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J M Cooper

Publications and source records attributed to J M Cooper.

At least 37 records · Page 2Linked to original sources
PubMed2002

Mitochondrial dysfunction in Friedreich's ataxia: from pathogenesis to treatment perspectives.

Friedreich's ataxia (FRDA), the most common inherited ataxia, is an autosomal recessive degenerative disorder caused by a GAA triplet expansion or point mutations in the FRDA gene on chromosome 9q13. The FRDA gene product, frataxin, is a widely expressed mitochondrial protein, which is severely reduced in FRDA patients. The demonstration that deficit of frataxin in FRDA is associated with mitochondrial iron accumulation, increased sensitivity to oxidative stress, deficit of respiratory chain complex activities and in vivo impairment of cardiac and skeletal muscle tissue energy metabolism, has established FRDA as a "new" nuclear encoded mitochondrial disease. Pilot studies have shown the potential effect of antioxidant therapy based on idebenone or coenzyme Q10 plus Vitamin E administration in this condition and provide a strong rationale for designing larger randomized clinical trials.

Antioxidants↗
PubMed2001

Temporal and spatial profiling of the modification of an electroactive polymeric interface using neutron reflectivity.

Electropolymerized films of the functionalized pyrrole, pentafluorophenyl-3-(pyrrol-1-yl)propionate (PFP), were reacted with a solution-phase nucleophile, ferrocene ethylamine. This reaction was chosen as a model representative of a postdeposition modification of the polymer membrane's properties. For the first time, a nondestructive method for direct chemical analysis of the reaction profile within the electrodeposited polymer membrane after nucleophilic substitution is presented. This was achieved through the application of in situ neutron reflectivity with supplementary analytical information concerning the film's chemical composition obtained from XPS, FT-IR, and electrochemical measurements. The results presented illustrate how, for a partially reacted film resulting from a short reaction time, the extent of reaction with ferrocene ethylamine is not homogeneous throughout the thickness of the film, but occurs predominantly at the polymer/solution interface. We show that the progress of the reaction within the polymer film is limited by the transport of reacting species in the dense regions of the membrane that are furthest from the solution interface. The data do not fit an alternative model in which there is spatially homogeneous progression of the reaction front throughout the bulk of the thin film polymer. Guided by the neutron reflectivity measurements, suitable modifications were made to the electrodeposition method to prepare films whose architecture resulted in faster rates of reaction.

Journal Article↗
PubMed2001

Nitric oxide enhances MPP(+) inhibition of complex I.

There is evidence that 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) toxicity is mediated through both inhibition of mitochondrial complex I and free radical generation. 7-Nitroindazole protects against MPTP toxicity in vitro and in vivo, and this appears to be related to its inhibition of nitric oxide (NO(*-)) synthase. We now show that the NO(*-) generator, glutathione-N-oxide, enhances the inhibitory action of 1-methyl-4-phenylpyridinium (MPP(+)) on complex I activity in brain submitochondrial particles. We propose that the NO(*-)-induced reversible inhibition of complex IV (cytochrome oxidase) potentiates the MPP(+)-induced irreversible free radical-mediated inhibition of complex I. Thus, NO(*-) may 'prime' the respiratory chain to the effects of MPP(+). These data provide evidence for an interaction between NO(*-) and MPP(+) at the level of the respiratory chain.

1-Methyl-4-phenylpyridinium↗
PubMed2001

Sensitivity of respiratory chain activities to lipid peroxidation: effect of vitamin E deficiency.

Rats fed a vitamin E-depleted diet for 48 weeks had undetectable levels of vitamin E in the gastrocnemius muscle and liver, leading to elevated malondialdehyde levels in both tissues and an elevated GSH level in muscle. Skeletal-muscle mitochondria showed decreased mitochondrial respiratory chain (MRC) activities, whereas liver MRC activities were increased. Exposure of normal rat liver submitochondrial particles (SMPs) to an in vitro NADPH-dependent lipid peroxidation system resulted in a dose-dependent increase in lipid peroxidation and inhibition of complex I and complex IV activities. Complex I exhibited greater sensitivity to lipid peroxidation than complex IV. At low and high NADPH concentrations, the rate of lipid peroxidation and the level of enzyme inhibition were essentially the same in liver SMPs from both vitamin E-deficient and control rats, suggesting that under these conditions, the loss of vitamin E did not exacerbate the effects of either lipid peroxidation or enzyme inhibition. These results indicate that normal vitamin E levels in liver mitochondria are not required for protection against lipid peroxidation and are consistent with the normal liver mitochondrial function in vitamin E-deficient animals. This suggests other antioxidants, such as ubiquinol and GSH, may be more important in protecting liver mitochondria and MRC from lipid peroxidation.

Animals↗
PubMed2001

Rescue of the Friedreich's ataxia knockout mouse by human YAC transgenesis.

We have generated and characterised transgenic mice that contain the entire Friedreich's ataxia gene (FRDA) within a human YAC clone of 370 kb. In an effort to overcome the embryonic lethality of homozygous Frda knockout mice and to study the behaviour of human frataxin in a mouse cellular environment, we bred the FRDA YAC transgene onto the null mouse background. Phenotypically normal offspring that express only YAC-derived human frataxin were identified. The human frataxin was expressed in the appropriate tissues at levels comparable to the endogenous mouse frataxin, and it was correctly processed and localised to mitochondria. Biochemical analysis of heart tissue demonstrated preservation of mitochondrial respiratory chain function, together with some increase in citrate synthase and aconitase activities. Thus, we have demonstrated that human frataxin can effectively substitute for endogenous murine frataxin in the null mutant. Our studies are of immediate consequence for the generation of Friedreich's ataxia transgenic mouse models, and further contribute to the accumulating knowledge of human-mouse functional gene replacement systems.

Animals↗
PubMed2001

Cardiac energetics are abnormal in Friedreich ataxia patients in the absence of cardiac dysfunction and hypertrophy: an in vivo 31P magnetic resonance spectroscopy study.

OBJECTIVE: Friedreich ataxia (FRDA), the commonest form of inherited ataxia, is often associated with cardiac hypertrophy and cardiac dysfunction is the most frequent cause of death. In 97%, FRDA is caused by a homoplasmic GAA triplet expansion in the FRDA gene on chromosome 9q13 that results in deficiency of frataxin, a mitochondrial protein of unknown function. There is evidence that frataxin deficiency leads to a severe defect of mitochondrial respiration associated with abnormal mitochondrial iron accumulation. To determine whether bioenergetics deficit underlies the cardiac involvement in Friedreich ataxia (FRDA) we measured cardiac phosphocreatine to ATP ratio non-invasively in FRDA patients. METHODS AND RESULTS: Eighteen FRDA patients and 18 sex- and age-matched controls were studied using phosphorus MR spectroscopy and echocardiography. Left ventricular hypertrophy was present in eight FRDA patients while fractional shortening was normal in all. Cardiac PCr/ATP in FRDA patients as a group was reduced to 60% of the normal mean (P<0.0001). In the sub-group of patients with no cardiac hypertrophy PCr/ATP was also significantly reduced (P<0.0001). CONCLUSION: Cardiac bioenergetics, measured in vivo, is abnormal in FRDA patients in the absence of any discernible deterioration in cardiac contractile performance. The altered bioenergetics found in FRDA patients without left ventricle hypertrophy implies that cardiac metabolic dysfunction in FRDA precedes hypertrophy and is likely to play a role in its development.

Adenosine Triphosphate↗
PubMed2001

Use of the 13C-octanoic acid breath test for assessment of solid-phase gastric emptying in dogs.

OBJECTIVE: To assess the 13C-octanoic acid breath test for determining gastric emptying in dogs. ANIMALS: 6 healthy adult dogs. PROCEDURE: Food was withheld for 12 hours before each test. Expired air was collected 30 minutes and immediately before each test and at frequent intervals thereafter for 6 hours. Concentration of 13CO2 in expired air was determined by use of continuous-flow isotope-ratio mass spectrometry. Basal concentration of 13CO2 was measured in dogs that were not fed a test meal. Effects of the standard unlabeled test meal on basal concentration of 13CO2 were then assessed. The optimum dose of substrate was determined by measuring 13CO2 concentration after ingestion of the standard test meal containing 50 or 100 mg of 13C-octanoic acid, whereas effect of energy density of the test meal on gastric emptying was determined after ingestion of the standard or high-energy labeled test meal. Gastric emptying coefficient (GEC), time to peak 13CO2 concentration (tmax), and half-dose recovery time (t(1/2)) were calculated. RESULTS: Basal concentration of 13CO2 in expired air was not significantly affected by ingestion of the unlabeled test meal. However, 13CO2 concentration significantly increased in a dose-dependent manner after ingestion of the labeled meal. Gastric emptying coefficient, and were significantly different between dogs fed the standard and high-energy test meals, indicating that ingestion of a high-energy meal delays gastric emptying. CONCLUSIONS AND CLINICAL RELEVANCE: The 13C-octanoic acid breath test may be a useful noninvasive and nonradioactive method for assessment of gastric emptying in dogs.

Animals↗
PubMed2001

Antioxidant treatment improves in vivo cardiac and skeletal muscle bioenergetics in patients with Friedreich's ataxia.

Friedreich's ataxia (FA) is the most common form of autosomal recessive spinocerebellar ataxia and is often associated with a cardiomyopathy. The disease is caused by an expanded intronic GAA repeat, which results in deficiency of a mitochondrial protein called frataxin. In the yeast YFH1 knockout model of the disease there is evidence that frataxin deficiency leads to a severe defect of mitochondrial respiration, intramitochondrial iron accumulation, and associated production of oxygen free radicals. Recently, the analysis of FA cardiac and skeletal muscle samples and in vivo phosphorus magnetic resonance spectroscopy (31P-MRS) has confirmed the deficits of respiratory chain complexes in these tissues. The role of oxidative stress in FA is further supported by the accumulation of iron and decreased aconitase activities in cardiac muscle. We used 31P-MRS to evaluate the effect of 6 months of antioxidant treatment (Coenzyme Q10 400 mg/day, vitamin E 2,100 IU/day) on cardiac and calf muscle energy metabolism in 10 FA patients. After only 3 months of treatment, the cardiac phosphocreatine to ATP ratio showed a mean relative increase to 178% (p = 0.03) and the maximum rate of skeletal muscle mitochondrial ATP production increased to 139% (p = 0.01) of their respective baseline values in the FA patients. These improvements, greater in prehypertrophic hearts and in the muscle of patients with longer GAA repeats, were sustained after 6 months of therapy. The neurological and echocardiographic evaluations did not show any consistent benefits of the therapy after 6 months. This study demonstrates partial reversal of a surrogate biochemical marker in FA with antioxidant therapy and supports the evaluation of such therapy as a disease-modifying strategy in this neurodegenerative disorder.

Adolescent↗
PubMed2000

Expression of mutant alpha-synuclein causes increased susceptibility to dopamine toxicity.

Mutations of the alpha-synuclein gene have been identified in autosomal dominant Parkinson's disease (PD). Transgenic mice overexpressing wild-type human alpha-synuclein develop motor impairments, intraneuronal inclusions and loss of dopaminergic terminals in the striatum. To study the mechanism of action through which mutant alpha-synuclein toxicity is mediated, we have generated stable, inducible cell models expressing wild-type or PD-associated mutant (G209A) alpha-synuclein in human-derived HEK293 cells. Increased expression of either wild-type or mutant alpha-synuclein resulted in the formation of cytoplasmic aggregates which were associated with the vesicular (including monoaminergic) compartment. Expression of mutant alpha-synuclein induced a significant increase in sensitivity to dopamine toxicity compared with the wild-type protein expression. These results provide an explanation for the preferential dopaminergic neuronal degeneration seen in both the PD G209A mutant alpha-synuclein families and suggest that similar mechanisms may underlie or contribute to cell death in sporadic PD.

Blotting, Western↗
PubMed2000

Oxidative-phosphorylation defects in liver of patients with Wilson's disease.

BACKGROUND: Wilson's disease (WD) is caused by mutations in a P-type ATPase and is associated with copper deposition in liver and brain. The WD protein is present in the trans-Golgi network and may also be imported into mitochondria. The WD protein functions as a P-type copper transporting ATPase in the Golgi but any action in mitochondria is at present unknown. METHODS: We studied mitochondrial function and aconitase activity in WD liver tissue and compared the results with those in a series of healthy controls and patients without WD. FINDINGS: There was evidence of severe mitochondrial dysfunction in the livers of patients with WD. Enzyme activities were decreased as follows: complex I by 62%, complex II+III by 52%, complex IV by 33%, and aconitase by 71%. These defects did not seem to be secondary to penicillamine use, cholestasis, or poor hepatocellular synthetic function. INTERPRETATION: The results show that there is a defect of energy metabolism in WD. The pattern of enzyme defects suggests that free-radical formation and oxidative damage, probably mediated via mitochondrial copper accumulation, are important in WD pathogenesis. These results provide a rationale for a study of the use of antioxidants in WD.

Adolescent↗
PubMed2000

Clinical, biochemical and molecular genetic correlations in Friedreich's ataxia.

Friedreich's ataxia (FRDA) is an autosomal recessive disorder with a frequency of 1 in 50 000 live births. In 97% of patients it is caused by the abnormal expansion of a GAA repeat in intron 1 of the FRDA gene on chromosome 9, which encodes a 210 amino acid protein called frataxin. Frataxin is widely expressed and has been localized to mitochondria although its function is unknown. We have investigated mitochondrial function, mitochondrial DNA levels, aconitase activity and iron content in tissues from FRDA patients. There were significant reductions in the activities of complex I, complex II/III and aconitase in FRDA heart. Respiratory chain and aconitase activities were decreased although not significantly in skeletal muscle, but were normal in FRDA cerebellum and dorsal root ganglia, although there was a mild decrease in aconitase activity in the latter. Mitochondrial DNA levels were reduced in FRDA heart and skeletal muscle, although in skeletal muscle this was paralleled by a decline in citrate synthase activity. Increased iron deposition was seen in FRDA heart, liver and spleen in a pattern consistent with a mitochondrial location. The iron accumulation, mitochondrial respiratory chain and aconitase dysfunction and mitochondrial DNA depletion in FRDA heart samples largely paralleled those in the yeast YFH1 knockout model, suggesting that frataxin may be involved in mitochondrial iron regulation or iron sulphur centre synthesis. However, the severe deficiency in aconitase activity also suggests that oxidant stress may induce a self-amplifying cycle of oxidative damage and mitochondrial dysfunction, which may contribute to cellular toxicity.

Aconitate Hydratase↗
PubMed2000

MitBASE : a comprehensive and integrated mitochondrial DNA database. The present status.

MitBASE is an integrated and comprehensive database of mitochondrial DNA data which collects, under a single interface, databases for Plant, Vertebrate, Invertebrate, Human, Protist and Fungal mtDNA and a Pilot database on nuclear genes involved in mitochondrial biogenesis in Saccharomyces cerevisiae. MitBASE reports all available information from different organisms and from intraspecies variants and mutants. Data have been drawn from the primary databases and from the literature; value adding information has been structured, e.g., editing information on protist mtDNA genomes, pathological information for human mtDNA variants, etc. The different databases, some of which are structured using commercial packages (Microsoft Access, File Maker Pro) while others use a flat-file format, have been integrated under ORACLE. Ad hoc retrieval systems have been devised for some of the above listed databases keeping into account their peculiarities. The database is resident at the EBI and is available at the following site: http://www3.ebi.ac.uk/Research/Mitbase/mitbas e.pl. The impact of this project is intended for both basic and applied research. The study of mitochondrial genetic diseases and mitochondrial DNA intraspecies diversity are key topics in several biotechnological fields. The database has been funded within the EU Biotechnology programme.

Animals↗
PubMed2000

Mitochondrial dysfunction and free radical damage in the Huntington R6/2 transgenic mouse.

Huntington's disease is a progressive neurodegenerative disease caused by an abnormally expanded (>36) CAG repeat within the ITI5 gene encoding a widely expressed 349-kd protein, huntingtin. The medium spiny neurons of the caudate preferentially degenerate in Huntington's disease, with the presence of neuronal intranuclear inclusions. Excitotoxicity is thought to be important in the pathogenesis of Huntington's disease; the recently described mitochondrial respiratory chain and aconitase defects in Huntington's disease brain are consistent with this hypothesis. A transgenic mouse model (R6/2) of Huntington's disease develops a movement disorder, muscle wasting, and premature death at about 14 to 16 weeks. Selective neuronal death in these mice is not seen until 14 weeks. Biochemical analysis of R6/2 mouse brain at 12 weeks demonstrated a significant reduction in aconitase and mitochondrial complex IV activities in the striatum and a decrease in complex IV activity in the cerebral cortex. Increased immunostaining for inducible nitric oxide synthase and nitrotyrosine was seen in the transgenic mouse model but not control mouse brains. These results extend the parallels between Huntington's disease and the transgenic mouse model to biochemical events and suggest complex IV deficiency and elevated nitric oxide and superoxide radical generation precede neuronal death in the R6/2 mouse and contribute to pathogenesis.

Animals↗
PubMed2000

Endometrial sampling techniques in the diagnosis of abnormal uterine bleeding.

There have been many advances in sampling of the endometrium. Ideas and technologies have evolved, increasing our ability to gather adequate specimens that provide reliable information about uterine cavity pathologies. No technique surpasses the sensitivity and specificity of hysteroscopy with directed biopsy. Owing to its superior diagnostic potential, hysteroscopy, even when performed in the office with narrow scopes (not significantly larger in diameter than the Pipelle catheter), leads to precise diagnosis and appropriate management of intrauterine pathologic conditions. For physicians who are untrained or lacking the equipment to perform diagnostic hysteroscopy with directed biopsy, simple in-office endometrial sampling techniques with no visual control provide a means to obtain reasonably reliable samples with negligible patient discomfort.

Biopsy↗
PubMed2000

Intraoperative and early postoperative complications of operative hysteroscopy.

With preoperative evaluation, meticulous technique, and vigilance for impending problems, intraoperative and early postoperative complications of operative hysteroscopy are largely preventable. Fluid overload is the most common serious complication. The hysteroscopist must understand the significant differences between hypotonic, electrolyte-free distention media and isotonic, electrolyte-containing media and their respective sequelae. As new operative tools become available, hypotonic and electrolyte-free distention media may become obsolete. The physiology and management of air embolism, the most grave intraoperative complication, are essential to the knowledge base of any active hysteroscopist. Mechanical accidents, anesthetic complications, laser and electrical injury, and infections can be reduced by knowledge and preparation. Technologic advances, ongoing research, and postgraduate training in hysteroscopic technique continue to expand the safe and beneficial applications of hysteroscopy into the next century.

Blood Loss, Surgical↗
PubMed2000

Late complications of operative hysteroscopy.

The late complications of operative hysteroscopy result from either persistent endometrium after ablation or myometrial damage during surgery. Residual endometrium can become neoplastic, cause pain, or support a pregnancy. Myometrial damage can produce catastrophic consequences during a later pregnancy. These long-term problems place the impetus on the operating physician to select patients carefully, prepare the endometrium, and operate in such a way as to minimize the likelihood of residual endometrium and unnecessary myometrial damage. The value of operative hysteroscopy for infertility secondary to adhesions and uterine septa is unequivocal. Hysteroscopic surgery offers increased fertility rates while avoiding the risks of open surgery. For the treatment of abnormal uterine bleeding, endometrial ablation can be performed safely, and the long-term benefits are durable. As more operative hysteroscopy is performed, more delayed complications will arise. Easy-to-perform global ablation techniques and multifunctional operative hysteroscopes have enticed more gynecologists to test the waters of endometrial ablation and operative hysteroscopy. Although they empower the hysteroscopist to offer more advanced and more valuable minimally invasive options to patients, these tools simultaneously can tempt the surgeon to forego meticulous preoperative evaluation. Evidence exists that too often women undergo surgery without complete diagnostic assessment. In one study, 50% of women underwent hysterectomy without any diagnostic evaluation of the endometrium. Hysterectomy possesses a saving grace in that it provides cover for many missed diagnoses. Conservative, nonextirpative procedures offer no such life raft. Meticulous diagnostic assessment and preoperative consideration of risk factors for residual endometrium and future pregnancy remain the keys to minimizing late complications.

Endometrial Neoplasms↗