Biomedical subjects

M A Verity

Publications and source records attributed to M A Verity.

At least 55 records · Page 3Linked to original sources

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↗

PubMed1990

Comparative observations on inorganic and organic lead neurotoxicity.

Environmental and occupational exposure to lead still generates concern, and recent studies have focused such concern on the role of body burden of lead during the fetal/neonatal period, especially in the genesis of disturbed central nervous system development. This discussion provides some comparative observations on the neurotoxicity of inorganic and organic lead species. The characteristics acute, predominantly cerebellar encephalopathy associated with neonatal high lead exposure contrasts to the subtle, axo-dendritic disorganization shown to be associated with low-level neonatal inorganic Pb2+ exposure. There is a preferential involvement of the hippocampus in both low-level inorganic Pb2+ and organolead exposure, and the clinical syndromes of irritability, hyperactivity, aggression, and seizures are common features of disturbed hippocampal function. Neurotransmitter system abnormalities have been described with inorganic Pb2+, but recent attention has focused on the abnormalities in glutamate, dopamine and/or gamma-aminobutyric acid (GABA) uptake, efflux, and metabolism. Abnormalities of GABA and glutamate metabolism are also found with the organolead species. While the pathogenesis is still unclear, the interactive role of Pb2+ on mitochondrial energy metabolism, Ca2+ uptake, intracellular Ca2+ homeostasis, and neurotransmitter influx/efflux is considered. Consideration is given to low-dose inorganic Pb2+ and organolead effects on mitochondrial and/or plasmalemmal membranes inducing either Cl-/OH- antiport-linked depolarization, inhibition of intracellular ATP biosynthesis and transduction. and/or abnormalities induced due to the preferential affinity of Pb2+ for intracellular Ca2(+)-cytoplasmic protein, e.g. calmodulin. Testable hypotheses are presented that may provide an understanding of the pathogenesis underlying dystrophic neuronal development under the influence of inorganic or organolead intoxication.

Animals↗

PubMed1990

Ionic modulation of triethyllead neurotoxicity in cerebellar granule cell culture.

While the molecular mechanism underlying triethyllead (TEL) neurotoxicity is unknown, we hypothesize that triethyllead mediates an accelerated Cl-/OH exchange across neuronal membranes leading to prolonged depolarization and neuronal cell injury. As a test of this hypothesis we have investigated the effect of external ion modulation on triethyllead neurotoxicity in cerebellar granule cell culture. Cultures were prepared from neonatal rats and used 10-20 days in vitro. Cytotoxicity was assessed by lactate dehydrogenase (LDH) release and trypan blue exclusion. A slow, dose-dependent (1-30 microM TEL) release of LDH occurred after a variable latent period dependent upon [TEL]. External replacement of [Cl-]e by Na isothionate dramatically shifted the dose response curve to the left reflecting an accelerated stimulation of LDH release, while replacement of extracellular [Na+]e with equimolar choline chloride had a minimal protective effect. Similarly, high [Mg2+]e or low [Ca2+]e did not protect or potentiate TEL cytotoxicity. The low [Cl-]e accelerated TEL cytotoxicity was dependent on medium pH: alkaline pH potentiated the cytotoxicity. Low [Cl-]e had no significant effect on culture ATP over 5 hrs. ATP reduction was markedly stimulated by TEL in low Cl- medium in contrast to the minimal decline in [ATP] in the control medium. The reduction of ATP in the low [Cl-]e medium occurred prior to LDH or trypan blue staining release confirming that such reduction in [ATP] was not secondary to cell damage. Substituting K sulfate or Na sulfate for the Cl(-)-free medium revealed marked loss of ATP without LDH release in control and TEL supplemented cultures. These observations provide supporting evidence for the role of an abnormal Cl- flux in mediating TEL-induced neurotoxic injury. Specifically, the membrane depolarization is proportional to the gradient imposed by Cl- efflux/OH influx, stimulated by low [Cl-]e. The rapid loss in ATP appeared early, was not a secondary reflection of neuronal damage but a result of a combination of increased ion flux at the plasma membrane, stimulation of Na+/K+ ATPase and direct TEL-induced inhibition of mitochondrial oxidative phosphorylation.

Adenosine Triphosphate↗

PubMed1990

Amyloidoma of the skull base.

Localized amyloid tumors of the central nervous system are rare. We present the case of a 59-year-old white man with a large expansile amyloidoma at the base of the skull. To our knowledge this is the second reported case of localized amyloid tumor involving the skull.

Amyloidosis↗

PubMed1989

MPTP is proconvulsant acutely but has no long-term effect in rodent models of seizure and epilepsy.

1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) was used to lesion the substantia nigra of rodents to look for changes in various animal models of epilepsy and seizures. MPTP, acutely administered to C57BL/6J mice, could cause seizures at high doses and enhanced maximal electroshock seizures at lower doses. Older mice were more sensitive to MPTP toxicity. MPTP given over 1 week to produce a 75% drop of striatal dopamine had no effect on seizure thresholds to pentylenetetrazol or picrotoxin and did not change the maximal electroshock seizure. Epileptic gerbils given maximally tolerated doses of MPTP had only a slight striatal dopamine reduction (32%) while seizures remained unaltered. The data are consistent with the hypothesis that chronic dysfunction of dopamine containing substantia nigra neurons have no significant influence on seizures in these animal models.

Animals↗

PubMed1989

Rapid cell death induced by methyl mercury in suspension of cerebellar granule neurons.

We have further investigated the cytotoxicity of methyl mercury (MeHg) in cerebellar granule neurons isolated from 5-12-day-old rats. At 20 microM MeHg adenosine triphosphate (ATP) levels were reduced to 30% of control within 15 minutes and 1% of control at three hours (h), while cell viability assayed by trypan blue exclusion was reduced to approximately 80% and 20% of control, respectively. When potassium cyanide (KCN) was used to reduce ATP levels greater than 95%, virtually no change in cell viability was observed during three h incubation. Potassium cyanide combined with cycloheximide and actinomycin D to inhibit ATP and macromolecule synthesis simultaneously caused substantially less cell death than that produced by MeHg. Comparable rates of cell death were obtained when the free-radical generating system, hypoxanthine plus xanthine oxidase, was included with KCN in the incubation. Murine hybridoma MHY206 cells, representing a non-neuronal cell type, were less sensitive to cell killing by MeHg compared to granule neurons at equivalent cell protein concentrations. A three h exposure to 20 microM MeHg resulted in the death of 96% of the granule neurons while only 27% of the hybridoma cells were permeable to trypan blue. The results suggest that additional cytotoxic mechanisms beyond perturbations of the main metabolic pathways are involved in the neurotoxic mechanism of action of MeHg in cerebellar granule neurons. The results also indicate that oxidative or free-radical-generating systems are capable of reproducing the temporal pattern of neuronal cell destruction manifested by MeHg.

Adenosine Triphosphate↗

PubMed1988

Dysmaturation neuromyopathy: correlation with minimal neuropathy in sural nerve biopsies.

Dysmaturation (neuro)myopathy without specific histochemical or cytoarchitectural characteristics accounts for many cases of hypotonia in infancy. We obtained a maturation profile for type I and type II fibers from birth to 6 years of age, from which a classification of fiber dysmaturation based on fiber-type hypotrophy and coefficient of fiber variation is presented. We analyzed the morphometric, ultrastructural, and single fiber teasing findings in the sural nerve of ten infants with hypotonia and dysmaturation myopathy based on the above classification. Data on endoneurial area, myelinated fiber density, proportion of large (greater than 6 micron) myelinated fibers, unmyelinated fiber density, regression analyses of myelin area:axon area, and mean myelin thickness were developed. Abnormalities in large myelinated fiber density (3 cases), disturbances in myelination index (5), and single fiber teasing abnormalities in internode length (1) were found. Ultrastructural abnormalities were observed and classified as group 0 changes similar to the five control nerves; group 1, in which rare fibers showed degeneration or basement membrane duplication; and group 2, which was characterized by multiple abnormalities including degenerate nuclei, amyelinate fibers, degeneration/regeneration, excessive basal lamina reduplication, and hypomyelination. This study provides evidence that minimal neuropathic abnormalities are present in the sural nerve of infants carrying a diagnosis of dysmaturation neuromyopathy.

Adolescent↗

PubMed1988

Brain cellular injury and recovery--horizons for improving medical therapies in stroke and trauma.

An edited summary of an Interdepartmental Conference arranged by the Department of Medicine of the UCLA School of Medicine, Los Angeles. The Director of Conferences is William M. Pardridge, MD, Professor of Medicine. After ischemic and traumatic brain injury, many cells may be rendered dysfunctional but are not irreversibly damaged or disrupted. The brain tissue may become metabolically deranged, and neurons, while still alive, are paralyzed and cannot create an action potential or conduct an electrical impulse. This injured brain tissue is in a precarious state of increased vulnerability. If the milieu of the favorable, they may recover; if it is slightly unfavorable, they may die. There is now evidence that reversibly injured brain tissue will die from an ischemic or hypoxic insult ordinarily tolerated by the normal brain. The major challenge of modern research in stroke and trauma is to define the chemical and metabolic milieu in which the injured brain exists and to define an ideal milieu for healing.

Adult↗

PubMed1988

Subacute perimyositis.

We describe a patient who developed a benign myopathy with features suggestive of subacute perimysial inflammation. There was no blood eosinophilia or infectious agent identified. Creatine phosphokinase was not significantly elevated. Electromyography showed a myopathic process. Muscle biopsy showed predominantly subacute perimysial inflammation with rare eosinophils. The patient recovered completely after therapy with glucocorticoids and a nonsteroidal antiinflammatory drug. The features of our case were compared to known causes of myositis with or without eosinophils. It may be part of the spectrum of relapsing eosinophilic perimyositis or may be a condition previously unreported.

Acute Disease↗

PubMed1987

Progressive subcortical gliosis of Neumann: a clinicopathologic study of two cases with review.

A clinico-pathological report is given of two cases of progressive dementia of fronto-temporal type associated with variable cortical neuronal loss and extensive subcortical and deep white matter gliosis. There was minimal demyelination of white matter, significant gliosis of thalamus and inferior olivary nuclei. The authors review the condition of progressive subcortical gliosis, compare such changes with white matter changes in other dementias, examine the relationship to Kraepelin's disease, contrast the disorder with atypical Pick's dementia, progressive dementia with motor neuron disease and Creutzfeldt-Jakob dementia.

Dementia↗

PubMed1987

Triethyllead inhibits gamma-aminobutyric acid binding to uptake sites in synaptosomal membranes.

Triethyllead (TEL), the active metabolite of tetraethyllead, was shown previously to inhibit selectively high-affinity Na+-dependent uptake of gamma-aminobutyric acid (GABA) into cerebrocortical synaptosomes. Such inhibition was not related to the Na+ gradient, Na+,K+-ATPase activity, [Cl-], or energy charge. We report here that TEL inhibits GABA binding to the presynaptic transporter involved in Na+-dependent uptake. Scatchard plot analysis of Na+-dependent [3H]GABA binding to a highly purified synaptic plasma membrane preparation revealed that 25 microM TEL reduced the Bmax by 44%, leaving the KD unchanged. This binding was reversible and predominantly involved membrane uptake sites, as characterized by pharmacological specificity to GABA ligands. Approximately 85% of specific GABA binding was considered membrane uptake site binding, as indicated by sensitivity to nipecotic acid and diaminobutyric acid, with relative insensitivity to muscimol, bicuculline methiodide, baclofen, and beta-alanine. With respect to previous data, these finding suggest that TEL inhibits Na+-sensitive high-affinity GABA uptake by interfering with GABA binding to its presynaptic transporter.

Animals↗

PubMed1987

Selective inhibition of synaptosomal gamma-aminobutyric acid uptake by triethyllead: role of energy transduction and chloride ion.

Triethyllead (TEL) is a CNS neurotoxin producing bizarre neurobehavioral changes. The principal objective of this study was to determine if TEL-induced defects in energy metabolism were responsible for the inhibition of synaptosomal Na+-dependent high-affinity uptake of gamma-aminobutyric acid (GABA). A dose-dependent inhibition of GABA uptake (ID50 = 10 microM TEL) was found during 30-s incubations. Uptake of glutamate was more resistant to the inhibitory effects of TEL. A TEL-induced Cl(-)-dependent synaptosomal deficit of ATP was observed. Such deficit in high-energy phosphate was time-dependent and did not occur in the absence of Cl- or as early as 30 s. Inhibition of GABA uptake, on the other hand, was a Cl(-)-independent phenomenon and was observed at as early as 30 s. TEL was not competitive with Na+ or GABA itself, as the effects of TEL were not overcome with high [Na+] or [GABA]. These results indicate that the locus of TEL inhibition of GABA uptake is not a Cl(-)-dependent event and does not involve a perturbed transmembrane electrochemical gradient, due to either an observed mitochondrial defect or an inhibition of Na+, K+-ATPase directly.

Adenosine Triphosphate↗

PubMed1987

Latency of mouse cytomegalovirus in sciatic nerve.

This report describes a mammalian model for exploring the role of virus in peripheral neuropathy. Schwann cells in culture were permissive for mouse cytomegalovirus (MCMV) replication. Intraperitoneal inoculation rarely led to sciatic nerve infection. Sciatic nerves infected by direct intraneural injection produced infectious virus and contained viral antigen at 4 days postinfection (pi). Nerves taken later, at 4 to 8 weeks pi, contained no infectious virus, but MCMV was present in a latent state because culture of nerve explants reactivated virus. The findings contrast the viral permissiveness of cultured Schwann cells to the latency observed in intact peripheral nerve.

Animals↗

PubMed1986

The anterior scalene muscle in thoracic outlet compression syndrome. Histochemical and morphometric studies.

Histochemical studies and morphometric fiber type analysis were done on biopsy specimens of anterior scalene muscle (ASM) from patients with thoracic outlet compression syndrome (TOS), without structural abnormality. Hypertrophy and atrophy factors were determined from muscle fiber histograms of ASM from controls, patients with TOS, and after scalene tenotomy. Scalene muscle from patients with TOS showed marked type 1 (tonic contracting) fiber predominance (85.1% +/- 5.1%) and type 1 fiber hypertrophy (55.6 +/- 2.7 microns). After tenotomy there is a reduction of type 1 fiber representation, selective atrophy in the type 1 fiber system (atrophy factor, 0.66 +/- 0.24), and increase of type 2 fibers. These distinctive changes indicate that ASM is uniquely structured in fiber composition to sustain prolonged contraction. The ASM in patients with TOS demonstrates an extraordinary adaptive transformation and recruitment response in the type 1 fiber system reflecting chronic increased tone or motor neuron stimulation. These observations form a basis for clarifying the structural and pathophysiologic changes in TOS.

Adult↗

PubMed1986

Search for virus nucleic acid sequences in postmortem human brain tissue using in situ hybridization technology with cloned probes: some solutions and results on progressive multifocal leukoencephalopathy and subacute sclerosing panencephalitis tissue.

In order to obtain a useful and readily applicable in situ hybridization (ISH) protocol for progressive central nervous system (CNS) diseases of unknown etiology that are possibly due to persistent viral infection, known and well described diseases were studied, namely, progressive multifocal leukoencephalopathy (PML) and subacute sclerosing panencephalitis (SSPE). The procedures described were validated by confirming results obtained by other investigators using histology, immunocytochemistry, electron microscopy, and ISH. A number of frequently encountered problems of tissue preparation are addressed as well as techniques to reduce autoradiography exposure times. A multi-staged specific, sensitive, reliable, and valid procedure for detection of viral genomes, mRNA and proteins is approached. Formalin-fixed and paraffin-embedded (FFPE) brain material from six patients who died with PML and one patient who died from SSPE were studied using ISH with a tritium-labeled cloned JC virus DNA probe and a measles-cloned nucleocapsid (NC) gene cDNA probe, respectively. This report constitutes a methodological framework as well as a detailed neuropathological analysis of identified brain cell populations within which in situ hybridization was detected. In early PML lesions, swollen nuclei or oligodendrocytes were the predominant cells labeled, whereas older lesions revealed increased numbers of reactive and bizarre hypertrophic astrocytes hybridized at the outer periphery of the demyelinated lesions. The hybridization varied greatly in intensity in different cells. Intense hybridization was noted very rarely in microglial cells, including rod cells and rarely in venular pericytes, intravascular mononuclear cells, or in vascular endothelial cells. These results, considered together with previous findings, indicate that in PML the viral infection runs different courses in the various cells: in astrocytes the viral genome persists for a long time inducing pathological changes in some cells. In oligodendrocytes the infection rapidly lyses the cells. There was a good correlation between chromatic changes observable in routinely stained sections and virus presence. In addition, in situ hybridization using a measles-NP-cloned probe in white matter from FFPE SSPE brain is presented confirming earlier results in SSPE cryopreserved brain.

Adult↗

PubMed1986

Influence of thyroid hormones on rat cerebellar cell aggregation and survival in culture.

In order to study the effect of thyroid hormones on rat cerebellar granule cells, cerebellar perikarya isolated from 5-7-day-old rats were cultured in the presence of normal fetal calf serum, fetal calf serum treated with Dowex-2 ion exchange resin to remove thyroid hormones, or ion exchange-treated serum resupplemented with physiological concentrations of T4 and T3. Granule cells grown under hypothyroid conditions showed abnormal cellular aggregation, neurite fasciculation and cell survival. Cell aggregation, which may be an in vitro correlate of cerebellar granule cell migration to the internal granule layer, was reduced by over 50% under hypothyroid conditions. The rate of protein synthesis in hypothyroid cultures was stimulated by as much as 3-fold compared to thyroid hormone-containing cultures consistent with a proposal that the normal developmental pattern of diminishing protein synthesis specific activity is delayed or prevented under hypothyroid conditions. In addition ultrastructural studies revealed abnormalities in the density of cold-stable microtubules in thyroid hormone-deficient cultures. These results demonstrate that thyroid hormones can influence granule neuron behavior in the absence of Purkinje cells. Furthermore, the observed defects bear numerous similarities to documented abnormalities within the hypothyroid cerebellum, suggesting that this in vitro culture system may serve as a useful model for studying the mechanism of action of thyroid hormones on the cells of the cerebellum.

Animals↗

PubMed1986

Mechanism of apparent transcription inhibition by methyl mercury in cerebellar neurons.

We have investigated the mechanism of inhibition of RNA synthesis by methyl mercury (MeHg) in isolated neonatal rat cerebellar cells. Each of the three component steps involved in the incorporation of exogenous [3H]uridine into cellular RNA was examined separately in whole-cell and/or subcellular preparations. Nuclear RNA polymerase activity was measured in preparations containing both free nuclei and whole cells. Incorporation of [3H]UTP into nuclear RNA was found to be unimpaired at concentrations of MeHg that inhibited whole-cell incorporation of [3H]uridine by greater than 75%. Cellular uptake of [3H]uridine was assayed in cerebellar cells treated with KCN to deplete ATP levels and block subsequent phosphorylation reactions of transported uridine. Uptake activity under these conditions was unaffected by MeHg. Measurement of intracellular phosphorylation of [3H]uridine indicated that inhibition of this activity closely paralleled that of RNA synthesis. Quantitation of individual uridine nucleotides by polyethyleneimine-cellulose TLC revealed reduced levels of UTP and UDP whereas levels of UMP were elevated, suggesting that impairment of phosphorylation was not the result of cellular ATP depletion but, more likely, a direct effect on phosphouridine kinase enzymes. This mechanism of MeHg-induced inhibition of RNA synthesis was confirmed by assays of uridine phosphorylation using cell-free extracts in which exogenous ATP was supplied.

Animals↗

PubMed1986

The neuropathology of AIDS. UCLA experience and review.

The central nervous system (CNS) has been examined at autopsy in 89 patients who died of the acquired immune deficiency syndrome (AIDS), including 14 patients who died primarily of neurologic complications of the disease. A total of 66 brains (74%) showed significant pathologic abnormalities, with opportunistic infections including cytomegalovirus (14) and cryptococcal (11) infections, progressive multifocal leukoencephalopathy (6), toxoplasmosis (6), and histoplasma microabscesses (1). Incidental Mycobacterium avium-intracellulare infection was found in 4 cases. Simultaneous CNS infection by more than one microorganism was encountered in 5 patients. Subacute (microglial nodule) encephalitis-related to cytomegalovirus infection or possibly brain infection by the causative agent of AIDS was present in 56 cases. Primary CNS lymphoma was noted in 3 patients. Secondary CNS deposits of lymphoma were found in 1 patient, and another patient had lymphomatoid granulomatosis. Vascular complications were not infrequently seen, and included infarcts secondary to vessel occlusion and disseminated intravascular coagulation in 4 patients and intracranial hemorrhage of variable severity in 13. White matter changes included vacuolar myelopathy (3 cases), central pontine myelinolysis (1 case), and foci of calcified, necrotizing leukoencephalopathy in pontocerebellar fibers of the basis pontis (2 cases). These findings highlight the variety of CNS complications in AIDS, some of which are not associated with clinical manifestations. Nevertheless, characterization of all lesions may be important in understanding the neurologic sequelae of AIDS.

Adult↗