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Biomedical subjects

F G Jennekens

Publications and source records attributed to F G Jennekens.

At least 37 records · Page 2Linked to original sources
PubMed1994

Elimination of superfluous neuromuscular junctions in rat calf muscles recovering from botulinum toxin-induced paralysis.

In order to determine the fate of the superfluous neuromuscular junctions (NMJs) formed during the course of botulinum toxin (BoTx)-induced paralysis, we have quantified the change in the total length of the nerve muscle contact area(s) following BoTx injection into rat calf muscles. The results indicate that: (1) at least some of the superfluous NMJs are eliminated following muscle recovery; (2) synapse elimination is a slow process, as 4 months after recovery it was not yet complete; (3) muscles with different content of type I and II fibers follow a different time course during synapse formation and elimination. We further investigated the possibility that the neural cell adhesion molecule (NCAM) would be the element whose loss from the NMJ might play a role in synapse elimination. Using immunofluorescence and immunoelectron microscopy we show that NCAM is exclusively localized between nerve terminals and Schwann cells and not between nerve terminals and muscle. This localization was maintained throughout paralysis and following recovery, suggesting that NCAM does not play a role in synapse elimination.

Animals↗
PubMed1994

Ciliary neurotrophic factor improves muscle fibre reinnervation after facial nerve crush in young rats.

In the present study we examined the effect of recombinant human ciliary neurotrophic factor (rH-CNTF) on muscle fibre reinnervation. After facial nerve crush, rats were treated systemically with either rH-CNTF (1 mg/kg per 48 h) or saline and were killed on days 10-13 after nerve crush when muscle fibre reinnervation becomes apparent. Blind counting of the number of reinnervated motor endplates and the length of the synaptophysin-positive staining was used to assess the effect of CNTF treatment on muscle fibre reinnervation in the whisker muscle. On day 10, both treatment groups showed a limited number of reinnervated motor endplates. Both the saline- and CNTF-treated rats showed a significant increase in the percentage of reinnervated motor endplates and in the length of the synaptophysin-positive staining with time. On days 10 and 11, there was no difference in muscle fibre reinnervation between the treated groups. On days 12 and 13, the CNTF-treated rats showed an increased muscle fibre reinnervation which was significant compared to the saline-treated rats. These results suggest that after facial nerve crush in young rats, CNTF enhances muscle fibre reinnervation, most probably by stimulating the intramuscular branching. There is no support for an effect of CNTF on nerve sprouting in the proximal axonal part or on axonal elongation; the CNTF effect on intramuscular branching might be mediated by the muscle fibres.

Animals↗
PubMed1994

Basic fibroblast growth factor immunoreactivity in the peripheral motor system of the rat.

We have used immunohistochemistry and electron microscopy to investigate the distribution of basic fibroblast growth factor (bFGF) in the peripheral motor system of the adult rat. In the lumbar segments of the spinal cord, bFGF immunoreactivity (bFGF-I) was seen in motor neurons and glial cells but not in axons. The neuronal immunostaining was seen as two or three intensely fluorescent spots in the nuclei with weak and more diffuse staining of the perinuclear cytoplasm. In the sciatic nerve, bFGF-I was seen in Schwann cells with strong intensity at the nodes of Ranvier. Axonal immunostaining could not be detected. At the electron microscopic level, the intense nodal immunostaining of Schwann cells was confirmed and was found to be localized to the Schwann cell membrane at the nodal gap. The intensity of staining decreased with distance from the node. In the soleus and gastrocnemius muscles, bFGF-I was seen at the motor endplates in sites corresponding to the motor nerve terminals in addition to faint staining within the muscle fibers. Electron microscopy showed that bFGF-I was localized within the nerve terminals. Histochemical localization of bFGF in the peripheral motor system is compatible with the functions ascribed for this protein in this system.

Animals↗
PubMed1994

Insulin-like and fibroblast growth factors in spinal cords, nerve roots and skeletal muscle of human controls and patients with amyotrophic lateral sclerosis.

Insulin-like growth factors (IGF-I and IGF-II) and fibroblast growth factors [acidic FGF (aFGF) and basic FGF (bFGF)] are trophic for motor neurones in vitro and (in laboratory animals) in vivo. An immunohistochemical investigation was performed on the distribution of these factors in the neuromuscular system of control patients and patients with amyotrophic lateral sclerosis (ALS). Comparisons were made with rat tissue. IGF-I immunoreactivity (IGF-I-IR) was seen in motor neurone cell bodies and axons, astroglia and Schwann cells, and in muscle fibres. IGF-II-IR was weak in all these cells. aFGF-IR was present in motor neurone cell bodies and axons, oligodendroglia and muscle fibres, but was not demonstrable in Schwann cells. bFGF-IR was present in motor neurone cell bodies and axons, and in astroglia, but was not seen in Schwann cells or muscle fibres. The distribution of the IGFs and FGFs in material from motor neurone disease (MND) and controls was similar. A role for any of these factors in the etiology of MND is, therefore, unlikely. IGF-I-IR and aFGF-IR were stronger in type II than in type I muscle fibres and were increased in denervated fibres. Species differences were found for IGF-I and bFGF. The function of these factors is apparently not entirely similar in humans and rats.

Adult↗
PubMed1994

GAP-43 and p75NGFR immunoreactivity in presynaptic cells following neuromuscular blockade by botulinum toxin in rat.

Peripheral nerve lesion results in changes in protein expression by neurons and denervated Schwann cells. In the present study we have addressed the question whether similar changes take place following functional denervation. Using immunohistochemistry and immunoelectron microscopy we examined changes in growth-associated protein (GAP-43) and low-affinity nerve growth factor receptor (p75NGFR) in rat gastrocnemius muscle following botulinum toxin-induced paralysis. GAP-43 and p75NGFR were selected because they are not expressed by mature intact motor neurons or Schwann cells, but are expressed following nerve lesion in both motor neurons and denervated Schwann cells. In control muscle, GAP-43 and p75NGFR immunoreactivity was seen only in nerve fibres near blood vessels. Two weeks after toxin injection, GAP-43 immunoreactivity could be seen at the motor endplates and in axons. Intensity of staining increased with longer survival and reached a peak between 4 and 8 weeks post-injection. Ultrastructurally, GAP-43 immunoreactivity was confined to nerve terminals and axons, whereas Schwann cells remained negative. Immunostaining for p75NGFR also increased following toxin injection and was detected in some terminal Schwann cells and in perineurial cells of small nerve fascicles near the paralyzed target cells, but not in axons. These results show that changes in expression of GAP-43 in motor neurons following functional denervation closely resemble the changes following anatomical interruption of nerve-muscle contact. GAP-43 was not expressed in Schwann cells, indicating that its upregulation in these cells is induced by loss of axonal contact or nerve degeneration products. There is no support for a role of p75NGFR in incorporation of neurotrophins in axons. The restriction of p75NGFR expression to terminal Schwann cells and perineurial cells in close proximity to the paralyzed target suggests a role for a target-derived signal or, alternatively, macrophages in eliciting this expression.

Animals↗
PubMed1994

Protection against cisplatin induced neurotoxicity by ORG 2766: histological and electrophysiological evidence.

Prolonged administration of the anti-tumor agent cisplatin may cause a neuropathy in patients. In an animal model, too, neurotoxicity, as evidenced by a decrease in H-related sensory nerve conduction velocity (SNCV), can be induced by repetitive injections of cisplatin. In an attempt to further the insight into the effects of cisplatin on the peripheral nervous system a combined electrophysiological and histomorphological investigation was performed on 2 groups of 6 rats, treated with cisplatin for 7.5 weeks, and a control group (n = 6). Concomitant administration of ORG 2766, an ACTH(4-9) analog, was previously shown to prevent cisplatin neurotoxicity in this model and more recently in patients as well. One group of rats was therefore co-treated with this peptide during the complete treatment period. A marked decrease in SCNV was observed in cisplatin/saline treated rats, but not in cisplatin/ORG 2766 treated rats. Though no statistically significant difference was seen in the total number of myelinated fibers in the sural nerves of cisplatin treated rats, a decrease in the proportion of thick myelinated fibers was present in the cisplatin/saline treated rats. This shift in fiber distribution was absent in ORG 2766 co-treated animals. Mean internodal distances and g-ratios were not affected, and signs of axonal degeneration, or de- or remyelination were not observed.

Adrenocorticotropic Hormone↗
PubMed1994

The status of HMSN type III.

The indistinctness of the HMSN type III concept of Dyck (1975) prompted us to evaluate the diagnostic criteria. Based on a literature review and the observations in five of our own cases, restricted criteria are formulated. We conclude that at present the diagnosis of AR HMSN type III can be applied reasonably to the condition of "congenital hypomyelination", which shows a congenital or early childhood onset, extremely slow motor nerve conduction velocities of less than 6-7 m s-1 in upper limbs, and in nerve biopsy only fibres with no or hardly any myelin and "onion bulbs" of basal lamina. Amyelination might be the most severe or earliest expression of congenital hypomyelination. The existence of an inherited type III with mainly classical onion bulbs is uncertain, as only sporadic cases have been described.

Age of Onset↗
PubMed1994

Polyneuropathy associated with monoclonal gammopathy of undetermined significance. A prospective study of the prognostic value of clinical and laboratory abnormalities.

The natural course of polyneuropathy associated with monoclonal gammopathy of undetermined significance (MGUS) is not well known. We therefore studied 32 untreated patients for a period of 5 years. Fifteen patients had an IgM M-protein, 15 an IgG and two an IgA. There was a male predominance, a mean age of onset at the end of the sixth decade and sensory signs were more pronounced than motor deficits. On entry into the study and during the 5 years of follow-up, we quantified the neuropathy in a standard way: totals of motor and sensory scores; vibration perception threshold; tapping tests; quantified Romberg test; electrophysiological parameters. A significant difference in the natural history between the polyneuropathy associated with IgM-MGUS and IgG/IgA-MGUS was found for the motor and sensory sum scores, the vibration perception threshold and the tapping tests. The polyneuropathy in IgM-MGUS is more progressive, with significantly more weakness and sensory signs, indicating that the neuropathies associated with IgM-MGUS and IgG/A-MGUS may be two different entities. A rapid progression of the neuropathy was found in five patients. We found no predictive factors for this severe progression of the neuropathy of these five patients. Of these five, three (two IgM, one IgG) developed a non-Hodgkin lymphoma.

Electrophysiology↗
PubMed1994

Chronic idiopathic axonal polyneuropathy: a five year follow up.

Seventy five patients with chronic idiopathic axonal polyneuropathy (CIAP) were studied for five years. The standardised and quantified neurological examination shows that progression of CIAP is slow, and handicap, if present, is not severe. During the follow up period a definite cause of the neuropathy was found in only four patients (two hereditary motor and sensory neuropathy type 2, one sensory chronic inflammatory demyelinating polyneuropathy, one alcoholic neuropathy). At the end of the follow up CIAP was not related to malignancy or gammopathy. Routine repetition of laboratory tests was not informative and these tests should be performed on clinical grounds only.

Aged↗
PubMed1993

Development of innervation of skeletal muscle fibers in man: relation to acetylcholine receptors.

The aim of this study was to establish the time scale of developmental changes in innervation of skeletal muscle fibers in man. Specimens of thigh and intercostal muscle from 19 embryos and 18 infants were examined with histological methods which enabled the discrimination between fetal (gamma) and adult (epsilon) types of acetylcholine receptors (AChRs). At 8 weeks of development, AChRs were distributed diffusely in the myotube membranes. Following onset of innervation in approximately the ninth week the length of the AChR positive area diminished and reached its shortest size at the sixteenth developmental week. At the sixteenth and eighteenth week some nerve terminals opposed the muscle membrane outside the AChR positive area. Decrease in the number of nerve terminals, strongly suggesting elimination of polyneuronal innervation, started in the sixteenth week and was completed in the twenty-fifth week. This fetal (gamma) type of AChR could no longer be demonstrated after the thirty-first week. The length of the end-plates as determined by the presence of AChRs increased again in the last week before birth and reached a plateau size by the end of the first year after birth. It is concluded that in man the transition from poly- to mononeuronal innervation takes place between the sixteenth and twenty-fifth weeks of development. The evidence available suggests that the retraction of nerve terminals is preceded by loss of AChRs from the muscle membrane facing the terminals. There is no relationship between retraction of nerve terminals and the switch from fetal to adult type of AChR. The size of the presynaptic apparatus changes little after the first year of life.

Child↗
PubMed1993

The neurotrophic analogue of ACTH(4-9) reduces the perineuronal microglial reaction after rat facial nerve crush.

Following peripheral nerve crush, microglial cells proliferate and migrate to motoneuron cell bodies of the injured nerves. Newly formed glial processes displace nerve terminals from the cell bodies. This process is known as synaptic stripping. In animal models of peripheral nerve diseases, the ACTH(4-9) analogue, ORG2766, was shown to facilitate axonal regeneration and to protect against experimental neuropathy. In the present study we examined the effect of ORG2766 on the microglial reaction. After facial nerve crush, rats were treated with either ORG2766 (75 micrograms/kg/48 h) or saline and were killed on day 2-6 after operation. Blind counting of the number of perineuronal glial cells in the facial nucleus was used to assess the effect of ORG2766 treatment on the microglial reaction. In the saline-treated animals the number of perineuronal glial cells per motoneuron cell body on the crushed side increased significantly. This number increased up to day 5 after operation and decreased significantly from day 5 to 6. After an initial increase in the peptide-treated animals, however, the number of perineuronal glial cells remained constant from day 3 onwards. Hence, on post-operation days 4 and 5, this number was significantly less than that seen in saline-treated animals. Microglial cells proliferate, presumably through signalling by injured motoneurons. It is suggested that the decrease in the number of perineuronal glial cells in the ORG2766-treated animals is the result of a peptide-induced reduction in the release of mediating signals/cytokines or, alternatively, increased protection of motoneurons by stress proteins. Further research should address the mechanism of action of ORG2766 in animal models of motoneuron disease.

Adrenocorticotropic Hormone↗
PubMed1993

Inflammatory cells in the peripheral nervous system in motor neuron disease.

We examined post-mortem material of the peripheral nervous system of 26 cases of motor neuron disease (MND) for the presence of lymphocyte subsets and macrophages. Findings were quantified and compared with those in control nerves. Lymphocytes in chronic and acute axonal degeneration were studied in sural nerve biopsy and animal material. Signs of demyelination were studied in MND and controls with infiltrates of T cells. A few T lymphocytes were scattered diffusely within the fascicles. The numbers did not differ between MND and controls. About half of the T cells was positive for CD45RA, the other half being positive for CD45RO. T cells were negative for CD25, CD54 and major histocompatibility complex (MHC)-class II. There were hardly any B lymphocytes. The numbers of lymphocytes in nerves with and without axonal degeneration did not differ. Increased MHC class II expression was present on denervated Schwann cells and macrophages in MND and in sural nerves with axonal degeneration. Macrophages were increased in number and in size, both in MND and in control material with axonal degeneration. No signs of demyelination were present either in MND or in controls. It is concluded that a T cell-mediated process in peripheral nerves in MND is very unlikely.

Adolescent↗
PubMed1993

Peripheral nerve lesions: the neuropharmacological outlook.

A review is presented of compounds with trophic effects on the peripheral nervous system. A distinction should be made between three types of effect: enhancement of neurone survival, stimulation of regeneration and induction or stimulation of collateral sprouting. On the basis of data currently available, laminin and insulin-like growth factor I are the most promising substances for regeneration of peripheral nerve lesions. Future investigations of laminin should provide an answer to the query whether local administration facilitates sprouts to cross the gap between proximal and distal nerve stumps. Further experiments are required on effects of systemic administration of IGF-I in animal models of peripheral nerve lesions before investigations can be initiated in man.

Animals↗
PubMed1993

Evaluation of electrophysiological and clinical tests in an exploratory trial of Org 2766 in motor neuron disease.

Twenty four patients with motor neuron disease (MND) participated in a double-blind, placebo-controlled trial with the ACTH 4-9 analog, Org 2766. Patients were examined three times during an 8 week treatment period, using a summated score for several manually and functionally tested muscles (sum score), myometry, jitter, fibre density (FD), macro motor unit potential (MUP), and supramaximal evoked muscle action potentials. No differences were found between Org 2766 and placebo treated patients. In an open 1 yr follow-up study, 5 out of 13 patients treated with Org 2766 died; the others showed continued progression of weakness. The methods used for assessment of muscle function were compared. The highest interest reliability was obtained in the sum score and myometry. Mean differences that might be detectable were relatively small for the sum score and myometry, and large for FD and MUP. We concluded that clinical function testing and myometry are superior to electromyographic measurements for assessment of changes in MND patients.

Action Potentials↗
PubMed1993

Deletion of the serine 34 codon from the major peripheral myelin protein P0 gene in Charcot-Marie-Tooth disease type 1B.

Charcot-Marie-Tooth disease type 1B (CMT1B) is genetically linked to chromosome 1q21-23. The major peripheral myelin protein gene, P0, has been cloned and localized to the same chromosomal region. P0 is a 28 kDa glycoprotein involved in the compaction of the multilamellar myelin sheet and accounts for more than half of the peripheral myelin protein content. We checked whether P0 is altered in CMT1B, and show here that a 3 basepair deletion in exon 2 of the P0 gene is present in all affected individuals of a CMT1B family. The mutation results in the deletion of serine 34 in the extracellular domain of P0, suggesting that alterations of P0 cause CMT1B.

Amino Acid Sequence↗