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Biomedical subjects

S J Young

Publications and source records attributed to S J Young.

At least 19 recordsLinked to original sources
PubMed1999

Modification of postsynaptic densities after transient cerebral ischemia: a quantitative and three-dimensional ultrastructural study.

Abnormal synaptic transmission has been hypothesized to be a cause of neuronal death resulting from transient ischemia, although the mechanisms are not fully understood. Here, we present evidence that synapses are markedly modified in the hippocampus after transient cerebral ischemia. Using both conventional and high-voltage electron microscopy, we performed two- and three-dimensional analyses of synapses selectively stained with ethanolic phosphotungstic acid in the hippocampus of rats subjected to 15 min of ischemia followed by various periods of reperfusion. Postsynaptic densities (PSDs) from both area CA1 and the dentate gyrus were thicker and fluffier in postischemic hippocampus than in controls. Three-dimensional reconstructions of selectively stained PSDs created using electron tomography indicated that postsynaptic densities became more irregular and loosely configured in postischemic brains compared with those in controls. A quantitative study based on thin sections of the time course of PSD modification indicated that the increase in thickness was both greater and more long-lived in area CA1 than in dentate gyrus. Whereas the magnitude of morphological change in dentate gyrus peaked at 4 hr of reperfusion (140% of control values) and declined thereafter, changes in area CA1 persisted and increased at 24 hr of reperfusion (191% of control values). We hypothesize that the degenerative ultrastructural alteration of PSDs may produce a toxic signal such as a greater calcium influx, which is integrated from the thousands of excitatory synapses onto dendrites, and is propagated to the neuronal somata where it causes or contributes to neuronal damage during the postischemic phase.

Animals↗
PubMed1999

Inhalant abuse and the abuse of other drugs.

AIMS: To examine the relationship between inhalant abuse and other substances of abuse. DESIGN: Survey using a structured interview administered by a single trained interviewer. SETTING: A juvenile detention facility. PARTICIPANTS: 209 children incarcerated at the facility over a 3-month period. SELECTION PROCEDURE: Consecutive sample. INTERVENTIONS: None. MEASUREMENTS/FINDINGS: The structured interview was adapted from the American Drug and Alcohol Survey, which has been extensively used to obtain substance abuse epidemiologic data. We collected information on inhalants, alcohol, marijuana, downers, pep pills, lysergic acid diethylamide (LSD), cocaine, designer drugs, phencyclidine (PCP), Talwin and Ritalin, speed, and narcotics. The chi-square or Fisher exact test were used when appropriate. Mean ages of initial experimentation were as follows: inhalants, 9.7 years; marijuana, 11.9 years; alcohol (inebriated), 12.0 years; cigarettes, 11.2 years; for the remaining substances of abuse, the mean age was 13.2-14.7 years. Thirty subjects had used inhalants. Significant relationships were found between inhalants and cocaine (p = .004), Talwin and Ritalin (p = .001), downers (p = .01), and narcotics (p = .003). CONCLUSIONS: For children incarcerated in a juvenile detention facility in our community, inhalant abuse is associated with the later use of other substances of abuse. If this finding is replicated in other populations, it underscores the need for effective preventive strategies.

Administration, Inhalation↗
PubMed1998

Altered long-term potentiation in the hippocampus of apolipoprotein E-deficient mice.

Recent studies suggest that apolipoprotein E (apoE) plays a neurotrophic role in the central nervous system and that an aberrant function of this molecule might result in neurodegeneration. Supporting this notion, apoE-deficient mice show neurodegenerative and cognitive alterations. To characterize physiological changes associated with synaptic damage and cognitive impairment in apoE-deficient mice, we investigated synaptic plasticity in the hippocampus of urethane anesthetized mice. Electrical stimulation was delivered to the perforant pathway and the resulting evoked field excitatory postsynaptic potential (EPSP) and population spike were recorded in the hilus. Long-term potentiation, as measured in the population spike, was reduced by 50% in apoE-deficient mice when compared to wild-type controls. In contrast, there were no significant differences in the evoked field EPSP between wild-type and apoE-deficient mice following high-frequency stimulation. These results support the notion that cognitive impairment and synaptic loss in the hippocampus of apoE-deficient mice might be associated with impaired long-term potentiation.

Animals↗
PubMed1998

Intravenous tenoxicam for analgesia following laparoscopic cholecystectomy.

In a double-blind, placebo-controlled clinical trial (power of 80% to detect a 30% reduction in morphine consumption, P < 0.05) we have determined that intraoperative intravenous administration of tenoxicam 40 mg during laparoscopic cholecystectomy, when compared with placebo, was associated with a significant reduction in consumption of morphine at 6 hours and 12 hours (P < 0.05) but not at 24 hours, when assessed by patient-controlled analgesia. Furthermore there was a significantly greater requirement for "rescue" analgesia with intramuscular morphine in the placebo group during the period of the study. There was no difference between the groups in pain scores, either at rest or on movement, nor in the incidence of nausea and vomiting. No patient in either group suffered a respiratory rate less than 8/min or oversedation at any time, and there were no other adverse effects.

Analgesia, Patient-Controlled↗
PubMed1997

Fine structure of the murine leptin receptor gene: splice site suppression is required to form two alternatively spliced transcripts.

The fine structure of the murine leptin receptor gene (Lepr) is described. Duplicated ligand binding domains (conserved among cytokine receptors) are found in eight exons (coding exons 3 to 6 and 8 to 11). Thus, it is possible that a single leptin receptor molecule could have two functional ligand binding domains. The transmembrane region of Lepr is in coding exon 16 while the juxtamembrane JAK docking site is in coding exon 17. For all membrane-bound forms, the transcript must include 17 invariant exons and 1 alternatively spliced 3' terminal exon. The transcript encoding the soluble receptor (Re) includes 14 coding exons and an alternatively spliced 3' terminal exon. We have identified two splice variants (Rc and Re) for which there are no intervening sequences between the two final exons. This unusual juxtaposition of exons requires that splice donor sites at the 5' end of the respective terminal exons be ignored in the production of these splice variants. We suggest that splice site suppression is responsible for the formation of two of the alternatively spliced forms of the mouse Lepr gene. The juxtaposition of two coding exons separated by a consensus splice donor sequence is the structural substrate for this mode of alternative splicing. We present evidence that the Rc form is expressed in human tissues while the Re form, the soluble receptor, is not expressed.

Alternative Splicing↗
PubMed1997

Electron tomography of neuronal mitochondria: three-dimensional structure and organization of cristae and membrane contacts.

The structure of neuronal mitochondria from chick and rat was examined using electron microscope tomography of chemically fixed tissue embedded in plastic and sliced in approximately 500 nm-thick sections. Three-dimensional reconstructions of representative mitochondria were made from single-axis tilt series acquired with an intermediate voltage electron microscope (400 kV). The tilt increment was either 1 degree or 2 degrees ranging from -60 degrees to +60 degrees. The mitochondrial ultrastructure was similar across species and neuronal regions. The outer and inner membranes were each approximately 7 nm thick. The inner boundary membrane was found to lie close to the outer membrane, with a total thickness across both membranes of approximately 22 nm. We discovered that the inner membrane invaginates to form cristae only through narrow, tubular openings, which we call crista junctions. Sometimes the cristae remain tubular throughout their length, but often multiple tubular cristae merge to form lamellar compartments. Punctate regions, approximately 14 nm in diameter, were observed in which the inner and outer membranes appeared in contact (total thickness of both membranes approximately 14 nm). These contact sites are known to a play a key role in the transport of proteins into the mitochondrion. It has been hypothesized that contact sites may be proximal to crista junctions to facilitate transport of proteins destined for the cristae. However, our statistical analyses indicated that contact sites are randomly located with respect to these junctions. In addition, a close association was observed between endoplasmic reticulum membranes and the outer mitochondrial membrane, consistent with the reported mechanism of transport of certain lipids into the mitochondrion.

Animals↗
PubMed1997

Electron tomography of large, multicomponent biological structures.

Electron tomography is an extremely useful method for deriving three-dimensional structure from electron microscope images. The application of this technique to the reconstruction of large, complex structures such as mitochondria is described in conjunction with several tools for segmentation, measurement, classification, and visualization. In addition, the use of massively parallel computers to perform the tomographic reconstruction efficiently using R-weighted backprojection or iterative techniques is described.

Algorithms↗
PubMed1997

Lesions in the dentate hilum and CA2/CA3 regions of the rat hippocampus produce cognitive deficits that correlate with site-specific glial activation.

Thirty male rats pressed a lever three times (FR3) when a stimulus light (sD) was off to obtain sucrose pellets. They were then evenly divided into sham Controls versus groups lesioned bilaterally in the hippocampus by stercotaxic injection of ibotenic acid into the dentate hilum (HIL) or the CA2/CA3 region (CA2/3). On measures of recall of the FR3-sD task taken during the initial 30 min of a postlesion test session, the CA2/3 and especially the HIL groups showed significant (p < .05) impairments relative to the Controls. During an ensuing 30-min period, rats were reshaped to criterion, beginning at FR1, and no appreciable intergroup differences were noted on this schedule or at FR1-sD. At FR2-sD, the HIL but not the CA2/3 group showed some impairment relative to Controls. At FR3-sD, both the CA2/3 and HIL groups had impaired task performance. An immunocytochemical index of glial activation showed higher reactivity in CA2/3 or the dentate hilum among CA2/3 or HIL animals, respectively, that was associated with the degree to which they showed an FR3-sD performance deficit.

Animals↗
PubMed1997

The health of a group of young Australians in a New South Wales juvenile justice detention centre: a pilot study.

OBJECTIVE: To consider the health profile of a sample of young, largely male Australians as assessed on their admission to a New South Wales Juvenile Justice Detention Centre. METHOD: A retrospective analysis of primary care nurse health records for 100 sequential admissions. RESULTS: Of the 97 males and three females (mean age = 15.9 years), 30 were Aboriginal and 39 did not live with either parent at the time of admission. Respiratory illness, such as bronchitis and asthma were common. These diagnoses were overshadowed by histories of significant physical injury. The sample was at high risk of sexually transmitted disease. Forty-six per cent had prior contact with a mental health professional, 26% reported they had thought of suicide and 9% reported having attempted suicide. There was a high prevalence of substance abuse. CONCLUSION: The health of these young Australians is at risk from every perspective. Improving the quality of their health assessments is an important issue for the clinicians who attend them as individuals and for policy makers who aim to reduce the considerable social and economic cost of juvenile crime. The discussion of these results from one centre has revealed opportunities to make such improvements. There is a need for a gathering of expertise to address the issue, preferably on a national basis.

Adolescent↗
PubMed1996

Amphetamine-induced changes in nigrostriatal terminal excitability are modified following repeated amphetamine pretreatment.

To investigate neural mechanisms associated with behavioral sensitization to amphetamine, we studied the effect of an intrastriatal infusion of amphetamine on nigrostriatal axon terminal electrical excitability in rats following withdrawal from repeated systemic treatment. Rats were injected with amphetamine 2.5 mg/kg s.c. or saline daily for 4 days. Either 24 h or 14 days after the last injection, extracellular recordings were obtained from dopaminergic neurons of the substantia nigra, in a blind design in which the experimenter did not know the pretreatment regime. In order to assess the electrical excitability of the nigrostriatal axonal field, neurons were activated antidromically by stimulating their terminal fields in the striatum. As previously reported, striatal infusion of amphetamine (1 microM/0.3 microliter) in control animals resulted in a significant reduction in excitability as indicated by an increase in striatal stimulus current necessary to evoke antidromic activity. In contrast, intrastriatal amphetamine administration to amphetamine-pretreated animals did not decrease excitability. Spontaneous firing rates and patterns of cell discharge did not differ between saline- and amphetamine-treated animals. The chronic amphetamine-induced change in the effect of an acute intrastriatal amphetamine infusion on nigrostriatal terminal excitability may be due to enduring alterations in the amphetamine-induced release of dopamine and other striatal neurotransmitters or to changes in the sensitivity of presynaptic hetero- and/or autoreceptors on the dopaminergic axons.

Amphetamine↗
PubMed1996

Glutamate-dependent long-term presynaptic changes in corticostriatal excitability.

We have previously shown that brief high frequency stimulation of the anteromedial prefrontal cortex induces a long-term decrease in excitability of the glutamatergic corticostriatal terminal field. In contrast, a long-term increase in presynaptic corticostriatal excitability may be induced by presenting two brief cortical tetanizing stimuli separated by 2-3 min such that the second tetanus coincides with a period of increased excitability elicited by the first. In the present study, we examined the glutamate receptor subtypes involved in these long-term changes in presynaptic excitability. A specific glutamate receptor antagonist was infused into the rat striatum 10-25 min prior to either a single or double cortical tetanic stimulation. To eliminate the participation of intrinsic striatal cells, a subset of animals received a striatal kainic acid lesion eight to 20 days before the recording experiment. Antagonists of the N-methyl-D-aspartate and metabotropic glutamate receptor subtypes were effective in blocking the decrease in excitability induced by single cortical tetanic stimulation whereas an antagonist of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate receptor did not prevent the induction of a long-term reduction in excitability. In contrast, each of these antagonists prevented the induction of a long-term increase in excitability. These long-term modifications in excitability of the presynaptic glutamate axon terminals appear to be induced by similar mechanisms to those postulated to operate in long-term potentiation and depression. These enduring changes in presynaptic excitability are likely to represent important mechanisms for the selective modification of information processing in the striatum.

Action Potentials↗
PubMed1996

Quantitative analysis of periodontal defects in a skull model by subtraction radiography using a digital imaging device.

This paper describes a quantitative study of periodontal defects produced in a skull model using subtraction images obtained with a digital imaging device, radiovisiography (RVG). Analysis using radiovisiography was compared to changes in weight and volume determined by physical measurements. Four types of periodontal defects were studied: 2-wall, 3-wall, crater, and furcation. All defects were fabricated on posterior teeth in alveolar bone and done with triplicate samples. Defects were made progressively larger in approximately 1 mm steps allowing examination of defects ranging from 1 mm to 5 mm. Radiographic images before and after each step were obtained with a radiovisiography system and subtracted. Changes in weight and defect volume were also recorded and compared to the results obtained after each step from the digital subtraction. For each defect type, a regression analysis was performed to compare changes in bone mass determined by weight with calculated bone loss determined by subtraction radiography or by volume measurements. When the calculated bone losses were compared to the true bone losses it was evident that the subtraction method frequently, but not always, underestimated the lesion sizes. For all lesions the average underestimation was 22%. The largest underestimation occurred with furcation lesions where the measured bone loss was underestimated on average by 67%. Two-walled lesions were underestimated by 30%, 3-wall lesions by 3%, and crater lesions were overestimated by 10%. Furthermore, the accuracy of each 1 mm step in bone loss varied considerably. At present, the imaging system is not sufficiently accurate to establish absolute determinations of the bone loss, but would be clinically useful in determining relative changes in bone loss or gain after treatment. In addition, caution must be taken in interpreting a given change in calculated bone loss, since considerable variation may result in either underestimation or overestimation of bone loss.

Alveolar Bone Loss↗
PubMed1996

Effects of nicotine on dopaminergic nigrostriatal axons requires stimulation of presynaptic glutamatergic receptors.

An electrophysiological method for evaluating changes in axonal excitability was used to examine presynaptic effects of the local striatal administration of nicotine on nigrostriatal dopaminergic terminal axons in the rat. To eliminate postsynaptic interactions, intrinsic striatal neurons were destroyed with a unilateral kainate lesion performed 10 to 15 days before the recording experiments. Excitability was assessed by determining the striatal stimulus current just sufficient to elicit an antidromic response from the striatal terminal field of a dopaminergic nigral neuron on 95% of the stimulus presentations. Local nicotine infusion (1-100 microM/0.3 microliter) produced a dose-dependent increase in excitability. Previous intrastriatal administration of the nicotine receptor antagonists mecamylamine or chlorisondamine blocked the nicotine effect and subsequent administration reversed the nicotine response. Increased dopamine autoreceptor stimulation, presumably resulting from nicotine-induced dopamine release, appeared to oppose the nicotine-induced increase in excitability. Accordingly, in animals in which dopamine synthesis was blocked with alpha-methyl-p-tyrosine (250 mg/kg, 12 and 2 h before recording), the nicotine-induced increase in terminal excitability was larger than in untreated rats. Simultaneous intrastriatal administration of the glutamate receptor antagonists, 6,7-dinitro-quinoxaline-2,3-dione and 2-amino-7-phosphonoheptanoate, prevented the nicotine-induced increase in excitability in animals with or without alpha-methyl-p-tyrosine pretreatment. We conclude that the nicotine-induced increase in nigrostriatal terminal excitability is an indirect effect resulting from a nicotine-evoked increase in glutamate release and a subsequent increase in the stimulation of presynaptic glutamate heteroreceptors on the dopamine-containing terminals.

Animals↗
PubMed1995

Aromatic L-amino acid decarboxylase immunoreactive cells in the rat striatum: a possible site for the conversion of exogenous L-DOPA to dopamine.

The efficacy of L-dihydroxyphenylalanine (L-DOPA) in ameliorating the symptoms of Parkinson's disease (PD) is attributed to its conversion to dopamine (DA) by the enzyme aromatic L-amino-acid decarboxylase (AADC) in the striatum. Although the site of this conversion in the DA-denervated striatum has yet to be identified, it has been proposed that L-DOPA could be converted to DA at non-dopaminergic sites containing AADC. In the present study, we used immunocytochemical techniques to examine the localization of AADC and DA in the striatum of rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal dopaminergic projection. In the DA-denervated striatum, we observed AADC-immunoreactive (-IR) cells with morphological characteristics similar to a class of small aspiny interneuron. Although usually obscured by a dense plexus of AADC-IR fibers, these cells could also occasionally be detected in the intact striatum. Acute administration of L-DOPA to DA-denervated animals elicited contralateral rotational behavior as well as a pronounced c-fos protein immunoreactivity in the striatum ipsilateral to the lesion. Following acute administration of L-DOPA, but not after acute saline, DA-IR cells were detected in the denervated striatum. These DA-IR cells are similar in morphology and were found in the same location as the AADC-IR cells. These results strongly suggest the existence of a class of AADC-containing striatal cells that can form DA from exogenous L-DOPA in the rat. In the DA deafferented striatum, DA produced by these cells from exogenous L-DOPA could be released to exert physiological effects on DA receptive tissue. It is possible that similar cells could contribute to the efficacy of L-DOPA in the treatment of Parkinson's disease.

Animals↗
PubMed1995

Electron microscopic evidence for neurotoxicity in the basal ganglia.

The dopaminergic projection from the substantia nigra to the neostriatum is vulnerable to several neurotoxins including 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), amphetamine, and 5-hydroxydopamine. We have treated rats or mice with these agents and examined various regions of their brains with a combination of Fink-Heimer, immunohistochemical, serial-section electron microscopic, and three-dimensional reconstruction methods. In addition to degenerating or swollen axons, we found darkened glial processes and some damage to postsynaptic cells and dendrites. The particular effects observed critically depend on experimental variables such as dose, time, species and strain and raise questions about the correlation of light and electron microscopic results. These studies provide the basis for a discussion of the advantages and disadvantages of an ultrastructural examination of the effects of neurotoxins.

Amphetamine↗
PubMed1995

Conditions for electron tomographic data acquisition.

The conventional algorithms employed in electron microscope tomography require that the series of images obtained from different orientations of the specimen each represent a parallel orthographic projection under uniform magnification. Electron microscope optics can produce distortions in images that may affect the accuracy of a tomographic reconstruction. These distortions result in images with differential rotation and magnification of regions of a thick or highly tilted specimen located at different distances with respect to the plane of focus. The distortions increase in magnitude and may significantly affect the accuracy of the tomographic data when images are acquired under current center misalignment or non-eucentric positioning of the specimen. An additional source of error can be introduced if the condenser lenses are adjusted to compensate for the intensity attenuation due to the increased beam path length as the specimen is tilted. The change in beam crossover position due to adjustment of the condensers alters the beam divergence and may introduce systematic changes in magnification over the tilt series. The process of alignment of the tilt series will propagate these errors to more central regions of the image. In most cases, with proper consideration, it is possible to minimize these errors to levels where they will have negligible effects on the resolution of the tomographic reconstruction.

Algorithms↗