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Biomedical subjects

M J Strong

Publications and source records attributed to M J Strong.

At least 37 records · Page 2Linked to original sources
PubMed1998

Nitric oxide synthase expression in cervical spinal cord in sporadic amyotrophic lateral sclerosis.

Nitration of neurofilament (NF) has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Evidence of such includes elevated 3-nitrotyrosine levels in spinal cord tissue and localized nitrotyrosine immunoreactivity with neurofilamentous aggregates in cortical and spinal motor neurons. To determine if neuronal nitric oxide synthase (nNOS) and inducible NOS (iNOS) are the sources of nitric oxide in sporadic ALS (sALS), particularly through over-expression of the enzyme, steady-state mRNA levels of these isoforms were studied by in situ hybridization. Paraffin-embedded, archival cervical spinal cord tissues from 7 sALS and 6 control cases were used. 35S-labeled riboprobes were generated from partial cDNAs. Immunohistochemistry was utilized to confirm results of iNOS hybridization. We observed that nNOS mRNA was constitutively expressed in cervical spinal motor neurons. However, iNOS mRNA and iNOS immunoreactivity was not observed in ALS or control motor neurons. Our observations suggest that the source of nitric oxide is the endogenous nNOS. Together with the results from other immunohistochemical studies, we further hypothesize a possible role of translational deregulation of nNOS in sALS.

Adolescent↗
PubMed1998

Case of the month: June 1997--a 42 year old man with left facial weakness.

A 42 yr old male presented with left facial weakness. MRI showed lesions affecting the distal seventh nerve and third division of the trigeminal nerve. The seventh nerve was biopsied and showed a malignant epithelioid schwannoma. The patient underwent extensive resection followed by irradiation. This is one of very few examples of intracranial malignant peripheral nerve sheath tumors and the first reported example of an intracranial malignant epithelioid schwannoma. The literature is reviewed and completeness of resection appears to be the most pertinent prognostic factor.

Adult↗
PubMed1997

Enhanced ex vivo cosedimentation of high molecular weight neurofilament protein (NFH) with microtubules following in vivo aluminum chloride exposure: inhibition of dephosphorylation-dependent dissociation.

We have investigated the effect of acute in vivo aluminum exposure on the subsequent ex vivo cross-linking of the high molecular weight neurofilament protein (NFH) with polymerized microtubules. Young adult female New Zealand white rabbits were inoculated intracisternally with 1000 micrograms of AlCl3 in 0.9% NaCl or with 0.9% NaCl alone, and killed 48 hours later. Following isolation of a cytoskeletal-enriched protein fraction from the cervical spinal cord, NFH was purified by either electroelution or column chromatography. Tubulin was isolated from New Zealand white rabbit brains by repeated temperature-dependent polymerization and depolymerization, purified over phosphocellulose, and cosedimented with either phosphorylated or dephosphorylated NFH. Following incubation for 30 minutes at 32 degrees C with tubulin in the presence of 20 microM Taxol, 1.0 mM MgCl2 and 1.0 mM GTP, the insoluble pellet containing NFH/microtubules was isolated. Both the pellet and supernatent were fractionated by SDS.PAGE and the amount of NFH present quantified by transmission densitometry following silver-staining. Results were identical regardless of the technique utilized for the purification of NFH. Control NFH preferentially cosedimented with microtubules when in the fully phosphorylated isoform, but remained in the soluble fraction following dephosphorylation. Phosphorylated NFH derived from AlCl3-inoculated rabbits demonstrated similar binding characteristics to control NFH, but following exhaustive dephosphorylation, exhibited a 4.5 fold induction of NFH/microtubule binding (p = 0.0314). Incubating dephosphorylated control NFH with microtubules in the presence of increasing concentrations of AlCl3 failed to induce similar cosedimentation. These experiments suggest that phosphorylation promotes NFH cross-linking to microtubules. In addition, the phosphorylation/dephosphorylation dependent regulation of NFH cross-linking to microtubules is disrupted following in vivo AlCl3 exposure by a mechanism that s independent of NFH/Al3+ binding.

Aluminum Chloride↗
PubMed1996

Can the mechanisms of aluminum neurotoxicity be integrated into a unified scheme?

Regardless of the host, the route of administration, or the speciation, aluminum is a potent neurotoxicant. In the young adult or developmentally mature host, the neuronal response to Al exposure can be dichotomized on morphological grounds. In one, intraneuronal neurofilamentous aggregates are formed, whereas in the other, significant neurochemical and neurophysiological perturbations are induced without neurofilamentous aggregate formation. Evidence is presented that the induction of neurofilamentous aggregates is a consequence of alterations in the posttranslational processing of neurofilament (NF), particularly with regard to phosphorylation state. Although Al has been reported to impact on gene expression, this does not appear to be critical to the induction of cytoskeletal pathology. In hosts responding to Al exposure without the induction of cytoskeletal pathology, impairments in glucose utilization, agonist-stimulated inositol phosphate accumulation, free radical-mediated cytotoxicity, lipid peroxidation, reduced cholinergic function, and altered protein phosphorylation have been described. The extent to which these neurochemical modifications correlate with the induction of a characteristic neurobehavioral state is unknown. In addition to these paradigms, Al is toxic in the immediate postnatal interval. Whether unique mechanisms of toxicity are involved during development remains to be determined. In this article, the mechanisms of Al neurotoxicity are reviewed and recommendations are put forth with regard to future research. Primary among these is the determination of the molecular site of Al toxicity, and whether this is based on Al substitution for divalent metals in a number of biological processes. Encompassed within this is the need to further understand the genesis of host- and developmental-specific responses.

Adult↗
PubMed1996

Spinal motor neuron neuroaxonal spheroids in chronic aluminum neurotoxicity contain phosphatase-resistant high molecular weight neurofilament (NFH).

It has previously been shown that a single intracisternal inoculum of AlCl3 in young adult New Zealand white rabbits will induce a dose-dependent phosphatase resistance of high molecular weight neurofilament protein (NFH) that is proportionate to the extent of neurofilamentous inclusion formation (Strong and Jakowec, 1994). To determine if the potential for dissolution of aluminum-induced neurofilamentous inclusions was dependent on the degree of NFH phosphatase resistance, we have examined NFH phosphatase sensitivity in a reversible chronic model of aluminum neurotoxicity. Rabbits receiving repeated intracisternal inoculums of 100 microgram AlCl3 at 28 day intervals until day 267 develop spinal motor neuron perikaryal and neuroaxonal neurofilamentous aggregates in a stereotypic, dose-dependent fashion. In the rabbits receiving inoculums until day 156 with survival until day 267 without further aluminum exposure, neuroaxonal spheroids remained prominent while perikaryal inclusions largely resolved. Immunoreactivity to a monoclonal antibody recognizing phosphorylated NFH (SMI 31) was abolished in perikaryal aggregates at each time interval by dephosphorylation with bovine alkaline phosphatase. However, neuroaxonal spheroids maintained their immunoreactivity. Using time-course dephosphorylation studies of spinal cord homogenates, we observed a significant reduction in the rate of dephosphorylation of NFH following 267 days of AlCl3 exposure (P < 0.05). These observations suggest that neuroaxonal spheroids contain phosphatase-resistant NFH isoforms and that the potential for resolution of intraneuronal neurofilamentous inclusions correlates with the susceptibility of NF within these inclusions to enzymatic dephosphorylation.

Alkaline Phosphatase↗
PubMed1996

Comparative study of chronic aluminum-induced neurofilamentous aggregates with intracytoplasmic inclusions of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is characterized neuropathologically by chromatolysis, Bunina bodies, hyaline inclusions, skein-like inclusions and axonal spheroids. Aluminum, a known neurotoxin, is the cause of dialysis encephalopathy and is considered to be a causative agent in high incidence foci of ALS in the western Pacific. We have developed an experimental model of motor neuron degeneration in New Zealand white rabbits using chronic low-dose intracisternal administration of aluminum and compared the clinical and neuropathological changes to those of human ALS. Aluminum-inoculated rabbits developed progressive hyperreflexia, hypertonia, limb splaying, gait impairment, muscle wasting, hindlimb paralysis and impaired tonic immobility responses without overt encephalopathic features over a 14-month period. Examination of spinal cords from these animals demonstrated the frequent occurrence and progressive development of anterior horn cell lesions that included small, round, argentophilic perikaryal inclusions similar to hyaline inclusions seen in human ALS. Other inclusions were more condensed and eosinophilic, while still others had neurofibrillary tangle-like morphologies. Axonal spheroids and neuritic thickenings were also prominent and were identical to those seen in human ALS. We believe that the similar and progressive development of neuropathological changes observed in the chronic aluminum-intoxication model, compared to human ALS, warrants further study to aid in understanding the cellular and molecular mechanisms of human motor neuron disease.

Aluminum↗
PubMed1996

Cognition, language, and speech in amyotrophic lateral sclerosis: a review.

Amyotrophic lateral sclerosis (ALS) is a progressive, adult-onset neurodegenerative disorder manifesting as a relentless loss of motor capabilities and, ultimately, death. Traditionally thought to affect solely the lower motor neurons and corticospinal tracts, recent studies suggest that the pathogenic process of ALS is more extensive, involving dysfunction of cortical grey and white matter with clinical correlates of impairment in cognition and language. The impact of speech and motor deficits are discussed in relation to the issues of assessment of cognition and language. Three case studies are presented for illustrative purposes. Finally, direction for future research to investigate cognitive dysfunction in ALS are presented.

Adult↗
PubMed1996

Proximal sciatic axotomy does not inhibit the induction of neurofilamentous inclusions following intracisternal aluminum chloride exposure.

We have previously demonstrated an acute, dose-dependent suppression of low molecular weight neurofilaments (NFL) and intermediate molecular weight neurofilaments (NFM) steady state mRNA levels while sparing those of high molecular weight (NFH) mRNA 48 hours (h) following the intracisternal inoculation of AlCl3 in young adult New Zealand white rabbits. To determine whether this alteration in NF steady state mRNA stoichiometry is a necessary prerequisite to the induction of neurofilamentous inclusions, we examined the response of spinal motor neurons to aluminum exposure in vivo following axotomy. Forty-eight h following a complete transection of the proximal sciatic nerve, rabbits were inoculated intracisternally with either 1000 microg AlCl3 in 100 microl 0.9% NaCl or 0.9% NaCl alone. Rabbits were killed at either 48 or 120 h post-inoculation, and the extent of neurofilamentous inclusion formation quantified in both the cervical and the lumbosacral cord. Following the axotomy, rabbits developed an ipsilateral hind-limb paralysis. In spinal motor neurons ipsilateral to the axotomy, chromatolytic changes were observed and both NFH and NFM mRNA levels were significantly reduced (p<0.001). At 48 h post-AlCl3 inoculation, 29% of motor neurons contralateral to the axotomy demonstrated inclusions, whereas 43% of ipsilateral motor neurons demonstrated inclusions (Fisher's test, two tailed, p = 0.0196). At 120 h post-axotomy 75% and 83%, respectively, of neurons were involved (p = 0.0212). Neurofilamentous inclusions did not form in NaCl-inoculated rabbits. These observations indicate that an altered stoichiometry of NF mRNA steady levels, with a relative overexpression of NFH mRNA, is not critical to the induction of neurofilamentous inclusions following AlCl3 exposure.

Aluminum Chloride↗
PubMed1996

Motor neuron disease presenting as acute respiratory failure: a clinical and pathological study.

Respiratory failure is rarely a presenting symptom of motor neuron disease. Seven patients with motor neuron disease who presented with acute respiratory failure of unknown cause and required mechanical ventilation were studied. They all had symptoms and signs suggestive of diaphragmatic weakness. Respiratory involvement seemed disproportionately severe, as six were ambulatory and only three noted limb weakness. Only one had tongue weakness and none had swallowing difficulty. Electrophysiological studies showed widespread denervation and, in particular, diaphragmatic involvement to explain the severe respiratory failure. Weaning from the ventilator was unsuccessful in all cases. The four patients examined at necropsy showed severe loss of anterior horns cells in the cervical cord, with only minimal upper motor neuron involvement. Motor neuron disease should be recognised as a cause of acute respiratory failure, secondary to diaphragmatic paralysis from involvement of phrenic motor neurons.

Acute Disease↗
PubMed1996

Sleep-disordered breathing in amyotrophic lateral sclerosis.

OBJECTIVE: The purpose of this study was to assess sleep and breathing in patients with amyotrophic lateral sclerosis (ALS) with bulbar muscle involvement. DESIGN: Prospective, controlled study of sleep and breathing measured during polysomnography. SETTING: University teaching hospital and referral center. PATIENTS: Patients with definite ALS and healthy age-matched control subjects. INTERVENTIONS: Eighteen ALS patients and 10 age-matched control subjects underwent one night of polysomnography. Thirteen patients with ALS were studied for a second night. RESULTS: The ALS patients had more arousals per hour (p = 0.008), more stage 1 sleep (p = 0.01), and a shorter total sleep time (TST) (279 +/- 69 vs 331.4 +/- 55.9 min, mean +/- SD, p = 0.04) than the control subjects. The ALS patients had mild sleep-disordered breathing with a greater apnea/hypopnea index (AHI) than the control subjects (p = 0.005). On the second night of polysomnography, there was an increase in TST (p = 0.003) and rapid eye movement (REM) sleep (p = 0.009), an improvement in sleep efficiency (p = 0.02), and less stage 1 sleep (p = 0.04). Eight ALS patients had sleep-disordered breathing consisting of periods of hypoventilation, predominantly during REM sleep. CONCLUSIONS: Sleep-disordered breathing occurs in patients with ALS and is similar to patients without ALS with respiratory muscle weakness. No obstructive sleep apnea was observed. One potential reason for its absence might be the inability of patients with respiratory muscle weakness to generate an inspiratory pressure greater than the upper airway closing pressure. This hypothesis should be addressed in future studies.

Aged↗
PubMed1995

Reversibility of neurofilamentous inclusion formation following repeated sublethal intracisternal inoculums of AlCl3 in New Zealand white rabbits.

In this report, we describe the clinical, topographical and immunohistochemical characteristics of neurofilament (NF) inclusion formation induced by the intracisternal inoculation of young adult New Zealand white rabbits at 28-day intervals with 100 micrograms AlCl3 over the course of 267 days. The ability to recover following cessation of aluminum exposure has also been assessed. The extent of neurofilamentous inclusion formation was proportionate to the cumulative amount of AlCl3 inoculated and initially consisted of fusiform axonal distention in the ventral spinal cord at day 51 following the initial inoculum. Spinal motor neuron perikaryal inclusions and discrete axonal spheroids were observed at day 107 and supraspinal neurofilamentous pathology by day 156. Perikaryal inclusions were immunoreactive to antibodies recognizing both poorly phosphorylated (SMI 32) and more highly phosphorylated high molecular weight NF (NFH). In contrast, axonal spheroids were intensely immunoreactive at all stages with antibodies recognizing highly phosphorylated NFH and an age-dependent NFH phosphorylation state (SMI 34) with only faint SMI 32 immunoreactivity. Immunoreactivity to an antibody recognizing ubiquitin-protein conjugates did not appear until day 156, whereas inclusions were not immunoreactive to antibodies recognizing either phosphatase-dependent or -independent microtubule-associated protein tau at any stage. Upon withdrawal from further AlCl3 exposure after intervals of 51, 107 or 156 days following the initial inoculum, clinical recovery ensued in all rabbits. In all but the most severely affected rabbits, perikaryal neurofilamentous inclusions resolved. However, axonal spheroids continued to be prominent. These studies demonstrate that the repetitive intracisternal inoculation of AlCl3 in New Zealand white rabbits induces a reversible process of neurofilamentous inclusion formation that preferentially affects motor neurons, and in which recovery will occur in those inclusions containing an admixture of both poorly and highly phosphorylated NFH.

Aluminum Chloride↗
PubMed1994

Dose-dependent selective suppression of light (NFL) and medium (NFM) but not heavy (NFH) molecular weight neurofilament mRNA levels in acute aluminum neurotoxicity.

We inoculated 5- to 6-week old New Zealand white rabbits intracisternally with either 100, 250, 500, 750, or 1000 micrograms of AlCl3 or 0.9% NaCl and correlated the extent of cervical motor neuron neurofilamentous inclusion formation at 48 h postinoculation with alterations in neurofilament (NF) mRNA levels. RNA was isolated from cervical spinal cord by the guanidine isothiocyanate method and individual RNA samples were normalized for poly(A+) content. Northern blot analysis was performed with cDNA probes for light (NFL), medium (NFM), and heavy (NFH) neurofilament subunit protein or with oligonucleotide probes for alpha-tubulin or actin. No significant alteration in the levels of alpha-tubulin, actin, or NFH mRNA were observed, regardless of the aluminum dose. In contrast, dose-dependent reductions in NFL and NFM mRNA levels occurred in direct proportion to the extent of neurofilamentous inclusion formation. While inoculums of NaCl or 100 or 250 micrograms AlCl3 induced neither inclusion formation or alterations in mRNA levels, both inclusion formation and reductions in the levels of NFL and NFM mRNA occurred thereafter, becoming maximal with inoculums of 1000 micrograms AlCl3. These experiments indicate that intracisternally administered AlCl3 acutely suppresses NFL and NFM mRNA levels without affecting those of NFH. This pattern is in distinct contrast to the uniform reductions of all NF mRNA transcript levels during neurogenesis or following axotomy, indicating a specific effect of aluminum upon steady-state levels of NF mRNA that correlates with the induction of neurofilamentous aggregates.

Aluminum Chloride↗
PubMed1994

Aluminum neurotoxicity: an experimental approach to the induction of neurofilamentous inclusions.

Acute or chronic aluminum neurotoxicity experiments in the rabbit suggest that aluminum can induce phosphorylation of neurofilamentous proteins. This may result in abnormal resistance to degradation or transport of neurofilament protein and so to the accumulation of neurofilaments in abnormal cells. The possible importance of this process in ALS is considered in relation to the neurofilamentous abnormalities characteristic of intraneuronal inclusions in ALS and in other neurodegenerative disorders.

Aluminum↗
PubMed1994

200 kDa and 160 kDa neurofilament protein phosphatase resistance following in vivo aluminum chloride exposure.

We have used time-course dephosphorylation experiments and two dimensional isoelectric focusing to assess the phosphorylation state of neurofilament (NF) proteins following the intracisternal inoculation of AlCl3. Littermates of New Zealand white rabbits, age 5-6 weeks, were inoculated with either 1000, 750, 500, 250 or 100 micrograms AlCl3 in 0.9% NaCl or 0.9% NaCl alone, killed 48 hours later and the NF-enriched cytoskeletal fraction isolated from the spinal cord. Neurofilamentous inclusions did not occur following inoculums of 100 or 250 micrograms AlCl3, but thereafter developed in increasing quantities in a dosage-dependent manner. Incubation of the NF-enriched fraction with E. Coli. alkaline phosphatase (enzyme: substrate 1:50) induced a replacement of the highly phosphorylated 200 kDa isoform of NFH with a more poorly phosphorylated 170 kDa isoform, confirmed by immunoblot analysis. This reaction was complete within 20 minutes with NF derived from NaCl, 100 or 250 micrograms AlCl3 inoculated rabbits and within 30 minutes for 500 micrograms AlCl3 inoculums. However, residual highly phosphorylated NFH isoforms persisted at 60 minutes for 750 micrograms inoculums and 90 minutes for that derived from 1000 micrograms AlCl3 inoculums. A similar inhibition of phosphatase activity was observed for NFM. Following two dimensional electrophoresis of the NF-enriched isolate, no alteration in the net phosphorylation state of individual NF subunit proteins was observed--regardless of the inoculum. These results demonstrate a dose-dependent induction of neurofilamentous inclusions in spinal motor neurons following intracisternal AlCl3 inoculation accompanied by increasing phosphatase resistance without a demonstrable alteration in NF net phosphorylation state.

Aluminum↗
PubMed1991

N-butyl benzenesulfonamide: a neurotoxic plasticizer inducing a spastic myelopathy in rabbits.

N-Butyl benzenesulfonamide (NBBS), a plasticizer used commercially in the polymerization of polyamide compounds, is neurotoxic. Young adult New Zealand white rabbits, inoculated repeatedly with NBBS by the intracisternal or intraperitoneal routes, developed a dose-dependent motor dysfunction characterized by limb splaying, hyperreflexia, hypertonia, gait impairment, and abnormal righting reflexes. Histopathological changes consisted of intramedullary thickening of the ventral horn axons, random neuroaxonal spheroids confined to brain stem nuclei and spinal motor neurons, and swollen dendritic processes of spinal motor neurons. Immunoreactivity to a monoclonal antibody against microtubule-associated protein-2 (MAP-2) was markedly increased in the dendrites of spinal motor neurons following thrice weekly intraperitoneal inoculations of NBBS for 4 months, whereas after 12 monthly intracisternal inoculations, MAP-2 immunoreactivity was absent or strikingly reduced in the same neuronal populations. Ultrastructurally, postsynaptic zones contained vacuoles and multilamellar bodies. These findings raise questions about the safety of NBBS to humans.

Animals↗