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Biomedical subjects

J T Coyle

Publications and source records attributed to J T Coyle.

At least 199 records · Page 11Linked to original sources
PubMed1986

The neurobiologic consequences of Down syndrome.

Trisomy of the whole or distal part of human chromosome 21 (HSA 21) (Ts21) results in Down Syndrome (DS), which is characterized in part by mental retardation and associated neurological abnormalities. Structural abnormalities observed frequently include reduced brain weight, decreased number and depth of sulci in the cerebral cortices, neuronal heterotopias, and reduced numbers of specific populations of neurons, such as granule cells, in the cerebral cortices. Abnormalities in the structure of cells, primarily of the dendrites, are observed in portions of the neuraxis, such as the hippocampus, cerebellum, and cerebral cortices. Functional abnormalities in membrane properties in peripheral structures and in neurotransmitter enzyme systems in both peripheral and central structures are observed also. Brains of DS individuals over the age of 40 exhibit the characteristic neuropathologic and neurochemical stigmata of Alzheimer's disease (AD). The cholinergic and noradrenergic systems appear to be particularly vulnerable. To elucidate the mechanisms responsible for these abnormalities, identification of the genes located in the distal part of HSA 21 and the systematic study of animal model systems with close genetic homology are essential.

Aging↗
PubMed1986

Mouse chimeras composed of trisomy 16 and normal (2N) cells: preliminary studies.

Many humans with trisomy 21 (Down Syndrome (DS)) have psychomotor and cognitive retardation, congenital heart disease, and hematologic abnormalities. Partial genetic homology exists between mouse chromosome 16 and human chromosome 21; thus, studies of the development of mice with trisomy 16 (Ts16) may provide important insights into the pathogenesis of these defects and into the mechanisms by which they arise in humans. Since Ts16 mice do not survive the late fetal period, chimeras have been formed between Ts16 and normal (2N) mouse embryos to rescue the Ts16 cells for postnatal studies. In this preliminary study of the postnatal development of such chimeras, we examined the proportion of Ts16 cells in a variety of tissues, including the coat, blood, placenta, heart, and brain. The Ts16 cells made significant contributions to almost all tissues examined. Aspects of the behavior and the neurochemistry of adult Ts16 less than-greater than 2N chimeras were found to differ significantly from control (2N less than-greater than 2N) chimeras and from animals of the two donor embryo strains. Ts16 cells comprised a substantial, but not predominant, proportion of cells in each brain region examined. Suggestions for definitive analyses are reviewed.

Animals↗
PubMed1986

Anorexia and altered serotonin metabolism in a patient with argininosuccinic aciduria.

We studied serotonin metabolism in a metabolically stable 7-year-old girl with argininosuccinic aciduria who had severe anorexia. The CSF concentration of 5-hydroxyindoleacetic acid (HIAA), the metabolite of serotonin, was markedly elevated at 79 ng/ml (normal 33 +/- 11 ng/ml). Altered serotonin metabolism was also reflected in the sleep EEG, which showed decreased REM sleep. Reducing her intake of tryptophan, the precursor of serotonin, from 35 mg/kg/day to 7 mg/kg/day resulted in a decrease in CSF concentration of HIAA to 20 ng/ml and the onset of spontaneous eating for the first time in 4 1/2 years. REM sleep increased from 3% to 9.5% of total sleep time. Two days after increasing tryptophan intake to 25 mg/kg/day, spontaneous feeding stopped, associated with a rise in CSF HIAA to 45 ng/ml. Caloric/carbohydrate intake was found to affect CSF HIAA levels and food intake in an additive manner with tryptophan intake. These observations suggest that altered serotonin metabolism affected feeding behavior in this child, and that this effect could be modified by changing tryptophan or carbohydrate intake.

Amino Acid Metabolism, Inborn Errors↗
PubMed1986

Primary degenerative dementia without Alzheimer pathology.

To define the pathology in cases of non-Alzheimer primary degenerative dementia (non-AD PDD), we have studied autopsies from four medical centres accessioned in consecutive years since 1976. Neurochemical studies of the basal forebrain-cortical (BF-C) cholinergic system have been conducted in cases from which frozen tissue was available. Twenty-two cases (mean age 70 years, range 47-86) in which the history was consistent with PDD, but which did not meet anatomic criteria for AD, were selected. Approximately 70 cases of PDD, which were accessioned in the same years and met the anatomic criteria for AD, were excluded. The pathologic findings permitted a classification into six groups: Lewy body disease (LBD), 4 cases; Pick's disease, 6 cases: cortical degeneration with motor neuron disease (CDmnd), 2 cases; hippocampal and temporal lobe sclerosis, 3 cases; few or nonspecific abnormalities, 5 cases; other disorders, 2 cases. Our findings suggest that LBD and Pick's disease account for a large proportion of cases of non-AD PDD in the presenile age group, but that a large number of other disorders occasionally present as PDD. Careful examination of the motor systems, as well as cerebral structures relate to cognitive function, is important in the neuropathologic evaluation. Lesions of the BF-C cholinergic system have been most consistent and severe in LBD, and have not been identified in CDmnd.

Aged↗
PubMed1986

Suspected adverse methylphenidate-imipramine interactions in children.

Two cases are presented which illustrate the dangers inherent in utilizing a polypharmacy approach in treating children with psychotropic medication. In each case, severe adverse effects, including cognitive and mood deterioration, were experienced by the child when treated with a combination of methylphenidate and imipramine. Possible mechanisms at the neurotransmitter level are described as postulated determinants for this pharmacological interaction.

Adolescent↗
PubMed1986

Cortical degeneration with swollen chromatolytic neurons: its relationship to Pick's disease.

We report two cases of dementia in which cortical degeneration with widespread swollen chromatolytic neurons (SCN) was the dominant pathologic feature. Each patient had received the diagnosis of Alzheimer's disease on the basis of clinical findings. There was no deficit of cortical choline acetyltransferase activity, assayed in one case, or lesions of the nucleus basalis of Meynert. The brains had moderate to marked frontal atrophy. Comparison of SCN with several other cerebral degenerative disorders indicates a similarity with certain features of the transmissible spongiform encephalopathies and with corticodentatonigral degeneration. The pathologic features of our cases are those of a number of other cases reported as "Pick's disease," and may represent an earlier stage in the pathogenetic process than the severe, sharply circumscribed atrophy with "nonspecific" cell loss and gliosis as the only microscopic residuals. Our findings re-emphasize the need to search for pathogenetically distinct subgroups which have been wholly or partially subsumed into the concept of Pick's disease.

Acetylcholine↗
PubMed1986

Synaptosomal transport of radiolabel from N-acetyl-aspartyl-[3H]glutamate suggests a mechanism of inactivation of an excitatory neuropeptide.

This study was undertaken to explore in synaptosomal preparations the disposition of N-acetyl-aspartyl-glutamate (NAAG), an endogenous acidic dipeptide neurotransmitter candidate. Radiolabel from N-acetyl-aspartyl[3H]glutamate was taken up rapidly into an osmotically sensitive compartment by rat brain synaptosomal preparations in a sodium-, temperature-, and time-dependent manner. HPLC analysis of the accumulated radiolabel indicated that the bulk of the tritium cochromatographed with glutamic acid and not with NAAG. In contrast, [14C]NAAG, labeled on the N-terminal acetate, was not taken up by the synaptosomal preparation. All effective inhibitors of synaptosomal, Na+-dependent [3H]glutamate uptake were found to exhibit similar potency in inhibiting uptake of tritium derived from [3H]NAAG. However, certain alpha-linked acidic dipeptides, structurally similar to NAAG, as well as the potent convulsant quisqualic acid inhibited synaptosomal transport of [3H]NAAG but were ineffective as inhibitors of [3H]glutamate transport. Together with a demonstration of disparities between the regional accumulation of radiolabel from [3H]NAAG and high-affinity [3H]glutamate uptake, these data suggest the presence in brain of a specific peptidase targeting carboxy-terminal glutamate-containing dipeptides that may be coupled to the Na+-dependent glutamate transporter. These findings provide a possible mechanism for NAAG inactivation subsequent to its release from nerve endings.

Amino Acids↗
PubMed1986

Behavioral and neurotransmitter changes in the urease-infused rat: a model of congenital hyperammonemia.

Rats implanted with subcutaneous or intraperitoneal osmotic minipumps infusing 0.8-1.25 IU urease/kg/h develop sustained hyperammonemia (range 137-497 microM, controls 88 +/- 51 microM +/- SD) for 5-7 days. Glutamine levels are also significantly elevated in plasma (677 +/- 166 versus 428 +/- 122 microM) and cerebral cortex (13.2 +/- 9.8 versus 4.7 +/- 2.8 nmol/mg tissue). Neurobehavioral abnormalities include decreased food intake and increased stereotypic activity. Increased serotonin turnover was suggested by elevated levels of tryptophan and 5-hydroxyindoleacetic acid in cerebral cortex, brain stem, and cerebellum of urease-infused compared to sham-operated animals. There were no changes in norepinephrine or gamma aminobutyric acid, and there was no correlation between the degree of hyperammonemia or glutaminemia and brain levels of tryptophan or biogenic amines. Animals receiving a tryptophan-deficient diet had significantly lower levels of tryptophan and 5-hydroxyindoleacetic acid in brain regions compared to animals receiving a normal tryptophan intake, under both control and hyperammonemic conditions. Despite the prevention of increased serotonin flux in hyperammonemic animals receiving a tryptophan-deficient diet, food intake and weight declined and there was increased stereotypic behavior.

Ammonia↗
PubMed1986

Prospective study of intake procedures in a child psychiatry clinic.

Two methods of patient intake in a child psychiatry outpatient clinic were compared. In one, appointments were made immediately upon request; in the second, completion of a parental questionnaire was required before an appointment was made. Results indicated that a commitment from the parent/guardian evidenced by completing a parent-questionnaire prior to the screening appointment 1) significantly increased the attendance rate at first appointments, and 2) increased compliance in follow-up treatment. These findings indicate the importance of improved communication between parents and clinic personnel in facilitating the treatment of children.

Appointments and Schedules↗
PubMed1985

Characterization of [3H]hemicholinium-3 binding associated with neuronal choline uptake sites in rat brain membranes.

Hemicholinium-3 (HCh-3) is a potent and specific inhibitor of the high-affinity choline transport process (HAChT) localized on cholinergic neurons. In this study, the specific binding of [3H]HCh-3 (120 Ci/mmol) was characterized in crude synaptic membranes prepared from rat brain. The binding of [3H]HCh-3 to forebrain membranes was saturable, reversible and specific with an apparent Kd under optimal conditions of 35 nM and a Bmax of 56 fmol/mg protein. The potency of various HAChT inhibitors correlated with their apparent affinities for the specific [3H]HCh-3 binding site. The specific binding of [3H]HCh-3 exhibited an uneven regional distribution in the adult rat brain that corresponded to the activity of the HAChT in these regions. Transsection of the fornix, which causes a degeneration of the septal hippocampal cholinergic pathway, resulted in comparable reductions of the specific [3H]HCh-3 binding and the specific activity of choline acetyltransferase, a presynaptic marker for cholinergic terminals in the hippocampal formation; the lesion did not affect the specific activity of glutamic acid decarboxylase, a presynaptic marker for GABAergic neurons within the hippocampus. Maximal binding occurred in the presence of 200 mM NaCl: potassium, lithium, rubidium and calcium substituted poorly for sodium; and bromide, fluoride, iodide, sulfate and phosphate were less effective anions than chloride. Increasing concentrations of NaCl increased the affinity of the site for [3H]HCh-3 with no significant effect on the maximal number of sites; the enhancement of affinity was due to a selective slowing of the rate of dissociation of the ligand from its binding site. These findings indicate that [3H]HCh-3 binds to the carrier site mediating the HAChT on cholinergic neurons; thus, this radioligand may be a useful probe for investigating this presynaptic component (HAChT) of cholinergic neurons.

Animals↗
PubMed1985

Regional brain levels of N-acetyl-aspartyl-glutamate: the effect of kindled seizures.

Rats were subjected to daily amygdaloid-kindling stimulation and sacrificed 48 h after their fifth stage-5 kindled seizure. Regional brain dissection was performed and the regions assayed for levels of N-acetyl-aspartyl-glutamate, an endogenous dipeptide specific to the brain and a putative excitatory neurotransmitter. Kindling produced significant increases in this dipeptide in the entorhinal cortex.

Amygdala↗
PubMed1985

Memory impairments following basal forebrain lesions.

The functional contribution of the nucleus basalis magnocellularis (NBM) and medial septal area (MSA) to memory was evaluated in 4 behavioral tasks. The tasks were postoperative acquisition of a win-stay spatial discrimination in a T-maze, a win-shift spatial discrimination on a radial arm maze, active avoidance in a shuttle box, and passive avoidance in a shuttle box. Bilateral lesions were made by injecting ibotenic acid (IBO) into the NBM or MSA. Control rats received operations in which no neurotoxin was injected. When compared to controls, rats with lesions in either the NBM or MSA had significantly impaired choice accuracy in the T-maze and radial maze tasks, took significantly fewer trials to reach criterion in the acquisition, but not the retention of an active avoidance task, and significantly more trials to reach criterion in the passive avoidance task. The results show that equivalent behavioral changes are obtained from lesions in the NBM and MSA in tasks that vary in their type of motivation, reinforcement, response-reinforcement contingency, and response. These behavioral changes suggest that the NBM and MSA may both be involved in memory.

Animals↗
PubMed1985

Basal forebrain lesions produce a dissociation of trial-dependent and trial-independent memory performance.

The behavioral effects of lesions in the basal forebrain (BF) of rats were evaluated using two tasks. The BF lesions included both the nucleus basalis magnocellularis (NBM) and the medial septal area (MSA). The first task was a Stone maze, which has 14 consecutive choice points and is a task of complex, trial-independent memory. BF lesions did not impair choice accuracy in this task. The second task was a win-shift spatial discrimination in a radial arm maze, which requires trial-dependent memory. BF lesions produced a significant decrease in choice accuracy in this task. These results demonstrate that BF lesions impair trial-dependent (working) memory but not trial-independent reference memory, and that task difficulty is not the sole factor determining whether BF lesions produce behavioral impairments.

Animals↗
PubMed1985

Immunohistochemical evidence for phenylethanolamine-N-methyltransferase-positive/tyrosine hydroxylase-negative neurones in the retina and the posterior hypothalamus of the rat.

Phenylethanolamine-N-methyltransferase (PNMT)-immunoreactive neurons were observed in the inner nuclear layer of the rat retina, apparently giving rise to fiber networks mainly in layer 3 of the inner plexiform layer. These neurons did not seem to contain tyrosine hydroxylase (TH)-like or dopamine-beta-hydroxylase (DBH)-like immunoreactivity and were much smaller and more numerous than the previously described TH-positive dopamine neurons. PNMT-positive, but TH- and DBH-negative neurons were also observed in small numbers in the basal posterior hypothalamus.

Animals↗
PubMed1985

Cerebrospinal fluid acetylcholinesterase activity in senile dementia of the Alzheimer type.

Acetylcholinesterase (AChE) activity was measured in cerebrospinal fluid (CSF) samples from 36 individuals, including 12 persons with Alzheimer's disease, 12 normal controls, and 12 patients with other dementias. AChE activity also was measured in 47 normal subjects whose ages ranged from 20 to 84 to evaluate the effect of age on AChE activity. CSF from patients with senile dementia of the Alzheimer type showed significantly lower mean AChE activity than in age-matched controls and patients with other dementia syndromes. No correlation was found between duration of illness, age, or severity of illness (as measured by the Mini-Mental State Examination score) and CSF AChE activity in Alzheimer's disease. AChE increased significantly over the age range of 20 to 84. CSF AChE activity may prove to be a useful diagnostic test to confirm the clinical diagnosis of moderate to severe Alzheimer's disease.

Acetylcholinesterase↗
PubMed1985

Fetal methylazoxymethanol acetate-induced lesions cause reductions in dopamine receptor-mediated catalepsy and stereotypy.

Telencephalic hypoplasia induced by methylazoxymethanol acetate (MAM) resulted in increased activity of tyrosine hydroxylase in the striatum, indicative of a relative increase in the density of dopaminergic terminals in the remaining tissue. Administration of the dopamine receptor stimulant, apomorphine, or the receptor blocker, haloperidol, produced less stereotypy and catalepsy, respectively, in rats lesioned with methylazoxymethanol, compared to controls. These behavioral changes probably resulted from the loss of striatal perikarya and consequent decrease in nigrostriatal dopaminergic target sites caused by methylazoxymethanol.

Animals↗