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Biomedical subjects

G R Stewart

Publications and source records attributed to G R Stewart.

At least 19 recordsLinked to original sources
PubMed1991

Excitotoxicity in the embryonic chick spinal cord.

Recent evidence implicates excitatory amino acids (EAAs), acting as excitotoxic agents, in the pathogenesis of neurological disorders involving the spinal cord. In this study, we used the chick embryo spinal cord as an in vitro model for studying the sensitivity of spinal neurons to the excitotoxic effects of EAA agonists. Compounds tested include the prototypic receptor-specific agonists, N-methyl-D-aspartate (NMDA), quisqualic acid (Quis), and kainic acid (KA), and the plant-derived excitotoxic food poisons, beta-N-oxalylamino-L-alanine, beta-N-methylamino-L-alanine, and domoic acid. Each agonist induced concentration-dependent acute degeneration of neurons distributed throughout the spinal cord. These cytopathological changes consisted of acute edematous degeneration of dendrosomal structures in the dorsal horn and intermediate zone, and dark cell changes with intracytoplasmic vacuolization of motor neurons; this damage is identical to that induced by excitotoxin agonists in other regions of the central nervous system. The NMDA receptor-specific antagonist MK-801 completely blocked toxicity of NMDA, and the nonNMDA antagonist CNQX preferentially blocked the toxicity of Quis- and KA-type agonists in the spinal cord. Our findings suggest that (1) the majority of spinal neurons have all three subtypes of EAA receptors, making them acutely vulnerable to excitotoxin exposure; and (2) EAA antagonists are effective in preventing excitotoxin-induced damage of the spinal cord.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1991

Age-related sensitivity to kainate neurotoxicity.

Domoate, a glutamate analog, is believed to be responsible for a seafood poisoning incident that caused acute neurological disturbances and chronic memory impairment in some victims, with the incidence of mortality and neuropsychological morbidity being highest among the aged. Domoate expresses neurotoxic (excitotoxic) activity in vitro by an action at the kainate subtype of glutamate receptor, and when administered to adult rats, it mimics kainate in causing status epilepticus and a severe seizure-brain damage syndrome. Because domoate is exceedingly expensive, we explored the feasibility of using kainate to study the age-linked features of domoate neurotoxicity. We administered kainate subcutaneously in various doses to young (5-6 months), middle-aged (12-13 months), and old (22-25 months) rats and found the middle-aged and old rats significantly more sensitive than young rats to the neurotoxic actions of kainate. Low doses of kainate, which were nontoxic to young rats, frequently triggered status epilepticus, associated brain damage, and precipitous death in old rats. Middle-aged rats were more sensitive than young rats, but less sensitive than old rats to kainate neurotoxicity. These results suggest that the kainate-treated rat may be a useful model for studying mechanisms underlying age-related aspects of the human domoate neurotoxic syndrome.

Age Factors↗
PubMed1990

Domoic acid: a dementia-inducing excitotoxic food poison with kainic acid receptor specificity.

Domoic acid (Dom), a rigid analog of the excitotoxic amino acids, glutamate and kainic acid, is believed to be the mussel neurotoxin responsible for a recent food poisoning incident in Canada that killed some people and left others with memory impairment. Since the literature contains very little information pertaining to Dom excitotoxicity, we have systematically evaluated the neuroexcitatory properties of Dom in vitro (cultured hippocampal neurons) and its neurotoxic properties both in vitro (chick embryo retina) and in vivo (adult rat). In the in vitro experiments, the properties of Dom were compared with those of kainic acid, N-methyl-D-aspartate (NMDA) and quisqualate, each of which is a prototypic agonist at a different subtype of glutamate receptor. Currents induced in hippocampal neurons by Dom and kainic acid were identical and displayed a linear current/voltage relationship (in contrast to NMDA currents) and were nondesensitizing (in contrast to quisqualate currents). Dom currents were not blocked by NMDA antagonists but were blocked by CNQX, an antagonist of non-NMDA receptors. In the chick embryo retina, Dom induced a lesion pattern having the same distinctive characteristics as a kainic acid lesion which differs from that induced by either NMDA or quisqualate, and the Dom lesion was blocked by CNQX but not by NMDA antagonists. Subcutaneous administration of Dom (2.5-3 mg/kg) to adult rats resulted in an acute seizure-brain damage syndrome almost identical to that induced in rats by KA (12 mg/kg) and having important features analogous to the neurotoxic syndrome observed in the human food poison victims.

Animals↗
PubMed1990

Excitotoxicity of L-dopa and 6-OH-dopa: implications for Parkinson's and Huntington's diseases.

Despite several decades of research aimed at elucidating the mechanisms underlying neuronal degeneration in Parkinson's and Huntington's diseases, these mysteries remain unfathomed. The brain contains high concentrations of the putative transmitters, glutamate and aspartate, which have neurotoxic (excitotoxic) potential and are thought to cause neuronal degeneration in certain acute neurological disorders. However, no mechanism has been identified by which these diffusely distributed agents might cause the regionally selective patterns of neuronal degeneration characterizing Parkinson's and Huntington's diseases. Here we report that L-DOPA, the natural precursor to dopamine, is a weak excitotoxin and its ortho-hydroxylated derivative, 6-OH-DOPA, is a powerful excitotoxin. We propose that an excitotoxic process mediated by L-DOPA or an acidic derivative such as 6-OH-DOPA might be responsible for degeneration of nigral neurons in Parkinson's disease or striatal neurons in Huntington's disease.

2-Amino-5-phosphonovalerate↗
PubMed1989

Comparison of behavioral effects of nucleus basalis magnocellularis lesions and somatosensory cortex ablation in the rat.

Cholinergic neurons in the nucleus basalis region of the forebrain project to various portions of the cerebral cortex, including somatosensory cortex. Degeneration of these neurons and their cortical projections is a major feature of the neuropathology of Alzheimer's disease. Injecting an excitotoxin into the basal forebrain to destroy nucleus basalis neurons provides a potentially useful animal model for studying the role of these neurons in Alzheimer's disease. Previously, we demonstrated that rats with nucleus basalis excitotoxin lesions performed poorly on a tactile discrimination task and on a test of working memory. In an effort to clarify further the role of impaired memory versus other types of impairment (e.g. disrupted somatosensory processing due to cholinergic deafferentation of somatosensory cortex), we compared a group of rats with bilateral nucleus basalis excitotoxin lesions and a group with bilateral somatosensory cortical ablations on a variety of behavioral tasks. Rats with nucleus basalis lesions performed as well as controls on a battery of neurological tests but exhibited increased emotionality unlike rats with somatosensory cortical ablations which performed poorly on the battery but were not hyperemotional. The two lesion groups were impaired significantly and to a comparable degree in performing two-choice tactile discriminations in a T-maze. In contrast, only rats with nucleus basalis lesions showed deficits in working memory as tested in an eight-arm radial maze. Both lesion groups performed comparably to sham controls on a test of reference memory involving a black/white discrimination in a T-maze. The findings suggest that rats with nucleus basalis lesions manifest disturbances in several of the same spheres (emotionality, somatosensory information processing, memory) that are disrupted in Alzheimer's disease and further confirm the utility of the excitotoxin lesion approach for studying the pathophysiology of Alzheimer's disease.

Animals↗
PubMed1988

Prophylactic cranial irradiation for limited non-small cell lung cancer.

Seventy-three patients with biopsy-proven limited non-small cell lung cancer (NSCLC) were entered on a combined modality study at the University of Washington. Seventy-five percent (55 of 73) of the patients had a histologic diagnosis of adenocarcinoma or large cell carcinoma, whereas 25% (18 of 73) had squamous cell carcinoma. After two cycles of chemotherapy, patients without evidence of progressive disease received prophylactic cranial irradiation (PCI) and chest radiotherapy, followed by two additional cycles of chemotherapy. Brain computed tomography (CT) scans were performed at 3-month intervals after completion of therapy in all patients, and were additionally performed whenever signs or symptoms developed suggesting neurologic dysfunction or recurrent brain disease. Sixty-five patients were treated with PCI. No clinical or CT evidence of recurrence in the brain has developed in patients who completed PCI. PCI appears to be effective in greatly reducing the incidence of brain relapse in patients with limited NSCLC.

Brain↗
PubMed1988

Fast neutron radiotherapy--an overview.

Fast neutron radiotherapy has been employed worldwide in the last two decades in the treatment of a variety of advanced malignancies. The basic principles behind neutron treatment will be summarized in this article, along with results to date of a number of clinical trials evaluating the effectiveness and toxicity of neutron radiotherapy.

Clinical Trials as Topic↗
PubMed1988

Choroid plexus carcinoma of the fourth ventricle. Report of a case in an infant.

An 8-month-old female infant with choroid plexus carcinoma presenting in the fourth ventricle is described. The patient was initially treated with combination chemotherapy due to her young age, but developed local tumor recurrence 13 months after beginning treatment. Staging studies to detect tumor seeding of the cerebrospinal fluid were negative, and the patient received posterior fossa radiotherapy. Although the primary tumor regressed with radiation treatment, widespread disease throughout the spinal subarachnoid space subsequently developed. Choroid plexus carcinoma has a significant tendency to metastasize through the cerebrospinal fluid, and treatment of the entire neuraxis should be strongly considered for patients with this disease.

Antibodies, Monoclonal↗
PubMed1987

Fibronectin-like immunoreactivity in the developing cerebral cortex.

In the developing cerebral cortex of the mouse, binding of antibodies directed against the extracellular matrix glycoprotein fibronectin occurs with a distinct temporal and spatial pattern. On the 10th embryonic day (E10), when the wall of the telencephalic vesicle is made up of only the proliferating cells of the ventricular zone, antifibronectin (aFN) binding is restricted to the blood vessels and pia-arachnoid. Fibronectin-like immunoreactivity first appears in the neuropil as small points of immunofluorescence among the earliest postmitotic neurons that form the preplate (E11-12). A short time later (E12-13), aFN immunoreactivity becomes more diffuse but continues to be restricted to the preplate. As newly arriving neurons form the cortical plate within the preplate (E13-14), aFN binding is present in the marginal zone above the cortical plate and in the subplate below it. Both the marginal zone and the subplate contain early afferents and the cells that were previously part of the preplate. Binding of aFN is transient; by E18-19 it has diminished to the point where it is no longer detectable except in the blood vessels and pia-arachnoid. The transient appearance of fibronectin-like immunostaining in the zones that contain early cortical afferents suggests that fibronectin plays a role in forming the migratory pathway for the growth cones of these axons. In this role it may be acting in concert with other extracellular matrix components such as hyaluronectin, glycosaminoglycans, and laminin, which have been shown to have similar spatial distributions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

N-methylaspartate: an effective tool for lesioning basal forebrain cholinergic neurons of the rat.

The ability of the excitotoxin, N-methyl-D,L-aspartic acid (NMA), to destroy basal forebrain cholinergic (BFC) neurons was evaluated. NMA (100 nmol) was directly injected into the peripallidum, a region containing a proportionately large number of cortically-projecting BFC neurons. Cholineacetyltransferase (ChAT) activity 10 days later was markedly and significantly reduced (up to 62%) in the cortex ipsilateral to the lesion. NMA induced a focal lesion affecting BFC neurons without damaging axons of passage or causing lesions distant from the site of injection. ChAT immunohistochemistry (IHC) was used to directly demonstrate loss of ChAT-positive neurons from the lesion site. This loss persisted at all survival times examined, from 2 days to 7.5 months post-injection.

Animals↗
PubMed1979

Rubber sump drainage of enterocutaneous fistulae.

Effective sump drainage of high enterocutaneous fistulae, together with alimentary rest and total parenteral nutrition, is now an integral part of the modern management of patients with this condition. The low tissue reactivity of the plastic and polymer materials currently used in most drainage tubes appears however, to be counterproductive to the establishment of a discrete fistula track and control of the fistula. A case is made for the use of red rubber sump drains for enterocutaneous fistulae. The greater tissue reactivity of rubber is reviewed and confirmed by animal experimentation. A method of rubber sump drainage of enterocutaneous fistulae developed during the management of 83 such fistulae is described.

Animals↗
PubMed1977

Early detection of breast cancer.

One thousand referred patients with breast symptoms, a history of breast disease, or a family history of breast carcinoma have been examined at a suburban breast clinic. This is a preliminary survey of the data and results so far obtained from the initial examination of these patients. The examination consisted of history-taking by means of a questionnaire, physical examination of the breasts, thermography and xeromammography. A report correlating the findings was forwarded to the referring doctor in each case and any necessary action was indicated in the report. Seventy-eight patients were thought to require biopsy of a suspicious lump or mammographic lesion (7.8% of the total number); 76 patients actually had biopsies, and 18 patients were found to have carcinoma of the breast (23.8% of the total number of patients who had biopsies). The overall incidence of carcinoma in the 1000 women attending the clinic was 1.8% at the initial visit. While general population screening for breast carcinoma may be hard to justify, from both the detection rate and an economic point of view, it would appear from our experience to date that screening of selected high-risk referred patients is justified and, in fact, desirable.

Adenocarcinoma↗
PubMed1973

The isolation and partial characterization of ribonuclease A from Bison bison.

1. Bison ribonuclease was isolated from pancreas glands of Bison bison by acid extraction, (NH(4))(2)SO(4) fractionation, affinity chromatography on Sepharose-5'-(4-aminophenylphosphoryl)uridine 2',3'-phosphate and ion-exchange chromatography on Bio-Rex-70. 2. The selectivity of the affinity column towards bison ribonuclease in heterogeneous protein solutions was greatly improved by employing piperazine buffers at pH5.3, which decreased non-specific interactions of other proteins. Rapid desorption from the affinity column was obtained with sodium phosphate buffer (pH3). 3. Bison ribonuclease has a total amino acid content very similar to ox ribonuclease. Inactivation of bison ribonuclease with iodoacetic acid leads to the formation of 0.62 residues of pi-carboxymethylhistidine and 0.36 residues of tau-carboxymethylhistidine. The amino acid composition of peptides isolated from diagonal peptide ;maps' and also of peptides isolated after pH1.6 and 2.4 two-dimensional high-voltage electrophoresis of a digest of bison ribonuclease labelled with pyridoxal 5-phosphate indicates that there is complete homology between ox and bison ribonucleases. 4. The Schiff-base attachment site of pyridoxal 5-phosphate was identified as lysine-41 by NaBH(4) reduction followed by peptide isolation.

Amino Acid Sequence↗