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Biomedical subjects

H Reichmann

Publications and source records attributed to H Reichmann.

At least 127 records · Page 7Linked to original sources
PubMed1995

1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline, a new inhibitor of complex I.

The neurotoxic agent MPP+ is an artificial substance producing a syndrome very similar to that of idiopathic Parkinson's disease. There are also naturally occuring neurotoxic substances under discussion like the group of isoquinoline and beta-carboline alkaloids. All these substances are more or less powerfull inhibitors of complex I of the mitochondrial oxidative phosphorylation. This study examined the effect of 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo), a putative in vivo condensation product of chloralhydrate and tryptamine, on the oxidative phosphorylation system compared to MPP+. Similar to MPP+, TaClo inhibits only the electron transfer from complex I towards ubiquinone. Demonstrating a 10-times more effective inhibition than MPP+, complex I activity is fully inhibited by 800 microM TaClo in brain homogenates and submitochondrial particles. By extending the preincubation time from 5 to 30 min complex I is already inhibited by 400 microM TaClo. Other derivates of TaClo as N-methyl-TaClo demonstrate an even greater inhibitory effect on complex I and especially on complex II activities.

1-Methyl-4-phenylpyridinium↗
PubMed1995

Long-term behavioural effects of TaClo (1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline) after subchronic treatment in rats.

1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo), which shows a great structural similarity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), when administered to rats lead to enhanced spontaneous locomotion when they were tested 4-9 days after subchronic injection at a daily dose of 0.2 mg/kg over a seven week period. However, 9 weeks after the end of the course of injections animals walked more slowly during 12 hours of nocturnal activity, and apomorphine-induced locomotion was decreased 12 weeks later. These results suggest that the drug may exert a progressive neurotoxic effect.

Analysis of Variance↗
PubMed1994

Chronic progressive external ophthalmoplegia is associated with a novel mutation in the mitochondrial tRNA(Asn) gene.

Chronic progressive external ophthalmoplegia (CPEO) is caused by a decreased oxidative phosphorylation (OXPHOS) activity due to large-scale deletions of the mitochondrial genome in 50% of the patients. The deletions encompass structural OXPHOS genes as well as tRNA genes, required for their expression so that the pathogenesis could be due to the deleted OXPHOS subunits or to an impaired mitochondrial translation. We have analyzed the mitochondrial genome of a patient presenting with CPEO for single base substitutions and discovered a novel heteroplasmic mutation in the tRNA(Asn) gene at position 5692 that converts a highly conserved adenine into a guanine. This mutation is unique because it is located at the transition of the anticodon loop to the anticodon stem and it leads to an additional base pair, thus reducing the number of loop-forming nucleotides from seven to five. Our findings suggest that CPEO can be caused by a single base substitution in a mitochondrial tRNA gene so that the mitochondrial protein synthesis becomes the rate limiting step in OXPHOS fidelity.

Base Sequence↗
PubMed1994

A rapid and sensitive PCR screening method for point mutations associated with mitochondrial encephalomyopathies.

Alterations of the mitochondrial DNA, encoding important parts of the cellular energy-generating system (oxidative phosphorylation, OXPHOS), are often associated with the occurrence of degenerative neuromuscular diseases. Especially point mutations in the mitochondrial tRNA genes, which cannot be complemented by the nuclear encoded tRNAs, are candidates for severe defects of the OXPHOS system. An A to G transition at nt 8344 in the tRNA(Lys) gene has been associated with MERRF disease whereas an A to G substitution at nt 3243 in the tRNA(Leu) gene has been linked to the MELAS syndrome. These two mtDNA alterations as well as point mutations in protein-coding genes can be detected simultaneously by an allele-specific amplification of the altered mtDNA. This assay allows the reliable detection of heteroplasmic point-mutations, even if the mutated DNA appears to a small extent of less than 1%.

Alleles↗
PubMed1994

Unaltered aconitase activity, but decreased complex I activity in substantia nigra pars compacta of patients with Parkinson's disease.

Substantia nigra pars compacta of seven patients who had died of Parkinson's disease, has been investigated for the iron-depending aconitase (reactions I and II). In addition we analysed respiratory chain enzymes. While complex I activity of the respiratory chain was significantly reduced, other enzymes of this pathway were unaltered. The citric acid cycle enzyme aconitase (reactions I and II) showed no difference between patients and controls. Thus this ferrous iron dependent and oxidatively sensitive enzyme is not affected by the unphysiological high amount of ferric iron and the 'oxidative stress' present in substantia nigra of parkinsonian patients.

Aconitate Hydratase↗
PubMed1994

Effect of lipoic acid on redox state of coenzyme Q in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and diethyldithiocarbamate.

We investigated the effects of a combined treatment of male C57Bl/6 mice with diethyldithiocarbamate and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the absence or presence of different forms of lipoic acid (Thioctacid TR; commonly used for treatment of diabetic polyneuropathies) on levels and redox states of alpha-tocopherol and coenzyme Q in vivo and on activities of various enzymes of energy metabolism ex vivo. Treatment of mice with diethyldithiocarbamate plus MPTP resulted in a decrease in dopamine (67%) and its major metabolites dihydroxyphenylacetic acid (38%) and homovanillic acid (37%) in striatum. alpha-Tocopherol levels were unaltered in striatum; however, the reduced forms of coenzyme Q were decreased in frontal cortex and hippocampus following diethyldithiocarbamate plus MPTP. In frontal cortex activity of NADH dehydrogenase was significantly inhibited by diethyldithiocarbamate plus MPTP ex vivo, suggesting that the neurotoxic metabolite of MPTP, 1-methyl-4-phenylpyridinium ion, is acting in brain regions other than striatum as well. Lipoic acid, administered 6 times, each at 90 min prior to MPTP, could not restore dopamine in striatum but in contrast maintained a normal ratio of the reduced form to the oxidized form of coenzyme Q, suggesting an interaction of lipoic acid with energy metabolism which seems, however, not only to be due to an activation of pyruvate dehydrogenase.

Animals↗
PubMed1994

Respiratory chain and mitochondrial deoxyribonucleic acid in blood cells from patients with focal and generalized dystonia.

An increasing number of neurodegenerative diseases seem to be associated with or even due to disturbances of cerebral energy metabolism. One generally accepted example is complex I deficiency in substantia nigra from patients with Parkinson's disease. Reports on a complex I defect in platelets from patients with dystonia led us to check for disturbances of the respiratory chain or of the mitochondrial genome in isolated mitochondria from patients with focal or generalized dystonia. We could not confirm the idea of mitochondrial disturbance in platelets from patients with dystonia because we did not find abnormal enzyme activities or any deletions of the mitochondrial genome. Thus, we do not think that blood cells such as platelets can serve as markers for neurodegenerative disorders such as dystonia.

Adult↗
PubMed1994

Impaired degradation of phytanic acid in cells from patients with mitochondriopathies: evidence for the involvement of ETF and the respiratory chain in phytanic acid alpha-oxidation.

Phytanic acid alpha-oxidation was studied in cultures of skin fibroblasts and myoblasts from patients with various defects of the respiratory chain in order to obtain information on the subcellular site and the mechanism of this pathway. In fibroblasts from patients with complex IV (cytochrome c oxidase) deficiency or glutaricaciduria type II, phytanic acid alpha-oxidation was reduced to 14% of normal, whereas in myoblasts from patients with complex I (NADH-Q reductase) deficiency, it was normal. Apparently, at least one step of phytanic acid alpha-oxidation occurs in mitochondria and in this process electrons are transferred to the respiratory chain via the electron-transfer flavoprotein (ETF).

Cells, Cultured↗
PubMed1994

A 400-kb tandem duplication within the dystrophin gene leads to severe Becker muscular dystrophy.

We describe a family with a large duplication of exons 2-16 of the dystrophin gene. It was characterized by immunocytochemistry, field-inversion gel electrophoresis and quantitative Southern blots. Our observations are of clinical interest in that they demonstrate an intermediate disease course despite a disrupted reading frame of dystrophin as postulated from exon-intron boundaries. We discuss possible mechanisms which may explain the unusual phenotype in our patient.

Adult↗
PubMed1994

Immunochemical quantification of sarcoplasmic reticulum Ca(2+)-ATPase and calsequestrin in muscle biopsies from patients with myotonia congenita and paramyotonia congenita Eulenburg.

A sensitive enzyme-linked immunoadsorbant assay was developed to quantify Ca(2+)-ATPase and calsequestrin from sarcoplasmic reticulum in human muscle biopsies. Tissue levels of Ca(2+)-ATPase and calsequestrin averaged 51.5 +/- 28.1 and 6.4 +/- 1.8 mg/g muscle protein, respectively, in control muscles (means +/- SD, n = 12). The high sensitivity and specificity of the antibodies make the assay a useful tool in the diagnosis of human neuromuscular disorders where defects in sarcoplasmic reticulum function may be expected. The assay was applied to muscle biopsies from patients with myotonia congenita and paramyotonia congenita Eulenburg. The calsequestrin concentration was normal in all patient muscles. The Ca(2+)-ATPase content was also within the normal range but varied considerably with the percentage distribution of slow-twitch fibres. This indicates that the prolonged relaxation observed in the muscles of patients with these disorders is not caused by faulty expression of Ca(2+)-ATPase and calsequestrin.

Adolescent↗
PubMed1994

Atraumatic needle reduces the incidence of post-lumbar puncture syndrome.

We investigated the occurrence of the post-lumbar syndrome (PPS) in relation to the puncture technique used, in a prospective randomised double-blind study comprising 100 patients. A new atraumatic 22-gauge cannula was compared with a 20-gauge cannula with a Quincke bevel. The atraumatic cannula is a needle with a tip shaped like a closed circular cone with a lateral opening, usually used with an outer cannula (introducer). The study showed that both the frequency of PPS and of acute complaints during lumbar puncture can be dramatically reduced with the atraumatic puncture technique. A marked PPS occurred after lumbar puncture with the 20-gauge cannula in 31% of patients, whereas only 5% of patients reported marked post-puncture symptoms after lumbar puncture with the atraumatic cannula.

Adult↗
PubMed1994

Multisystem triglyceride storage disorder without ichthyosis in two siblings.

A four-year-old boy presented with hepatomegaly, vacuolized granulocytes (Jordans' anomaly) and slightly progressive myopathy as signs of multisystem triglyceride storage disease. The nine-year-old sister of the patient also showed Jordans' anomaly and early fatigability, but no overt weakness. Biochemical analysis revealed normal values for carnitines, carnitine palmityl transferase in serum and striated muscle, and beta-oxidation enzymes in striated muscles. Distribution of non-membrane-bound lipids in granulocytes, fibroblasts, smooth muscle cells and striated muscle was compatible with Chanarin-Dorfman syndrome. In contrast to Chanarin-Dorfman syndrome, our patients lacked congenital ichthyosis.

Child↗
PubMed1994

Carnitine analysis in normal human red blood cells, plasma, and muscle tissue.

We studied the distribution of carnitine in different compartments of the human body. Esterified and nonesterified carnitine was determined in plasma, red blood cells, and muscle tissue of 25 patients with clinically and biochemically normal carnitine metabolism. We found a close correlation of plasma and muscle carnitine, but carnitine in red blood cells seems to represent a carnitine compartment of its own. It is probably less related with fatty acid metabolism of the mitochondria than with cell membrane stabilization or buffer function for Na-K-ATPase.

Adult↗
PubMed1994

Single muscle fibre analyses in 2 brothers with succinate dehydrogenase deficiency.

We report 2 brothers with hypertrophic cardiomyopathy, lipid storage and skeletal mitochondrial myopathy. Biochemical analyses detected complex II (succinate dehydrogenase) deficiency of the respiratory chain. Single fiber analyses using a microphotometer were performed and revealed reduced succinate dehydrogenase activity in all muscle fibers. This report shows the validity of kinetic microphotometric analysis in revealing complex II defects.

Adult↗
PubMed1994

Unaltered respiratory chain enzyme activity and mitochondrial DNA in skeletal muscle from patients with idiopathic Parkinson's syndrome.

There is good evidence that patients with Parkinson's disease have respiratory chain dysfunction in their substantia nigra. Since mitochondrial cytopathies due to enzyme defects in the respiratory chain are predominantly manifested in tissues with a high oxidative metabolism we analyzed oxidative energy metabolism in skeletal muscle from 6 patients with Parkinson's disease. Control muscles were from subjects of the same age group. Histological and histochemical analyses showed no morphological abnormalities found in mitochondrial myopathies. Biochemical analyses of the various complexes of the respiratory chain were normal. Since 13 subunits of complexes I, III, IV and V of the respiratory chain are encoded by the mitochondrial genome we performed Southern blot and PCR analyses in skeletal muscle from patients and controls and found no disease-specific increase in deletions or insertions of the mitochondrial genome. Therefore, we do not think that skeletal muscle reflects the mitochondrial disturbance in Parkinson's disease found in the substantia nigra.

Aged↗
PubMed1994

Gasoline vapors induce severe rhabdomyolysis.

A young patient developed rhabdomyolysis after accidentally inhaling gasoline vapors. Although there had been no preexistent myopathy, the caffeine and halothane contracture test classified the patient as being malignant hyperthermia-susceptible (MHS). Abnormal contractures also occurred after exposure of muscle bundles to benzine (at 0.01%); in four control tests, benzine-induced contractures (at 0.1%) could be elicited in MHS, but not in normal, muscles. The complex composition of benzine seems to contain potentially hazardous agents that trigger MH.

Adult↗
PubMed1994

Multiple symmetric lipomatosis: abnormalities in complex IV and multiple deletions in mitochondrial DNA.

Multiple symmetric lipomatosis (MSL) is a rare disorder of middle life characterized by large nonencapsulated lipomas distributed around the neck, shoulders, and other axial regions. Neurologic involvement, particularly peripheral neuropathy, is frequent. The pathogenesis of the syndrome is still unknown, but ragged-red fibers are occasionally present in muscle of affected patients, suggesting a mitochondrial abnormality. We studied 11 unrelated patients with MSL by means of neurophysiology, muscle morphology, muscle biochemistry, Southern blot, and PCR analysis of mitochondrial DNA. All patients were men aged 41 to 63 years. Clinical or electrophysiologic signs of a sensorimotor polyneuropathy were present in nine patients, eight of whom had a history of alcoholism. In muscle biopsy specimens, the most prominent feature was pathologic subsarcolemmal aggregates of mitochondria. Biochemical analysis of respiratory chain enzymes revealed a moderate but significant decrease of cytochrome c oxidase activity as compared with age-matched controls. In one patient, Southern blot analysis showed multiple deletions of mitochondrial DNA. We conclude that mitochondrial dysfunction is common in MSL and may be based on identifiable defects in the mitochondrial genome.

Adult↗