[Muscular atrophy as a symptom]. / Das Symptom Muskelatrophie.

Muscular atrophy is a symptom characterized by the loss of normal muscle mass. It is caused by a decline in the total number of muscle cells, or by a substantial decline in the substance of individual muscle cells. It has been associated with a preceding muscle weakness. Muscular atrophy occurs late in the course of a disease. Due to the limited ability of muscle cells to regenerate, it is frequently irreversible. Hence the aim is to detect the early stages of muscular decline and to prevent outright muscular atrophy. To achieve this it is necessary to be aware of the large number of diseases that can induce this in order to ensure timely referral to a specialist.

[Muscle dystrophies]. / Muskeldystrophien.

BACKGROUND: In histologic studies, the volumetric status of the intralabyrinthine fluids is judged by the position of the endolymphatic membranes. Bulging of the membranes, commonly known as endolymphatic hydrops, is assumed to be caused by excess of endolymph. The opposite situation, retraction of the membranes is, however, only incidentally described and relatively little attention has been paid to its significance. Almost one hundred years ago Wittmaack described retraction of the endolymphatic membranes, which has since been considered to be preparation artifact - a concept that essentially remains unchallenged. To test the validity of this long held premise, we examined two sets of temporal bones from different centers. MATERIAL AND METHODS: We studied the following collections: 1. The Wittmaack collection in Hamburg, Germany. The original material of 67 temporal bones (patient ages 0-92 years, average age 35.2 years) on which Wittmaack based his opinions. 2. For comparison and to exclude age related phenomena, 125 temporal bones from 73 children between the ages newborn to ten years (average age 13.4 months, median 1.5 months) from the temporal bone collection of the Department of Otolaryngology Tufts University School of Medicine. All specimens were studied by light microscopy. Retraction was defined as depression of Reissner's membrane toward the stria vascularis and the Organ of Corti in more than one cochlear turn and was graded into mild, moderate and severe. Additionally the saccule, utricle and semicircular ducts were examined for collapse. RESULTS: The reevaluation of the 67 temporal bones described by Wittmaack, including those of 7 children below the age of 10 years, showed retraction of Reissner's membrane in 81% compared to 33% of the temporal bones from the Tufts collection. In contrast to the high incidence of retraction in the cochlear duct, fewer saccules (12%) and utricles (4%) were collapsed in the Tufts collection. In the Wittmaack collection no significant differences between the underlying diseases were found, however in the Tufts collection the group of children who suffered from extracochlear infections and malignancies had a higher frequency of retraction. CONCLUSION: Mild retraction might be to some extent physiologic or even artifactual. Severe retraction, however, is a definitive finding that is a part of a local or regional otopathologic process. Of material, it is quite possible that Wittmaack's original observations of what he called "hypotonic collapse" was of viral origin (viruses were not known during Wittmaack's time), ototoxicity or even of genetic origin.

Cloning of neuronal mtDNA variants in cultured cells by synaptosome fusion with mtDNA-less cells.

Synaptosome cybrids were used to confirm the presence of heteroplasmic mtDNA sequence variants in the human brain. Synaptosomes contain one to several mitochondria, and when fused to mtDNA-deficient (rho degrees ) mouse or human cell lines result in viable cybrid cell lines. The brain origin of mouse synaptosome cybrid mtDNAs was confirmed using sequence polymorphisms in the mtDNA COIII, ND3 and tRNA(Arg)genes. The brain origin of the human synaptosome cybrids was confirmed using a rare mtDNA Mbo I polymorphism. Fusion of synaptosomes from the brain of a 35-year-old woman resulted in 71 synaptosome cybrids. Sequencing the mtDNA control region of these cybrid clones revealed differences in the number of Cs in a poly C track between nucleotide pairs (nps) 301 and 309. Three percent of the cybrid clones had mtDNAs with 10 Cs, 76% had nine, 18% had eight and 3% had seven Cs. Comparable results were obtained by PCR amplification, cloning and sequencing of mtDNA control regions directly from the patient's brain tissue, but not when the control region was amplified and cloned from a synaptosome cybrid homoplasmic for a mtDNA with nine Cs. Thus, we have clonally recovered mtDNA control region length variants from an adult human brain without recourse to PCR, and established the variant mtDNAs within living cultured cells. This confirms that some mtDNA heteroplasmy can exist in human neurons, and provides the opportunity to study its functional significance.

Processing of artificial peptide-DNA-conjugates by the mitochondrial intermediate peptidase (MIP).

Import of DNA from the cytoplasm into the mitochondrial matrix is an obligatory step for an in organello site-directed mutagenesis or gene therapy approach on mitochondrial DNA diseases. In this context, we have developed an artificial DNA translocation vector that is composed of the mitochondrial signal peptide of the ornithine transcarbamylase (OTC) and a DNA moiety. While this vector is capable of directing attached passenger molecules to the mitochondrial matrix, the recognition of this artificial molecule by the endogenous mitochondrial signal peptide processing machinery as well as the cleavage of the peptide plays a pivotal role in the release of the attached DNA. To study the proteolytic processing of the artificial vector, various signal peptide-DNA-conjugates were treated with purified mitochondrial intermediate peptidase. When the leader peptide is directly linked to the DNA moiety without an intervening spacer, MIP processing is prevented. Cleavage of the peptide can be restored, however, when the first ten amino acid residues of the mature part of OTC are appended at the carboxy-terminal end of the signal peptide. Our results show that artificial peptide-DNA-conjugates are recognized by the mitochondrial proteolytic machinery, and therefore an interference of the peptide with the DNA function can be excluded.