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Biomedical subjects

S Leonard

Publications and source records attributed to S Leonard.

At least 91 records · Page 5Linked to original sources
PubMed1998

Nicotinic receptors, smoking and schizophrenia.

Neuronal nicotinic acetylcholine receptor expression was examined in schizophrenia. The incidence of smoking in schizophrenia is remarkably high and nicotine has been found to normalize an auditory evoked potential deficit seen in most subjects who suffer from this disease. Antagonists and agonists of a specific subset of this receptor family, the alpha7 nicotinic receptor, were found to regulate the gating of filtering of auditory information in both humans and in an animal model. The alpha7 gene has been cloned and a polymorphic dinucleotide repeat near the gene was used for linkage analysis, showing the alpha7 locus to be linked to the P50 deficit. Expression of the alpha7 receptor, which binds nicotine with low affinity, is reduced in the hippocampus of schizophrenics. [3H]-nicotine binding, a measure of the high affinity nicotinic receptors, was also decreased in schizophrenics and does not increase in response to tobacco use, as is seen in control subjects. The results of these studies suggest the presence of abnormal expression and function of the neuronal nicotinic receptor gene family in schizophrenia.

Journal Article↗
PubMed1997

Comparison of the regional expression of nicotinic acetylcholine receptor alpha7 mRNA and [125I]-alpha-bungarotoxin binding in human postmortem brain.

Neuronal nicotinic acetylcholine receptors are expressed in the human central nervous system. A specific subtype of this receptor family, the alpha7 nicotinic acetylcholine receptor, is thought to be the principal alpha-bungarotoxin (alphaBTX)-binding protein in mammalian brain. Although the expression of this receptor subtype has been characterized in rat, no study has specifically compared the expression of both the alpha7 gene and the localization of BTX binding sites in human brain. Expression of alpha7 mRNA and receptor protein in human postmortem brain tissue was examined by in situ hybridization and [125I]-alpha-bungarotoxin autoradiography, respectively, with particular emphasis on regions associated with sensory processing. Regions with high levels of both alpha7 gene expression and [125I]-alphaBTX binding include the nucleus reticularis of the thalamus, the lateral and medial geniculate bodies, the basilar pontine nucleus, the horizontal limb of the diagonal band of Broca, the nucleus basalis of Meynert, and the inferior olivary nucleus. High-to-moderate levels of alpha7 probe hybridization were also seen in the hippocampus and the cerebral cortex; however, there was a reduced or variable degree of [125I]-alphaBTX binding in these regions compared with the level of probe hybridization. In most brain regions, [125I]-alphaBTX binding was localized to neuronal cell bodies similar in morphology to those that exhibited alpha7 hybridization, suggesting that the high-affinity [125I]-alphaBTX binding sites in the human brain are likely to be principally composed of alpha7 receptor subtypes.

Animals↗
PubMed1997

Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus.

Inheritance of a defect in a neuronal mechanism that regulates response to auditory stimuli was studied in nine families with multiple cases of schizophrenia. The defect, a decrease in the normal inhibition of the P50 auditory-evoked response to the second of paired stimuli, is associated with attentional disturbances in schizophrenia. Decreased P50 inhibition occurs not only in most schizophrenics, but also in many of their nonschizophrenic relatives, in a distribution consistent with inherited vulnerability for the illness. Neurobiological investigations in both humans and animal models indicated that decreased function of the alpha 7-nicotinic cholinergic receptor could underlie the physiological defect. In the present study, a genome-wide linkage analysis, assuming autosomal dominant transmission, showed that the defect is linked [maximum logarithm of the odds (lod) score = 5.3 with zero recombination] to a dinucleotide polymorphism at chromosome 15q13-14, the site of the alpha 7-nicotinic receptor. Despite many schizophrenics' extremely heavy nicotine use, nicotinic receptors were not previously thought to be involved in schizophrenia. The linkage data thus provide unique new evidence that the alpha 7-nicotinic receptor gene may be responsible for the inheritance of a pathophysiological aspect of the illness.

Auditory Perception↗
PubMed1997

Desensitization of mutant acetylcholine receptors in transgenic mice reduces the amplitude of neuromuscular synaptic currents.

While the slow onset of desensitization of nicotinic acetylcholine receptors (AChRs), relative to the rate of acetylcholine removal, excludes this kinetic state from shaping synaptic responses in normal neuromuscular transmission, its role in neuromuscular disorders has not been examined. The slow-channel congenital myasthenic syndrome (SCCMS) is a disorder caused by point mutations in the AChR subunit-encoding genes leading to kinetically abnormal (slow) channels, reduced miniature endplate current amplitudes (MEPCs), and degeneration of the postsynaptic membrane. Because of this complicated picture of kinetic and structural change in the neuromuscular junction, it is difficult to assess the importance of the multiple factors that may be responsible for the reduced endplate current amplitudes, and ultimately the clinical syndrome. In order to address this we have used a transgenic mouse model for the SCCMS that has slow AChR ion channels and reduced endplate responsiveness in the absence of any of the degenerative changes. We found that the reduction in MEPC amplitudes in these mice could not be explained by either reduced AChR number or by reduced AChR channel conductance. Rather, we found that the mutant AChRs in situ manifested an activity-dependent reduction in sensitivity that caused diminished MEPC and endplate current amplitude with nerve stimulation. This observation demonstrates that the basis for the reduction in MEPC amplitudes in the SCCMS may be multifactorial. Moreover, these findings demonstrate that, under conditions that alter their rate of desensitization, the kinetic properties of nicotinic AChRs can control the strength of synaptic responses.

Animals↗
PubMed1997

No evidence for a physiological coupling between melatonin and glucocorticoids.

Much has been speculated about the existence of a physiological coupling between melatonin and glucocorticoid secretion and about a possible anti-stress action of melatonin. We examined the relationship between melatonin and glucocorticoid secretion under close-to-physiological conditions, when the plasma concentration of either melatonin or glucocorticoids was elevated acutely or chronically in both rats and humans. Tryptophan administration caused a massive rise of plasma melatonin, but had no effect on corticosterone levels in rats or on cortisol levels in humans. The acute and long-lasting exposure of rats to uncontrollable stress resulted in a significant rise of adrenal corticosterone secretion, but had no effect on circulating melatonin levels. Orchectomy caused an initial increase in circulating corticosterone (when melatonin was unaffected) and a delayed rise in circulating melatonin (when corticosterone levels were normalized). In humans, no correlation was found between the nocturnal urinary excretion of melatonin and cortisol, either among healthy subjects, or among patients suffering from panic disorder (with an increased urinary excretion of cortisol) or among insomnia patients (with a high incidence of low melatonin secretion). Furthermore, no evidence was found for a suppressive action of melatonin on dexamethasone-mediated thymus regression in rats and on dexamethasone-mediated suppression of lymphocyte proliferation in vitro. Taken together, the results of this study provide no evidence for the existence of mutual influences between melatonin and glucocorticoid secretion, nor do they support the proposed attenuation of glucocorticoid-mediated effects on target cells or tissues by melatonin under physiological conditions.

Adult↗
PubMed1997

Oxidative stress in silicosis: evidence for the enhanced clearance of free radicals from whole lungs.

We hypothesized that reactive oxygen species (ROS) may be involved in the pathogenesis of silicosis. To investigate ROS' dependent pathophysiological processes during silicosis we studied the kinetic clearance of instilled stable nitroxide radicals (TEMPO). Antioxidant enzymes' superoxide dismutase (SOD) and glutathione peroxidase (GPx), and lipid peroxidation were also studied in whole lungs of rats exposed to crystalline silica (quartz) and sham exposed controls. Low frequency L-band electron spin resonance spectroscopy was used to measure the clearance of TEMPO in whole-rat lungs directly. The clearance of TEMPO followed first order kinetics showing significant differences in the rate for clearance between the diseased and sham exposed control lungs. Comparison of TEMPO clearance rates in the sham exposed controls and silicotic rats showed an oxidative stress in the rats exposed to quartz. Studies on the antioxidant enzymes SOD and GPx in the lungs of silicotic and sham exposed animals supported the oxidative stress and accelerated clearance of TEMPO by up regulated levels of enzymes in quartz exposed animals. Increased lipid peroxidation potential in the silicotics also supported a role for enhanced generation of ROS in the pathogenesis of silica-induced lung injury. These in vivo experiments directly demonstrate, for the first time, that silicotic lungs are in a state of oxidative stress and that increased generation of ROS is associated with enhanced levels of oxidative enzymes and lipid peroxidation. This technique offers great promise for the elucidation of ROS induced lung injury and development of therapeutic strategies for the prevention of damage.

Animals↗
PubMed1997

Augmentation of pulmonary reactions to quartz inhalation by trace amounts of iron-containing particles.

Fracturing quartz produces silica-based radicals on the fracture planes and generates hydroxyl radicals (.OH) in aqueous media. .OH production has been shown to be directly associated with quartz-induced cell damage and phagocyte activation in vitro. This .OH production in vitro is inhibited by desferrioxamine mesylate, an Fe chelator, indicating involvement of a Fenton-like reaction. Our objective was to determine if Fe contamination increased the ability of inhaled quartz to cause inflammation and lung injury. Male Fischer 344 rats were exposed 5 hr/day for 10 days to filtered air, 20 mg/m3 freshly milled quartz (57 ppm Fe), or 20 mg/m3 freshly milled quartz contaminated with Fe (430 ppm Fe). High Fe contamination of quartz produced approximately 57% more reactive species in water than quartz with low Fe contamination. Compared to inhalation of quartz with low Fe contamination, high Fe contamination of quartz resulted in increases in the following responses: leukocyte recruitment (537%), lavageable red blood cells (157%), macrophage production of oxygen radicals measured by electron spin resonance or chemiluminescence (32 or 90%, respectively), nitric oxide production by macrophages (71%), and lipid peroxidation of lung tissue (38%). These results suggest that inhalation of freshly fractured quartz contaminated with trace levels of Fe may be more pathogenic than inhalation of quartz alone.

Administration, Inhalation↗
PubMed1997

Effect of smoking history on [3H]nicotine binding in human postmortem brain.

Chronic nicotine administration in animal models evokes a dose-dependent increase in brain nicotinic receptor numbers. Genetically determined variability in nicotinic receptor number in different mouse strains has also been reported, which is thought to affect sensitivity to nicotine, as well as the development of tolerance. Humans self-administer nicotine principally in the form of cigarettes and other tobacco products. The present study compared [3H]nicotine binding in human postmortem brain from thalamus and hippocampus of nonsmoking subjects, subjects who had variable life-long smoking histories and subjects who had quit smoking. A significant increase was seen in [3H]nicotine binding in both hippocampus and thalamus of subjects with life-long smoking histories. In the hippocampus, this change resulted from a change in total receptor number (Bmax), with no change in receptor affinity (Kd). There was also a positive correlation between the degree of smoking, as measured by the average reported packs smoked per day, and the number of nicotine binding sites found in both the hippocampus and thalamus, showing that humans exhibit a dose-dependent increase in brain nicotinic receptor binding. Receptor levels in these brain regions after smoking cessation were at or below those found in the control population, which indicated that smoking-induced changes are reversible after cessation of nicotine treatment. These results suggest that increases in nicotinic receptor levels in the human brain may underlie nicotine tolerance and addiction in smokers.

Adult↗
PubMed1996

A study of the factors in hip replacement dislocation. Part 2.

Dislocation is a dramatic and distressing common complication following total hip replacement. The first article describing this study, published last week, considered some of the factors thought to predispose to dislocation. The authors emphasised the multifactorial nature of hip replacement dislocation and in this second article they examine the factors relating to acetabular position and orientation, and femoral component placement.

Causality↗
PubMed1996

A study of the factors in hip replacement dislocation. Part 1.

This is the first of two articles which describe a clinical and radiographic review of the reasons for dislocation in patients who have received customised total hip replacements. The researchers compared the alignment of 19 arthroplasties which had dislocated with 347 which had not. A number of factors were considered including pre- and post-operative factors, femoral component placement, component head size, and acetabular position and orientation. It was found the the femoral head size had the greatest influence on dislocation. However, the researchers point out that dislocation on these patients is a multifactoral problem and that prevention, through effective pre-operative and post-operative patient education in relation to care of the hip and mobilising, should be encouraged. They also advocate a multidisciplinary approach to improve patient outcomes. The second article will appear next week.

Adult↗
PubMed1996

Expression of insulin-like growth factor-1 (IGF-1) and IGF-binding protein 2 (IGF-BP2) in the hippocampus following cytotoxic lesion of the dentate gyrus.

Receptor binding and gene expression of several members of the IGF gene family were examined in the rat brain following lesion of the hippocampal dentate gyrus granular cells by intradentate colchicine injection. Dentate granular cell loss was accompanied by extensive reactive gliosis in the lesioned hippocampus and damaged overlying cortex, as verified by the increase in GFAP mRNA and BS-1 lectin binding. At 4 days post-lesion, 125I-IGF-2 binding was dramatically increased within the lesioned dentate gyrus and damaged overlying cortex, and corresponded temporally and anatomically with increased IGF-BP2 gene expression following the lesion. Increased IGF-BP3 gene expression was only observed in the overlying cortex at 10 days post-lesion, and corresponded with an increase in 125I-IGF-1 binding at the injured surface of the cortex. Type-2 IGF receptor mRNA expression was reduced to background levels in the lesioned dentate gyrus, suggesting that IGF-BP2 was a major component of the observed increase in 125I-IGF-2 binding. In situ hybridization also revealed a prominent increase in IGF-1 mRNA expression by 4 days post-lesion, which was localized within the lesioned dentate gyrus and damaged cortical areas, and was shown to be expressed by microglia. While no IGF-2 mRNA expression was observed within the CNS, either prior to, or following the lesion, IGF-2 mRNA expression was observed in the choroid plexus, meningeal membranes, and in blood vessel endothelium, providing a potential source for the transport of IGF-2 into the CNS. In the injured CNS, increased IGF-BP2 expression may act to maintain or transport IGF-1 or IGF-2, as well as modulate the local autocrine and paracrine actions of the IGFs. Increased microglial IGF-1 expression following colchicine treatment correlates with the timing of a number of post-traumatic events within the CNS, suggesting that IGF-1 may have a role as a neuroprotectant for surviving neurons and signal for local neuronal sprouting, as well as a role in reactive astrogliosis.

Animals↗
PubMed1996

Genetic correlation of inhibitory gating of hippocampal auditory evoked response and alpha-bungarotoxin-binding nicotinic cholinergic receptors in inbred mouse strains.

One function of the hippocampus is to ascertain the novelty of incoming sensations and encode significant new information into memory. The regulation of response to repeated stimuli may prevent overloading of this function by redundant sensory input. Recent pharmacological studies implicate the role of alpha-bungarotoxin-sensitive nicotinic cholinergic receptors in the inhibition of hippocampal response to repeated auditory stimuli. The number of hippocampal alpha-bungarotoxin-sensitive receptors has a major genetic determinant, as demonstrated by a significant variance between different inbred mouse strains. The purpose of the present study was to determine whether there was a related genetic correlation for the gating of auditory response. Nine inbred mouse strains, representing a continuum of hippocampal alpha-bungarotoxin binding, were tested for the electrophysiological response to repeated auditory stimulation, followed by whole hippocampus membrane alpha-bungarotoxin binding studies. Several parameters of the auditory evoked response showed significant genetic variance over the nine strains, and a significant correlation was found between hippocampal alpha-bungarotoxin binding and both the amplitude of the initial evoked response and its inhibition to repeated auditory stimuli. There was no correlation of the auditory evoked response with high-affinity nicotine binding. These data further support the hypothesis that alpha-bungarotoxin-sensitive nicotinic receptors are involved in the regulation of hippocampal response to repeated auditory stimuli and suggest that this function is genetically controlled.

Acoustic Stimulation↗
PubMed1996

31P magnetic resonance spectroscopy studies in schizophrenia.

Phospholipid metabolism abnormalities have been suggested by a number of postmortem brain and red blood cell studies in schizophrenia. 31P magnetic resonance spectroscopy enables the examination of phospholipid metabolism in living patients. These in vivo studies have demonstrated that schizophrenic patients have lower prefrontal levels of phosphomonoesters and higher levels of phosphodiesters compared to matched controls. Patients with psychotic depression also seem to show lower levels of phosphomonoesters compared to controls. This suggests that membrane phospholipid differences may not be specific to schizophrenia. Preliminary 31P magnetic resonance spectroscopy studies at high field strength on postmortem temporal lobe samples show no differences between treated schizophrenic patients and controls for phosphoethanolamine and phosphocholine which are the main constituents of the phosphomonoester peak. Further studies are underway in the prefrontal region. While 31P magnetic resonance spectroscopy studies have demonstrated membrane phospholipid abnormalities in schizophrenia, it is not clear whether these findings are specific to schizophrenia or part of a generalized membrane phospholipid abnormality.

Humans↗
PubMed1996

Schistosoma mansoni in IL-4-deficient mice.

Immunopathology and immune responses to Schistosoma mansoni were examined in IL-4 -/- mice. IL-5 and IL-10 production by lymphoid cells stimulated with soluble egg antigen (SEA), peripheral eosinophilia and serum levels of soluble IL-4 receptor but not IgE were all significantly elevated over background normal levels in IL-4 -/- mice as a result of infection. Additionally, IL-10 and IL-5 in addition to IL-2 and IFN-gamma transcripts were equally evident in diseased liver tissue from infected IL-4 -/- and wild-type mice. Nevertheless, analysis of antigen-stimulated IL-2, IL-4, IL-5, IL-10 and IFN-gamma production by lymphoid organ cells from infected or egg-injected IL-4 -/- mice revealed a more Th1-like pattern of cytokine production (IFN-gamma > IL-5) than in (wild-type) mice in which a stronger type 2 response to SEA was detectable (IL-4, IL-5 > IFN-gamma). Despite this, at 8 and 16 weeks after infection, liver pathology, as indicated by the size, cellularity, cellular composition and collagen content of granulomas, was similar in IL-4 -/- and wild-type animals. As in wild-type animals, granuloma size at week 16 was smaller than at week 8, indicating that modulation had occurred in the absence of IL-4. Differences in pathology were seen only when eggs were experimentally embolized to the lungs, in which case IL-4 -/- mice made smaller granulomatous responses than did wild-type animals. These data clearly show that IL-4 is not necessary for the hepatic granuloma formation which occurs during experimental schistosomiasis.

Animals↗
PubMed1996

Nicotinic receptor function in schizophrenia.

Schizophrenia can be partially characterized by deficits in sensory processing. Biochemical, molecular, and genetic studies of one such endophenotype, the P50 auditory-evoked potential gating deficit, suggest that one of the neuronal nicotinic receptors, the alpha 7 nicotinic receptor, may function in an inhibitory neuronal pathway involved in this phenotype. The P50 deficit is normalized in nongating subjects by nicotine. Although most schizophrenia patients are heavy smokers, the effects of nicotine may be transient, as alpha 7 receptors are known to desensitize rapidly. In an animal model of the P50 gating deficit, antagonists of the alpha 7 nicotinic receptor block normal gating of the second of paired auditory stimuli. Regional localization of receptor expression includes areas known to function in sensory filtering. An inhibitory mechanism, in the hippocampus, may involve nicotinic stimulation of gamma-aminobutyric acid (GABA)ergic interneurons, resulting in decreased response to repetitive stimuli. Expression of the alpha 7 receptor is decreased in hippocampal brain tissue, dissected postmortem, from schizophrenia subjects. The P50 deficit is inherited in schizophrenia pedigrees, but it is not sufficient for disease development and thus represents a predisposition factor. Linkage analysis between the P50 deficit in multiplex schizophrenia pedigrees and deoxyribonucleic acid (DNA) markers throughout the genome yielded positive lod scores to DNA markers mapping to a region of chromosome 15 containing the alpha 7 nicotinic receptor gene. Elucidation of possible interactions of the P50 with other factors, known to be important in the etiology of the disease, is important in determining an overall pathobiology of schizophrenia.

Animals↗
PubMed1995

Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia.

This study tests the hypothesis that nicotinic cholinergic receptors, including those sensitive to the antagonist alpha-bungarotoxin, are decreased in the hippocampus of schizophrenics. The hypothesis is derived from the finding that alpha-bungarotoxin causes a defect in the inhibitory gating of auditory-evoked potentials in laboratory animals that resembles a defect in auditory sensory gating observed in schizophrenics. Nicotine transiently normalizes this psychophysiological deficit in schizophrenic patients. Postmortem brain tissue was obtained from eight schizophrenic and eight age-matched nonschizophrenic subjects. Sections of the hippocampus were labeled with [125I alpha-bungarotoxin and imagined by autoradiography. Binding of the nicotinic agonist [3H]-cytisine was determined in tissue homogenates. alpha-Bungarotoxin labeled a population of putative interneurons in the hippocampus, primarily in the dentate gyrus and the CA3 region of Ammon's horn. This labeling was significantly decreased in the tissue from the schizophrenic patients, with seven or eight patients below the range of the nonschizophrenic subjects. There was also a significant decrease in the binding of cytisine. The results were not related to generalized hippocampal cell loss, drug exposure at time of death, or smoking history. This initial study suggests that schizophrenic patients have fewer nicotinic receptors in the hippocampus, a condition which may lead to failure of cholinergic activation of inhibitory interneurons, manifest clinically as decreased gating of response to sensory stimulation.

Adult↗