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Biomedical subjects

H H Goebel

Publications and source records attributed to H H Goebel.

At least 91 records · Page 5Linked to original sources
PubMed1997

DNA-fragmentation and expression of apoptosis-related proteins in experimentally denervated and reinnervated rat facial muscle.

Muscle fibres may undergo apoptotic cell death in several neuromuscular disorders such as denervated muscle fibres in spinal muscular atrophies. We investigated DNA-fragmentation (in situ by the TUNEL-method) and expression of apoptosis-associated proteins in experimentally denervated and reinnervated rat facial muscle up to 24 weeks after surgery to evaluate the rate and time lapse of apoptotic muscle fibre loss. While denervated muscle displayed constantly high rates of DNA-fragmentation, denervated and immediately reinnervated muscle showed a distinct decrease of primarily elevated DNA-cleavage, finally resembling rates of normal controls. Denervated muscle fibres revealed strong immunoreactivity of the anti-apoptotic proteins bcl-2 and bcl-xL, and the pro-apoptotic factor bax. In reinnervated muscle fibres, only bcl-2 was constantly upregulated while bcl-xL and bax diminished after the 7th week. The present findings indicate that denervation may prompt muscle fibres to activate an intrinsic 'suicide' programme to undergo apoptosis. High levels of bcl-2 after denervation may sustain cell survival until reinnervation, e.g. after accidental nerve damage or in neurodegenerative disorders. Furthermore, increasing levels of bcl-2 are able to neutralize high apoptosis-promoting bax levels. Interventions modifying DNA-fragmentation and the expression of apoptosis-related proteins may lead to new therapeutic concepts in denervating disorders of muscle in the absence of other primary therapies.

Animals↗
PubMed1997

DNA-fragmentation and expression of apoptosis-related proteins in muscular dystrophies.

Although numerous sarcolemmal protein defects in muscular dystrophies have been identified, the mechanisms linking these defects and muscle fibre degeneration are not fully characterized. As there is evidence that apoptosis is part of muscle fibre loss in dystrophin-deficient mdx-mice, apoptotic muscle fibre death may also play a role in humans with muscular dystrophies. We investigated in-situ DNA-fragmentation by the TUNEL-method and expression of apoptosis-related proteins immunohistochemically in 14 children suffering from deficiencies of dystrophin, adhalin, and merosin, and found TUNEL-positive chromatin-cleavage of muscle fibre nuclei in about 10% of non-necrotic muscle fibres. DNA-fragmentation also occurred in groups of 'necrotic and regenerating' muscle fibres with labelling of nuclei in myogenic cells and phagocytizing macrophages. These lesions also revealed expression of apoptosis-promoting factors, such as bax and ICE, inducing cleavage of myofilaments, and of the apoptosis-inhibiting proteins bcl-XL and bcl-2 which neutralized high bax levels. Mimicking embryonal myogenesis, chromatin-fragmentation in 'necrotic and regenerating' areas seems to be part of the regulating events in muscle regeneration to eliminate excessive proliferating satellite cells. Nevertheless, macrophages are also affected by apoptosis after successful removal of necrotic fibres. In humans, DNA-fragmentation and expression of apoptosis-related proteins indicate that apoptosis plays a role in muscle degeneration and regeneration in muscular dystrophies.

Apoptosis↗
PubMed1996

Phenotype of arylsulfatase A-deficient mice: relationship to human metachromatic leukodystrophy.

Metachromatic leukodystrophy is a lysosomal sphingolipid storage disorder caused by the deficiency of arylsulfatase A. The disease is characterized by progressive demyelination, causing various neurologic symptoms. Since no naturally occurring animal model of the disease is available, we have generated arylsulfatase A-deficient mice. Deficient animals store the sphingolipid cerebroside-3-sulfate in various neuronal and nonneuronal tissues. The storage pattern is comparable to that of affected humans, but gross defects of white matter were not observed up to the age of 2 years. A reduction of axonal cross-sectional area and an astrogliosis were observed in 1-year-old mice; activation of microglia started at 1 year and was generalized at 2 years. Purkinje cell dendrites show an altered morphology. In the acoustic ganglion numbers of neurons and myelinated fibers are severely decreased, which is accompanied by a loss of brainstem auditory-evoked potentials. Neurologic examination reveals significant impairment of neuromotor coordination.

Animals↗
PubMed1996

Glucocorticoid-sensitive hereditary inclusion body myositis.

We report a hereditary muscle disorder with features of inclusion body myositis (IBM) in two adult sisters with slowly progressive asymmetrical muscle weakness. The findings of light microscopic and ultrastructural investigations of muscle biopsy specimens were consistent with a diagnosis of IBM. Both patients improved and stabilized on immunosuppressive treatment with corticosteroids and azathioprine. This differentiates our patients from other sporadic and familial cases of IBM. Clinical and histological features are described and compared with those of other previously reported families with IBM.

Female↗
PubMed1996

Immunohistochemistry of primary central nervous system malignant rhabdoid tumors: report of five cases and review of the literature.

Malignant rhabdoid tumors (MRT) are characterized by a typical light microscopic morphology with uniformly round tumor cells, vacuolated cytoplasm with occasional round, hyaline intracytoplasmic, periodic acid-Schiff-positive inclusions, vesicular nuclei with prominent nucleoli and positive immunoreactivity for vimentin. The histogenesis of MRT is controversial. Five cases of primary central nervous system (CNS) rhabdoid tumors in children are presented. Immunohistochemical, light and electron microscopic features are compared with primary CNS malignant rhabdoid tumors reported in the literature. Expression of various neurofilaments in our cases of primary CNS rhabdoid tumors was prominent and we therefore favor a neural differentiation of extrarenal intracerebral rhabdoid tumors.

Brain Neoplasms↗
PubMed1996

A mild adult myopathic variant of type IV glycogenosis.

Type IV glycogenosis is usually a rapidly progressive disease of early childhood, causing death before 4 years of age. It is characterized by hepatosplenomegaly, cirrhosis, and chronic hepatic failure. Muscle involvement is generally overshadowed by liver disease. A mild non-infantile variant of type IV glycogenosis has been described in a few patients. In some of them, the patients suffered foremost from chronic progressive myopathy. We here report on a female patient aged 51 years who had experienced difficulties in climbing stairs for 2 years due to leg weakness. EMG revealed a myopathic pattern. The muscle biopsy findings revealed polyglycosan bodies. Biochemical investigation showed absence of branching enzyme in muscle but not in leukocytes and fibroblasts.

Adult↗
PubMed1996

DNA fragmentation and BCL-2 expression in infantile spinal muscular atrophy.

Chromatin cleavage, a hallmark of apoptosis, was identified by in situ labeling in 55 +/- 7% of the muscle fibers in infantile spinal muscular atrophy (ISMA) and, to a lesser extent, in peripheral neuropathy indicating that DNA fragmentation is not specific to ISMA but a common feature in defect innervation. However, as DNA breaks are also known as a temporary process in differentiating myotubes DNA fragmentation may not always proceed to cell death. Therefore, it is currently not certain whether high rates of DNA fragmentation in ISMA are part of delayed muscle maturation due to neuronal defect or part of fibre breakdown. While atrophic muscle fibres in peripheral neuropathy displayed strong expression of bcl-2, a protein delaying onset of apoptosis, only 30% of the ISMA cases revealed weak bcl-2 expression assuming that immature muscle fibers are not able to produce a sufficient level of bcl-2.

Aged↗
PubMed1996

Macrophages in multiple sclerosis.

Macrophages are important effector cells involved in the pathogenesis of demyelination in multiple sclerosis (MS). Macrophage differentiation was studied in a series of 158 MS plaques from 43 patients obtained at different stages of the disease. Macrophages were identified by immunocytochemistry using a panel of antibodies recognizing different formalin- and paraffin-resistant macrophage activation antigens. The number of cells stained with each antibody was related to the demyelinating activity of the lesions as detected by the presence of myelin degradation products as well as to the category of MS tissue. Highest numbers of macrophages were observed in actively demyelinating and early remyelinating lesions using immunocytochemistry for the panmacrophage marker Ki-M1P. Lower numbers were encountered in inactive, demyelinated or late remyelinated lesions. The acute stage inflammatory macrophage markers MRP14 and 27E10 were selectively expressed in early and late active lesions, thus allowing the identification of actively demyelinating lesions. The chronic stage inflammatory macrophage marker 25F9, in contrast, showed a continuous expression also in inactive lesions. The different types of MS tissue revealed significant differences in their macrophage response. The most intense macrophage infiltration was seen in acute MS cases whereas lesions of early and late chronic MS showed lower macrophage levels. These findings indicate a differentiated pattern of macrophage activation in MS depending on the stage of the demyelinating activity as well as on the category of MS tissue. Furthermore, these macrophage markers give new parameters for staging the inflammatory and demyelinating activity of MS lesions.

Acute Disease↗
PubMed1996

The neuronal ceroid-lipofuscinoses.

The neuronal ceroid lipofuscinoses (NCL) are a relatively frequent group of progressive neurodegenerative disorders in children with similar, but not identical, clinical and morphological features, entailing different clinical groups, some of which have been found to represent different genetic entities, ie, infantile (INCL) or CLN1, late-infantile (LINCL) or CLN2, juvenile (JNCL) or CLN3, and a Finnish variant of LINCL or CLN5. Within the clinical pentad are included seizures, motor disturbances, visual impairment, dementia, and familial occurrence in an autosomal-recessive fashion. The ultrastructure of accruing lipopigments is diagnostically required to recognize an individual patient's NCL by showing granular lipopigments in INCL, curvilinear profiles (with or without fingerprint profiles) in LINCL and fingerprint profiles (with or without curvilinear profiles) in JNCL. Identification of genes for INCL and JNCL, together with electron microscopy in LINCL, allows safe prenatal diagnosis which is still impossible by biochemical techniques, unlike other lysosomal disorders. However, both cause and pathogenesis of the individual forms of NCL are still unknown, and therapy is gravely insufficient.

Adolescent↗
PubMed1996

Dystrophinopathies.

The discovery of the subsarcolemmal muscle fiber protein dystrophin has, to a certain extent, replaced former nosological terms of Duchenne (DMD) and Becker (BMD) muscular dystrophies by the term dystrophinopathies. The immunohistochemical and Western blot analysis of dystrophin has not only enlarged the clinical spectrum of dystrophinopathies, but has also made carrier detection of DMD more reliable, particularly in manifesting carriers without family history. Moreover, prenatal muscle biopsy, under selected circumstances, can show presence or absence of dystrophin, ie, in the latter case an affected male fetus. Molecular genetics have provided a wealth of genetic details in the dystrophinopathies, but therapy has not yet succeeded to a similar extent, on the contrary, myoblast transplantation has not resulted in any clinical improvement.

Adolescent↗
PubMed1996

Congenital myopathies.

The congenital myopathies (CM) are a group of non or little progressive neuromuscular conditions, often hereditary, delineated by morphological techniques, ie, enzyme histochemistry and electron microscopy. The catalogue of CM entailing well known "classic" conditions as central core disease, nemaline myopathy, and centronuclear myopathy has continuously been expanded, now comprising some 40 conditions. Nosologic advances have occurred with immunohistochemical techniques that show generalized or focal protein abnormalities within muscle fibers of certain CM, but at much slower pace as to localization of CM genes. So far, only those for central core disease, nemaline myopathy, and myotubular myopathy have been reported. Epidemiological rarity and nosographic controversy of CM have contributed to this lack of molecular genetic progress in CM.

Adolescent↗
PubMed1996

Normal superoxide radical production in the neuronal ceroid-lipofuscinoses.

The neuronal ceroid-lipofuscinoses (NCL) are a group of inherited progressive encephalopathies. Striking histomorphological feature of the NCL is the accumulation of storage material within the lysosomes in neural and extraneural cells. The basic underlying defect causing the disease is not known. Presupposing a disturbance in lipid peroxidation, some authors recommend antioxidant treatment to slow down the progression of the disease. In this study, the superoxide radical production of polymorphonuclear leukocytes as one potential source of reactive oxygen species was measured in this disorder for the first time. No significant difference in this production between affected individuals and healthy controls could be detected. Our findings cast doubt on the therapeutic benefit of antioxidant treatment.

Adolescent↗
PubMed1996

Cytokine expression profile in idiopathic inflammatory myopathies.

Cytokines have been shown to be potent inducers of major histocompatibility complexes (MHC) class I and II as well as of cell adhesion molecules in muscle tissue cultures, indicating that cytokines may play a role in mediating muscle fiber damage in inflammatory myopathies. We found in 21 cases of autoimmune myositis various amounts of inflammatory cells expressing interleukin (IL)-1 alpha and -beta, IL-2, IL-4, tumor necrosis factor (TNF) -alpha and -beta, and interferon (IFN)-gamma and its receptor. Muscle fibers displayed enhanced expression of IL-1 alpha and -beta, IL-2, and TNF-alpha. Upregulation of cytokines was strongest at sites of cellular infiltration typical for the respective myositis subtype. There was no correlation between the cytokine expression and the grade of inflammation. To a lesser extent, cytokines were also present in Duchenne muscular dystrophy expressed by muscle fibers positive for TNF-alpha and by phagocytic mononuclear cells. Expression of cytokines by the muscle fiber may enable the muscle fiber to induce and mediate the process of autoimmunization and antigen-expression by itself without primary presence of inflammatory cells. Cytokine-expressing muscle fibers may enhance the cytolytic potential of cytotoxic cells and the muscle fiber may serve as source and target.

Cytokines↗
PubMed1996

Inflammatory myopathies.

As well as myositis caused by infectious agents, there is a spectrum of inflammatory myopathies representing diseases with autoimmune response. Subtypes differing in clinical features and morphological characteristics have been described. This review will emphasize new advances and recent efforts to identify pathogenetic mechanisms and immunological mediators of autoimmune myopathies.

Autoantibodies↗
PubMed1996

Neuronal ceroid-lipofuscinosis--late-infantile or Jansky-Bielschowsky type--revisited.

The tissues from three patients with late-infantile NCL originally described by Max Bielschowsky became available to apply modern techniques such as fluorescence microscopy, electron microscopy and immunohistochemistry. While regular tinctorial preparations of the tissues documented a neuronal storage disorder in all three patients' tissues, the accumulated material proved to be autofluorescent, showed the ultrastructure of curvilinear lipopigments, and reacted strongly with an antibody against the subunit-C of mitochondrial ATP synthase, a major component of lipopigments in NCL and also with an antibody against sphingolipid activator proteins. Thus, these modern morphological techniques demonstrated that the originally described three siblings with late-infantile "amaurotic familial idiocy" really had neuronal ceroid-lipofuscinosis of the late-infantile or Jansky-Bielschowsky type, according to current diagnostic criteria. This type of archival study may also contribute to the mosaic of medical history.

Brain↗
PubMed1996

Tenascin in denervated human muscle.

Tenascin is a large oligomeric glycoprotein of the extracellular matrix. Its location is innervated muscle tissues. We investigated immunohistologically, using two monoclonal antibodies (mah) against Tenascin, biopsied denervated human muscle of children and adults. Tenascin was present in the interstitial space among denervated muscle fibres. Accumulation of Tenascin in denervated adult muscle tissue was frequent, accumulation in denervated muscle tissue of children was sparse and weak. The two antibodies reacted correspondingly. Tenascin was not only found in the vicinity of atrophic muscle fibres, but also close to normally sized fibres, suggesting an early stage of denervation even before reduction of muscle fibre volume.

Adult↗