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Biomedical subjects

N J Dodd

Publications and source records attributed to N J Dodd.

At least 19 recordsLinked to original sources
PubMed1996

Evidence for free radical generation after primary percutaneous transluminal coronary angioplasty recanalization in acute myocardial infarction.

In animal models, oxygen-derived free radicals have been found to be important mediators of reperfusion injury to ischemic but viable myocardium. However, in humans, there is no direct evidence of free radical production after the restoration of coronary artery patency in acute myocardial infarction. The purpose of this study was to quantitate and assess the time course of free radical production in coronary venous outflow in patients with acute myocardial infarction undergoing successful recanalization of the infarct-related artery by primary percutaneous transluminal coronary angioplasty (PTCA). Primary PTCA was performed in 17 patients with acute myocardial infarction of < 6 hours duration. Direct free radical production was assessed by coronary venous effluent blood sampling before PTCA and at timed intervals up to 24 hours (or 48 hours in 6 patients) after recanalization. All samples were added to the spin trapping agent alpha-phenyl N-tert butyl nitrone and analyzed by electron paramagnetic resonance spectroscopy. Vessel patency resulted in a sharp increase in free radical signal. Relative to the level before PTCA, the changes reached statistical significance after only 15 minutes (p < 0.05). Peak signals were observed between 1 1/2 and 3 1/2 hours (p < 0.001), then declined up to 5 hours. A second increase in signal level was detected between 18 and 24 hours despite no angiographic evidence of reocclusion. A gradual decline was observed after 24 hours. These findings provide the first direct and quantitative evidence of free radical production in the immediate postrecanalization phase after thrombotic occlusion of a major coronary artery in humans.

Aged↗
PubMed1995

Low-level direct electrical current therapy for hepatic metastases. I. Preclinical studies on normal liver.

Low-level direct electrical current has shown promise as a potential therapeutic modality (direct current therapy; DCT) in the treatment of malignant disease, including metastases, but to date much experimental work has been empirical and has added little to our knowledge of the mechanisms involved. As a prerequisite to a clinical trial for metastases in the liver, we have employed an in vivo liver model to examine the quantitative and qualitative relationships between electrode polarity, charge and tissue necrosis. Two distinct regions of necrosis were induced, distinguishable histologically and by magnetic resonance imaging: (i) a cylindrical region of primary necrosis centred on the electrode, its volume directly proportional to the charge passed, but greater at the anode than cathode; and (ii) a wedge-shaped infarct, apex at the electrode and base extending to the liver edge. The extent of this infarct was again greater at the anode than the cathode, but showed a sigmoidal relationship with charge. Results indicate pH changes at the electrodes as likely mediators of tissue injury, but show also that significant distant ischaemic injury can occur as a consequence of primary damage. These findings should be considered when selecting tumours for possible direct current therapy and when determining the sites of electrode placement.

Animals↗
PubMed1995

Free radicals and food irradiation.

Ionizing radiation can be used to control insect and microbial infestation of foodstuffs, inhibit sprouting, delay ripening and reduce the dangers from food-poisoning bacteria. Irradiation produces free radicals, most of which decay rapidly, although some are more persistent. These latter radicals can be detected and characterized by electron spin resonance (ESR). In bone and other calcified tissues, the radiation-induced radicals are distinguishable from naturally occurring radicals, and their stability makes them ideal for radiation dosimetry. The radicals induced in plant material, such as seeds and dried spices, are generally indistinguishable from the endogenous radicals and decay over a period of days or weeks. However, in many of these materials, a radiation-specific radical can be detected at low concentration, thereby permitting identification of irradiated samples, although precluding accurate dosimetry. ESR, although not universally applicable, currently provides the most specific method for the detection of irradiated food.

Electron Spin Resonance Spectroscopy↗
PubMed1994

The effects of low-level direct current therapy on a preclinical mammary carcinoma: tumour regression and systemic biochemical sequelae.

Low-level direct electric current has been shown to be capable of destroying tumour tissue. Using an early-passage subcutaneous murine mammary carcinoma, the relationships between the volume of tumour destruction, charge and polarity have been examined. The results revealed a direct correlation between charge passed and absolute volume regression when the intratumoral electrode was made either an anode or a cathode. Tumour destruction for a given charge was significantly greater following anodic than cathodic treatment. A direct correlation was also observed between the percentage volume of prompt treatment-induced regression and the in situ end point of tumour growth delay. During the course of these experiments, a highly reproducible toxic effect was discovered, which has not been previously reported for this modality. An anodic charge greater than 10.6 coulombs or a cathodic charge greater than 21.6 coulombs resulted in 100% mortality at 24-72 h, while lower charges had no influence on mortality. Quantitative assays of a number of blood parameters showed that mortality was associated with serum electrolyte imbalances and appeared to be the result of the metabolic load of tumour breakdown products. These effects are similar to the tumour lysis or surgical crush syndromes and should not constitute a significant problem in clinical practice, where the tumour mass to total body mass ratio will normally be much smaller.

Animals↗
PubMed1993

Free-radical generation during angioplasty reperfusion for acute myocardial infarction.

We describe direct and quantitative evidence of free-radical production in the early stage after recanalisation in a patient undergoing primary coronary angioplasty for acute myocardial infarction. After successful initial dilation, the procedure was complicated by re-occlusion of the artery at the same site, with subsequent fall in free-radical generation. After repeat angioplasty, recanalisation was again accompanied by increased free-radical production.

Angioplasty, Balloon, Coronary↗
PubMed1990

Anthralin-derived transients--II. Formation of the radical by spontaneous fragmentation of both singlet and triplet states of the 10,10'-dehydrodimer: radical pair multiplicity effects.

The singlet and triplet states of the anthralin (1,8-dihydroxy-9-anthrone) dehydrodimer have been produced selectively in benzene via pulsed laser excitation and pulse radiolysis respectively. The lifetime of S1 is less than or equal to 30 ps, that of T1 short but unspecified. Both states fragment spontaneously to yield a pair of anthralin radicals. The singlet radical pair predominantly undergoes geminate recombination within the solvent cage. In contrast, the corresponding triplet radical pair undergoes essentially exclusive cage escape to give the anthralin free radical (lambda max 370, 490 and 720 nm) which recombines under normal diffusive conditions. Both recombination processes lead, at least in part, to one or more species which have been assigned as tautomeric forms of the original dimer. The anthralin free radical in benzene is insensitive to the vitamin E model 6-hydroxy-2,2,5,7,8-pentamethylchroman and reacts only slowly with oxygen.

Anthralin↗
PubMed1989

The measurement of radiocaesium in sheep by an in vivo technique.

This paper discusses the use of a large sodium iodide detector to determine gamma-ray emitting radionuclides in living animals, and in particular the application of the technique to investigations that have followed the Chernobyl reactor accident. A series of experiments to validate the technique is presented. The detector and its associated electronics and data collection equipment are sufficiently robust for use in the field, and ancillary equipment to immobilize subjects such as sheep and cattle are readily available. Although the in vivo procedure underestimates activity concentrations in muscle tissue compared to results from samples obtained post mortem, the advantage is that the same animal can be measured repeatedly and reproducibly.

Animals↗
PubMed1989

The ESR detection of irradiated food.

Previous work has shown that the calcified tissues in several foods give rise to characteristic ESR spectra on irradiation. Further foods have now been examined. Mussel and crab shells give large signals, compared with bones of poultry, beef or frog, while prawn cuticle gives a smaller signal. The limits of detection of irradiation vary between species but are below the doses likely to be used commercially. Quantitative estimation of dose can be achieved by re-irradiation and extrapolation to zero signal.

Electron Spin Resonance Spectroscopy↗
PubMed1989

In vivo magnetic resonance imaging of the effects of photodynamic therapy.

Nuclear magnetic resonance (NMR) proton imaging and measurements of the parameters T1 and T2, have been carried out in vivo on the murine mammary tumour T50/80. Tumours had been treated 24 h previously by photodynamic therapy (PDT, using haematoporphyrin derivative and 630 nm laser light). Proton images clearly demarcated a high signal-intensity region on the side of the tumour closest to the incident light beam, while the parts of the tumour more remote from the beam resembled the images from untreated controls. Both T1 and T2 values were raised in the high-intensity region. This high-intensity region was shown to correspond to PDT-induced histological necrosis, the low-intensity region to histologically intact tumour. Linear regression analysis of the relationship of depth of necrosis measured histologically and 'depth of necrosis' measured from the NMR images, yielded a slope of 0.93 (r2 = 0.95).

Animals↗
PubMed1988

Distribution of 5-doxylstearic acid in the membranes of mammalian cells.

Concentration-dependent spin broadening of ESR spectra of the nitroxide 5-doxylstearic acid has been used to evaluate the distribution of 5-doxylstearic acid in the membranes of intact mouse thymus-bone marrow (TB) and Chinese hamster ovary (CHO) cells. TB cells, CHO cells, erythrocytes, and isolated plasma membranes from CHO cells were labelled with 5-doxylstearic acid and the peak to peak linewidths of the central line of the resulting ESR spectra were measured. The measured line widths were linearly dependent on the amount of 5-doxylstearic acid incorporated into the sample over the range of 0-0.18 mol nitroxide per mol lipid. In erythrocytes, the relationship between linewidths approximated a linear function at lower concentrations of 5-doxylstearic acid, up to 0.07 mol nitroxide per mol lipid. The amount of broadening of the central line for a given amount of 5-doxylstearic acid was far less for intact cells than for either erythrocytes or plasma membrane, indicating that the 5-doxylstearic acid samples a much larger lipid pool in the intact cells. With the broad assumption that the mobility of the 5-doxylstearic acid is similar in different membranes, the size of the lipid pool sampled by 5-doxylstearic acid is approximately equal to the total cellular lipid in intact cells. If a given concentration of 5-doxylstearic acid sampled only the plasma membrane of TB or CHO cells, we would expect to see a linewidth corresponding to a 12-20-fold greater local concentration of 5-doxylstearic acid than was observed, since the plasma membranes of CHO and TB cells represent only 5-8 percent of the total cellular lipid. Therefore, the 5-doxylstearic acid must distribute into most or all cellular membranes of intact cells and is not localized in the plasma membrane alone.

Animals↗
PubMed1988

Plutonium and Cs-137 in autopsy tissues in Great Britain.

Tissues removed at autopsy from members of the general public contain significantly higher concentrations of plutonium and 137Cs in west Cumbrians than in people from three other regions of Great Britain. Several autopsy cases from Cumbria showed unusually high values of plutonium. Subsequently it was found that the subjects had been former employees of British Nuclear Fuels.

Autopsy↗
PubMed1987

The phase behaviour of dispersions of Bis-Azo PC: photoregulation of bilayer dynamics via lipid photochromism.

A phospholipid, 1,2-bis(4-(n-butyl)phenylazo-4'-phenylbutyroyl)phosphatidylcholine (Bis-Azo PC), has been synthesised and shown to form stable bilayer vesicles. Light-scattering measurements and differential scanning calorimetry show that a dispersion of the lipid has a cooperative phase transition at a similar temperature to that of dipalmitoylphosphatidylcholine, which Bis-Azo PC resembles in overall size. The phase behaviour of Bis-Azo PC has been investigated by fluorescence spectroscopy and using a series of spin-labelled fatty acid probes. Fluorescence measurements using chlorophyll a as probe sense the onset of the cooperative phase transition, but this is not clearly revealed by any of the spin probes tested. Hysteresis in the phase transition is detected both by light scattering measurements and by fluorescence spectroscopy. No transition is observed for a lipid analogue having a palmitic acid chain and a single azo-containing substituent. Bis-Azo PC is reversibly photochromic, isomerising on exposure to ultraviolet light to a photostationary state mixture where cis isomer predominates. Electron microscopy shows that photoisomerisation decreases average vesicle size, and light scattering and calorimetry demonstrate that the cooperative phase transition is abolished. Illumination with visible light establishes a new photostationary state where trans isomer predominates, and the phase transition is restored. The ability to modulate bilayer phase behaviour reversibly has possible application to relaxation studies of bilayer membrane function, and to drug delivery research.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1987

Quinidine and melittin both decrease the fluidity of liver plasma membranes and both inhibit hormone-stimulated adenylate cyclase activity.

Increasing concentrations of either quinidine or melittin gave a dose-dependent inhibition of both the glucagon- and fluoride-stimulated activities of adenylate cyclase in the liver plasma membranes. At similar concentrations these agents increased the order of liver plasma membranes as detected by a fatty acid ESR probe, doxyl stearic acid. This increase in bilayer order (decrease in 'fluidity') is suggested to explain the inhibitory action of quinidine on adenylate cyclase activity but only in part contributes to the inhibitory action of melittin on adenylate cyclase. Arrhenius plots of fluoride-stimulated activity became non-linear in the presence of either quinidine or melittin, with a single well-defined break occurring at around 12 degrees C in each instance. Arrhenius plots of the glucagon-stimulated activity also exhibited such a novel break at around 12 degrees C when either quinidine or melittin were present as well as exhibiting a break at around 28 degrees C, as was seen in the absence of these ligands. The fatty acid spin probe inserted into liver plasma membranes detected a novel lipid phase separation occurring at around 12 degrees C when either quinidine or melittin was present and showed that the lipid phase separation occurring at around 28 degrees C in native membranes was apparently unaffected by these ligands.

Adenylyl Cyclases↗
PubMed1986

Acidic phospholipid species inhibit adenylate cyclase activity in rat liver plasma membranes.

Incubation of rat liver plasma membranes with liposomes of dioleoyl phosphatidic acid (dioleoyl-PA) led to an inhibition of adenylate cyclase activity which was more pronounced when fluoride-stimulated activity was followed than when glucagon-stimulated activity was followed. If Mn2+ (5 mM) replaced low (5 mM) [Mg2+] in adenylate cyclase assays, or if high (20 mM) [Mg2+] were employed, then the perceived inhibitory effect of phosphatidic acid was markedly reduced when the fluoride-stimulated activity was followed but was enhanced for the glucagon-stimulated activity. The inhibition of adenylate cyclase activity observed correlated with the association of dioleoyl-PA with the plasma membranes. Adenylate cyclase activity in dioleoyl-PA-treated membranes, however, responded differently to changes in [Mg2+] than did the enzyme in native liver plasma membranes. Benzyl alcohol, which increases membrane fluidity, had similar stimulatory effects on the fluoride- and glucagon-stimulated adenylate cyclase activities in both native and dioleoyl-PA-treated membranes. Incubation of the plasma membranes with phosphatidylserine also led to similar inhibitory effects on adenylate cyclase and responses to Mg2+. Arrhenius plots of both glucagon- and fluoride-stimulated adenylate cyclase activity were different in dioleoyl-PA-treated plasma membranes, compared with native membranes, with a new 'break' occurring at around 16 degrees C, indicating that dioleoyl-PA had become incorporated into the bilayer. E.s.r. analysis of dioleoyl-PA-treated plasma membranes with a nitroxide-labelled fatty acid spin probe identified a new lipid phase separation occurring at around 16 degrees C with also a lipid phase separation occurring at around 28 degrees C as in native liver plasma membranes. It is suggested that acidic phospholipids inhibit adenylate cyclase by virtue of a direct headgroup specific interaction and that this perturbation may be centred at the level of regulation of this enzyme by the stimulatory guanine nucleotide regulatory protein NS.

Adenylyl Cyclase Inhibitors↗
PubMed1986

Increased hydroxyl radical production in liver peroxisomal fractions from rats treated with peroxisome proliferators.

Electron spin resonance (e.s.r.), using the spin trap 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), has been employed to measure hydroxyl radical production in liver peroxisome-enriched fractions isolated from male Alpk/Ap rats administered chemicals known to cause peroxisome proliferation. The DMPO-OH adduct was found to decay to an e.s.r. silent species so rapidly in the presence of the native peroxisome-enriched fraction as to preclude any measurements in this system. All of the experiments were therefore carried out in the presence of cyanide in order to visualise the DMPO-OH adducts, although a consequence of this was the inhibition of the peroxisomal catalase activity. The DMPO-OH adduct was identified in fractions from both control and treated animals in the presence of palmitoyl CoA as substrate and was found to be present at 3-4 times the control value in animals orally administered di(2-ethylhexyl)phthalate (2000 mg/kg), clofibrate (200 mg/kg) or methyl clofenapate (25 mg/kg) for 9 days. The rate of production of hydroxyl radicals was also greater in fractions from treated animals. The fatty acyl CoA oxidase system of liver peroxisome-enriched fractions has now been shown to produce increased levels of hydrogen peroxide and hydroxyl radicals in the presence of a suitable substrate. Despite such evidence from in vitro enzyme systems, evidence of genotoxicity in vivo is still required to confirm the hypothesis linking such reactive oxygen species to the carcinogenicity observed in rodents with certain peroxisome proliferators.

Animals↗