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Biomedical subjects

N R Cashman

Publications and source records attributed to N R Cashman.

At least 73 records · Page 4Linked to original sources
PubMed1990

Neurologic sequelae of domoic acid intoxication due to the ingestion of contaminated mussels.

In late 1987 there was an outbreak in Canada of gastrointestinal and neurologic symptoms after the consumption of mussels found to be contaminated with domoic acid, which is structurally related to the excitatory neurotransmitter glutamate. We studied the neurologic manifestations in 14 of the more severely affected patients and assessed the neuropathological findings in 4 others who died within four months of ingesting the mussels. In the acute phase of mussel-induced intoxication, the patients had headache, seizures, hemiparesis, ophthalmoplegia, and abnormalities of arousal ranging from agitation to coma. On neuropsychological testing several months later, 12 of the patients had severe anterograde-memory deficits, with relative preservation of other cognitive functions. Eleven patients had clinical and electromyographic evidence of pure motor or sensorimotor neuronopathy or axonopathy. Positron-emission tomography of four patients showed decreased glucose metabolism in the medial temporal lobes. Neuropathological studies in the four patients who died after mussel-induced intoxication demonstrated neuronal necrosis and loss, predominantly in the hippocampus and amygdala, in a pattern similar to that observed experimentally in animals after the administration of kainic acid, which is also structurally similar to glutamate and domoic acid. We conclude that intoxication with domoic acid causes a novel and distinct clinicopathologic syndrome characterized initially by widespread neurologic dysfunction and then by chronic residual memory deficits and motor neuronopathy or axonopathy.

Animals↗
PubMed1990

Cellular isoform of the scrapie agent protein participates in lymphocyte activation.

The scrapie agent protein (Sp33-37 or PrPSc) is the disease-associated isoform of a normal cellular membrane protein (Cp33-37 or PrPC) of unknown function. We report that normal human lymphocytes and lymphoid cell lines, but not erythrocytes or granulocytes, express PrPC mRNA and protein. PrPC is detectable on the surface of lymphocytes; the surface immunoreactivity is sensitive to phosphatidylinositol-specific phospholipase C, indicating glycosyl-phosphatidylinositol membrane anchorage. Lymphocyte PrPC surface abundance is increased by cell activation, and polyclonal antibodies to PrPC suppress mitogen-induced activation. We conclude that PrPC is a lymphocyte surface molecule that may participate in cell activation.

Animals↗
PubMed1990

Immunoregulatory properties of T-cell lines derived from the systemic and intrathecal compartments: a phenotypic and functional study.

To determine whether immune regulation can differ within the intrathecal and systemic compartments, we compared phenotypic markers and functional properties of in vitro anti-CD3 monoclonal antibody-stimulated, interleukin 2-expanded lymphoid cell lines simultaneously derived from peripheral blood and cerebrospinal fluid of individual donors (n = 9). We found that the proportions of total CD8+ T cells and of the putative CD8+ suppressor effector subset (CD28-) were lower in the cell lines derived from cerebrospinal fluid compared with cultures derived from peripheral blood (p less than 0.025 and p less than 0.005, respectively; paired t test), whereas the total CD4+ T-cell proportion was higher (p less than 0.025). For a donor subgroup with "normal" peripheral blood cell-mediated activated suppressor function (63 +/- 2%), mean suppressor cell function mediated by unfractionated or CD8(+)-enriched cells derived from cerebrospinal fluid was significantly lower (38 +/- 7%; p less than 0.01, paired t test). For a donor subgroup with "low" peripheral blood cell-mediated suppression (-1 +/- 10%), suppression mediated by cerebrospinal fluid cells was also "low" (9 +/- 12%). Our results support the postulate that the immune response may be differentially regulated between the central nervous system and peripheral blood compartments.

Adult↗
PubMed1990

DNA cytosine methylation in brain of patients with Alzheimer's disease.

We developed a novel quantitative assay to test the hypothesis that defects in DNA cytosine methylation might be responsible for the brain chromatin abnormalities and transcriptional alterations observed in patients with Alzheimer's disease (AD). We found no significant difference in percent methylation of CCGG sites from brain DNA of 44 patients with AD compared with 20 normal subjects. These results, however, would not exclude genomic redistribution of methylcytosine in AD, or disturbed methylation of a limited population of critical brain-specific genes.

Aged↗
PubMed1989

Isoelectric focusing studies of serum and cerebrospinal fluid in patients with antecedent poliomyelitis.

The post-poliomyelitis syndrome (PPS) refers to symptoms of new weakness, fatigue, and pain years after recovery from acute poliomyelitis. Oligoclonal IgG bands have been reported in the cerebrospinal fluid (CSF) from PPS patients, suggesting that the syndrome is immune mediated or caused by persistent viral infection. We studied 15 paired serum and CSF samples and 6 unpaired CSF samples from a total of 21 patients with a prior history of poliomyelitis. Quantitative immune studies failed to show evidence for increased intrathecal IgG production relative to patients with noninflammatory central nervous system (CNS) disease. We found definite oligoclonal IgG bands in the CSF from only 1 patient, who also carried a diagnosis of multiple sclerosis. An isoelectric focusing poliovirus antigen overlay study showed evidence that suggested a CNS-specific antipoliovirus immune response in only 1 patient. Our results fail to support a dysimmune or persistent viral cause for post-poliomyelitis progressive muscular atrophy or PPS.

Adult↗
PubMed1989

Characterization of lymphoid cells isolated from human gliomas.

To analyze the phenotypic profile of lymphoid cells freshly isolated from surgically resected human gliomas, a double-immunostaining technique was developed which permitted the investigators simultaneously to distinguish between hematogenous and tumor cell populations and to detect expression of lymphocyte-monocyte subset-specific antigens on hematogenous cells. With this technique, the profiles of tumor-infiltrating lymphocytes (TIL's) derived from high- and low-grade gliomas were compared with phenotypes of lymphocytes concurrently isolated from peripheral blood. The total leukocyte cell yield from high-grade glioma cases exceeded that of low-grade cases. In nine high-grade glioma cases the proportion of CD8-positive cells was increased within the TIL population (41.2% +/- 1.9%, mean +/- standard error of the mean) as compared to the corresponding peripheral blood lymphocyte (PBL) population (30.8% +/- 4.1%, p less than 0.05). The proportion of natural killer HNK-positive cells, some of which bear the CD8 antigen (although not necessarily the pan T cell antigens CD2 and CD3), was also increased in the TIL's (41.9% +/- 4.2%) compared to that found in PBL's (32.1 +/- 5.6%, p less than 0.05) of high-grade glioma cases. The observed phenotypic pattern of high-grade glioma TIL's is similar to that reported based on immunohistochemical analysis of tumor tissue sections, suggesting that the techniques described here resulted in isolation of lymphoid cells representative of TIL's.

Antigens, CD↗
PubMed1987

Late denervation in patients with antecedent paralytic poliomyelitis.

The development of new weakness, fatigue, and pain decades after acute paralytic poliomyelitis is a recognized syndrome. We conducted a controlled study of this syndrome by analyzing clinical, electromyographic, and muscle-biopsy features in 18 patients with a history of poliomyelitis--13 reporting 1 to 20 years of new weakness and 5 without new symptoms. The patients with new weakness also reported new muscle atrophy (9 of 13) and fatigue (10 of 13), symptoms not reported by the controls. The age at the time of acute poliomyelitis, severity of poliomyelitis, residual disability, number of years since acute poliomyelitis, and age at the time of study were comparable in the weakening and control groups. Evidence of remote denervation consistent with antecedent poliomyelitis was demonstrated in all patients by electromyography or muscle biopsy or both. In addition, active denervation (as evidenced by spontaneous activity on conventional electromyography, increased jitter on single-fiber electromyography, or atrophic myofibers) was found in 12 patients in the weakening group and in all 5 controls. Immunohistochemical detection of myofibers expressing the neural-cell adhesion molecule corroborated ongoing denervation in both patient groups. When muscle data from both groups were pooled, correlations were observed between the extent of past reinnervation and the degree of ongoing motor-unit instability. We conclude that the extensive reinnervation of denervated muscle that occurs in paralytic poliomyelitis may be followed by late denervation of the previously reinnervated muscle fibers. Electromyographic and muscle-biopsy evidence of ongoing denervation does not distinguish between stable patients with prior paralytic poliomyelitis and those with new weakness.

Adult↗
PubMed1987

Neural cell adhesion molecule in normal, denervated, and myopathic human muscle.

The neural cell adhesion molecule (N-CAM) is a cell-surface glycoprotein that may mediate some intercellular adhesive interactions in the nervous system. In adult rat muscle, N-CAM is concentrated near neuromuscular junctions and on satellite cells, but is nearly undetectable in nonsynaptic portions of myofibers. However, N-CAM is abundant throughout myofibers in denervated and regenerating muscles. Using affinity-purified antibodies to N-CAM, we were able to demonstrate a similar distribution and regulation of N-CAM in human muscle. Myofiber N-CAM was not detectable immunohistochemically in any of 10 normal biopsies or in 4 biopsies that were abnormal but showed no evidence of fiber denervation or regeneration. N-CAM was present, however, at end plates, nerves, and satellite cells in normal human muscle. In contrast, myofiber N-CAM was detected in 16 of 16 patients with histological evidence of denervation and in 10 of 10 patients who had myopathy with degenerating/regenerating myofibers. In addition, 2 of 2 histologically nondiagnostic biopsies from patients with amyotrophic lateral sclerosis contained N-CAM-positive myofibers. Immunoblot analysis also detected N-CAM in denervated and myopathic, but not normal, human muscle. These results suggest that N-CAM may play a role in muscle reinnervation or regeneration and that N-CAM immunohistochemistry may complement conventional techniques in the diagnosis of neuromuscular disease.

Antigens, Surface↗
PubMed1987

Neurological manifestations of the post-polio syndrome.

Patients with late effects of poliomyelitis, i.e., PPS, are being seen at an ever increasing frequency by general physicians, neurologists, and orthopedists. An appropriate time interval for the onset of late manifestations has elapsed since the major epidemics of poliomyelitis in the 1940s and 1950s. Post-polio neurological manifestations primarily include new weakness, atrophy, muscle pain, and fasciculations. Fortunately, the weakness is of a very slow, progressive nature. Abnormal laboratory studies include routine EMG, demonstrating chronic denervation; SFEMG, demonstrating increased fiber density, increased jitter, and blocking; and muscle biopsy most often revealing fiber-type grouping of chronic denervation and small isolated angular (or angulated) fibers and group atrophy in some series, both suggestive of active denervation. Unfortunately, both EMG and muscle biopsy studies suffer from a lack of specificity as they do not appear to distinguish asymptomatic from symptomatic (new weakness, PPMA) patients with prior poliomyelitis. Although the cause of PPMA is unknown, electrophysiological (SFEMG) and muscle biopsy studies suggest that the process involves a loss or dropout of axon terminals of reinnervated motor units. The axons terminal dropout could be due to dysfunction in the cell soma, the axon, or the terminals themselves. Whether motor neuron exhaustion, a persistent viral infection, or immune-mediated mechanisms play a role in the pathogenesis of the late weakness is unclear at present and will require further investigation. Treatment at this time is of a supportive nature. A major controversy involves the role of strengthening exercises in these patients since experimental animal studies suggest that excessive exercise of denervated muscles leads to increased weakness. Clearly, a better understanding of PPS and PPMA will allow more effective management of these patients' problems and might also provide insight into other motor neuron and neuromuscular junction diseases.

Aging↗
PubMed1986

Accessory cell competence of ovine oligodendrocytes in mitogenic activation of human peripheral T cells.

The multiple sclerosis (MS) plaque is characterized by mononuclear inflammatory cell infiltration, demyelination, loss of oligodendrocytes (OGC), and proliferation of astrocytes. Although antigen-specific, Ia-dependent cellular immune mechanisms have been sought in plaque pathogenesis, Ia-independent T cell activation has not been actively investigated. We examined a potential role of OGC in accessory cell-dependent T cell mitogenesis with the anti-T3 monoclonal antibody OKT3. OGC isolated from ovine white matter on sucrose density gradients were uniformly negative for esterase activity, unlike ovine monocytes. Purified human T cells did not exhibit significant proliferation in 3-day cultures with OKT3, autologous peripheral blood adherent cells (PBAC), or ovine OGC. When T cells were cultured with either PABC or OGC in the presence of OKT3, brisk mitogenesis was observed. Thus, OGC have the capacity to function as accessory cells in the mitogen-induced proliferation of T cells.

Animals↗
PubMed1986

Intrathecal interferon in subacute sclerosing panencephalitis.

Five patients with clinically advanced subacute sclerosing panencephalitis (SSPE) were given human leukocyte interferon (IFN) by the lumbar route, 1 million IU every other day for a total of 30 days. Intrathecal IFN produced a meningeal inflammatory reaction in all patients and was associated with transient hemiparesis in 1. It persisted in the cerebrospinal fluid at measurable levels for 48 hours after a single injection. Although improvement was temporally related to intrathecal IFN in 1 patient, it is not clear whether this was induced by IFN or a spontaneous remission. A randomized controlled trial would be necessary to evaluate IFN critically as a therapy for SSPE.

Adolescent↗
PubMed1986

N-acetyl-beta-hexosaminidase beta locus defect and juvenile motor neuron disease: a case study.

A patient with partial deficiency of N-acetyl-beta-hexosaminidase (Hex) developed a progressive motor neuron syndrome beginning at age 7, characterized by dysarthria, muscle wasting, fasciculations, and pyramidal tract dysfunction. Minor clinical features have included tremor and late distal sensory abnormalities. Rectal biopsy at age 24 demonstrated membranous cytoplasmic bodies in submucosal ganglion cells. Biochemical evaluation revealed nearly absent Hex B activity in serum, leukocytes, and fibroblasts, with partial Hex A activity in serum and leukocytes, and low normal Hex A activity in fibroblasts. Motor neuron disease can be a presentation of a Hex beta locus defect, in addition to the previously recognized Hex alpha locus defects.

Adult↗
PubMed1985

N-acetyl-beta-hexosaminidase B deficiency in cultured fibroblasts from a patient with progressive motor neuron disease.

A patient with a 20-year history of progressive motor neuron disease was previously found to have profoundly low levels of N-acetyl-beta-hexosaminidase (Hex) in serum and leukocytes; Hex activity in cultured skin fibroblasts was in the low normal range. By thermal inactivation and cellulose acetate electrophoresis, the residual activity appeared to be Hex A. In the present study, the residual activity in cultured skin fibroblasts was further characterized as Hex A by thermal inactivation at reduced temperatures and ion exchange chromatography; no evidence was obtained for a diffusible inhibitor of Hex activity. After labeling with [3H]leucine, immunoprecipitation with polyclonal antibody to Hex B, and SDS-polyacrylamide gel electrophoresis, both alpha and beta polypeptide chains were visualized, confirming the presence of Hex A. The results suggest that, in the patient's fibroblasts, a defect in beta-chain synthesis or processing precludes the self-association of beta-chains to form Hex B, but does not prevent the association of alpha- and beta-chains to form Hex A.

Cells, Cultured↗
PubMedDate not supplied

Lymphocyte content of amyloid precursor protein is increased in Down's syndrome and aging.

We quantified cellular amyloid precursor protein (APP) in ethanol-permeabilized peripheral lymphocytes from 13 subjects with Alzheimer's disease (AD), 11 subjects with Down's syndrome (DS), and 13 healthy elderly and 31 healthy young controls. APP content was analyzed by indirect immunofluorescence and flow cytometry, using the 22C11 monoclonal antibody (mAb) directed against an N-terminal domain of APP. Authenticity of 22C11 APP signal was confirmed by immunoblotting and flow cytometry studies with the mAb 6E10, directed against the A beta domain of APP. Consistent with gene dosage, patients with DS had 1.51-fold higher lymphocyte APP signal than age-matched normal young subjects (corrected p < 0.05). Both AD patients and elderly control groups had significantly increased lymphocyte APP signal compared to young controls (either comparison corrected p < 0.01). Indeed, increasing age in non-DS subjects was significantly correlated with lymphocyte APP (r = 0.508, p < 0.0001), such that APP immunoreactivity more than doubled from 20 to 80 years. Lymphocyte APP was nonsignificantly higher in AD vs. aged controls in this small sample. Increased cellular APP content in DS and aging may correspond to generalized alterations in expression or processing of this molecule, and suggests a novel determinant for the timing of AD onset.

Adult↗