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H Schmalbruch

Publications and source records attributed to H Schmalbruch.

At least 37 records · Page 2Linked to original sources
PubMed1996

Electromyographical and motor performance studies in the pmn mouse model of neurodegenerative disease.

The mouse autosomal recessive mutation progressive motor neuronopathy (pmn) results in early onset motor neuron disease with rapidly progressive hindlimb paralysis, severe muscular wasting, and death at around 6 weeks of age. This mutant provides opportunities for testing novel therapeutic strategies, including the administration of trophic factors, to prevent the degeneration of diseased neurons. The construction of a strain expressing the pmn and the Extra-toe (Xt) phenotypes allows the detection, and therefore the treatment, of affected progeny before the onset of the clinical weakness. Electromyography is the most appropriate technique for a longitudinal study in which a given individual is examined repeatedly. We present the results of an electrophysiological and behavioral exploration of the pmn disease and show that electromyography is a powerful tool for following the course of the disease and evaluating potential therapies relevant to motor neuron diseases.

Action Potentials↗
PubMed1996

Fatal congenital myopathy with actin filament deposits.

We present the clinical and morphological findings in a case of progressive congenital myopathy. The symptoms present at birth included severe general muscular hypotonia, diffuse muscular atrophy, arthrogryposis, absence of spontaneous movements, and left ventricular hypertrophy. A biopsy specimen taken from the gastrocnemius muscle when the patient was 2 weeks old revealed deposits which consisted of actin filaments as shown by electron microscopy. The infant was occasionally respirator dependent but was mostly able to breathe unassisted. At the age of 5 months he died of respiratory failure. The actin filament deposits may explain the clinical findings.

Actins↗
PubMed1996

Natural killer cells and macrophages in immature denervated rat muscles.

Neonatally denervated muscle fibers of rat atrophy, degenerate, and eventually vanish unless they are reinnervated. Immunohistochemistry of hindlimb muscles denervated for 4 to 8 weeks showed OX8+ and also 3.2.3+ natural killer (NK) cells and ED1+ macrophages, which were much more frequent between atrophic non-reinnervated fibers than between reinnervated fibers. OX19+ T cells and OX33+ B cells were rare. Electron micrographs 4 to 15 weeks after denervation showed typical medium-sized lymphocytes and large lymphocytes with dense granules in close contact with muscle fibers of 1 to 3 micrometer diameter. Blunt projections of lymphocytes penetrated the basal lamina of the muscle fibers and established membrane contacts. The basal lamina of atrophic fibers had been invaded by slender projections of cytoplasm-rich stellate or fusiform cells, which seemed to strip them of their basal lamina. Thin fibers without basal lamina were engulfed by the stellate cells that in several aspects resembled fibrocytes but that presumably corresponded to the ED1+ macrophages seen by light microscopy. Electron microscopy and in situ nick translation demonstrated the rare appearance of apoptotic myonuclei. It is suggested that lymphocytes and macrophages are involved in the breakdown of neonatally denervated muscle fibers, and that apoptosis following contact with NK cells may represent the mode of cell death.

Animals↗
PubMed1996

Multiple autoimmune manifestations in monoclonal gammopathy of undetermined significance and chronic lymphocytic leukemia.

In 18 cases of monoclonal gammopathy of undetermined significance, MGUS (monoclonal gammopathy of undetermined significance), admitted for diagnosed or suspected peripheral neuropathy, 11 patients showed other co-existing autoimmune manifestations. Two had POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-component, and skin symptoms), the others mainly endocrinopathy and polyclonal pseudolymphoma. There were 13 cases of sensorimotor neuropathy, two cases of neuritis, while neuropathy could not be confirmed in three cases. Compared with a retrospective review of autoimmunity in a randomly selected CLL (chronic lymphocytic leukemia) cohort of 115 patients, 13 out of 42 patients with clinical and/or laboratory features of autoimmunity showed co-expression of autoimmune signs, the dominating traits being Coombs positive AIHA (auto-immune hemolytic anemia), platelet autoantibodies, endocrinopathy mainly associated with the thyroid gland, serological and/or rheumatological symptoms, but only one case of sensorimotor neuropathy. Viewed from a current model of acquired autoimmunity it is perhaps not surprising that such autoimmunity is seen predominantly in patients with monoclonal gammopathy. Thus, a high concentration of cross-reacting polyreactive autoantibodies related to the M-component might be present in these patients. Furthermore, quantitative defects of the immunoglobulins including the hypogammaglobulinemia associated with M-components can presumably give rise to a defect of the anti-idiotypic network's regulation of natural autoantibodies and autoimmune manifestations in vivo. Such autoimmune manifestations, which are easily overlooked in CLL may call for additional treatment with immunosuppression and/or intravenous, polyclonal IgG.

Adult↗
PubMed1996

Animal models of neuropathies.

Neuropathy in animals is either genetically determined or is provoked by chemical compounds or physical injury. Diabetes in mice and rats may be spontaneous or induced, but a true copy of diabetic neuropathy in man is not yet available. Painful neuropathy occurs after nerve constriction or neuroma formation. A mouse mutant with delayed Wallerian degeneration demonstrates the pivotal role of this process for the regeneration of injured axons. Surprisingly, the neurotoxic effect of cisplatin which is severe in cancer patients has not yet unambiguously been reproduced in animals. Genetically determined diseases in mutants or transgenic animals may affect the myelination of peripheral axons. 'Trembler mice' are deficient in myelin and possibly correspond to CMT IA in man. The relation of sensory neuronopathies in mice, rats and dogs to human diseases is not yet clear. Motor neuronopathies in experimental animals have attracted much interest, because the recent discovery of motoneuronotrophic factors has raised high hopes. Most of the mutants described have not been appropriately studied, and the mouse mutant 'motoneurone disease' (mnd) eventually was found to have Batten's disease. None of the few more thoroughly studied models is probably a copy of human disease, although they may none the less help to test new therapies.

Animals↗
PubMed1996

Nerve and muscle biopsy in a case of hereditary motor and sensory neuropathy type III with basal lamina onion bulbs.

A girl presented at age 8 months with generalized hypotonia and areflexia. The parents were unrelated and without symptoms. At the age of 2 years and 10 months she was able to stand and walk with support. Intellectual development was normal. The mean fibre size in the lateral vastus muscle was normal, the variability was slightly increased. Type I and II fibres tended to be aggregated, but there was no type grouping. Motor and sensory nerve conduction velocities were less than 6 m/s. The sural nerve lacked myelin sheaths, and large non-myelinated axons were surrounded by concentric layers ('onion bulbs') of basal lamina material. The disease was classified as 'autosomal recessive hereditary motor and sensory neuropathy type III(HMSN (III) with basal lamina onion bulbs'. The muscle biopsy findings suggest that congenital amyelination or hypomyelination does not necessarily result in neurogenic atrophy.

Biopsy↗
PubMed1995

Neurotrophin-4/5 postpones the death of injured spinal motoneurons in newborn rats.

We have compared the short- and long-term effects of Neurotrophin-4/5 (NT-4/5) on the survival of spinal motoneurons in neonatal rats. To this aim, the sciatic nerve was cut in newborn rats and NT-4/5 or buffer were applied to the proximal nerve stem in a gelfoam as well as by daily local injection. The number of motoneurons or ventral root fibers was determined 4, 11, and 14 days later. Four days after received NT-4/5 lost only 19% + 2.7% (540 + 81). No systemic effect on the contralateral motoneurons was observed. Surprisingly, 11 and 14 days following the operation, the loss of motoneurons and of ventral root fibers was the same in buffer and NT-4/5 treated animal despite the daily treatment. Thus, although NT-4/5 is a potent survival factor for motoneurons in culture and can transiently prevent the death of motoneurons in vivo, it can not, under these experimental conditions, permanently rescue lesioned motoneurons. These results indicate that other trophic factors or combinations of factors may be required to permanently prevent the death of spinal motoneurons and that the short term survival promoting effects of neurotropic factors in motoneuron lesion models can not be used to predict their therapeutic potential in chronic neurodegenerative disorders.

Animals↗
PubMed1995

Effects of age on aneural regeneration of soleus muscle in rat.

1. The ability of autografted soleus muscles to regenerate without innervation was investigated in young (two groups: 17 days or 35 g and 5 weeks or 100 g) and old (10 weeks or 300 g and 19 months or 700 g) rats. 2. Tetanic force and fibre area of the regenerated muscles were followed in 35, 100 and 300 g rats and found to reach a maximum 10-15 days after the operation and then declined. 3. Maximal tetanic force and fibre area were greater in old than in young rats; the largest increase was seen between 100 and 300 g rats. The relaxation phase of the twitch became shorter in the 700 g animals. The force per cross-sectional area appeared to fall with age. The length of the new fibres, inferred from the width of the length-force curve, increased only slightly with age. 4. Ten days after grafting, autophagocytosis of necrotic fibres was completed in young but not in old rats. The new fibres in young rats had one central nucleus per cross-section and fibre size was unimodally distributed; fibres in old rats had multiple internal nuclei and the size distribution was bimodal due to the presence of large fibres. 5. Previous results indicating greater muscle regeneration in young than in old rats may reflect more vigorous reinnervation in young animals rather than a greater myogenic potential. Increased fibre size of regenerated muscles of old compared with young rats may be attributed to the larger amount of necrotic material which is mitogenic for satellite cells, or to age-dependent changes of the expression of cell adhesion molecules. Enhanced lateral fusion of myotubes would give rise to large fibres with multiple internal nuclei.

Aging↗
PubMed1995

The mouse mutation progressive motor neuronopathy (pmn) maps to chromosome 13.

Analysis of polymorphic markers segregating in both intra- and interspecific crosses has allowed us to map the autosomal recessive mutation progressive motor neuronopathy (pmn) to mouse Chr 13. Although this mutation, based on its histological description, was reported as a model for infantile spinal muscular atrophy of the Werdnig-Hoffmann type, its localization to a region that is not homologous with human 5q makes it unlikely to be a homologue to SMA. The presence of the Extra-toe (Xt) locus in proximity to pmn will help in the detection of affected progenies before the onset of the degenerative process.

Animals↗
PubMed1995

Polymer encapsulated cell lines genetically engineered to release ciliary neurotrophic factor can slow down progressive motor neuronopathy in the mouse.

Ciliary neurotrophic factor (CNTF) has recently generated great interest due to its potential as a therapeutic agent for the treatment of human neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Because the systemic half-life of CNTF is only in the order of a few minutes, continuous delivery of this trophic factor could be attractive or even necessary in the therapy of these diseases. One promising technique involves the polymer encapsulation of cells which have been genetically modified to secrete neurotrophic factors. The polymer capsules can be implanted into animals and effect the slow release of the protein for several months. The encapsulation technique immuno-isolates the foreign cells from host immune cells and at the same time prevents tumour formation by the transplanted cells. In this study, we have used progressive motoneuronopathy (pmn) mice to determine the extent to which encapsulated cell lines secreting CNTF could alter the course of the disease. pmn/pmn homozygotes present severe loss of myelinated motor fibres and a significant reduction of facial motoneuron cell bodies. The mice develop weakness of the hindlimbs and die during the sixth week after birth. We found that CNTF delayed the disease progression by increasing the survival time by 40% and by improving motor function as assessed by three behavioural tests. Moreover, histological counts of the phrenic nerve myelinated axons and facial nucleus motoneurons indicated a significant reduction of motoneuron loss. These results suggest that polymer-encapsulated cells releasing neurotrophic factors may provide a potential delivery system for treating neurodegenerative diseases such as ALS.

Animals↗
PubMed1995

Satellite cells and myonuclei in long-term denervated rat muscles.

BACKGROUND: The percentage of satellite cells rapidly decreases in aneurally regenerating soleus muscles of rat. Also denervation of intact muscles causes fiber loss and regeneration, but the fate of satellite cells is unknown; myonuclei have been suggested to undergo changes resembling those in apoptotic cells. METHODS: Rat soleus and extensor digitorum longus (EDL) muscles were denervated at birth or at age 5 weeks and investigated after periods of up to 38 weeks. At least 400 myonuclei in each muscle were assessed by electron microscopy, and satellite cell nuclei were counted. In situ nick translation and tailing were performed after 30 weeks denervation in order to demonstrate DNA breaks associated with apoptosis. RESULTS: Myotubes indicating regeneration were prominent in the adult denervated soleus and deep layers of EDL muscles after 7 weeks and in the superficial parts of EDL muscle after 16 weeks. The percentage of satellite cell nuclei slowly decreased to less than one fifth of normal after 20-30 weeks. Almost all satellite cells had vanished 10 weeks after neonatal denervation. Degenerating myonuclei in adult, but not in neonatally denervated muscles, remotely resembled apoptotic nuclei of lymphocytes, but no evidence of DNA breaks was found. CONCLUSION: Denervation of rat skeletal muscles causes, in addition to fiber atrophy, loss of fibers with subsequent regeneration. Proliferation of satellite cells under aneural conditions may lead to exhaustion of the satellite cell pool. This process is more rapid in growing than in adult muscles. Myonuclei in denervated muscles do not show DNA breaks which can be demonstrated by in situ nick translation.

Age Factors↗
PubMed1994

Immunocytochemistry of M-cadherin in mature and regenerating rat muscle.

BACKGROUND: Cadherins are transmembrane proteins mediating calcium-dependent cell-cell adhesion in a cell type-specific manner by means of homophilic binding. M(muscle)-cadherin is a recently detected member of the cadherin family. METHODS: We have investigated the localization of M-cadherin in normal and aneurally regenerating skeletal muscle of rat by means of pre-embedding immunocytochemistry. The antibody was directed against the extra-cellular domain of M-cadherin. RESULTS: Myoblasts and myotubes in regenerating muscles tended to be arranged in clusters enclosed by a common basal lamina. Satellite cells of mature muscle fibers were attached to the underlying fiber without separating basal lamina. Reactivity for M-cadherin was restricted to the plasma membranes of myoblasts and satellite cells, and was most intense at the membrane areas facing adjacent myotubes or myofibers. Myoblasts interposed between two myotubes were stained on the entire surface. The adjacent plasma membrane of the otherwise negative myotube or muscle fiber, was stained as well, and extracellular reaction product was in the gap between the cells. CONCLUSION: The cellular localization of M-cadherin may indicate that M-cadherin is involved in calcium-dependent adhesion between satellite cells and muscle fibers or, by means of interposed myoblasts, between the clustered myotubes in a regenerating muscle.

Animals↗
PubMed1994

Autosomal dominant distal myopathy with desmin storage: a clinicopathologic and electrophysiologic study of a large kinship.

A large family is described with an autosomal dominant distal myopathy, the nature of which prompts the reevaluation of current classifications of these disorders. The disease begins in early to middle adulthood with gait disturbance due to distal leg weakness, and progresses over 5-10 years to involve all extremities, as well as bulbar, respiratory, and facial muscles. There is frequent cardiac involvement, manifest by arrhythmias, conduction blocks, and congestive failure, resulting in premature demise. On electromyography there is prominent spontaneous activity, short duration motor unit potentials, and polyphasia. Muscle biopsies from multiple family members at different stages of the disease are characterized by desmin storage and autophagocytosis. This distal myopathy differs from other phenotypically similar disorders in its rapidity of progression, fatal course and pathologic features. The role and specificity of excessive desmin accumulation in this and other myopathic and cardiac disorders are unknown.

Adult↗
PubMed1994

A comparison of the morphology of denervated with aneurally regenerated soleus muscle of rat.

Soleus muscles of rats were denervated, treated with bupivacaine and autografted in order to induce aneural regeneration or only denervated. After 2-70 days, muscles were fixed and embedded in epoxy resin for light and electron microscopy. Regenerating muscles after 2 and 5 days consisted of a necrotic core and a rim of new fibres; the necrotic core had disappeared by day 10. The fibre size (mean cross-sectional area) was 139 microns2 after 10 days; it decreased to 22 microns2 after 70 days. Denervated muscle fibres measured 26 microns2 after 70 days. The sarcomere pattern was regular in 10-day regenerates but later degenerated. There were signs of fibre breakdown; immature regenerating fibres were still found after 70 days. Denervated muscles already contained a few new myotubes at 10 days; at 40 and 70 days fibre loss and regeneration were distinct. The percentage of satellite cells relative to myonuclei (normal 8%) doubled within the first 10 days after necrosis and then fell to less than one fourth of normal. Denervation for 70 days increased threefold the percentage of satellite cells in some muscles and in others caused a decrease to half of normal. The number of fibre cross-sections in regenerated muscles was about 3000 after 10-70 days; this was roughly the same number as in normal soleus muscles. The true number of fibres, however, may have been smaller because regenerated fibres tend to branch. It is concluded that aneurally regenerating muscle fibres reach a high degree of structural differentiation, but then atrophy, degenerate and vanish; they are replaced by new fibres, which do not reach the size of the first fibres, presumably because the satellite cell pool without innervation eventually becomes exhausted. The slow and non-synchronized breakdown of denervated soleus muscle fibres induces proliferation of satellite cells as in necrotized muscles; those muscles which had fewer satellite cells than normal after 70 days might already be showing exhaustion.

Animals↗
PubMed1994

Contractile properties of aneurally regenerated compared with denervated muscles of rat.

The time course of aneural regeneration in slow-twitch soleus muscles of young adult rats was studied and compared with the changes following denervation in soleus and fast extensor digitorum longus muscles. Regeneration was induced by auto-grafting after treatment with bupivacaine; isometric contractions were recorded from 5 to 70 days later. Force was detected at 5 days; at 12 days force was maximal (at least 20% of original) and thereafter fell exponentially. Force varied normally with total fibre area, except at 5 and 71 days when force generating capacity was low. Contraction and relaxation in the twitch were longer than normal (maximally at 5 days), and were closer to denervated soleus than EDL; in contrast, the maximal rate of rise of force was as high as that of denervated EDL and much higher than in denervated soleus. It is suggested that the muscle was fundamentally fast contracting, but the twitches were probably slow because of greater than normal activation following a single stimulus--a hypothesis supported by twitch:tetanus ratios that were higher than in denervated muscles. Tetanic force was much more sensitive than normal to changes of muscle length from optimum, despite the fact that the lengths of regenerated muscles were similar to those of contralateral muscles. The properties of denervated soleus gradually approached those of regenerated soleus, probably because of replacement of original fibres by regenerated ones.

Animals↗
PubMed1994

Juvenile Kearns-Sayre syndrome initially misdiagnosed as a psychosomatic disorder.

We have investigated a 15 year old girl with progressive external ophthalmoplegia, including bilateral ptosis and retinal rod and cone cell dysfunction with atypical retinal pigmentation, complicated by cerebellar ataxia, partial cardiac conduction block, and diabetes mellitus. In infancy she had a severe crisis of bone marrow depression, and as a child she suffered from hypersensitivity to light, increasing fatigue, and vertigo, signs that were initially though to be psychosomatic. Histological examination showed mitochondrial myopathy, and subsequent mitochondrial DNA (mtDNA) analysis showed a deletion of approximately 5500 base pairs in 35 to 40% of her muscle mtDNA. We therefore conclude that this patient has developed the Kearns-Sayre syndrome after a Pearson syndrome-like crisis in her first year of life.

Adolescent↗
PubMed1994

Early peripheral nerve regeneration after crushing, sectioning, and freeze studied by implanted electrodes in the cat.

Regeneration of axons after Wallerian degeneration is influenced by various factors localized to the distal nerve stump. We have examined elongation of axons to assess the relative influence of basal lamina and of Schwann cells in lesions with and without interruption of the Schwann cell tubes. In particular, we wanted to follow the growth of axons throughout the same distal nerve stump. Silicone cuff and patch electrodes with multiple contacts were therefore implanted around hindlimb nerves proximal and distal to the lesion. The tibial nerve was cut and sutured (15 nerves) or crushed (10 nerves). A 20-25-mm-long segment distal to the lesion was in addition frozen in four crushed and in seven sectioned nerves to eliminate the Schwann cells. Six unlesioned tibial nerves from four cats served as control. Reinnervation of plantar muscle occurred 42-54 d after nerve crushing and 42-84 d after nerve sectioning (P < 0.01). Regeneration was followed by weekly electrophysiological observations that allowed serial identification of the fastest-growing individual axons, with conduction velocities of 0.5-3 m/sec and amplitudes of 0.15-0.5 microV. Unmyelinated axons were present at the most distal lead of the electrode array from which action potentials were identified. The rate of elongation after both crushing and crush+freeze was 3-4 mm/d, and after sectioning only 2.5 mm/d (P < 0.01). Freezing in addition to sectioning was associated with even slower elongation of 1.2 mm/d. Distal to the frozen portion of the nerve elongation accelerated. Our findings suggest that regeneration was slowed throughout the nerve distal to a sectioning compared with a crushing lesion, and that depletion of Schwann cells only influenced axonal elongation after interruption of the basal lamina. This suggests that the basal lamina tubes at the lesion site may facilitate the action of neurotropic factors of distal origin.

Action Potentials↗