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Biomedical subjects

E Byrne

Publications and source records attributed to E Byrne.

At least 55 records · Page 3Linked to original sources
PubMed1996

Mitochondrial DNA polymorphism in substantia nigra.

Inefficiencies in mitochondrial respiration mainly affecting complex I and IV activities, occur with increasing age and have been suggested as a possible etiological factor in age-related neurodegenerative diseases. It has been suggested that this finding may be explained by an accumulation of mtDNA mutations. We hypothesise that some polymorphic mitochondrial genomes encode less efficient respiratory protein subunits and are therefore less tolerant of acquired mutations. If this hypothesis is correct, individuals with 'less efficient' mtDNA genotypes may be predisposed both to more rapid biological aging and to neurodegenerative disease. In this study we investigate the substantia nigra mtDNA composition from 4 elderly individuals (2 non-parkinsonian and 2 with idiopathic Parkinson's disease) to determine whether there is sufficient polymorphism to account for different possible respiratory efficiencies. THe mitochondrial tRNAArg, tRNAHis, tRNAScr, tRNALeu(CUN), ND4L, ND4 and ND5 genes as well as parts of the ND3 and ND6 subunit coding regions were analysed (4221 bp), revealing the presence of multiple deletions and 48 discrete polymorphic sites. These included 23 missense, two tRNA and one nonsense polymorphism. Eight of the missense polymorphisms caused nonconservative amino acid replacements at sites of moderate to high evolutionary constraint. These findings suggest that mtDNA diversity in the ageing brain may account for a range of bioenergetic outcomes. The variation in mtDNA genotype involves both inherited (fixed familial) polymorphism and superimposed acquired mutations.

Aged↗
PubMed1996

Quantitative measure of muscle strength and size in chronic alcoholism: an early indication of tissue damage.

We measured quadriceps strength and thickness in 101 male alcoholic patients and in 58 controls in order to investigate the force-size relationships of skeletal muscle in an alcoholic population. The relationship of these parameters with the duration of alcoholism, nutritional status and biochemical and haematological markers of heavy chronic alcohol use was investigated. Alcohol consumption of more than 42 standard drinks (420 g alcohol) per week for at least 5 years is associated with muscle weakness and wasting. There was no evidence of under-nutrition in these alcoholic subjects and muscle wasting occurred independently of peripheral neuropathy, a history of muscle pain, abnormalities of liver enzymes and elevation of mean red cell corpuscular volume. Quantitation of muscle size and strength in heavy drinkers may provide a useful early indicator of health impairment in alcoholics.

Journal Article↗
PubMed1996

Sporadic Leber hereditary optic neuropathy in Australia and New Zealand.

BACKGROUND: Leber hereditary optic neuropathy (LHON) is one of the more common forms of hereditary optic neuropathy and one of the few mitochondrial neuropathies. Prior to the advent of molecular DNA testing, the diagnosis depended on the recognition of typical fundal changes, as well as a family history of maternal transmission. Sporadic cases were therefore diagnosed with a level of uncertainty. The aim of this study is to identify the proportion of patients with idiopathic bilateral optic neuropathy/atrophy who are suffering from LHON. METHODS: Requests were sent to all ophthalmologists and neurologist in Australia and New Zealand for blood or hair follicle samples of patients with diagnosis of bilateral optic neuropathy/atrophy of uncertain aetiology for DNA testing by restriction endonuclease analysis. RESULTS: One hundred and forty-four samples were received, of which 96 were sporadic cases of idiopathic optic atrophy. Eleven of these sporadic patients were found to harbour pathogenetic mitochondrial point mutations associated with LHON. CONCLUSIONS: Our results indicated that 11% of patients with bilateral optic neuropathy/atrophy of uncertain aetiology are suffering from LHON. Comparing this data with all the known familial cases of LHON, we report that at least 8% of all LHON cases in Australia are sporadic. We concluded that mtDNA testing for LHON in patients with idiopathic optic atrophy should be included in the initial laboratory work-up.

Australia↗
PubMed1996

Respiratory chain encephalomyopathies: a diagnostic classification.

Mitochondrial encephalomyopathies are a heterogenous group of disorders with various biochemical defects of the respiratory chain (RC). Due to the considerable phenotypic diversity of the RC encephalomyopathies, they are included in the differential diagnosis of many cases of multisystem disease. Aside from clinical evaluation and family history, diagnosis can be supported by many other sources. The complexity of diagnostic information can make it difficult for the clinician to establish the level of certainty at which a RC cytopathy is diagnosed in atypical cases. We review the parameters (clinical, pathological, biochemical and molecular) which are used to aid diagnosis of RC encephalomyopathy and identify levels of abnormality in each that strongly or less strongly support the diagnosis. A system is developed that allows classification of the diagnosis in possible, probable and definite categories of certainty, which will be of value to the clinician.

Biomarkers↗
PubMed1995

RNA-protein interactions in the ribonucleoprotein T-complexes in a mitochondrial extract from Leishmania tarentolae.

We have investigated protein-RNA interactions and the incorporation of [alpha-32P]UTP into the guide RNA and mRNA components of the 'T-complexes' in a mitochondrial extract from Leishmania tarentolae. The terminal uridylyl transferase-containing complex T-IV is probably involved in the maturation of the 3'-oligo(U) tail of the gRNAs, but the biological function and biochemical nature of the remaining T-complexes is not known. We have found that the relative extent of labeling of the RNA components is dependent on the UTP concentration: at low levels, the main endogenous RNA components labeled are the gRNAs in T-IV; at higher levels, the mRNAs in all of the T-complexes are preferentially labeled. We also show a tentative correlation in the migration pattern of UTP-labeled T-complexes and complexes which bind exogenous labeled RNA. The relative extent of binding to specific complexes is dependent upon the type of RNA. Most of the interactions between the labeled RNAs and proteins can be disrupted by heparin or a large excess of rRNA, but two labeled complexes were resistant to competition. Most of the binding of labeled exogenous gRNA is disrupted by competition with a large excess of rRNA, but predigestion of the extract with micrococcal nuclease and saturation with rRNA uncovered a high affinity complex, which involves at least two proteins interacting with the bound gRNAs. A knowledge of the RNA and protein components may aid in understanding the biological roles of these RNP complexes.

Animals↗
PubMed1995

Isometric strength and thickness relationships in human quadriceps muscle.

The isometric Maximum Voluntary Contraction (MVC) of the right quadriceps femoris muscle was measured in 82 females and 58 males using a chair dynamometer and their mid-thigh quadriceps thickness was measured using real-time B-mode ultrasound. Statistically significant relationships (ranging from P < 0.001 to P < 0.0001) were found between quadriceps MVC, quadriceps thickness and body weight for both males and females. A significant inter-sex difference was present in the MVC-weight and MVC-thickness relationships, with males tending to have a higher MVC for a given body weight (P < 0.0001) and for a given muscle thickness (P < 0.0001). The inter-sex difference in the force-size relationship may relate to the previously demonstrated larger size of type 2b fibres and to the greater force generating capacity of these fibres compared with type 1 fibres.

Adult↗
PubMed1995

Early onset of multiple sclerosis with autopsy confirmation.

A female had her first generalized epileptic seizure at age 11 yrs. Apart from intermittent seizures she remained well until 15 yrs of age when she developed double vision, unsteadiness and bilateral plantar responses which resolved spontaneously. Brain MRI scan at this stage revealed changes typical of multiple sclerosis. She died at 17 yrs of age from asthma and epilepsy. Autopsy confirmed the presence of multiple sclerosis and showed the disease to be very active. We consider it likely that multiple sclerosis was present at the age of 11 yrs when she had her first epileptic seizure. This case of multiple sclerosis is presented because of the rarity of the early age of onset, unusual presentation with epilepsy, marked activity of disease and early death. Also it is uncommon to have autopsy confirmation of such disease.

Adolescent↗
PubMed1995

The therapy of respiratory chain encephalomyopathy: a critical review of the past and current perspective.

The mitochondrial respiratory chain encephalomyopathies represent an important group of multisystem disorders. No curative treatment is currently available. A number of measures have been reported to have a theoretical potential to improve respiratory function. These treatment strategies have variable scientific support, many reports being anecdotal. We critically review the various therapeutic measures employed and suggest future treatment directions.

Benzoquinones↗
PubMed1995

Contrasting histochemical features of various mitochondrial syndromes.

A comparative histochemical analysis of the prevalence and cytochrome oxidase staining characteristics of ragged-red fibres in limb skeletal muscles was performed in 19 patients spanning four distinct mitochondrial syndromes: chronic progressive external ophthalmoplegia; myoclonus epilepsy with ragged-red fibres; mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes; and pure limb myopathy. The percentage occurrence of non-ragged red but cytochrome oxidase negative fibres was additionally noted. Ragged-red fibres and cytochrome oxidase-negative fibres were generally more prevalent in the chronic progressive external ophthalmoplegia syndrome than in myoclonus epilepsy ragged-red fibres syndrome or mitochondrial myopathy encephalopathy lactic acidosis and stroke-like episodes syndrome. Isolated cytochrome oxidase-negative fibres were a common finding in each phenotypic syndrome except pure limb myopathy and could involve any of the major fibre types non-specifically. Ragged-red fibres were devoid of cytochrome oxidase activity in chronic progressive external ophthalmoplegia, but commonly displayed activity in the other three syndromes providing a clue to syndromal differentiation on a histochemical basis.

Adolescent↗
PubMed1995

Cost of care for ambulatory patients with low back pain.

BACKGROUND: Low back pain is a common presenting complaint in primary care, and the rate of utilization of resources among physicians treating this condition varies. Charges associated with the care of patients with low back pain were analyzed for a series of patients in a multispecialty group practice setting. METHODS: One hundred seventy managed care patients were selected for review. Use of laboratory, plain radiography, magnetic resonance imaging (MRI), subspecialty referrals, and physical therapy was examined based on patient characteristics and physician specialty. Appropriateness of MRI and lumbar spine radiography according to published criteria was also studied. RESULTS: Overall utilization was higher for patients who were referred to a subspecialist, and costs for visits to subspecialists were higher. Charges for physician services and MRI accounted for a majority of the total charges. Patients who were referred for subspecialty care or MRI but did not meet criteria for utilization of these resources comprised 6% of the study population but accounted for 27% of the total charges. Five of 14 patients undergoing MRI did not meet the published clinical criteria determining need for MRI, and 10 of 17 patients referred to subspecialists did not meet referral criteria. Other patients who met criteria for MRI or subspecialty consultation did not receive these services. Seventeen percent of the patients referred for physical therapy had a symptom duration of 2 weeks or less at the time of referral and accounted for 17% of all physical therapy charges. CONCLUSIONS: The majority of costs associated with care for low back pain in this study were attributable to physician charges and the use of MRI. Charges for subspecialty physician services, lumbar spine radiographs, and MRI in patients not meeting appropriate criteria accounted for 19% of all costs.

Adult↗
PubMed1994

Characterization of two classes of ribonucleoprotein complexes possibly involved in RNA editing from Leishmania tarentolae mitochondria.

The molecular mechanism of RNA editing in trypanosomatid mitochondria is an unsolved problem. We show that two classes of ribonucleoprotein complexes exist in a mitochondrial extract from Leishmania tarentolae and appear to be involved in RNA editing. The 'G' class of RNP complexes consists of 170-300 A particles which contain guide RNAs and proteins, show little terminal uridylyl transferase (TUTase) activity and exhibit an in vitro RNA editing-like activity. The 'T' class consists of approximately six RNP complexes, the endogenous RNA of which can be self-labeled with [alpha-32P]UTP. The most abundant T complex, T-IV, is visualized by electron microscopy as 80-140 A particles. This complex exhibits TUTase activity in the native gel and contains guide RNAs. Both G and T complexes are possibly involved with RNA editing in vivo. These results are a starting point for the analysis of the biochemistry of RNA editing.

Animals↗
PubMed1994

Rapid and noninvasive screening of patients with mitochondrial myopathy.

In recent years, several point mutations in the mitochondrial genome have been associated with human disease. PCR Polymerase Chain Reaction/restriction endonuclease based techniques provide a reliable method for screening large numbers of specimens for many of the reported mutations. Muscle tissue usually carries the mutations and has been used in earlier studies. We describe a technique for analysis of mtDNA derived from hair follicles for a range of mutations. Both the 3243 A-->G MELAS and 8344 A-->G MERRF mutations were detected in mtDNA from hair follicles. In patients where both muscle and hair were screened, the mutation load was apparently higher in muscle. Furthermore, in patients positive for a given mutation, all the hair follicles analysed were shown to harbour the mutation, although the proportion of wild type to mutant mtDNA was found to somewhat vary. The advantages of this method are (1: six hair follicles provide sufficient mtDNA for analysis of at least 20 different mutations, and (2: specimen collection and transport to a central laboratory are easier than for other tissues. Our studies show that hair follicles constitute a reliable specimen for mitochondrial mutation screening at a diagnostic level.

DNA, Mitochondrial↗
PubMed1994

A novel mtDNA deletion in an infant with Pearson syndrome.

Pearson syndrome is a multisystem mitochondrial disorder of infancy that is associated with deletions in the mitochondrial DNA (mtDNA) genome. We report a study on a male infant with Pearson syndrome. Assessment of oxidative phosphorylation activity indicated combined respiratory-chain defects in muscle, liver and fibroblasts; in particular, activity of complex I was reduced. Analysis of the patient's mtDNA identified a novel heteroplasmic 2.461 kb deletion, present at levels greater than 50% of the total mtDNA in the tissues examined. The deletion spanned nucleotides 10368 to 12828 and was flanked by a 3 bp GCC direct repeat sequence. Gene sequences affected are subunits 3, 4, 4L and 5 of complex I, and tRNAs for arginine, histidine, serine and leucine. Our findings correlate with the multiorgan involvement observed in Pearson syndrome.

Base Sequence↗
PubMed1994

Mitochondrial DNA polymorphism in disease: a possible contributor to respiratory dysfunction.

Intergenomic variation in the human mitochondrial genome was examined in 27 mtDNA sequences using a pairwise analysis technique. Analysis of 16 of these mtDNA sequences from patients with mitochondrial cytopathies indicated a wide range between different mitochondrial genes in the degree of nucleotide variation from the standard Cambridge sequence. Mean complex I polymorphic frequencies in cytopathic (CPEO, MERRF, MELAS and LHON collectively) patients and in LHON patients differed significantly from controls (P < or = 0.05, t). Total mean sequence divergence (mean number of diverging nucleotides between two sequences per 100 bp) over the entire mtDNA coding region was 0.21% for cytopathies (n = 16) as opposed to 0.18% for a control group (n = 4). Within the cytopathy group, the greatest pairwise divergence was observed in ND3 and ND6 subunits of complex I (0.46 and 0.70% respectively) and the magnitude of specific gene divergences differed considerably from those observed for the corresponding genes in the control population. The extent to which the increased variation in ND3 and ND6 is a general phenomenon applicable to all subjects rather than a finding specific to cytopathies cannot be stated with certainty given the small control group. Regardless as to which of these suggestions is correct, the possibility exists that increased nucleotide variation in certain mitochondrial ND subunits may contribute to respiratory inefficiency through a cumulative effect of a series of polymorphisms of minor individual mutagenic potential.

DNA, Mitochondrial↗
PubMed1994

Heterogeneity in the phenotypic expression of the mutation in the mitochondrial tRNA(Leu) (UUR) gene generally associated with the MELAS subset of mitochondrial encephalomyopathies.

BACKGROUND: Point mutations in the mitochondrial (mt) genome underlie a number of neurological disorders. Some are well defined including the myoclonus epilepsy ragged red fibre syndrome (MERRF) and the mitochondrial encephalopathy lactic acidosis stroke like episode syndrome (MELAS). However, other clinical phenotypes are less distinctive and mitochondrial studies are often included in the workup in complex neurological syndromes of uncertain aetiology. AIMS: We investigated 27 consecutive patients with varied clinical phenotypes referred to our laboratory for mtDNA studies to determine the incidence of recognised point mutations in a patient group with a range of phenotypes including many where mt disease was possible but did not fall into a classical syndrome. METHODS: The recognised point mutations were detected by amplification of the appropriate DNA fragment by PCR followed by restriction-endonuclease digestion of the normal and mutant species. RESULTS: The A-G base substitution mutation at nucleotide (nt)3243 in the tRNA(Leu) gene of mtDNA which is present in the majority of cases of MELAS syndrome, was detected in four cases, only one of whom had typical MELAS symptoms. Their clinical manifestations ranged from mild deafness to a mixture of chronic progressive external ophthalmoplegia symptoms (CPEO) and stroke like episodes. The nt3243 mutation was also identified in one of seven mtDNA deletion negative CPEO cases. CONCLUSIONS: The presentation of the mtDNA mutation at nt3243 appears therefore to be quite variable with some mild phenotypes as well as severe phenotypes observed. In general, the chance of finding a mitochondrial point mutation in a patient with an atypical clinical phenotype is small.

Adult↗
PubMed1994

Single fibre EMG studies in chronic fatigue syndrome: a reappraisal.

Single fibre EMG studies were carried out on the right extensor digitorum communis muscle in 30 subjects with chronic fatigue syndrome and in 30 age and sex matched controls. Abnormal jitter was seen in five patients with chronic fatigue syndrome. Slight but significant differences between the mean consecutive differences in the remainder of the chronic fatigue subjects and the control subjects were recorded. Overall the differences were so minor that it seems unlikely that a disturbance of neuromuscular function as reflected by jitter measurement has a pathogenetic role. It is suggested that the increased jitter seen may be explained by the effects of the variability of motor unit firing rates on the myogenic component of the jitter.

Adult↗
PubMed1994

Biopsy proven polymyositis in Victoria 1982-1987: analysis of prognostic factors.

Prognostic factors were analysed in 77 patients with idiopathic inflammatory myopathy identified over a 5 year period. Formal statistical tests did not differentiate useful prognostic indices and a polymyositis disability score was devised in an attempt to gain some prognostic information. Partial (47%) or full (31%) recovery were seen in most cases with no recovery of strength (9%) and death (11%) being less common outcomes. Onset before the age of 50 and duration of symptoms of less than 12 months prior to presentation were favourable prognostic features, and treatment with regimes other than steroid therapy alone a probable favourable indicator. Level of creatine kinase (CK) at presentation and histopathological separation of dermatomyositis or polymyositis failed to alter prognosis. Most patients who died did so within the initial 6 months of treatment. Four of five patients < 50 years old with either a fatal outcome or no improvement were treated with steroids alone. Large multi-centre studies are required to provide reliable data about prognostic factors in idiopathic inflammatory myopathies and the methodology used in this study can only be regarded as providing pointers towards possible prognostic factors rather than being definitive.

Adolescent↗