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Biomedical subjects

E Holme

Publications and source records attributed to E Holme.

At least 91 records · Page 5Linked to original sources
PubMed1990

Neuropathology in Kearns-Sayre syndrome.

The neuropathological changes found at autopsy in a case of Kearns-Sayre syndrome are described. We have previously analyzed the respiratory chain function in isolated muscle mitochondria and also described a large deletion of muscle mitochondrial DNA (mtDNA) in this case. The neuropathological examination revealed prominent neuronal degeneration and gliosis of the basal ganglia and there were bilateral areas of softening and total loss of nerve cells in the lenticular nuclei. The pallidum and caudate nucleus disclosed accumulation of iron-containing pigment. The white matter in the cerebrum, brain stem and cerebellum showed widespread and focally accentuated spongy change due to splitting of myelin lamellae. It is suggested that deficiency of respiratory chain enzymes due to the mtDNA deletion is of pathogenetic importance in the development of the described changes.

Adult↗
PubMed1990

3-Hydroxydicarboxylic aciduria--a fatty acid oxidation defect with severe prognosis.

We describe five patients with a suspected defect in the beta-oxidation of fatty acids characterized by a massive excretion of 3-hydroxydicarboxylic acids in the urine and accumulation of 3-hydroxy fatty acids in serum during acute illness. Long-chain and medium-chain acyl-coenzyme A dehydrogenases in fibroblasts were normal in all patients. Four of them died of cardiomyopathy and liver insufficiency at 3 to 14 months of age. Two of the patients had elder siblings who had died unexpectedly in early infancy. These patients differ from previously described patients with beta-oxidation defects.

Dicarboxylic Acids↗
PubMed1990

Metabolic effects of controlled-release metoprolol in hypertensive men with impaired or diabetic glucose tolerance: a comparison with atenolol.

In a double-blind, randomized, cross-over study with a single-blind placebo run-in period a new controlled-release (CR) formulation of metoprolol 200 mg once daily was compared with atenolol tablets 100 mg once daily in 22 patients (age 60.9 +/- 0.93 (SE) years) with primary hypertension and impaired or diabetic glucose tolerance. Each period lasted for three weeks. The two agents produced similar blood pressure 3 h as well as 24 h after drug intake. Three hours after drug intake, heart rate was lower on atenolol than metoprolol CR treatment, indicating a higher degree of beta-receptor blockade for atenolol at this point in time, when the plasma concentration of atenolol was most likely to be close to its peak. Concentrations of blood glucose, serum insulin, and serum C-peptide in the fasting state or after an oral glucose load did not differ between the active agents. HbA1c was marginally, but significantly, lower on atenolol than metoprolol CR treatment. No differences were found in serum levels of total, low density lipoprotein (LDL), and high density lipoprotein (HDL) cholesterol or apoA-I, and apoB lipoproteins or triglycerides. In comparison to the placebo run-in period, both agents showed an unexpected improvement in glucose tolerance, a decrease in HDL cholesterol and for metoprolol CR a small, but significant decrease in LDL cholesterol. Thus, treatment with metoprolol CR tablets producing even plasma levels without high peak concentrations and conventional atenolol treatment had similar effects on metabolic control in hypertensive men and abnormal glucose tolerance.

Aged↗
PubMed1990

Progressive increase of the mutated mitochondrial DNA fraction in Kearns-Sayre syndrome.

We have performed morphologic and biochemical studies in three pediatric cases of Kearns-Sayre syndrome. All cases had heteroplasmy with a high percentage of mitochondrial DNA (mtDNA) with deletion in muscle. The deletions were mapped to the same region of mtDNA but were of different sizes. The same type of deletion could also be detected in fibroblasts from all cases but the percentage was considerably lower. In two cases, an increase with time of the mutated mtDNA fraction in muscle was found and this increase paralleled the progression of the disease. Oximetric evaluation of respiratory-chain function in isolated muscle mitochondria showed a complex I deficiency in one case and was normal in the two other cases. Comparison of the fractional concentration of mtDNA with deletion in muscle and isolated mitochondria showed that the isolated mitochondria were not representative of the mitochondrial population in muscle. Mitochondria with high percentage of mtDNA with deletion were selectively lost. The finding of different mitochondrial populations is in good agreement with the morphology. One case spontaneously recovered from an infantile sideroblastic anemia before the development of Kearns-Sayre syndrome. The anemia was of the same type as that in Pearson's syndrome, a mitochondrial disorder with high amounts of mtDNA with deletion in blood cells. These findings indicate that the phenotype of a mtDNA deletion disorder can change with time and is governed by the fractional concentration of mtDNA with deletion in different tissues.

Adolescent↗
PubMed1989

Carnitine deficiency induced by pivampicillin and pivmecillinam therapy.

Short-term administration of pivampicillin and pivmecillinam resulted in a reduction of serum carnitine concentration and an increase in excretion of acylcarnitine in urine. These changes persisted for more than ten days after cessation of therapy. In seven girls on long-term treatment with a mixture of pivampicillin and pivmecillinam the mean total serum carnitine concentration fell to 15% (7-27%) of pretreatment values. The acylcarnitine fraction was 11-57% of total carnitine, compared with less than 2% before treatment. Muscle carnitine concentrations in two girls treated with the antibiotics for 22 and 30 months were only 10% of the mean reference value. These concentrations in serum and muscle are in the range encountered in patients with carnitine deficiencies of other aetiologies in which life-threatening metabolic crises may arise. The risk of adverse effects from prodrugs that give rise to pivalic acid should be seriously considered, particularly in patients under metabolic stress.

Adolescent↗
PubMed1989

Cytochrome c oxidase deficiency in infancy.

Five children with early onset of muscle weakness, lactic acidosis and deficient cytochrome c oxidase staining in the muscle biopsy were studied. By oximetric assay of the respiratory chain of isolated mitochondria, cytochrome c oxidase deficiency was confirmed in four of the cases, while one case showed only a slight decrease of cytochrome c oxidase activity but considerably reduced activity when assayed spectrophotometrically. The muscle biopsies exhibited mitochondrial structural abnormalities and lipid storage in the four cases with oximetrically confirmed cytochrome c oxidase deficiency, while the biopsy of the case with markedly reduced activity of cytochrome c oxidase only in the enzyme-histochemical and spectrophotometrical assays had normal morphology. The light microscopical staining of cytochrome c oxidase in the four cases with oximetrically confirmed deficiency showed deficient staining of the enzyme in all extrafusal fibres in three cases but one of the cases had normal enzyme-histochemical activity of cytochrome c oxidase in about 25% of the fibres. In two cases muscle spindles were included in the biopsy. The intrafusal fibres showed normal enzyme-histochemical activity of cytochrome c oxidase. Ultrastructural examination of the enzyme distribution in two of the cases revealed great heterogeneity of the mitochondria. The structurally abnormal mitochondria were usually deficient of enzyme activity. The mitochondria of endothelial cells appeared to have normal activity. Immunohistochemical staining with polyclonal antibodies to cytochrome c oxidase revealed presence of immunoreactive material corresponding to the localisation of mitochondria in all cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Biopsy↗
PubMed1989

Hydroxylation of aspartic acid in domains homologous to the epidermal growth factor precursor is catalyzed by a 2-oxoglutarate-dependent dioxygenase.

3-Hydroxyaspartic acid and 3-hydroxyasparagine are two rare amino acids that are present in domains homologous to the epidermal growth factor precursor in vitamin K-dependent plasma proteins as well as in proteins that do not require vitamin K for normal biosynthesis. They are formed by posttranslational hydroxylation of aspartic acid and asparagine, respectively. The first epidermal growth factor-like domain in factor IX (residues 45-87) was synthesized with aspartic acid in position 64, replacing 3-hydroxyaspartic acid. It was used as substrate in a hydroxylase assay with rat liver microsomes as the source of enzyme and reaction conditions that satisfy the requirements of 2-oxoglutarate-dependent dioxygenases. The synthetic peptide stimulated the 2-oxoglutarate decarboxylation in contrast to synthetic, modified epidermal growth factor (Met-21 and His-22 deleted and Glu-24 replaced by Asp) and synthetic peptides corresponding to residues 60-71 in human factor IX. This indicates that the hydroxylase is a 2-oxoglutarate-dependent dioxygenase with a selective substrate requirement.

Amino Acid Sequence↗
PubMed1988

Biotin-responsive multiple carboxylase deficiency in an 8-year-old boy with normal serum biotinidase and fibroblast holocarboxylase-synthetase activities.

An 8-year-old boy with late onset multiple carboxylase deficiency is described. Biotinidase deficiency and holocarboxylase-synthetase deficiency have been excluded. A very slow biochemical response to biotin was found. The decrease in urinary organic acid excretion followed first-order kinetics with a half-life of about 50 days. The initially low carboxylase activities in thrombocytes were increased but not normalized after 3 months of treatment.

Amidohydrolases↗
PubMed1987

Mitochondrial encephalomyopathy. A variant with heart failure and liver steatosis.

We report the clinical and autopsy findings in a young man of 18 with a chronic progressive disorder comprised of lactic acidosis, mental deterioration, and epileptic seizures which were sometimes accompanied by stroke-like episodes with transient hemiparesis and cortical blindness. He died of congestive heart failure. The autopsy showed lesions of the gray matter of the brain. Both the putamen and parieto-occipital cortex showed loss of neurons and proliferation of macrophages, astrocytes and vessels. There was marked loss of neurons in the inferior olives, and slight reduction of the number of Purkinje cells. Skeletal muscle studies revealed ragged-red fibers and structurally abnormal mitochondria. The heart was enlarged: accumulations of mitochondria occurred in the muscle fibers. The liver exhibited marked fatty degeneration. Biochemical analyses showed normal activities of pyruvate dehydrogenase in thrombocytes, pyruvate carboxylase in lymphocytes, biotinidase in serum as well as succinate dehydrogenase and cytochrome c oxidase. The features of this disorder differ in many respects from cases of mitochondrial encephalomyopathy previously reported and cannot be assigned to any specific disease entity.

Acidosis, Lactic↗
PubMed1986

Decreased C3b receptors (CR1) on erythrocytes from patients with systemic lupus erythematosus.

Using 125I-F(ab')2 anti-CR1 we have measured C3b receptors (CR1) on the erythrocytes of 56 normal individuals 26 patients with systemic lupus erythematosus (SLE) and 24 with rheumatoid arthritis (RA). The mean number of CR1 sites in SLE (1150/cell) but not RA (1460/cell) was significantly lower (P less than 0.01) than normal (2200/cell). Although the cumulative frequency curve for normals showed minor inflections at frequencies of 18% and 64%, these were not sufficiently marked to permit us to conclude that they distinguished subpopulations of different CR1 phenotypes. Measurement of CR1 numbers of two normal families and four families of SLE patients indicated that low CR1 numbers aggregated in families as did high CR1 numbers, a finding which suggests that CR1 numbers are under genetic control. However, certain observations in SLE patients indicated that low CR1 numbers could be an acquired abnormality. These included, (a) absent CR1 phenotype in a patient whose family had moderate and high CR1 numbers, (b) increasing CR1 numbers as SLE patients went into remission, (c) CR1 numbers were lower in patients with active compared with inactive disease and (d) CR1 numbers were different in each of two sets of identical twins (Fig. 4A). Our conclusions are that, (a) genetic factors probably influence CR1 numbers in normal individuals, (b) that our findings were not inconsistent with the two codominant allele models (Wilson et al., 1982), and (c) the low CR1 phenotype of SLE patients may be secondary to the disease process.

Arthritis, Rheumatoid↗
PubMed1985

Pyruvate-carboxylase deficiency with urea cycle impairment.

We report a case of pyruvate-carboxylase deficiency (EC 6.4.1.1, McKusick 26615) with neonatal onset of lactic acidosis, hyperammonemia, and citrullinemia. The patient developed signs of severe liver damage and died at 13 days of age after increasing metabolic acidosis and severe bleedings. The pyruvate-carboxylase activity in fibroblasts was less than 1% of controls, but normal activities of propionyl-CoA carboxylase (EC 6.4.1.3) and 3-methylcrotonyl-CoA carboxylase (EC 6.4.1.4) were found. To prepare for early prenatal diagnosis of pyruvate-carboxylase deficiency, the activity of the enzyme has been measured in chorionic villus samples.

Acidosis↗