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Biomedical subjects

L Thomson

Publications and source records attributed to L Thomson.

At least 19 recordsLinked to original sources
PubMed2000

Cytochrome c nitration by peroxynitrite.

Peroxynitrite (ONOO(-)), the product of superoxide (O(2)) and nitric oxide (.NO) reaction, inhibits mitochondrial respiration and can stimulate apoptosis. Cytochrome c, a mediator of these two aspects of mitochondrial function, thus represents an important potential target of ONOO(-) during conditions involving accelerated rates of oxygen radical and.NO generation. Horse heart cytochrome c(3+) was nitrated by ONOO(-), as indicated by spectral changes, Western blot analysis, and mass spectrometry. A dose-dependent loss of cytochrome c(3+) 695 nm absorption occurred, inferring that nitration of a critical heme-vicinal tyrosine (Tyr-67) promoted a conformational change, displacing the Met-80 heme ligand. Nitration was confirmed by cross-reactivity with a specific antibody against 3-nitrotyrosine and by increased molecular mass compatible with the addition of a nitro-(-NO(2)) group. Mass analysis of tryptic digests indicated the preferential nitration of Tyr-67 among the four conserved tyrosine residues in cytochrome c. Cytochrome c(3+) was more extensively nitrated than cytochrome c(2+) because of the preferential oxidation of the reduced heme by ONOO(-). Similar protein nitration patterns were obtained by ONOO(-) reaction in the presence of carbon dioxide, whereupon secondary nitrating species arise from the decomposition of the nitroso-peroxocarboxylate (ONOOCO(2)(-)) intermediate. Peroxynitrite-nitrated cytochrome c displayed significant changes in redox properties, including (a) increased peroxidatic activity, (b) resistance to reduction by ascorbate, and (c) impaired support of state 4-dependent respiration in intact rat heart mitochondria. These results indicate that cytochrome c nitration may represent both oxidative and signaling events occurring during .NO- and ONOO(-)-mediated cell injury.

Animals↗
PubMed1999

Peroxynitrite affects Ca2+ transport in Trypanosoma cruzi.

Macrophages play an important role against Trypanosoma cruzi infection, via superoxide, nitric oxide, and peroxynitrite production. Peroxynitrite has been shown to be highly cytotoxic against Trypanosoma cruzi epimastigotes. Calcium is involved in many vital functions of the parasites, being its intracellular concentration governed by several transport systems, involving mitochondrial and non-mitochondrial compartments. In this paper, we report the effect of peroxynitrite on the calcium uptake systems, as studied by digitonin-permeabilized trypanosomes in the presence of arsenazo III. Peroxynitrite, at biologically relevant concentrations produced within phagosomes (250-750 microM), inhibited calcium uptake in a dose-dependent manner. Peroxynitrite decreased the mitochondrial membrane potential obtained in the presence of tetramethyl-p-phenylenediamine (TMPD)/ascorbate. In addition, a decrease of the non-mitochondrial Ca(2+)-uptake, concomitant with the inactivation of a Ca(2+)-dependent ATPase activity, was observed. HPLC analyses of the cellular adenine nucleotide pool showed a time-dependent decrease of ATP content and energy charge of the parasite; however this drop in ATP levels was significantly delayed with respect to decrease of the ATP-dependent Ca(2+)-transport. We conclude that the disruption of calcium homeostasis by peroxynitrite may contribute to the observed cytotoxic effects of macrophages against T. cruzi.

Adenine Nucleotides↗
PubMed1999

Transcatheter closure of a large coronary artery fistula with the Amplatzer duct occluder.

We report the successful percutaneous closure of a large coronary artery fistula from the obtuse marginal artery to the right ventricle in an 8-month-old boy using the Amplatzer duct occluder. The device was positioned and deployed via the venous system, using a guidewire that had been advanced via the aorta, coronary artery, and fistula to the venous circulation. Cathet. Cardiovasc. Intervent. 48:188-190, 1999.

Cardiac Catheterization↗
PubMed1999

Microglia increase as photoreceptors decrease in the aging avian retina.

PURPOSE: There is evidence that microglial activation occurs with normal aging in some regions of the brain of rodents. We investigated the pattern of microglia in the retinas of young and aged quail and pigeons to determine if age-related retinal changes evoked migration of microglia into the outer retina. In quail we also investigated the correlation between activated microglia and age-related photoreceptor loss. METHODS: Microglia were identified with the monoclonal antibody QH1 in cryosectioned eyes from pigeons, ages 2 to 20 years (n = 14), and in paraffin sections from six-month (n = 15) and one-year-old quail (n = 30). Rounded microglia in the photoreceptor layer were counted in consecutive 400x fields from temporal to nasal. Photoreceptor counts were made from 10 quail retina flat mounts. The photoreceptor number was compared to the number of microglia in corresponding regions of the same retina. RESULTS: Rounded microglia were detected among the photoreceptors of pigeons and quail. Significantly more of these microglia were found in peripheral than in central regions close to the pecten (pigeon p < 0.002 and quail p < 0.01). Furthermore, more microglial cells were present among peripheral photoreceptors of older quail (p < 0.03) and pigeons (p < 0.05) than in the younger birds. In the peripheral retina of the older quail, microglia were significantly and inversely related to the number of photoreceptors (r2 = 0.9; p < 0.001). CONCLUSIONS: Increased microglial were observed in the peripheral retina of both old quail and old pigeons. In the quail, the rounded (activated) microglia were distributed preferentially in regions of greatest photoreceptor loss. Microglial activation does not appear to be a general phenomenon of the aging retina, but in quail activation appears directly related to photoreceptor loss. It is unclear at this time how the change in microglia shape and distribution is related to their neuroprotective / neurotoxic potential.

Aging↗
PubMed1998

Randomised controlled trial of effects of early discharge after surgery for breast cancer.

OBJECTIVE: To determine the effect of early discharge from hospital after surgery for breast cancer on physical and psychological illness. DESIGN: Randomised controlled trial comparing discharge two days after surgery (before removal of drain) with standard management (discharge after removal of drain). SETTING: Regional breast unit. SUBJECTS: 100 women with early breast cancer undergoing mastectomy and axillary node clearance (20) or breast conservation surgery (80). MAIN OUTCOME MEASURES: Physical illness (infection, seroma formation, shoulder movement) and psychological illness (checklist of concerns, Rotterdam symptom questionnaire, hospital anxiety and depression scale) preoperatively and at one month and three months postoperatively. RESULTS: Women discharged early had greater shoulder movement (odds ratio 0.28 (95% confidence interval 0.08 to 0.95); P = 0.042) and less wound pain (odds ratio 0.28 (0.10 to 0.79); P = 0.016) three months after surgery compared with women given standard management. One month after surgery scores were significantly lower on the Rotterdam symptom questionnaire in patients who were discharged early (ratio of geometric mean scores 0.73 (0.55 to 0.98) P = 0.035), but rates of psychological illness generally did not differ between groups. CONCLUSIONS: Increased rates of physical or psychological illness did not result from early discharge after surgery for breast cancer. This policy can be recommended for patients with support at home.

Adult↗
PubMed1998

Defining the outcome of immunosuppression withdrawal after liver transplantation.

Successful immunosuppression withdrawal should benefit the natural history of organ transplantation patients. To identify the clinical hazards of removing drug treatment and possible characteristics that predict a favorable outcome in long-term liver recipients, immunosuppression was withdrawn completely and the clinicopathological outcome documented in 18 liver recipients. Indication for transplantation, HLA matching, early rejection history, and presence of microchimerism were examined as predictors of outcome. Chimerism was determined by polymerase chain reaction-based examination for donor-specific HLA-DRB1 alleles and Y-gene-specific nucleotide sequences. At 3 years, 5 patients (28%) remained completely off immunosuppression; 12 patients (67%) experienced histological graft changes: acute rejection in 4, portal tract inflammation/hepatitis in 7, and necrosis in 1. Hepatitis B or C viral infections did not account for the nonrejection patterns. Unmasking of systemic disorders occurred. Chimerism, demonstrated in 7 patients (39%), with skin the optimal tissue, was not associated with tolerance. Parameters associated with successful drug withdrawal were transplantation for non-immune-mediated liver disorders, fewer donor-recipient HLA A, B, and DR mismatches, and a low incidence of early rejection. Immunosuppression withdrawal is a feasible option in a proportion of selected liver recipients, but identification of tolerant patients remains imprecise.

Adult↗
PubMed1997

Ca2+-independent permeabilization of the inner mitochondrial membrane by peroxynitrite is mediated by membrane protein thiol cross-linking and lipid peroxidation.

Peroxynitrite anion, the reaction product of superoxide and nitric oxide, is a potent biological oxidant, which inactivates mammalian heart mitochondrial NADH-coenzyme Q reductase (complex I), succinate dehydrogenase (complex II), and ATPase, without affecting cytochrome c oxidase (complex IV). In this paper, we evaluated the effect of peroxynitrite on mitochondrial membrane integrity and permeability under low calcium concentration. Phosphate buffer was used in most of our experiments since Hepes, Tris, mannitol, and sucrose were found to inhibit the oxidative chemistry of peroxynitrite. Peroxynitrite (0.1-1.0 mM) caused a dose-dependent decrease in the ability of mitochondria to build up a membrane potential when N,N,N',N'-tetramethyl-p-phenylenediamine/ascorbate were used as substrate. Elimination of the membrane potential was accompanied by penetration of the osmotic support (KCl/NaCl) into the matrix as judged by the parallel occurrence of mitochondrial swelling. This swelling was partially inhibited by dithiothreitol (DTT) or butylated hydroxytoluene (BHT) and was insensitive to ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid, ADP, and cyclosporin A. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of solubilized membrane proteins indicated that alterations in membrane permeability were associated with the production of protein aggregates due to membrane protein thiol cross-linking. The protective effect of DTT on both mitochondrial swelling and protein polymerization suggests the involvement of disulfide bonds in the membrane permeabilization process. In addition, the increase in thiobarbituric acid-reactive substances and the partial inhibitory effect of BHT indicate the occurrence of lipid peroxidation. These results support the idea that under our experimental conditions peroxynitrite causes mitochondrial structural and functional alterations by Ca2+-independent mechanisms through lipid peroxidation and protein sulfhydryl oxidation.

Animals↗
PubMed1997

Psychosocial factors predicting employee sickness absence during economic decline.

Psychosocial factors such as work characteristics, life events, social support, and personality were examined as predictors of the change in medically certified sickness absence observed during a period of severe economic decline. Longitudinal data, derived from self-reports and register-based information relating to 763 local government employees, were collected at 3 points during a 5-year period: before the economic decline, during the nadir of that decline, and immediately after the nadir. After the effects of prior absence and demographic and lifestyle variables had been partialed out, the results of multiple Poisson regression analyses showed that work characteristics play a major role in forthcoming sickness absences. Negative life events and the personality trait sense of coherence (in women) also predicted forthcoming absence rate. Social support did not relate to absences either in men or in women.

Adult↗
PubMed1997

Endothelin-1 levels in induced sputum samples from asthmatic and normal subjects.

BACKGROUND: Endothelin-1 (ET-1) is a potent bronchoconstrictor which may have a role in the pathogenesis of asthma. The levels of ET-1 in saliva, induced sputum, and plasma from asthmatic and non-asthmatic subjects were compared. METHODS: Sputum induction was performed on 28 asthmatic subjects and nine normal volunteers. ET-1 levels were measured in plasma, saliva, and sputum samples and reversed phase high performance liquid chromatography (RP-HPLC) was performed on saliva and sputum samples. RESULTS: ET-1 was present in the following order of concentration in both normal and asthmatic subjects: saliva > sputum > plasma (saliva, median 30.1 and 23.9 pg/ ml, respectively; sputum, median 15.5 and 11.2 pg/ml; plasma, median 3.1 and 3.6 pg/ ml). There were no differences between asthmatic and normal subjects in the levels of ET-1 in each fluid. The levels of ET-1 in asthmatic subjects were not influenced by whether or not they were taking inhaled steroids. RP-HPLC of sputum and saliva confirmed the presence of ET-1 in these fluids. CONCLUSIONS: Levels of ET-1 can be measured in saliva and sputum obtained by sputum induction in asthmatic and healthy subjects and, although no difference was found in basal levels of ET-1 in sputum, saliva and plasma between normal subjects and asthmatics without bronchoconstriction, it is apparent that ET-1 is produced or released locally within the respiratory tract in concentrations higher than those in plasma.

Adult↗
PubMed1996

Lay theories of heroin addiction.

This study examined the structure and determinants of lay people's implicit theories of heroin addiction. A questionnaire was derived from interviews with lay people about their beliefs and theories of heroin addiction and academic literature on the subject. One hundred and forty-four subjects completed the questionnaire, in which they rated 105 statements about the causes, correlates and cures of heroin addiction. The three parts of the questionnaire were individually factor analyzed and a clear, interpretable factor structure emerged for each. The factors seemed similar to explicit academic theories, but the exception was beliefs about cure, which did not show overall support for the most clinically used models. When the three factor analyses were combined into a single 'higher-order' factor analysis four factors emerged, labelled moralistic, psychosocial, sociocultural and drug treatment, which reflect more or less coherent views on the nature of heroin addiction. Subjects' political beliefs was the greatest (demographic and attitudinal) determinant of lay beliefs in these factors, with experience of addiction, addicts, drugs and age also highly correlated. Vote was the main determinant and best predictor of the four 'higher-order' structured lay theories: right-wing voters emphasizing moralistic and individualistic theory and left-wing voters supporting the psychological and societal ideas. Implications for policy and interventions to addicts of these lay theories are considered.

Adolescent↗
PubMed1996

Evidence that the HLA DQA1*03 allele confers protection from chronic HCV-infection in Northern European Caucasoids.

In the search for factors which may influence susceptibility to and outcome from chronic hepatitis C virus (HCV) infection, few studies have considered the influence of host genes. In the present investigation we have performed HLA DRB1, DQA1, DQB1, and DPB1 genotyping on 104 northern European patients with chronic HCV infection and 177 racially and geographically matched controls. Three HLA class II alleles, DRB1*0403, DQA1*03, and DQB1*0302 were present at a significantly lower frequency in patients compared with controls (4.9% vs. 13%, 20.7% vs. 41.2%, and 11.4% vs. 30.5%, respectively) though only two DQB1*0302 and DQA1*03 were significant after correction for multiple testing (pc = 0.038, and pc = 0.046, respectively). No further HLA associations with chronic HCV infection were observed and there was no correlation between stage of disease and HLA genotype. These data provide the first suggestion that susceptibility to chronic HCV infection may be influenced by the hosts' HLA DQ alleles.

Alleles↗
PubMed1995

Kinetics of cytochrome c2+ oxidation by peroxynitrite: implications for superoxide measurements in nitric oxide-producing biological systems.

Cytochrome c3+ has been extensively used for the detection of superoxide produced in biological systems due to its fast superoxide-mediated reduction to cytochrome c2+. However, another biomolecule which is sometimes cogenerated with superoxide, nitric oxide, reacts with superoxide at almost diffusion-controlled rates (6.7 x 10(9) M-1 s-1), leading to the production of a highly oxidizing species, peroxynitrite anion (ONOO-). In this work we report that peroxynitrite readily oxidizes cytochrome c2+ to cytochrome c3+ in an ascorbate-reversible manner. The reaction between peroxynitrite and cytochrome c2+ occurs with a second-order rate constant of 2.3 x 10(5) M-1 s-1. The pH dependence of the apparent second-order rate constants as well as the effect of different scavengers indicated that peroxynitrous acid (ONOOH) in the ground state was the actual species responsible of cytochrome c2+ oxidation. The activation enthalpy, free energy, and entropy were +10.8 kcal mol-1, +11.8 kcal mol-1, and -3.15 cal mol-1 K-1, respectively, in agreement with the proposed reaction mechanism. Additionally, our results imply that when quantitating superoxide by the cytochrome c3+ reduction method, the existence of a simultaneous generation of nitric oxide and peroxynitrite may lead to an underestimation of the rates of superoxide production.

Cytochrome c Group↗
PubMed1995

School attainment, cognitive ability and motor function in a total Scottish very-low-birthweight population at eight years: a controlled study.

The prevalence of learning problems and of cognitive and motor impairment in a total geographically based very-low-birthweight population (N = 324) was compared at eight years of age with that in a population comprising two classroom peers, matched for gender and age (N = 590). 15 per cent of those with birthweights less than 1000g and 6 per cent of those weighing 1000 to 1499 g attended special schools. Index children in main-stream schools performed significantly less well in tests of neuromotor function than their comparison groups. Their mean IQs were 90.4 and 93.7 for those below and above 1000 g, respectively, while their comparison groups' IQs were 102.5 and 101.2. In all cognitive subscales apart from that testing short-term auditory sequential memory, both index groups were less competent. They were also less able in Word Reading and Basic Number Skills. These children placed heavy demands on mainstream schools, with 52 per cent and 37 per cent of the index groups, respectively, requiring learning support compared with 16 per cent in both comparison groups.

Achievement↗
PubMed1991

Cytochrome c-catalyzed oxidation of organic molecules by hydrogen peroxide.

Cytochrome c catalyzed the oxidation of various electron donors in the presence of hydrogen peroxide (H2O2), including 2-2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS), 4-aminoantipyrine (4-AP), and luminol. With ferrocytochrome c, oxidation reactions were preceded by a lag phase corresponding to the H2O2-mediated oxidation of cytochrome c to the ferric state; no lag phase was observed with ferricytochrome c. However, brief preincubation of ferricytochrome c with H2O2 increased its catalytic activity prior to progressive inactivation and degradation. Superoxide (O2-) and hydroxyl radical (.OH) were not involved in this catalytic activity, since it was not sensitive to superoxide dismutase (SOD) or mannitol. Free iron released from the heme did not play a role in the oxidative reactions as concluded from the lack of effect of diethylenetriaminepentaacetic acid. Uric acid and tryptophan inhibited the oxidation of ABTS, stimulation of luminol chemiluminescence, and inactivation of cytochrome c. Our results are consistent with an initial activation of cytochrome c by H2O2 to a catalytically more active species in which a high oxidation state of an oxo-heme complex mediates the oxidative reactions. The lack of SOD effect on cytochrome c-catalyzed, H2O2-dependent luminol chemiluminescence supports a mechanism of chemiexcitation whereby a luminol endoperoxide is formed by direct reaction of H2O2 with an oxidized luminol molecule, either luminol radical or luminol diazoquinone.

Ampyrone↗