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M A Verity

Publications and source records attributed to M A Verity.

At least 19 recordsLinked to original sources
PubMed1992

Ca(2+)-dependent processes as mediators of neurotoxicity.

The Ca2+ ion exerts a profound influence on cellular processes and an understanding of control mechanisms of intracellular Ca2 homeostasis while complex is mandatory in this discussion. The identification and recognition of prolonged sustained increase in [Ca2+]i as a manifestation of neurotoxin-induced destabilization of [Ca2+]i homeostasis will be related to a variety of neurotoxicant-induced cell injuries. The sites of toxicant interaction with ATP-regulated Ca2+ pumps located in the neuronal/glial membrane and/or calciosomes; availability of Ca2+ proteins; disruption in mitochondrial mechanisms for Ca2+ storage; triggers of voltage-dependent Ca2+ channels and modulation of the Na+/Ca2+ exchanger will be identified and related to presumptive toxin action. Failure of one or more of these systems will result in continuous elevation of ionized [Ca2+]i--a reflection of Ca2+ destabilization. The targets resulting from Ca2+ destabilization will be identified, to include phospholipase C activation, PLA2 activation, protein kinase C (PKC) translocation, and activation of Ca(2+)-dependent calpain 1. The use of specific inhibitors of neurotoxicity, e.g., natural sphingolipids, sphingosine, down regulation of PKC, inhibitors and activators of adenylate cyclase, and antiprotease agents will allow for investigation of the role of these final common pathways in the evolution of neurotoxicity.

Animals↗
PubMed1992

Neurotoxins and environmental poisons.

Recent applications of modern neurobiological techniques have provided an impetus to understanding mechanisms of neurotoxicity. Environmental chemicals, including aluminium, and the organocompounds of mercury, lead and tin, may trigger neurodegenerative disorders. Regional differences in toxicity may be related to the complexity of the amino acid excitatory systems and the ability of individual cell systems to handle long-term abusive stimulation.

Animals↗
PubMed1991

Effects of interferon-gamma and its interaction with retinoic acid on human neuroblastoma differentiation.

Differentiation-promoting effects of interferon-gamma (IFN-gamma), both alone and in combination with retinoic acid (RA), were studied on the human neuroblastoma cell line, LA-N-5. The results show that IFN-gamma inhibited the growth and induced morphological differentiation in a dose- and time-dependent manner with measurable effects appearing at 20-40 IU/ml after 3 to 4 days of treatment in vitro. Acetylcholinesterase activity, used as a biochemical index of neuroblastoma differentiation, increased up to 2.5-fold in the presence of IFN-gamma with a half maximal concentration of approximately 100 IU/ml. Concomitantly, modest IFN-induced increases (less than or equal to 2-fold) in choline acetyltransferase (ChAT) and tyrosine hydroxylase (TH) activities were seen. Combination treatment of cells with IFN-gamma and RA resulted in synergistic effects on morphological differentiation, growth inhibition and induction of ChAT. Reversal of IFN-gamma's ability to influence neuroblastoma cell growth as well as potentiate the anti-tumor effects of RA was obtained in the presence of an antibody against the IFN-gamma receptor, implying receptor-mediated physiological events. Taken together, these data confirm the differentiating effects of IFN-gamma on human neuroblastoma cells and suggest that combination therapy with RA may be beneficial in the treatment of this disease.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1991

Infantile Pompe's disease, lipid storage, and partial carnitine deficiency.

A diagnosis of infantile Pompe's disease (glycogenosis type II) was made by muscle biopsy on a 6-month-old infant boy seen with hypotonia, weakness, and developmental regression. Histochemistry and electron microscopy revealed a vacuolar myopathy with massive glycoge accumulation associated with increased neutral lipid as demonstrated on Oil Red O reactions. Pleomorphic, hypertrophic mitochondria with distortion of cristae and electron-dense deposits within the matrix were identified. Acid alpha-1,4-glucosidase activity was absent but associated with increased neutral maltase activity and a variable compensatory rise in activity of other lysosomal enzymes. Biochemical studies demonstrated low free carnitine, normal acylcarnitine, increased activity of carnitine palmityl and acyl transferases, and other enzymes of beta-oxidation with the notable exception of low normal beta-hydroxyacyl-CoA dehydrogenase activity. The explanation for the lipid accumulation is uncertain but is likely related to the combination of low carnitine concentration in muscle, low beta-hydroxyacyl CoA dehydrogenase, representing a rate limiting enzyme of beta-oxidation, and nonspecific defective mitochondrial function.

Carnitine↗
PubMed1991

Fatal hemorrhage in a cerebral pilocytic astrocytoma-adult type.

A 69-year-old female presented with a 6-week history of left-sided weakness and a large cerebral mass on computed tomographic scan and magnetic resonance imaging. The patient subsequently had an acute intracerebral hemorrhage with uncal and tonsillar herniation. Postmortem examination revealed an acute cerebral hemorrhage from a pilocytic astrocytoma-adult type. These cerebral neoplasms are rarely associated with hemorrhage.

Aged↗
PubMed1991

Paradoxical potentiation by low extracellular Ca2+ of acute chemical anoxic neuronal injury in cerebellar granule cell culture.

Acute chemical anoxic injury was produced in primary cerebellar granule cell cultures incubated with iodoacetate (IAA) alone or IAA combined with potassium cyanide (KCN). Cytotoxicity was assessed using Trypan blue exclusion or LDH release. Four millimolars of KCN induced approx 30% neuron death at 3 h, whereas greater than 50% cell death was produced by 0.2 mM IAA. No potentiation of cytotoxicity was observed by IAA + KCN. A total of 0.2 mM IAA produced an early major reduction of intracellular ATP prior to the onset of neuron injury or reduction in intracellular glutathione (GSH). Medium Na+ replacement by choline, K+, or methylglucamine protected against IAA-induced neuronal injury, reduced the rate of decline of intracellular ATP but had no effect on intracellular GSH. Some 80% neuronal survival was obtained when Na+ was deleted from the medium even after the intracellular ATP had been reduced to less than 10% of control. Removal of Ca2+ from the medium had no effect on control culture, Trypan blue exclusion, GSH, or ATP, but potentiated the onset and magnitude of IAA-induced cytotoxicity. ATP and GSH decline. Loading of granule cells with the Ca2+ chelator Fura-2 did not influence IAA-induced cytotoxicity in control or low Ca2+ media. Addition of 50 microM glutamate had a minimal cytotoxic effect over 3 h and the combined addition of 0.2 mM IAA plus 50 microM glutamate did not potentiate IAA-induced injury. The glutamate receptor antagonists, D-2-amino-5-phosphonovaleric acid (APV) or kynurenate did not block IAA-induced injury in control medium but inhibited the potentiation of toxicity seen in the low Ca2+ medium. This study suggests the use of IAA as a chemical anoxic agent in cerebellar granule cell culture. The early, dose-dependent decline in ATP may be dissociated from GSH change. Acute IAA-induced injury is Na+/Cl- dependent but paradoxically potentiated in low Ca2+ medium. The low Ca2+ potentiated component was sensitive to glutamate/NMDA receptor antagonists and associated with reduction of intracellular GSH.

2-Amino-5-phosphonovalerate↗
PubMed1991

Neuromuscular manifestations of L-tryptophan-associated eosinophilia-myalgia syndrome: a histomorphologic analysis of 14 patients.

The recent delineation of a clinical syndrome marked by eosinophilia, myalgia, and scleroderma-like skin changes associated with L-tryptophan use has necessitated the Centers for Disease Control to initiate a health alert. The likely association of L-tryptophan ingestion with a syndrome that mimics eosinophilic fasciitis (Shulman's syndrome) further identifies an environmental agent associated with an inflammatory sclerosing rheumatic disease process. In this report, we present the clinical, morphologic, and enzyme histochemical findings in muscle, skin, and fascia biopsies from 14 cases fulfilling the Center for Disease Control diagnostic criteria for L-tryptophan-associated eosinophilia-myalgia syndrome. The clinical syndrome reveals a high incidence of arthralgia, elbow contracture, and clinical neuropathy. The absence of significant change in creatine kinase or sedimentation rate allows for diagnostic separation from other inflammatory myopathies. Histoenzymatic features in muscle biopsies reveal a preferential epimysial-perimysial noneosinophilic infiltration characterized by acid phosphatase reactive histiocytosis, nonnecrotizing venulitis, perineural inflammation within dermis and perimysium, type II fiber atrophy with superimposed denervation features, and perifascicular alkaline phosphatase reactivity representing early neofibroplasia. The constellation of changes in skin, fascia, and muscle, with the defined clinical syndrome, allows for accurate differentiation from allied syndromes, including eosinophilic polymyositis, scleroderma, idiopathic polymyositis/dermatomyositis, polyarteritis nodosa, and toxic oil syndrome. Accurate differentiation from eosinophilic fasciitis still rests on a history of L-tryptophan ingestion.

Adult↗
PubMed1991

Oxidative mechanisms underlying methyl mercury neurotoxicity.

Cerebellar granule cells from 5-12-day-old rats can be incubated in suspension at 37 degrees C for up to 3 hr with minimal decline in viability. Methyl mercury was found to produce time- and concentration-dependent cell killing with greater than 85% cell death after 3 hr exposure to a concentration of 20 microM. Previously characterized inhibition of protein and RNA synthesis as well as known methyl mercury-induced defects in cellular ATP production have been shown to be incapable of causing this degree of cell death. Here we report that methyl mercury induced a concentration-dependent increase in membrane lipoperoxidation and a rapid decline in reduced glutathione in this cerebellar neuronal preparation. Hydrogen peroxide at 5 mM was found to closely reproduce each of the cytotoxic effects manifested by methyl mercury suggesting that oxidizing conditions produced by methyl mercury may account for the observed cell death. Methyl mercury-induced lipoperoxidation was not the cause of cell death since malonaldehyde production could be blocked by alpha-tocopherol or EDTA without appreciable protecting against cell death. Significant protection from methyl mercury-induced cell death was observed, with EGTA, deferoxamine and KCN. We propose that oxidative events contribute to the toxic mechanism of action of methyl mercury in isolated cerebellar granule neurons.

Animals↗
PubMed1991

The effects of dynamic tension and reduced graft size on muscle regeneration in rabbit free muscle grafts.

In a study of 28 adult New Zealand White rabbits, the influence of tension and size on muscle regeneration in tibialis anterior free muscle grafts (without vascular anastomoses) was examined 6 months after transplantation. Three laboratory models were studied: (1) whole dynamic (WD) graft (allowing ankle excursion and, therefore, variable dynamic physiologic tension), (2) whole static (WS) graft (constant, fixed length and, thus, only isometric tension), and (3) longitudinally sliced (reduced radius) dynamic (SD) model. Bilateral orthotopic grafts of the tibialis anterior muscle were performed in 24 rabbits (eight animals in each of the three different model groups). Controls consisted of normal tibialis anterior muscle from four age-matched rabbits. All tibialis anterior muscle grafts were examined histologically (fiber counts) and functionally (determined by in situ contractile properties under maximal stimulation conditions). The WD grafts demonstrated a significantly higher number of regenerated fibers per muscle cross section (4819 +/- 589) than the WS (2221 +/- 603) or SD (1919 +/- 732) grafts. The amount of tetanic tension in the WD grafts was 35 percent of the control and twice as much as that of the WS grafts (WD 1.0 +/- 0.2 kg versus WS 0.5 +/- 0.4 kg; p less than 0.05). The SD grafts produced approximately one-third as much maximum tetanic tension as the WD grafts (0.3 +/- 0.1 kg versus 1.0 +/- 0.2 kg), demonstrating that the amount of recovery was similar in these two dynamic models, since only the longitudinal middle third of the muscle was grafted in the SD model. Free muscle grafts under dynamic tension, which allows excursion, have shown a greater amount of muscle-fiber regeneration and restoration of function compared with a graft with fixed length. The positive effect of dynamic mechanical tension on small autogenous free muscle grafts (without vascular anastomoses) is clinically significant in the reconstruction of facial and hand neuromuscular deficits when blood vessels are not available for reanastomosis. Future studies using the tibialis anterior WD and SD transplant models will strengthen our understanding of the events of spontaneous revascularization and skeletal muscle regeneration.

Analysis of Variance↗
PubMed1990

Modulation of intracellular cyclic adenosine monophosphate levels and the differentiation response of human neuroblastoma cells.

We have tested the ability of various compounds to raise intracellular cyclic AMP (cAMP) levels and, either alone or in combination with retinoic acid (RA), to promote differentiation of two "RA-resistant" sublines of LA-N-5 human neuroblastoma cells, designated LA-N-5HP and LA-N-5R9. Direct activation of adenylate cyclase by forskolin and cholera toxin increased intracellular cAMP levels over 10-fold in both cell lines after 1 h of treatment, after which the levels slowly declined for the next 16 to 24 h. After 5 days of continuous treatment, cAMP levels still remained 2- to 7-fold elevated above controls and were accompanied by a decrease in cell proliferation and an increase in neurite outgrowth. All these effects were exaggerated when the agents were combined with phosphodiesterase enzyme inhibitors. Increasing cAMP levels (up to 24-fold) with N6,O2'-dibutyryl cyclic AMP (dbcAMP) or 8-bromo-cAMP also resulted in decreased proliferation and an increase in morphological differentiation. Isoproterenol and epinephrine did not alter cAMP levels and had no discernible biological effects. Of the agents that raised cAMP levels, only dbcAMP caused an increase in acetylcholinesterase activity. This effect was duplicated with sodium butyrate and prostaglandin E1 in the absence of an increase in cAMP. RA promoted differentiation but also had little effect on cAMP levels. Combination treatment of cells with RA plus agents that raised cAMP levels resulted in greater degrees of differentiation than seen with single agent treatments. We conclude that: (a) the cAMP synthetic and degradative pathways are functional in LA-N-5HP and LA-N-5R9 cells; (b) elevation of cAMP is sufficient for inhibiting proliferation and promoting neurite outgrowth from these cells, but is not a necessary condition for inducing differentiation; and (c) elevation of intracellular cAMP potentiates the differentiation-inducing activity of RA.

Acetylcholinesterase↗
PubMed1990

Association of L-tryptophan and an illness resembling eosinophilic fasciitis. Clinical and histopathologic findings in four patients with eosinophilia-myalgia syndrome.

The Centers for Disease Control has recently reported an association between the use of oral L-tryptophan preparations and a disease marked by severe myalgia, peripheral eosinophilia, and neuromuscular and cutaneous abnormalities. They have labeled the condition eosinophilia-myalgia syndrome. We report here the clinical and histopathologic findings in 4 patients who developed an illness resembling eosinophilic fasciitis following the initiation of oral L-tryptophan supplementation.

Adult↗
PubMed1990

Menthol blocks dihydropyridine-insensitive Ca2+ channels and induces neurite outgrowth in human neuroblastoma cells.

Voltage-gated Ca2+ channels were identified in LA-N-5 human neuroblastoma cells using the Ca2+ sensitive fluorescent probe, fura-2. Using a variety of "classical" Ca2+ channel blockers, we have demonstrated the presence of both dihydropyridine (DHP)-sensitive and -insensitive channel types that can be activated by depolarization of the cells with either high K+ or gramicidin in the bathing solution. Brief exposure of LA-N-5 cells to menthol blunted the depolarization-induced Ca2+ influx though both DHP-sensitive and DHP-insensitive channels. This effect is concentration dependent (50% maximal blocking effect with 0.25 mM menthol), rapid in onset, and readily reversible. The specificity of the Ca2(+)-channel blocking effect of menthol was demonstrated in parallel studies using compounds with similar structures: menthone blocked Ca2+ channels with about half the potency of menthol, while cyclohexanol was without effect. Addition of either menthol or menthone to LA-N-5 cultures induced neurite outgrowth, cellular clustering, and reduction of cell growth in a dose-dependent fashion that correlated with the ability of these compounds to inhibit the DHP-insensitive Ca2+ influx. Cyclohexanol had no biologic activity. Taken together, the parallel potency for blockade of DHP-insensitive Ca2+ influx with the biologic activity of menthol suggests a role for certain types of Ca2+ channels in triggering growth and morphologic changes in LA-N-5 cells.

Acetylcholinesterase↗
PubMed1990

Cultured human brain capillary endothelial cells are permissive for infection by human cytomegalovirus.

Human cytomegalovirus (HCMV) infection is associated with a variety of systemic and neurologic diseases. In vitro HCMV growth is usually studied in fibroblasts, while in vivo HCMV growth is frequently observed in a wide variety of cell types including glia, neurons, and human brain capillary endothelial (HBCE) cells. To examine the biology of HCMV in HBCE cells, we have established a procedure for isolating these cells from human brain temporal lobectomies. Greater than 99.0% of these cultured cells were identified as HBCE cells on the basis of positive staining for factor VIII-related antigen-Von Willebrand's factor (F VIII) and Ulex Europaeus agglutinin I (UEA I). HCMV antigens were detected by immunocytochemistry in HBCE cells after infection with strain AD 169. Intracellular virions were observed in infected cells by electron microscopy and infectious virus was released from HBCE cells. In addition, infected cells were confirmed as endothelial cells by double staining with antibodies to F VIII and HCMV.

Antibodies, Viral↗
PubMed1990

Multiple sulfatase deficiency: clinical, neuropathological, ultrastructural and biochemical studies.

We describe the clinical, pathological, ultrastructural and biochemical features in the case of a 15-year-old boy with multiple sulfatase deficiency. Clinical abnormalities included hypotonia, retarded psychomotor development, hepatosplenomegaly, pigmentary degeneration of the retina, myoclonic seizures, aortic insufficiency and quadriplegia. Urinalysis revealed increased heparan sulfate. At necropsy, aortic and mitral valves revealed nodular thickening and periodic acid-Schiff (PAS)-positive, metachromatic granules in renal proximal tubules. The brain weighed 400 g and demonstrated cerebral and cerebellar atrophy with a retrocerebellar meningeal cyst. Cortical neurons contained periodic acid-Schiff-positive and cresyl violet-reactive granules. White matter demonstrated brown metachromasia and intense fibrillary gliosis. Conjunctival fibroblasts contained amorphous vacuoles with dense osmiophilic nucleoid cores. Pleomorphic extracellular, intraneural and intraglial inclusions were noted in the brain. Activities of arylsulfatase A, B and C were diminished markedly in autopsied tissue from brain, liver, and kidney (0, 0 and less than 10% of control activities, respectively). Partial deficiencies of iduronate sulfatase and heparan sulfatase were noted in different tissues. Variable decreased enzyme activities were expressed in leukocytes: arylsulfatase A, less than 33%; B, 40%; and C, 90%; heparan sulfatase, 2%; and iduronate sulfatase was not detectable. Near normal activities were found in cultured fibroblasts.

Adolescent↗
PubMed1990

Methyl mercury stimulates protein 32P phospholabeling in cerebellar granule cell culture.

Cultures of cerebellar granule neurons have been utilized to examine morphological and biochemical consequences of methyl mercury (MeHg). Exposure to MeHg for 24 h was found to exert toxic effects at concentrations below 1 microM characterized by neuron degeneration and neuritic varicosities. Dose-response and time course profiles for cell death were established using the 51Cr release assay, which revealed that 1 microM MeHg produced 15% cell death at 24 h, progressing to 50% at 48 h. Labeling of cultures with [32P]orthophosphate following 24-h exposure to 1 microM MeHg disclosed abnormalities in both protein and lipid phosphorylation. After 24-h exposure to 5 microM MeHg, phospholabeling of protein and lipid increased 174 and 128%, respectively, compared with controls. This stimulation of phosphorylation appeared to be neuron specific since cultures enriched in cerebellar glial cells and devoid of granule neurons displayed dose-dependent inhibition of total phosphorylation. Measurement of 32P labeling of ATP using a cyclic AMP-dependent protein kinase assay in conjunction with the firefly luciferase assay for ATP indicated no significant change in either total ATP levels or [32P]ATP specific activity at 1 or 4 h as a function of [MeHg]. Studies measuring 32P-phosphoprotein turnover indicated that MeHg had no effect on intracellular protein phosphatase activity. We conclude that one of the manifestations associated with in vitro cerebellar granule cell neurotoxicity is an abnormality in protein phosphorylation that is independent of [32P]ATP specific activity and protein phosphatase activity.

Adenosine Triphosphate↗
PubMed1990

Altered patterns of protein phosphorylation and synthesis caused by methyl mercury in cerebellar granule cell culture.

In the preceding report we demonstrated a dose-dependent increase in 32P-phosphoprotein labeling after 24-h exposure of cultured cerebellar granule neurons to methyl mercury (MeHg), a response that was not observed in glial cultures. In the present study we have examined 32P-labeled phosphoproteins by two-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis. At concentrations of 0.5 and 1 microM, which were not extensively cytotoxic, MeHg enhanced phosphorylation of numerous acidic proteins, particularly a cluster of proteins with Mr approximately 28,000 and pI approximately 5.7-5.9 (pp 28/5.7-5.9) and a protein with Mr approximately 58,000 and pI approximately 5.6. The pp28 cluster displayed considerable two-dimensional pattern variability from one experiment to the next, suggesting susceptibility to subtle structural modifications. Time course studies revealed that increased 32P phospholabeling of pp28/5.7-5.9 was detectable after 12-h exposure to 3 microM MeHg and reached values of 300-500% of control by 24 h. These studies also showed that among the 21 proteins analyzed by two-dimensional densitometry, 32P phospholabeling of four proteins increased by 20-50% and of two proteins decreased by 20-50% after 24-h treatment. However, exposure to 10 microM MeHg produced stimulation of pp28/5.7-5.9 32P phospholabeling within 2 h. Under these conditions a relatively high stimulation (sevenfold) of pp28/5.7 phospholabeling occurred, while pp28/5.9 32P phospholabeling was only moderately (5-20%) enhanced. 35S and 32P double-label analysis of cells treated with 0, 0.5, and 1 microM MeHg indicated specific stimulation of 32P phospholabeling of these proteins without increased polypeptide synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Mesolimbocortical dementia: clinico-pathological studies on two cases.

The clinicopathological findings are presented of two cases of mesolimbocortical dementia. Both cases were characterised by late onset slowly progressive personality changes and progressive intellectual deterioration without clinical Parkinsonism. Neuropathological findings revealed non-specific neuronal degeneration, Holzer and GFAP positive gliosis primarily affecting the limbic system, caudate, thalamus and substantia nigra. The pathological findings coincide with the distribution of the non-striatal dopaminergic pathways and suggest an intrinsic involvement of these pathways to account for the clinical and pathological manifestations.

Aged↗