided into two groups. In one group, there is atherosclerosis with a new vascular event involving coronary thrombosis, which initiates acute myocardial ischemia. In the other group, there is chronic high-grade stenosis due to atherosclerosis, but there is no recent vascular change; the myocardium in this group shows scarring from a previously healed infarction acting as a substrate for reentrant ventricular arrhythmias. A study of 168 consecutive cases of sudden coronary death in London showed 73.3% to have had a recent coronary thrombotic lesion, giving a ratio of 2.7:1 for patients with versus patients without new acute myocardial ischemia. The widely differing ratios reported in the literature probably reflect the patterns of case selection. Prodromal pain immediately before the onset of ventricular fibrillation in a patient without previous known coronary disease selects for a thrombotic cause and acute myocardial ischemia. Absence of pain in a patient known to have had a previous infarction selects for a primary arrhythmia on the basis of preexisting myocardial hypertrophy and/or scarring.

Acute Disease↗
PubMed1991

Primary restrictive cardiomyopathy: clinical and pathologic characteristics.

Twenty-four patients with restrictive cardiomyopathy were identified at St. Thomas' Hospital during a 17-year period. All had endomyocardial biopsy, but in two patients the biopsy specimens were small and nondiagnostic. Seven patients had amyloidosis and five had other specific heart muscle diseases. The remaining 10 patients with primary restrictive cardiomyopathy had myocyte hypertrophy or interstitial fibrosis, or both. Patients with primary restrictive cardiomyopathy presented earlier but survived longer after presentation than did those with amyloidosis. In each group, survival after cardiac catheterization was related to cardiac index but not to filling pressures. Primary restrictive cardiomyopathy was associated with complete heart block in four patients, two of whom had skeletal myopathy. One had a family history of dominantly inherited skeletal myopathy. Primary restrictive cardiomyopathy was present in a mother and daughter. Two other patients had a family history of heart failure, sudden death or complete heart block, alone or in combination, at a young age. Restrictive hemodynamics and complete heart block were present in patients even in the absence of significant fibrosis. The data suggest that primary restrictive cardiomyopathy may be a distinct myopathy with dominant inheritance and incomplete penetrance that is expressed morphologically as myocyte hypertrophy and interstitial fibrosis. Skeletal myopathy may be associated with the cardiomyopathy.

Adolescent↗