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Biomedical subjects

M Naumann

Publications and source records attributed to M Naumann.

At least 19 recordsLinked to original sources
PubMed1995

Neurological multisystem manifestation in multiple symmetric lipomatosis: a clinical and electrophysiological study.

Multiple symmetric lipomatosis (MSL) is characterized by a typical neck and shoulder distribution of subcutaneous lipomata and is often associated with polyneuropathy. Occasionally, the central nervous system (CNS) can be involved. Twelve of 14 patients in this retrospective study had clinical or electrophysiological evidence of a predominantly axonal polyneuropathy. Among those were 10 with alcohol abuse, but 2 patients without alcohol abuse also showed clinical or electrophysiological polyneuropathy. Clinical CNS involvement was present in 4 patients. CNS dysfunction was documented by evoked potentials in 8 subjects [prolonged latency or low amplitude of the motor response following cortical magnetic stimulation (4 patients), abnormal visually evoked potentials (4 patients) or somatosensory evoked potentials (SEP) (4 patients)]. These findings were compared to 10 chronic alcoholics without clinical signs of MSL. Five of these showed mild sensory neuropathy. Additionally, 2 also had delayed SEP latencies. Motor evoked potentials were normal in all controls. We propose that the multisystem involvement in MSL demonstrated here cannot be attributed to alcohol abuse alone. Biochemical studies have suggested mitochondrial dysfunction as the basis of the widespread neurological pathology in MSL.

Adult↗
PubMed1995

Mitochondrial dysfunction in adult-onset myopathies with structural abnormalities.

Three patients with chronic progressive external ophthalmoplegia of adult-onset, generalized muscle atrophy and myalgia are described. Two patients fulfilled the histological criteria for centronuclear myopathy, the third those for fiber-type disproportion. Additionally, typical ragged red fibers were found in all muscle specimens, and several muscle fibers were cytochrome c oxidase negative. NADH and succinate dehydrogenase stains showed increased subsarcolemmal accumulation of mitochondria. To determine whether these findings are coincidental or whether they indicated an additional mitochondrial disorder, all patients were investigated using biochemical analysis of the respiratory chain, molecular genetics, magnetic resonance spectroscopy of quadriceps muscle and ergometry. These tests suggested an additional mitochondrial dysfunction. Mitochondrial dysfunction seems to be more common in this group of myopathies than previously estimated, and may be of importance in the pathogenesis of these disorders.

Adult↗
PubMed1995

Sarcoid myopathy and mitochondrial respiratory chain defects: clinicopathological, biochemical and molecular biological analyses.

We report on a 33-yr-old female patient with myalgia, CK values up to 3500 Ul-1 and proximal weakness. An initial muscle biopsy showed myositis. One year later an enlarged lymph node was investigated and sarcoidosis diagnosed. In a second muscle biopsy inflammatory cells and morphological characteristics of mitochondrial myopathy were found. Biochemical analyses indicated a 50% reduction in complex II activity of the respiratory chain. Due to failure in clinical improvement a third muscle biopsy was performed in 1990 where only 19% of normal complex II activity was present. Southern blot analysis of the mitochondrial genome was normal. Thus for the first time we describe a patient with sarcoid myopathy and a complex II deficiency. Our interpretation is that a pre-existing complex II defect became clinically relevant because of additional sarcoid myopathy.

Adult↗
PubMed1994

Activation of NF-kappa B in vivo is regulated by multiple phosphorylations.

The activation of nuclear factor kappa B (NF-kappa B) in intact cells is mechanistically not well understood. Therefore we investigated the modifications imposed on NF-kappa B/I kappa B components following stimulation and show that the final step of NF-kappa B induction in vivo involves phosphorylation of several members of the NF-kappa B/I kappa B protein families. In HeLa cells as well as in B cells, TNF-alpha rapidly induced nuclear translocation primarily of p50-p65, but not of c-rel. Both NF-kappa B precursors and I kappa B alpha became strongly phosphorylated with the same kinetics. In addition to the inducible phosphorylation after stimulation, B lymphocytes containing constitutive nuclear NF-kappa B revealed constitutively phosphorylated p65 and I kappa B alpha. Phosphorylation was accompanied by induced processing of the precursors p100 and p105 and by degradation of I kappa B alpha. As an in vitro model we show that phosphorylation of p105 impedes its ability to interact with NF-kappa B, as has been shown before for I kappa B alpha. Surprisingly, even p65, but not c-rel, was phosphorylated after induction in vivo, suggesting that TNF-alpha selectively activates only specific NF-kappa B heteromers and that modifications regulate not only I kappa B molecules but also NF-kappa B molecules. In fact, cellular NF-kappa B activity was phosphorylation-dependent and the DNA binding activity of p65-containing NF-kappa B was enhanced by phosphorylation in vitro. Furthermore, we found that the induction by hydrogen peroxide of NF-kappa B translocation to the nucleus, which is assumed to be triggered by reactive oxygen intermediates, also coincided with incorporation of phosphate into the same subunits that were modified after stimulation by TNF-alpha. Thus, phosphorylation appears to be a general mechanism for activation of NF-kappa B in vivo.

B-Lymphocytes↗
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

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↗
PubMed1994

Neuroprotection by dopamine agonists.

Research on Parkinson's disease has led to new hypotheses concerning the mechanisms of neurodegeneration and to the development of neuroprotective agents. Recent findings of impaired mitochondrial function, altered iron metabolism and increased lipid peroxidation in the substantia nigra of parkinsonian patients emphasize the significance of oxidative stress and free radical formation in the pathogenesis of Parkinson's disease. Present research is therefore focussing on improvements in neuroprotective therapy to prevent or slow the rate of progression of the disease. Possible neuroprotective strategies include free radical scavengers, monoamine oxidase-B inhibitors, iron chelators and glutamate antagonists. Recent studies point to the possibility of achieving neuroprotection in ageing and parkinsonism by the administration of dopamine agonists. In the rat, the dopamine agonist pergolide appears to preserve the integrity of nigrostriatal neurones with ageing. The prevention of age-related degeneration may be achieved as a result of a decreased dopamine turnover and reduced conversion of dopamine to toxic compounds. In our own study, bromocriptine treatment prevented the striatal dopamine reduction following MPTP administration in the mouse. These results suggest that the neurotoxic effects of MPTP can be prevented by bromocriptine. Monotherapy with the dopamine agonist lisuride in the early stages of Parkinson's disease delays the need for the initiation of levodopa treatment to a similar extent as has been reported for L-deprenyl. It remains to be shown whether this is due to neuroprotective efficacy of the dopamine agonist or to a direct symptomatic effect.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1993

[Is chronic dermato- or polymyositis misdiagnosed as "weakness of old age"?].

Two women, aged 72 (case 1) and 77 (case 2) were referred for neurological diagnosis because of progressive muscular weakness, for 4 and 18 months, respectively, which had finally led to dysphagia and required mechanical ventilation. The cause of the disease in case 1 was classical dermatomyositis. Creatinine kinase concentration, never previously measured, was 950 U/l. In case 2 there was polymyositis, previously not considered as she had a diabetic polyneuropathy and muscle enzyme concentration was normal. In both cases the correct diagnosis was speedily confirmed by electromyography and muscle biopsy. Immunosuppressive treatment was largely successful in reversing the symptoms (case 1: initially 500 mg methylprednisolone daily, reduced to 50 mg daily within 6 weeks; case 2: 500 mg methylprednisolone daily for 1 week, then 100 mg daily plus 150 mg azathioprine with maintenance dosage of 20 mg glucocorticoid daily).--These two cases demonstrate that, particularly in the elderly, dermatomyositis and polymyositis should be considered in the differential diagnosis of progressive general weakness.

Aged↗
PubMed1993

Common structural constituents confer I kappa B activity to NF-kappa B p105 and I kappa B/MAD-3.

The vertebrate NF-kappa B/c-rel inhibitors MAD-3/I kappa B alpha, I kappa B gamma/pdI and bcl-3 all share a conserved ankyrin repeat domain (ARD) consisting of six complete repeats, a short acidic motif and/or an incomplete seventh repeat. We present here a detailed analysis of the domain in p105/pdI and MAD-3/I kappa B involved in inhibition of DNA binding and in protein interaction with rel factors. We demonstrate that in both cases an acidic region and six ankyrin-like repeats are sufficient and required for protein interaction with the rel factors. However, for p105/pdI to achieve the high affinity needed to suppress DNA binding, an incomplete seventh repeat is required in addition. Both pdI and MAD-3 associate with rel proteins by forming heterotrimeric complexes, as shown by native gel analysis and by cross-linking. Furthermore, we demonstrate that deletion of only three amino acids in the first repeat converts the subunit specificity of the p105 ARD into that of MAD-3/I kappa B. We conclude that functionally the ARD in these molecules has a modular structure, with different subregions determining the specificity for the NF-kappa B subunits p50 and p65.

Amino Acid Sequence↗
PubMed1993

Focal myositis of the temporal muscle.

Focal myositis is a rare inflammatory disease of the skeletal muscle that may involve any part of the body. We present a 19-year-old man with a short history of a painful pseudotumor in the right temporal region. MRI pictures showed a swollen right temporal muscle and muscle biopsy revealed the characteristic histological and immunocytochemical findings of polymyositis.

Adult↗
PubMed1993

Progression of myopathology in Kearns-Sayre syndrome: a morphological follow-up study.

We report on the progression of myopathology by comparing two biopsies from a patient with a Kearns-Sayre-Syndrome. The first biopsy was taken in 1979 and showed 10% ragged-red fibers. Myopathic changes were slight including internal nuclei and fiber splitting in 10% of the fibers. Electron microscopy revealed typical mitochondrial abnormalities with regard to number and shape. In 1989 a second biopsy was performed for an extended analysis of mitochondrial DNA. This time less than 5% of all fibers were ragged-red. Severe myopathic changes could be detected which so far has rarely been reported in mitochondrial cytopathy.

Blotting, Southern↗
PubMed1993

Comparative study of histopathological alterations during intestinal infection of mice with pathogenic and non-pathogenic strains of Yersinia enterocolitica serotype O:8.

Yersinia enterocolitica is an invasive pathogen capable of causing a wide spectrum of gastrointestinal diseases in man. While there is a considerable body of data on the invasiveness of Y. enterocolitica in vitro, little is known about the events in vivo leading to the translocation of the bacteria from the intestinal lumen into the ileal tissue. There is no detailed ultrastructural information describing the course of infection of pathogenic Y. enterocolitica in comparison with an avirulent strain. We compared a virulent plasmid-bearing strain and an isogenic avirulent plasmid-free derivative strain of Y. enterocolitica serotype O:8 at the ultrastructural level, in the established model of murine yersiniosis. At 12 h post-inoculation we found no indications of an active invasion of the intestinal epithelium, although microcolonies of the pathogenic strain were detectable closely under the follicle-associated epithelium of the Peyer's patches. The plasmid-bearing strain of Y. enterocolitica affected the gut-associated lymphoid tissue which was destroyed 36 h post-infection. Unlike the pathogenic strain of Y. enterocolitica, the nonpathogenic plasmid-free strain caused no detectable morphological alterations in the ileal tissue by this time. Morphological evidence is provided that Yersinia does not invade the ileal epithelium in an active manner, as has been observed in vitro, but appears to be transported across the epithelial barrier by M-cells.

Animals↗
PubMed1993

Immunological analysis of the plasmid-encoded proteins from the highly pathogenic Yersinia enterocolitica serogroup O8 and the less pathogenic serogroup O3.

The plasmid-encoded proteins of the pathogenic Yersinia enterocolitica serogroups O3 and O8 were analysed with respect to their immunological relationship. Common epitopes on yersinia outer-membrane proteins (YOPs) and released proteins (RPs) were recognised by orally-induced antisera against living bacteria and by monospecific antisera induced against single RPs of Y. enterocolitica serogroup O8. A major difference between the pathogenic serogroups O3 and O8 was YOP42, which was detected only in the outer membrane of the highly pathogenic O8+ bacteria. The YOP42 may be responsible for the greater virulence of serogroup O8 bacteria.

Animals↗
PubMed1993

NF-kappa B precursor p100 inhibits nuclear translocation and DNA binding of NF-kappa B/rel-factors.

The NF-kappa B precursor p100 (lyt-10, p97, p98) generates after proteolytic processing a 52 kDa subunit, which can bind to kappa B-motifs. A deregulated form of the p100 gene, which is structurally altered by a t(10;14) translocation, has a potential oncogenic role in certain human B cell lymphomas. In this study p100 was analysed for its ability to interact with its own processing product p52, with p50, the product of the NF-kappa B precursor p105, and with other NF-kappa B/rel-proteins. As demonstrated by a combination of Western blot analysis, band shift analysis and indirect immunofluorescence labelling of transfected cells, p100 itself was localized in the cytoplasm and indiscriminately retained each co-expressed NF-kappa B subunit. Thereby it simultaneously inhibited their DNA binding activities. Thus, a major function of p100 is, like p105, to associate with subunits of the rel multigene family in the cytoplasm in an I kappa B-like fashion. The similarity between p100 and p105 is also reflected by equivalent protein interactions of their processing products: like NF-kappa B-p50, also NF-kappa B-p52 heteromerised promiscuously with all rel-factors tested. Moreover, p52 efficiently interacts with the candidate oncogene product Bcl-3 and also binds to the basic-leucine zipper protein NF-IL6.

Amino Acid Sequence↗
PubMed1992

Candidate proto-oncogene bcl-3 encodes a subunit-specific inhibitor of transcription factor NF-kappa B.

The NF-kappa B subunits p50 and p65 and the product of the rel proto-oncogene are members of a growing class of transcription factors with a unique DNA-binding and dimerization domain. Nuclear transfer of each of these factors is controlled by cytoplasmic inhibitors, and regulated by specific stimuli. The inhibitors I kappa B-alpha and -beta and pp40 recognize either p65 or the c-rel protein. We show here that the proto-oncogene bcl-3, believed to be involved in certain human B-cell leukaemias, encodes a protein that functions as an I kappa B-like molecule for native NF-kappa B but is specific for the p50 subunit. The ankyrin repeat domain of the bcl-3 product is shown to mediate complex formation with NF-kappa B dimers by contracting the conserved dimerization domain of NF-kappa B.

B-Cell Lymphoma 3 Protein↗