Platelet mitochondrial function in Leber's hereditary optic neuropathy.

We report the effect of the 11,778 and 3460 base pair mitochondrial DNA mutations, found in Leber's hereditary optic neuropathy (LHON), on platelet mitochondrial respiratory chain enzyme activity. We measured respiratory chain enzyme activities in platelets from 4 patients with the 3460 mutation, 17 patients with the 11,778 mutation and compared them with those of 41 healthy age-matched controls. We observed a 67% (P < 0.

Hypoglycaemia in paediatric admissions in Mozambique.

We studied the incidence and clinical associations of hypoglycaemia in an acute medical paediatric service in Maputo, Mozambique. Of 603 children, 43 (7.1%) were hypoglycaemic.

Indices of oxidative stress and mitochondrial function in individuals with incidental Lewy body disease.

Brain tissue from normal individuals with incidental Lewy bodies and cell loss in pigmented substantia nigra neurons (asymptomatic Parkinson's disease) and age-matched control subjects without nigral Lewy bodies was examined biochemically. There was no difference in dopamine levels or dopamine turnover in the caudate and putamen of individuals with incidental Lewy body disease compared to control subjects. There were no differences in levels of iron, copper, manganese, or zinc in the substantia nigra or other brain regions from the individuals with incidental Lewy body disease compared to those from control subjects.

Mitochondrial DNA mutation underlying Leigh's syndrome: clinical, pathological, biochemical, and genetic studies of a patient presenting with progressive myoclonic epilepsy.

An 18-year-old male patient presented with clinical and radiological evidence of Leigh's syndrome (LS), having developed progressive myoclonic epilepsy and ataxia 11 years previously. Muscle biopsy showed cytochrome oxidase deficiency but no ragged red fibres. Autopsy confirmed the diagnosis of LS; there was additional degenerative change in the cerebellum and dentate and olivary nuclei, and an axonal peripheral neuropathy.

Dorsal root ganglion proteins in Friedreich's ataxia.

The polypeptide composition of dorsal root ganglia from 8 human controls, 6 Friedreich's ataxia (FA) patients and 1 patient with diabetic neuropathy was studied by sodium dodecyl sulphate (SDS)-polyacrylamide gel electrophoresis (PAGE). Silver-stained gels demonstrated a decrease in a 40-kDa protein in FA patients. This protein appeared to be present in normal amounts in the diabetic ganglion, suggesting that this 40-kDa protein deficiency was not simply a reflection of reduced neuronal numbers but may be specific for FA.

Myopathy in vitamin E deficient rats: muscle fibre necrosis associated with disturbances of mitochondrial function.

Vitamin E deficiency in rats gives rise to a neuromuscular syndrome that includes a peripheral neuropathy as well as generalised muscle wasting and weakness. This is probably related to damage by oxygen-derived free radicals. In the present study, histological examination of lower limb muscles showed widespread myopathic changes which included the presence of amorphous electron-dense inclusions and tubular aggregates in muscle fibres and muscle fibre necrosis.

Iron induced oxidative stress and mitochondrial dysfunction: relevance to Parkinson's disease.

Inactivation of the mitochondrial respiratory chain in response to iron-induced oxidative stress has been studied in cultured cells. Iron loading resulted in malonaldehyde production, decreased levels of glutathione and reduced specific activities of both complexes I and IV of the respiratory chain. These results are discussed with respect to idiopathic Parkinson's disease, which is associated with increased iron levels and a specific decrease in complex I activity in the substantia nigra.

Mitochondrial cytopathies.

Defects of the mitochondrial respiratory chain and mutations of mitochondrial DNA have now been associated with a wide range of human diseases. The precise pathogenetic mechanisms by which these biochemical abnormalities induce tissue dysfunction are not understood. The identification of a mutation in the proline anticodon and in the 12S RNA genes of mitochondrial DNA are interesting new additions to the catalogue of pathogenetic mutations of this genome.

Smoking and mitochondrial function: a model for environmental toxins.

Defects of the human mitochondrial respiratory chain have been associated with several diseases including, most recently, certain neurodegenerative disorders. Several studies have used platelet mitochondrial function as a means to determine the potential contribution of respiratory chain defects to the pathogenesis of Parkinson's disease. Platelet biochemistry is subject to modulation by numerous factors that may circulate in the blood, including environmental agents, some of which may be relevant to mitochondrial dysfunction and neuronal toxicity.

Nuclear complementation restores mtDNA levels in cultured cells from a patient with mtDNA depletion.

We have studied cultured skin fibroblasts from a patient with a fatal mitochondrial disease manifesting soon after birth. These fibroblasts were found to grow only in the presence of pyruvate and uridine, a characteristic of cells lacking mtDNA (rho0 cells). Southern blot and PCR analyses confirmed that the patient's fibroblasts contained less than 2% of control levels of mtDNA.

The use of toxins to elucidate neural function and disease.

In some cases, toxins can be useful tools to produce models of human disease. This is especially so with neurotoxins, which have been used to simulate disease in both the central and peripheral nervous systems. However, it is important to be cautious in extrapolating the biochemical consequences of the toxins to the respective human disorder.

Mitochondrial disorders.

Several different types of mitochondrial DNA mutations have now been identified in a wide spectrum of human disorders. There is some correlation between certain of these mutations and the patient's clinical phenotype, although this relationship is not absolute. The mechanisms by which these mutations produce respiratory chain deficiency and the dysfunction of different tissues are unknown.

Malaria: living with drug resistance.

The epidemiological factors associated with the development and spread of drug-resistant malaria have been recently explored by Wemsdorfer in a paper in which he looked at parasite-drug-human-vector interactions that affect the occurrence and dynamics of drug resistance. The question that decision-makers must be asking themselves, as we face the 21st century, is: how will we live with drug resistance? Allan Schapira, Peter Beales and M. Elizabeth Halloran are ideally placed to consider this question.

Free radicals and mitochondrial dysfunction in Parkinson's disease.

The precise relationship of the complex I deficiency in PD to the dopaminergic cell death and aetiology of this disorder is as yet unknown. However, evidence is accruing that this mitochondrial defect may play a central role in the cascade of events that terminates in nigral neuronal loss. Further work needs to be carried out to determine the molecular mechanisms that underlie the complex I deficiency as these may provide important indicators to the ultimate cause of PD.

Comparison of intramuscular and intravenous quinine for the treatment of severe and complicated malaria in children.

To compare the efficacy and side effects of intramuscular (i.m.) and intravenous (i.

Successful outcome of progressive multifocal leukoencephalopathy with cytarabine and interferon.

The prognosis of patients with progressive multifocal leukoencephalopathy is poor, with few patients showing remission or surviving. We describe a 37-year-old man who developed progressive multifocal leukoencephalopathy in association with sarcoidosis. Despite treatment with cytarabine and acyclovir, he continued to deteriorate.

Platelet mitochondrial function in Parkinson's disease. The Royal Kings and Queens Parkinson Disease Research Group.

There is increasing evidence that defective function of the mitochondrial enzyme NADH CoQ reductase (complex I) is involved not only in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity, but also in idiopathic Parkinson's disease (PD). Complex I deficiency has been identified in PD substantia nigra and appears to be disease-specific and selective for the substantia nigra within the central nervous system. We describe a method for preparation of an enriched mitochondrial fraction from 60 mL blood.

New insights into the cause of Parkinson's disease.

Current concepts as to the cause of Parkinson's disease (PD) suggest an inherited predisposition to environmental or endogenous toxic agents. Study of the substantia nigra after death in PD has highlighted three major changes: (1) evidence of oxidative stress and depletion of reduced glutathione; (2) high levels of total iron, with reduced ferritin buffering; and (3) mitochondrial complex I deficiency. Which of these is the primary event, generating a secondary cascade of changes culminating in nigral cell death, is unknown.

Analyses of mitochondrial respiratory chain function and mitochondrial DNA deletion in human skeletal muscle: effect of ageing.

The analysis of human skeletal muscle mitochondria revealed a progressive decline in mitochondrial respiratory chain function with age. The activities affected to the greatest extent were those of complexes I and IV which were decreased by 59% and 47% respectively between the ages of 20-30 years and 60-90 years of age. Quantitation of the 5 kb 'common' deletion of mtDNA using PCR revealed a progressive accumulation with age, from approximately 1 in 100,000 at 21 years to 1 in 10,000 at 56 years and 1 in 5000 at 78 years of age.

Mitochondrial function in neurodegeneration and ageing.

The mitochondrial respiratory chain and oxidative phosphorylation system are responsible for the production of ATP by aerobic metabolism. Defects of the respiratory chain are increasingly recognised as important causes of human disease, and neurodegenerative disorders in particular. This article will seek to review the clinical and biochemical effects of respiratory chain defects, and summarise what is known about the molecular mechanisms that underlie them.