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Biomedical subjects

M J Jackson

Publications and source records attributed to M J Jackson.

At least 19 recordsLinked to original sources
PubMed2004

Role of mitochondrial superoxide dismutase in contraction-induced generation of reactive oxygen species in skeletal muscle extracellular space.

Contractions of skeletal muscles produce increases in concentrations of superoxide anions and activity of hydroxyl radicals in the extracellular space. The sources of these reactive oxygen species are not clear. We tested the hypothesis that, after a demanding isometric contraction protocol, the major source of superoxide and hydroxyl radical activity in the extracellular space of muscles is mitochondrial generation of superoxide anions and that, with a reduction in MnSOD activity, concentration of superoxide anions in the extracellular space is unchanged but concentration of hydroxyl radicals is decreased. For gastrocnemius muscles from adult (6-8 mo old) wild-type (Sod2(+/+)) mice and knockout mice heterozygous for the MnSOD gene (Sod2(+/-)), concentrations of superoxide anions and hydroxyl radical activity were measured in the extracellular space by microdialysis. A 15-min protocol of 180 isometric contractions induced a rapid, equivalent increase in reduction of cytochrome c as an index of superoxide anion concentrations in the extracellular space of Sod2(+/+) and Sod2(+/-) mice, whereas hydroxyl radical activity measured by formation of 2,3-dihydroxybenzoate from salicylate increased only in the extracellular space of muscles of Sod2(+/+) mice. The lack of a difference in increase in superoxide anion concentration in the extracellular space of Sod2(+/+) and Sod2(+/-) mice after the contraction protocol supported the hypothesis that superoxide anions were not directly derived from mitochondria. In contrast, the data obtained suggest that the increase in hydroxyl radical concentration in the extracellular space of muscles from wild-type mice after the contraction protocol most likely results from degradation of hydrogen peroxide generated by MnSOD activity.

Animals↗
PubMed2004

Tissue engineering of a human sized and shaped auricle using a mold.

OBJECTIVES: The creation of a tissue-engineered auricle was initially successful in an immunocompromised nude mouse model. Subsequently, an immunocompetent porcine model successfully generated a helical construct. We wished to evaluate the novel technique of using a mold to create a complete, anatomically refined auricle in a large animal model. METHODS: Mixtures of autogenous chondrocytes and biodegradable polymers were used inside a perforated, auricle shaped hollow gold mold. Three biodegradable polymers (calcium alginate, pluronic F-127, and polyglycolic acid) were used to retain the seeded chondrocytes inside the mold. These molds, along with a control, were implanted subcutaneously in the abdominal area of 10 animals (pigs and sheep). The constructs were removed after 8 to 20 weeks and were assessed by gross morphology and histology. RESULTS: All the gold implants were well tolerated by the animals. The implants using calcium alginate (n = 3) generated constructs of the exact shape and size of a normal human ear; the histology demonstrated mostly normal cartilage with some persistent alginate. The implants with pluronic F-127 (n = 3) resulted in cartilage with essentially normal histology, although leakage outside the molds and external cartilage generation was noted. Polyglycolic acid implants (n = 3) produced no useful cartilage because of an inflammatory reaction with fibrosis. The empty control mold (n = 1) demonstrated only a very small amount of fibrous tissue inside. CONCLUSION: A tissue-engineered human sized auricle of normal anatomic definition can be generated in an immunocompetent large-animal model using a mold technique. Although further refinements will be necessary, the technique appears promising for potential use in patients with microtia.

Absorbable Implants↗
PubMed2003

Effect of vitamin C supplements on antioxidant defence and stress proteins in human lymphocytes and skeletal muscle.

Oxidative stress induces adaptations in the expression of protective enzymes and heat shock proteins (HSPs) in a variety of tissues. We have examined the possibility that supplementation of subjects with the nutritional antioxidant, vitamin C, influences the ability of lymphocytes to express protective enzymes and HSPs following exposure to an exogenous oxidant and the response of skeletal muscle to the physiological oxidative stress that occurs during exercise in vivo. Our hypothesis was that an elevation of tissue vitamin C content would reduce oxidant-induced expression of protective enzymes and HSP content. Lymphocytes from non-supplemented subjects responded to hydrogen peroxide with increased activity of superoxide dismutase (SOD) and catalase, and HSP60 and HSP70 content over 48 h. Vitamin C supplementation at a dose of 500 mg day-1 for 8 weeks was found to increase the serum vitamin C concentration by ~50 %. Lymphocytes from vitamin C-supplemented subjects had increased baseline SOD and catalase activities and an elevated HSP60 content. The SOD and catalase activities and the HSP60 and HSP70 content of lymphocytes from supplemented subjects did not increase significantly in response to hydrogen peroxide. In non-supplemented subjects, a single period of cycle ergometry was found to significantly increase the HSP70 content of the vastus lateralis. Following vitamin C supplementation, the HSP70 content of the muscle was increased at baseline with no further increase following exercise. We conclude that, in vitamin C-supplemented subjects, adaptive responses to oxidants are attenuated, but that this may reflect an increased baseline expression of potential protective systems against oxidative stress (SOD, catalase and HSPs).

Adult↗
PubMed2003

Post-exercise vitamin C supplementation and recovery from demanding exercise.

The aim of this study was to investigate whether post-exercise vitamin C supplementation influences recovery from an unaccustomed bout of exercise. Sixteen male subjects were allocated to either a placebo (P; n=8) or vitamin C (VC) group ( n=8). Subjects performed a prolonged (90-min) intermittent shuttle-running test, and supplementation began after the cessation of exercise. Immediately after exercise the VC group consumed 200 mg of VC dissolved in a 500 ml drink, whereas the subjects in the P group consumed the drink alone. Later on the same day and then in the morning and evening of the following 2 days, subjects consumed additional identical drinks. Plasma VC concentrations in the VC group increased above those in the P group 1 h after exercise and remained above P values for the 3 days after exercise. Nevertheless, post-exercise VC supplementation was not associated with improved recovery. Post-exercise serum creatine kinase activities and myoglobin concentrations were unaffected by supplementation. Muscle soreness and the recovery of muscle function in the leg flexors and extensors were not different in VC and P groups. Furthermore, although plasma concentrations of interleukin-6 and malondialdehyde increased following exercise, there was no difference between VC and P groups. These results suggest that either free radicals are not involved in delaying the recovery process following a bout of unaccustomed exercise, or that the consumption of VC wholly after exercise is unable to deliver this antioxidant to the appropriate sites with sufficient expediency to improve recovery.

Adaptation, Physiological↗
PubMed2003

Damage to developing mouse skeletal muscle myotubes in culture: protective effect of heat shock proteins.

Damage to skeletal muscle occurs following excessive exercise, upon reperfusion following ischaemia and in disease states, such as muscular dystrophy. Key mechanisms by which damage is thought to occur include a loss of intracellular calcium homeostasis, loss of energy supply to the cell, increased activity of oxidising free radical-mediated reactions and activation of apoptosis pathways. An increased cellular content of heat shock proteins (HSPs) has been shown to protect skeletal muscle against some forms of damage, although the mechanistic basis of this protection is not clearly understood. The aim of this study was to establish a cell culture-based model of damage to C2C12 skeletal muscle cells using the calcium ionophore, A23187 and the mitochondrial uncoupler, 2,4-dinitrophenol (DNP) as damaging agents. Treatment of cells with 1 mM DNP for 60 min resulted in the release of 63.5 % of intracellular creatine kinase (CK) activity over the 3 h experimental period. Treatment of cells with 10 microM A23187 for 30 min resulted in the release of 47.9 % of CK activity. Exposure of myotubes to a period of hyperthermia resulted in a significant increase in their content of HSP25, HSP60, HSC70 (heat shock cognate) and HSP70. This increase in HSPs was associated with significant protection against both DNP-induced and A23187-induced damage to the myotubes. These results indicate that an increased content of HSPs may provide protection against the muscle damage that occurs by a pathological increase in intracellular calcium or uncoupling of the mitochondrial respiratory chain.

Animals↗
PubMed2003

Training for infrainguinal bypass surgery.

BACKGROUND: Despite satisfactory results for surgery performed by trainees, vascular surgeons need to improve training methods to ensure that aspiring surgeons are adequately trained with less clinical exposure during fewer dedicated years of training. OBJECTIVES: To review the wide range of workshop, laboratory and seminar-room based methods available to train for the diverse range of skills required for distal arterial revascularisation. Training methods include anastomotic suturing skills with bench-top training apparatus, working with realistic plastic models and prosthetic conduits, cadaveric dissections and virtual-reality simulations. Many of these also provide excellent opportunities for objective assessment of technical skills and trainees' progress. DESIGN AND METHODS: A review of the literature on surgical education, surgical skills training and assessment. An evaluation of some of the apparatus, facilities, training curricula and courses, currently available to European trainees, is carried out. CONCLUSIONS: Many methods are now available to allow focused training for particular skills in non-clinical settings. Objective tools are also available that allow assessment of trainees at many levels or practicing surgeons. These technical skills assessment methods are important for trainees and surgeons who, in the future, will increasingly need to demonstrate competence in vascular surgery.

Clinical Competence↗
PubMed2003

Skeletal muscles of aged male mice fail to adapt following contractile activity.

Skeletal muscle adapts rapidly following exercise by the increased production of heat-shock proteins (HSPs). The aim of this study was to examine the ability of muscle from adult and aged mice to produce HSPs following non-damaging exercise. Adult and aged B6XSJL mice were anaesthetized and their hind limbs were subjected to isometric contractions. At different time points, muscles were analysed for HSP production by Western and Northern blotting and by electrophoretic mobility-shift assay. HSP protein and mRNA levels in muscles from adult mice increased significantly following exercise. This was not evident in muscles of aged mice. In contrast, binding of the transcription factor heat-shock factor 1 (HSF1) was not grossly altered in muscles of aged mice compared with adult mice. The data suggest that the inability of muscles of aged mice to produce HSPs appears to be due to alterations during gene transcription.

Adaptation, Physiological↗
PubMed2002

UVR-induced oxidative stress in human skin in vivo: effects of oral vitamin C supplementation.

Previous studies of cultured skin cells and murine skin in vivo have indicated that UVR-induced damage involves the generation of reactive oxygen species and depletion of endogenous antioxidant systems. In order to explore the relevance of this to UVR-induced damage to human skin, we have undertaken a detailed examination of the time-course of changes in markers of oxidative stress in human skin following exposure to physiological amounts of UVR in vivo. In addition, we have examined the skin bioavailability of a common nutritional antioxidant, vitamin C, and have assessed the effects of supplementation on markers of oxidative stress. Our hypothesis was that acute exposure of human skin to UVR in vivo would lead to oxidation of cellular biomolecules that could be prevented by prior vitamin C treatment. A UVR-challenge of 120 mJ/cm2 of broadband UVB (peak 310 nm, range 270-400 nm) was applied to buttock skin of 8 healthy volunteers. This caused a rapid and significant rise in activity of skin catalase at 1 h and an increase in the oxidized/total glutathione ratio at 6 h post-UVR. AP-1 DNA binding also peaked at 1-6 h post-UVR, then declined rapidly to baseline levels. No significant changes were seen in skin malonaldehyde content. Oral vitamin C supplements (500 mg/day) were taken by 12 volunteers for 8 weeks resulting in significant rises in plasma and skin vitamin C content. Supplementation had no effect on the UVR-induced erythemal response. The skin malonaldehyde content was reduced by vitamin C supplementation, but surprisingly, reductions in the skin content of total glutathione and protein thiols were also seen. We speculate that this apparently paradoxical effect could be due to regulation of total reductant capacity by skin cells, such that vitamin C may have been replacing other reductants in these cells. No evidence was obtained for an effect of the supplementary vitamin C on the mild oxidative stress seen in human skin following UVR exposure.

Adult↗
PubMed2002

Neonatal lungs--can absolute lung resistivity be determined non-invasively?

The electrical resistivity of lung tissue can be related to the structure and composition of the tissue and also to the air content. Conditions such as pulmonary oedema and emphysema have been shown to change lung resistivity. However, direct access to the lungs to enable resistivity to be measured is very difficult. We have developed a new method of using electrical impedance tomographic (EIT) measurements on a group of 142 normal neonates to determine the absolute resistivity of lung tissue. The methodology involves comparing the measured EIT data with that from a finite difference model of the thorax in which lung tissue resistivity can be changed. A mean value of 5.7 +/- 1.7 omega(m) was found over the frequency range 4 kHz to 813 kHz. This value is lower than that usually given for adult lung tissue but consistent with the literature on the composition of the neonatal lung and with structural modelling.

Child, Preschool↗
PubMed2002

Neonatal lungs: maturational changes in lung resistivity spectra.

The electrical resistivity of lung tissue can be related to the structure and composition of the tissue and also to the air content. Electrical impedance tomographic measurements have been used on 155 normal children over the first three years of life and 25 pre-term infants, to determine the absolute resistivity of lung tissue as a function of frequency. The results show consistent changes with increasing age in both lung tissue resistivity (5.8 ohm m at birth to 20.9 ohm m at 3 years of age) and in the changes of resistivity with frequency (Cole parameter ratio R/S=0.41 at birth and 0.84 at 3 years of age). Comparison with a lung model showed that the measurements are consistent with maturational changes in the number and size of alveoli, the extracapillary blood volume and the size of the extracapillary vessels. However, the results show that the process of maturation is not complete at the age of three years.

Adult↗
PubMed2002

The actions of a D-1 agonist in MPTP treated primates show dependence on both D-1 and D-2 receptor function and tolerance on repeated administration.

The potent and long acting D-1 receptor agonist, A-77636 reverses motor deficits in MPTP treated common marmosets following subcutaneous or oral administration. We now explore the effects of acute versus repeated administration of A-77636 and the relative roles of D-1 and D-2 receptor involvement in its antiparkinsonian actions. Acute oral administration (0.18-9.0 mg/kg) or subcutaneous administration (0.036-1.08 mg/kg) of A-77636 produced well co-ordinated bouts of discontinuous locomotor activity. There was no evidence of repetitive or stereotyped movements. However, oral administration of A-77636 (1.44 mg/kg) on alternate days for 10 days produced tolerance to the increase in locomotor activity and improvement of disability. Pretreatment with the D-1 antagonist SCH 23390 (0.625, 2.5 or 5.0 mg/kg, intraperitoneally), produced a dose dependent reduction in locomotor activity and antagonised the reduction in disability scores following administration of A-77636 (0.36 mg/kg, subcutaneously). The inhibitory effects of SCH 23390 lasted for some 2-5 hours after which the activity of A-77636 was gradually restored. Unexpectedly, pretreatment with the D-2 antagonist raclopride (1.25, 5.0 or 20.0 mg/kg, intraperitoneally), dramatically diminished the antiparkinsonian effects of A-77636 (0.36 mg/kg, subcutaneously) in a dose dependent manner. The dependence of the antiparkinsonian activity of A-77636 on intact D-2 receptor function, suggests a need for endogenous D-2 receptor tone to express D-1 mediated locomotor activity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2002

Behavioural and immunohistochemical changes following supranigral administration of sonic hedgehog in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets.

Sonic hedgehog (SHH) has trophic actions on dopaminergic cell cultures and protects them from MPP(+) toxicity but its in vivo actions have not been explored. We now investigate the effects of unilateral supranigral administration of SHH on nigro-striatal function in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets. SHH (0.1 or 1.0 microg) or vehicle was stereotaxically injected into the region of the right substantia nigra twice with an interval of 5 weeks between administrations. The first or second administration of low dose SHH (0.1 microg) did not significantly improve motor disability or locomotor activity compared to time-matched vehicle-treated animals. There was, however, an approximately 30% improvement in both motor disability and locomotor activity following the first administration of high dose SHH (1.0 microg). No further improvements occurred following the second high dose SHH treatment. Acute oral administration of L-3,4-dihydroxyphenylalanine (L-DOPA) produced a smaller increase in locomotor activity and greater reversal of motor disability in animals treated with SHH than occurred in vehicle-treated common marmosets. In the substantia nigra pars compacta, ipsilateral to SHH administration, the number of tyrosine hydroxylase-positive neurones was increased by 21% (P > 0.05) and 57% (P < 0.05) in low and high dose SHH groups respectively compared to the untreated contralateral hemisphere. There was no difference in the number of glial fibrillary acidic protein-positive cells. SHH may improve nigro-striatal function by restoring tyrosine hydroxylase positivity. This is reflected by an improvement in basal disability and a reduction in the lesion-induced response to L-DOPA.

Animals↗
PubMed2002

Effects of micronutrient supplements on u.v.-induced skin damage.

Development of an orally-administered systemic agent that could reduce the effects of u.v. exposure on skin could potentially have a major effect on the incidence of skin cancers and photo-ageing. A number of micronutrients have been suggested to have metabolic properties that could induce this protection, and our data indicate that n-3 polyunsaturated fatty acids are particularly effective in this role. The mechanisms of action of n-3 polyunsaturated fatty acids appear to depend on their anti-inflammatory properties, acting to reduce the u.v.-induced release of cytokines and other mediators from a variety of skin cell types.

Aging↗
PubMed2001

Measurement of free radical production by in vivo microdialysis during ischemia/reperfusion injury to skeletal muscle.

Microdialysis techniques have been used to detect hydroxyl radical and superoxide release into the interstitial space of anaesthetized rat anterior tibialis muscles during a period of prolonged (4 h) limb ischemia and subsequent reperfusion. Data indicate that reperfusion of the ischemic skeletal muscle was associated with a large increase in hydroxyl radical activity in the interstitial space, which may contribute to the significant oxidation of muscle glutathione, protein thiols, and lipids also seen in this model. No evidence for release of superoxide into the interstitial space was found during reperfusion, although this was observed during electrically stimulated contractile activity of the rat limb muscle. These data imply that therapeutic approaches aimed at reduction of hydroxyl radical generation in the interstitial fluid are more likely to be beneficial in reduction of skeletal muscle reperfusion injury than approaches designed to scavenge superoxide radicals.

Animals↗
PubMed2001

Antiparkinsonian activity and dyskinesia risk of ropinirole and L-DOPA combination therapy in drug naïve MPTP-lesioned common marmosets (Callithrix jacchus).

De novo administration of long-acting dopamine agonists, such as ropinirole, to patients with Parkinson's disease or to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated subhuman primates produces a lower incidence of dyskinesia than occurs with L-DOPA. This study compares the intensity of dyskinesia produced by combinations of L-DOPA and ropinirole and by these drugs alone, using the MPTP-treated common marmoset model of Parkinson's disease. The objective is to determine the optimum therapeutic strategy for the long-term control of Parkinson's disease with a minimal risk of dyskinesia. MPTP-treated marmosets received either L-DOPA alone, ropinirole alone, or one of two combinations of these drugs (either L-DOPA dominant or ropinirole dominant) daily for 28 days in doses titrated to produce a similar improvement in disability and increase in locomotion. In the group receiving L-DOPA alone, there was a trend for peak dose locomotor activity to increase and the duration of drug effect to decline over the period of the study. L-DOPA alone induced marked dyskinesia over the period of treatment, in contrast to ropinirole which produced a low intensity of involuntary movements. The L-DOPA dominant combination initially produced little dyskinesia, but this became increasingly intense as the study progressed. In contrast, the ropinirole dominant combination produced no greater intensity of dyskinesia than was produced by ropinirole alone. These data suggest that in early Parkinson's disease, the use of ropinirole alone or in combination with a low-dose L-DOPA might delay the induction of dyskinesias while improving motor performance.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2001

Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease.

We describe here a previously unknown, dominantly inherited, late-onset basal ganglia disease, variably presenting with extrapyramidal features similar to those of Huntington's disease (HD) or parkinsonism. We mapped the disorder, by linkage analysis, to 19q13.3, which contains the gene for ferritin light polypeptide (FTL). We found an adenine insertion at position 460-461 that is predicted to alter carboxy-terminal residues of the gene product. Brain histochemistry disclosed abnormal aggregates of ferritin and iron. Low serum ferritin levels also characterized patients. Ferritin, the main iron storage protein, is composed of 24 subunits of two types (heavy, H and light, L) which form a soluble, hollow sphere. Brain iron deposition increases normally with age, especially in the basal ganglia, and is a suspected causative factor in several neurodegenerative diseases in which it correlates with visible pathology, possibly by its involvement in toxic free-radical reactions. We found the same mutation in five apparently unrelated subjects with similar extrapyramidal symptoms. An abnormality in ferritin strongly indicates a primary function for iron in the pathogenesis of this new disease, for which we propose the name 'neuroferritinopathy'.

Adult↗