VII International Congress on neuromuscular diseases, Munich, September 16-22, 1990.
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Animals↗
Biomedical subjects
E Byrne
Publications and source records attributed to E Byrne.
The chronic fatigue syndrome: a reappraisal and unifying hypothesis.
The chronic fatigue syndrome is one of the most common medical problems in Western countries. Research work in virology, immunology, metabolic medicine and psychiatry in this area is reviewed and a disease model proposed. The chronic fatigue syndrome can be considered as a continuum ranging from cases with chronic viraemia on the one hand to instances of frank psychiatric illness on the other. In the majority of patients the fully evolved syndrome may involve an interaction of premorbid factors (psychological, immunological), environmental trigger factors (virus) and enhancing factors (emotional response to illness). A Venn diagram is a convenient way of expressing this concept.
Fatigue Syndrome, Chronic↗
A tRNA(Lys) mutation in the mtDNA is the causal genetic lesion underlying myoclonic epilepsy and ragged-red fiber (MERRF) syndrome.
Skeletal muscle mtDNA of three patients with mitochondrial encephalomyopathy, characterized clinically by myoclonic epilepsy and ragged-red fiber (MERRF) syndrome, has been sequenced to determine the underlying molecular defect(s). An A-to-G substitution of nt 8344 in the tRNA(Lys) gene, a substitution suggested to be associated with MERRF encephalomyopathy, was detected in these patients. Abnormal patterns of mitochondrial translation products were observed in the skeletal muscle of patients, consistent with the expected consequential defect in protein synthesis. The genealogical studies of the three patients, as well as mtDNA from one published MERRF patient and from nine other normal and disease controls, revealed that the tRNA(Lys) mutations in the MERRF patients have arisen independently. These observations provided evidence that the base substitution is a causal mutation for MERRF.
Adult↗
Oxidative energy failure in post-mitotic cells: a major factor in senescence.
A significant decline with age in state III respiration rates has been documented in man and experimental animals in several tissues. Focal areas of cytochrome oxidase negativity, resembling those in skeletal muscle fibres in patients with chronic progressive external ophthalmoplegia (CPEO) syndromes, appear in old age. The mitochondrial genome is susceptible to mutation because of a high turnover rate, ineffective DNA repair mechanisms and a hostile environment rich in free radicals. The available data supports the development of mitochondrial failure in old age in fixed post-mitotic tissues suggesting that mitochondrial failure may be central to the senescent process.
Aging↗
Sensory examination.
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Acquired Immunodeficiency Syndrome↗
Antimitochondrial autoantibodies of primary biliary cirrhosis as a novel probe in the study of 2-oxo acid dehydrogenases in patients with mitochondrial myopathies.
Autoantibodies present in the autoimmune disease primary biliary cirrhosis react by immunoblotting with four human skeletal muscle mitochondrial antigens of 70 kDa, 52 kDa, 50 kDa and 45 kDa, identified as the lipoate acetyl transferases (E2) of the pyruvate dehydrogenase, component X of E2 pyruvate dehydrogenase, E2 of 2-oxo glutarate dehydrogenase and E2 of branched-chain 2-oxo acid dehydrogenase complexes respectively. These autoantibodies have been employed as a novel probe to study whether there is a defect in the synthesis of the 2-oxo acid dehydrogenase complexes in patients with mitochondrial respiratory chain disorders. The reactive antigens are present normally in four patients with oculomyopathy in whom partial deletions of the mtDNA have been detected, and in two patients with MERRF and MELAS encephalomyopathy. Thus, unlike in the yeast Saccharomyces cerevisiae, there appear to be no regulatory interactions which coordinate the assembly of the mitochondrial respiratory chain with the development of the pyruvate dehydrogenase complex, which plays an important role in regulating the flow of metabolic intermediates to oxidative energy metabolism.
3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
Development of a high-titer retrovirus producer cell line capable of gene transfer into rhesus monkey hematopoietic stem cells.
Retroviral-mediated gene transfer into primitive hematopoietic cells has been difficult to achieve in large-animal models. We have developed an amphotropic producer clone that generates greater than 10(10) recombinant retroviral particles (colony-forming units) per ml of culture medium. Autologous rhesus monkey bone-marrow cells were cocultured with either high (2 x 10(10) colony-forming units/ml) or low (5 x 10(6) colony-forming units/ml) titer producer clones for 4-6 days and reinfused into sublethally irradiated animals. The proviral genome was detected in blood and bone-marrow cells from all three animals reconstituted with cells cocultured with the high-titer producer cells. In contrast, three animals reconstituted with bone marrow cocultured with the low-titer producer clone exhibited no evidence of gene transfer.
Animals↗
Mitochondrial myopathies and myoencephalopathies.
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Humans↗
Biochemical and morphological studies of skeletal muscle in experimental chronic alcoholic myopathy.
Experimental alcoholic myopathy was induced in rats by a combination of prolonged alcohol intake (mean 15.3 g ethanol/kg/day for up to 10 weeks) and a short fast. In view of literature evidence for impairment of both glycolytic and oxidative metabolism in alcoholic myopathy, we combined histological and histochemical observations with biochemical studies comprising assay of all glycolytic enzymes and measurement of respiration rates and cytochrome content in isolated intact mitochondria. The predominant histological finding was Type IIb fibre atrophy, while levels of the glycolytic enzymes aldolase, pyruvate kinase and lactate dehydrogenase were significantly depressed. Evidence of rhabdomyolysis was seen in a minority of animals. Mean mitochondrial respiratory rates were significantly lower with the Site I substrate glutamate in alcohol-treated animals. It is postulated that chronic alcoholic myopathy is associated with glycolytic deficiency and that acute rhabdomyolysis may arise from a superimposed mitochondrial failure, resulting in a severe energy crisis in muscle.
Alcoholism↗
Infantile mitochondrial disease.
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Central Nervous System Diseases↗
Decline in skeletal muscle mitochondrial respiratory chain function: possible factor in ageing.
State III (activated) mitochondrial respiration rates with pyruvate/malate, glutamate/malate, and succinate as substrates were assayed in isolated intact skeletal muscle mitochondria in 29 subjects aged 16-92 years. There was a significant negative correlation between respiration rate and age with all substrates tested. A similar trend was seen for respiratory enzyme activities assayed in muscle homogenate. These findings suggest a substantial fall in mitochondrial oxidative capacity in ageing muscle, which may contribute to reduced exercise capacity in elderly people. Mitochondrial respiratory failure may contribute to the ageing process in other organs.
Adult↗
Prolonged aerobic exercise: physiological studies in rat gastrocnemius with additional observations on the effects of acute mitochondrial blockade.
Protracted low frequency (1 and 5 Hz) stimulation of rat gastrocnemius in vivo leads to fatigue and fall out of glycolytic fibres with the development of a stable twitch response with continuation of the stimulus train. This model was used to examine the physiological effects of acute mitochondrial blockade on oxidative fibre function with the injection of a mitochondrial uncoupler (dinitrophenol) and a site I inhibitor (diphenyleneiodonium) intraarterially after a stable twitch response had developed. Dinitrophenol leads to progressive failure of contractility, closely followed by action potential failure and electrically silent contracture: external work accelerated this sequence but it also developed in resting muscle suggesting that DNP lead to active ATP hydrolysis and a more severe energy depletion than that encountered in human disease states. Diphenyleneiodonium also leads to progressive twitch tension and action potential failure but contracture was late and inconstant, considerable recovery in twitch parameters was seen with rest and restimulation lead to pathological fatiguability of twitch tension. This model has some similarity to human mitochondriopathies with pathological fatiguability. This acute model should allow ready testing of any therapeutic approaches which bypass respiratory chain blocks.
Animals↗
Guillain-Barré syndrome and related conditions in Victorian teaching hospitals 1980-84.
Cases of Guillain-Barré syndrome, its variants, and chronic inflammatory demyelinating neuropathy presenting during the period 1980-84 were identified through computer-based record systems. Case notes were examined, and cases that did not meet standard criteria for diagnosis were excluded. A hundred and ten patients were identified, giving an annual adult incidence rate of 0.9/100,000 and a male:female ratio of 1.3:1. The majority of cases developed severe tetraparesis, but unusual presentations included the Miller-Fisher variant, paraplegia, and bibrachial involvement. There was wide variation in peak disability, ranging from ambulant with weakness (32%), through bedfast but without significant respiratory involvement (29%), to respiratory involvement requiring admission to an intensive care unit (38%). Of those discharged directly home, the average hospital stay for those less than 50 years was 27 days, whilst that for those over 50 was 49 days. CSF protein was measured in 87 patients, and was greater than or equal to 0.6 g/L in 76% of these. Nerve conduction studies were performed in 52 patients, and were abnormal in 90% of these. Guillain-Barré syndrome and allied conditions represent a major drain on health resources, and the need to provide adequate plasmapheresis facilities for patients early in the course of severe disease is stressed.
Adolescent↗
Concept of the month: implementing King's Conceptual Framework at the bedside.
Acknowledging the use of conceptual frameworks as the future of nursing, administrators are searching for methods to incorporate theory into practice. The challenge is to do this in a way that is meaningful and useful to the nurse at the beside. The authors describe how one directorate, in a 650-bed community hospital, developed a program that enabled nurses to understand and apply Imogene King's systems and concepts to their practice.
Humans↗
Mitochondrial DNA deletion in encephalomyopathy.
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Adult↗
Current perspectives in the study of human mitochondriopathies.
Recent advances in the study of human mitochondriopathies are discussed, and the impact that modern molecular-biology techniques are likely to have on the understanding of both the disease mechanisms and the basic mechanisms of mitochondrial assembly are reviewed.
DNA, Mitochondrial↗
Idiopathic chronic fatigue and myalgia syndrome (myalgic encephalomyelitis): some thoughts on nomenclature and aetiology.
Myalgic encephalomyelitis is a misnomer that describes epidemics of probable hysterical illness and bears no definite relationship to chronic fatigue and myalgia syndrome. The relationship of idiopathic fatigue syndromes to fatigue syndromes after well-defined viral illnesses such as glandular fever is also unclear. Detailed studies of muscle histochemistry and biochemistry in idiopathic chronic fatigue and myalgia syndrome do not support a defect in intermediate metabolism. The aetiology of this syndrome is unknown and it is not yet clear whether it has an organic or a non-organic basis.
Chronic Disease↗
Progression from MERRF to MELAS phenotype in a patient with combined respiratory complex I and IV deficiencies.
Identical twins developed myoclonic epilepsy in their teens. One twin remained mildly affected but the other went on to develop sensorineural deafness and ataxia with lactic acidosis and ragged red fibres leading to a diagnosis of mitochondrial encephalopathy. Multiple stroke-like episodes with hemiparesis followed, indicating progression from a MERRF to a MELAS phenotype. Biochemical studies revealed a severe deficiency of mitochondrial NADH-ubiquinone reductase and a moderate deficiency of cytochrome aa3. Western immunoblotting experiments using polyclonal antibodies raised against human placental cytochrome oxidase identified a similar profile of bands to those seen in controls, supporting the view that cytochrome aa3 deficiency in this case may be a secondary consequence of a failure of assembly related to a severe proximal respiratory chain defect.
Acidosis, Lactic↗