Alcohol and drug abuse.

Neurological complications are well recognized with alcohol abuse, and an increasing amount of literature is emerging describing neurological disease as a complication of other drugs of addiction (recreational drugs). This review covers recent papers related to alcohol and drug abuse.

Frequency-specific amplification of heart rate rhythms using oscillatory tilt.

Heart rate rhythms have been demonstrated to parallel specific psychological processes. Efficient experimental control of the amplitude of these rhythms would allow evaluation of bidirectional psychophysiological hypotheses. This experiment was performed to examine the specificity of the heart rate rhythm response to oscillatory head-up tilt.

The molecular genetics of mitochondrial cytopathies: the Melbourne experience.

Mitochondrial DNA is a unique, maternally inherited molecule encoding several subunits of the respiratory enzyme chain. In several mitochondrial cytopathies mutations have been described in this genome viz. large-scale heteroplasmic deletions in syndromes with progressive external ophthalmoplegia and point mutations in MELAS and MERRF encephalomyopathies.

Biochemical and molecular investigation of mitochondrial disease: an illustrative case showing the value of a multifaceted approach.

Detailed biochemical and molecular investigations in a patient with Kearns-Sayre syndrome are presented. Polarographic studies in isolated mitochondria revealed a global impairment in respiratory capacity consistent with an admixture of functional and non-functional mitochondria. Cytochrome difference spectra revealed a selective deficiency in cytochrome aa3.

Familial dystonic choreoathetosis with myokymia; a sleep responsive disorder.

A family is presented with paroxysmal dystonic choreoathetosis transmitted as a dominant trait over five generations. The family is unusual in the marked responsiveness of the episodes to short periods of sleep in several members, in the very variable age of onset, and in the association with prominent myokymia in some cases. These overlap features suggest a link between paroxysmal dystonic choreoathetosis and familial paroxysmal ataxia with myokymia.

Normal variants of human mitochondrial DNA and translation products: the building of a reference data base.

A good standard reference for the highly polymorphic human mitochondrial DNA (mtDNA) sequence is essential for studies of normal and disease-related nucleotide variants in the mitochondrial genome. A consensus sequence for the human mitochondrial genome has been derived from thirteen unrelated mtDNA sequences. We report 128 nucleotide variants of the human mtDNA sequence, and 62 amino acid variants of the human mitochondrial translation products, observed in the coding region of these mtDNA sequences.

Mitochondrial genome distribution in histochemically cytochrome c oxidase-negative muscle fibres in patients with a mixture of deleted and wild type mitochondrial DNA.

In situ hybridization studies were performed on a series of chronic progressive external ophthalmoplegia patients harbouring large mitochondrial DNA deletions, using intra- and extra-deletional probes. Clear differences in the distribution of wild type and deleted mitochondrial genomes were seen in both ragged-red and non-ragged red, cytochrome c oxidase-negative fibres, with an accumulation of deleted genomes in the subsarcolemmal zone. Wild type genome content was normal or decreased in the cytochrome c oxidase-negative regions of one case, but in two patients, wild type mtDNA content in cytochrome c oxidase-negative regions was either normal (most fibres) or increased (occasional fibres).

Mitochondrial DNA sequence analysis in congenital myotonic dystrophy.

Mitochondrial genetic modifying factors have been suspected in several autosomally inherited diseases. The congenital variant of myotonic dystrophy, in which there is striking maternal inheritance pattern, is a likely candidate disease. To investigate this possibility, we sequenced completely the mitochondrial genome in 2 patients with congenital myotonic dystrophy.

Mitochondrial theory of senescence: respiratory chain protein studies in human skeletal muscle.

In view of a previously demonstrated negative correlation between stage III respiratory activity in human mitochondria and increasing age, the relationship between human respiratory chain complex protein content and age was investigated. Quantitative immunoblot studies were carried out using holo complex I, III and IV antibody probes in human skeletal muscle mitochondrial homogenate from patients of varying ages. No significant negative correlation between increased age and respiratory complex chain protein content was seen for either total complex activity or for any of the subunits which could be reliably identified.

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.

Painful sciatic neuropathy following cardiac surgery.

Ten patients developed bilateral asymmetrical lower limb sensori-motor or motor deficits associated with prominent causalgic pain after cardiac surgery. The clinical and electrophysiological abnormalities indicated bilateral proximal sciatic nerve lesions, although in several cases the distinction from a diffuse ischaemic axonopathy was difficult to make. This pattern of postcardiac surgery peripheral neurological dysfunction has not been previously described but is likely to relate either to the intra-operative posturing technique for access to the saphenous veins and/or the upright posture used to nurse patients in the immediate post-operative period and is in keeping with the previously demonstrated susceptibility of peripheral nerves to pressure palsy during cardiac surgical procedures.

Affinity chromatography isolation of human cytochrome oxidase and small-scale Western immunoblot probing of the enzyme complex in mitochondrial cytopathy patients.

Isolation of human cytochrome oxidase by a one-step affinity chromatography procedure on a Sepharose 4B-ferrocytochrome c matrix following solubilization with the nonionic detergent laurylmaltoside yields an enzyme isolate of adequate purity for producing polyclonal antisera. Such an antiserum produced a distinctive immunoreactive profile in Western immunoblot studies to that reported using the enzyme isolated with ionic detergents. A sensitive and highly reproducible Western immunoblotting method is described for probing mitochondrial fractions prepared from small frozen skeletal muscle biopsies with an antiserum against the human placenta cytochrome oxidase.

Hemitonic seizures: etiological and diagnostic considerations.

Intermittent unilateral tonic posturing of the limbs may relate to focal motor epilepsy, intermittent dystonia or hysteria, and diagnosis may be difficult. Five patients are presented who illustrate two distinct hemitonic syndromes which we believe to be epileptic, namely forced elevation of one arm and paroxysmal hemispasm. It is suggested that these attacks follow an irritative lesion involving the supplementary motor cortex and a deep lesion involving striatothalamic projections respectively.

Mitochondrial encephalomyopathies: a correlation between neuropathological findings and defects in mitochondrial DNA.

Neuropathological studies were carried out in two patients with mitochondrial encephalomyopathies in whom the underlying lesions in muscle mitochondrial DNA (mtDNA) and respiratory enzyme complexes have been investigated. The first, a man with Kearns-Sayre syndrome, died at the age of 49 years. Autopsy showed an old parietal lobe infarct, diffuse spongiform leukoencephalopathy of cerebral and cerebellar white matter and mild spongiform change in deep grey matter and brainstem nuclei.

Functional respiratory chain studies in subjects with chronic progressive external ophthalmoplegia and large heteroplasmic mitochondrial DNA deletions.

The functional consequences of large heteroplasmic mtDNA deletions were investigated in a group of 6 patients with chronic progressive external ophthalmoplegia (CPEO) syndromes. State III respiration rates corrected for age were low with site I and II substrates in all cases and cytochrome oxidase activity was depressed. The severity of impairment varied and is consistent with inclusion of a variable percentage of non-functioning mitochondria (with deleted mtDNA) in the pellet.

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.

Functional respiratory chain studies in mitochondrial cytopathies. Support for mitochondrial DNA heteroplasmy in myoclonus epilepsy and ragged red fibers (MERRF) syndrome.

Mitochondrial respiratory chain function was investigated with polarographic and enzymatic studies, and correlated with immunoblot studies using a battery of probes against respiratory chain holocomplexes in a series of patients with myoclonus epilepsy and ragged red fibers (MERRF) syndrome. State III respiration rates in intact skeletal muscle mitochondria were normal in two cases, suggested site I deficiency in one case and a mid-respiratory defect in another. Immunological studies of complex I showed reduced levels of several subunits with the apparent absence of two bands (which at 45 and 42 kDa, coincide with the predicted electrophoretic mobility of the ND5 gene product) in one case.

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.

Chronic progressive external ophthalmoplegia in patients with large heteroplasmic mitochondrial DNA deletions: an immunocytochemical study.

Immunocytochemical studies with a holocomplex antibody battery in patients with chronic progressive external ophthalmoplegia, with and without large mitochondrial DNA deletions, revealed positive (and often increased) immunoreactivity for all complexes studied in histochemically cytochrome oxidase (COX)-negative areas, suggesting a compensatory up-regulation of these components. Similar findings were observed with subunit-specific probes directed against both nuclear- and mitochondrially encoded gene products. Comparison of staining intensities between the different complexes revealed significantly more variability in COX-negative than COX-positive fibres, suggesting disordered stoichiometric control during up-regulation.

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.