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Biomedical subjects

G Maguire

Publications and source records attributed to G Maguire.

At least 19 recordsLinked to original sources
PubMed2005

Monitoring enzyme replacement therapy in Fabry disease--role of urine globotriaosylceramide.

Anderson-Fabry disease (referred to as Fabry disease) is an X-linked disorder characterized by a deficiency of the lysosomal enzyme alpha-galactosidase A and the subsequent accumulation in various tissues of globotriaosylceramide (Gb(3)), the main substrate of the defective enzyme. Enzyme replacement therapy (ERT) offers a specific treatment for patients with Fabry disease, though monitoring of treatment is hampered by a lack of surrogate markers of response. In this study, the efficacy of long-term ERT in six Fabry hemizygotes and two symptomatic heterozygotes has been evaluated. Patients were administered recombinant alpha-galactosidase A every 2 weeks for up to a year. The efficacy of ERT was assessed by monitoring symptomatology and renal function. Urinary glycolipid concentration was estimated by a novel tandem mass spectrometric method. Urine glycolipid (Gb(3)) was elevated at baseline and fell impressively on ERT where patients were hemizygotes and in the absence of renal transplantation. In heterozygotes and in a recipient of a renal allograft, elevations and changes in urine glycolipids were less pronounced. In one patient, after several months of ERT, there was a transient increase in Gb(3) concentrations to baseline (pre-ERT) levels, associated with the presence of antibodies to the recombinant alpha-galactosidase A. The marked decline in urine Gb(3) on ERT, and its subsequent increase in association with an inhibitory antibody response, suggest that this analyte deserves further investigation as a potential marker of disease severity and response to treatment.

Adult↗
PubMed2005

Homocysteine, renal disease and cardiovascular disease in a remote Australian Aboriginal community.

BACKGROUND: Rates of renal and cardiovascular disease are high among Aboriginal Australians living in remote communities. Nutritional problems, in particular low folate levels, are also common. This suggests that increased homocysteine concentrations might be widespread, and a possible contributor to the high rates of cardiovascular disease. AIMS: To examine homocysteine concentrations, and their relationships to folate levels, and to markers of renal disease and cardiovascular disease in a remote Aboriginal Australian community METHODS: As part of a cross-sectional survey among adults in one community, homocysteine concentrations, concentrations of the crucial determinants (red blood cell (RBC) folate, vitamin B(12) and the C677T methylene tetrahydrofolate reductase polymorphism) and cardiovascular risk factors were examined. RESULTS: Among 221 people, geometric mean homocysteine concentration was 11.8 micromol/L (range: 11.1-12.5 micromol/L), with 57/221 (26%) values > or =15.0 micromol/L. Higher concentrations were associated with older age, male gender, lower RBC folate and lower vitamin B(12) concentrations and homozygosity for C677T. Homocysteine concentrations were not related to the presence of albuminuria, other than over the overt albuminuria range. Homocysteine concentrations were inversely correlated with calculated glomerular filtration rate (GFR). Carotid intima-media thickness, however, was not related to homocysteine concentration. In multivariate analyses, age, male gender, lower RBC folate concentrations, lower vitamin B(12) concentrations, lower calculated GFR and the C677T polymorphism were all associated with homocysteine concentrations. CONCLUSIONS: Homocysteine concentrations were consistent with previous limited reports in Aboriginal communities. Although superficially they are similar to reports from non-Aboriginal settings, the younger age of this cohort and the association of homocysteine concentrations with age suggest that age-specific concentrations are higher among Aboriginal Australians. In addition to dietary determinants, the high prevalence of apparently reduced renal function renal disease appears to be an important determinant of homocysteine concentrations in remote Aboriginal communities. The role of homocysteine concentrations as a potential mediator of the high rates of cardiovascular disease remains to be determined.

Adult↗
PubMed2003

Borderline nuclear change in cervical smears: five-year follow-up.

Borderline nuclear changes (BNC) account for 5-20% of cervical smears, and their outcome is unpredictable. Current management involves repeat smears at 6-mo intervals, for a further 12 mo with referral for colposcopy, if the changes persist. Given the uncertainty surrounding the natural history of BNC and the claim that many patients are further investigated unnecessarily and potentially "overtreated," the aim of this study was to determine the outcome for patients with a diagnosis of BNC to define whether the management protocol is appropriate for this patient group in our laboratory. A total of 808 patients with BNC were followed up. There was a 4.05% progression to high-grade dyskaryosis, and most of these were detected within the first year of follow-up. This at least justifies the early and intense follow-up of this patient group until a reliable "triage tool" is adopted to pre-select those patients with BNC who will progress or revert to negative.

Cell Nucleus↗
PubMed1999

Cannabinoid CB1 receptors and ligands in vertebrate retina: localization and function of an endogenous signaling system.

CB1, a cannabinoid receptor enriched in neuronal tissue, was found in high concentration in retinas of rhesus monkey, mouse, rat, chick, goldfish, and tiger salamander by using a subtype-specific polyclonal antibody. Immunolabeling was detected in the two synaptic layers of the retina, the inner and outer plexiform layers, of all six species examined. In the outer plexiform layer, CB1 was located in and/or on cone pedicles and rod spherules. Labeling was detected in some amacrine cells of all species and in the ganglion cells and ganglion cell axons of all species except fish. In addition, sparse labeling was found in the inner and/or outer segments of the photoreceptors of monkey, mouse, rat, and chick. Using GC/MS to detect possible endogenous cannabinoids, we found 3 nmol of 2-arachidonylglycerol per g of tissue, but no anandamide was detectable. Cannabinoid receptor agonists induced a dramatic reduction in the amplitude of voltage-gated L-type calcium channel currents in identified retinal bipolar cells. The presence and distribution of the CB1 receptor, the large amounts of 2-arachidonylglycerol found, and the effects of cannabinoids on calcium channel activity in bipolar cells suggest a substantive role for an endogenous cannabinoid signaling system in retinal physiology, and perhaps vision in general.

Animals↗
PubMed1999

Spatial heterogeneity and function of voltage- and ligand-gated ion channels in retinal amacrine neurons.

The spatial distribution of ion channels within amacrine cells of the tiger salamander retina was studied using patch recording in the retinal slice preparation. By focally puffing kainate, GABA and glycine at amacrine cell processes in the inner plexiform layer, it was determined that the cell's glutamate receptors were located in a confined region of the processes near the soma, while glycine and GABA receptors were located throughout the processes. Likewise, similar techniques in conjunction with voltage steps demonstrated that voltage-gated sodium channels were located throughout the cell and were shown to generate sodium-dependent spikes, while only the processes contained voltage-gated calcium channels. These results suggest that this form of transient amacrine cell collects its excitatory synaptic inputs in a region confined to a central annular region near the soma, that the signal is actively propagated throughout its processes by voltage-gated sodium channels and that calcium-dependent neurotransmitter release of glycine from this neuron can occur throughout its processes. Thus, excitatory signals are collected in the processes near the soma, inhibitory signals throughout the processes and excitation is probably propagated throughout the processes of the amacrine cell.

Ambystoma↗
PubMed1999

Rapid desensitization converts prolonged glutamate release into a transient EPSC at ribbon synapses between retinal bipolar and amacrine cells.

The mechanisms underlying the conversion of prolonged glutamate release from ribbon synapses in bipolar cells to sustained and transient excitatory postsynaptic responses in identified retinal amacrine cells were studied in tiger salamander (Ambystoma tigrinum) retina. A retina slice preparation with whole cell patch recording techniques under voltage- and current-clamp conditions was used to assay the electrical properties of bipolar and amacrine cells. Amacrine cells were categorized into two basic forms: (i) transient amacrine cells that respond to a step of light with a burst of spikes only at the transitions of the step; and (ii) sustained amacrine cells that respond with continuous spiking during the entire light step. The two cell types each had a characteristic morphology: transient amacrine cells possessed wide dendritic fields (chi = 375 microns), while sustained cells had much more narrowly confined dendritic fields (chi = 85 microns). Whole cell voltage-gated currents of the transient and sustained cell types were not significantly different. Both cell types had spikes that were sensitive to tetradotoxin (TTX, 0.3 microM) with voltage deflections of up to 100 mV. Light-evoked excitatory synaptic currents relaxed rapidly in transient neurons (tau 1/2 = 100 ms) and more slowly in sustained neurons (tau 1/2 = 1.2 s). EPSCs in both cells reversed near 0 mV. Rapid application of glutamate or kainate elicited rapidly desensitizing ionic currents (tau 1/2 = 85 ms) followed by a slowly desensitizing component. Cyclothiazide, a drug that eliminates rapid desensitization, lengthened the time course of the glutamate gated current from tau 1/2 = 85 ms to about 3 s, and the relaxation kinetics of the glutamatergic EPSC from tau 1/2 = 85 ms to about 1.0 s. These data suggest that a key determinant in forming transient versus sustained responses in amacrine cells of vertebrate retina is the differences in their excitatory, glutamatergic synaptic inputs, and that rapid desensitization of glutamate receptors plays a role in converting the presynaptic signal associated with sustained glutamate release into a postsynaptic, transient signal at the ribbon synapse.

Action Potentials↗
PubMed1999

Localization of cannabinoid CB1 receptors in the human anterior eye and retina.

PURPOSE: To determine the presence and distribution of CB1 cannabinoid receptors within the human eye. METHODS: A subtype-specific affinity-purified polyclonal antibody to the cannabinoid CB1 receptor was used to determine CB1 localization. Postmortem human eyes were fixed in methacarn and embedded in paraffin. Sagittal sections were mounted on slides and immunostained using antibodies to the CB1 receptor. Antibody binding was detected either by using peroxidase conjugated secondary antibodies and developing with diaminobenzidine or by using fluorescent secondary antibodies. RESULTS: Strong CB1 receptor labeling was detected in the ciliary epithelium, the corneal epithelium, and endothelium of the anterior human eye. Strong-to-moderate levels of CB1 staining were found in the trabecular meshwork and Schlemm's canal. Moderate labeling was detected in the ciliary muscle and in the blood vessels of the ciliary body. Moderate-to-light labeling also was detected in the sphincter papillae of the anterior human eye. Staining for CB1 receptors also was detected in human retina. The two synaptic layers of the retina and the inner and outer plexiform layers, were both moderately stained for CB1. In addition, moderate labeling was detected in the inner nuclear layer, and the ganglion cell layer. Strong labeling was detected in the outer segments of photoreceptors. No staining was observed in the corneal stroma or in the choroid. CONCLUSIONS: The wide distribution of cannabinoid CB1 receptors in both the anterior eye and the retina of humans suggests that cannabinoids influence several different physiological functions in the human eye.

Adult↗
PubMed1998

Postsynaptic responses of horizontal cells in the tiger salamander retina are mediated by AMPA-preferring receptors.

The postsynaptic responses of sign-preserving second-order retinal neurons (horizontal cells (HCs) and off-bipolar cells) are mediated by CNQX-sensitive AMPA/KA glutamate receptors. In this study we used receptor-specific allosteric regulators of desensitization and selected antagonists to determine the glutamate receptor subtypes in tiger salamander horizontal cells. Two approaches were employed in this study. The first was to measure postsynaptic currents induced by exogenously applied glutamate under voltage clamp conditions in living retinal slices; and the second was to record voltage responses controlled by endogenous glutamate released from photoreceptors in whole retinas. Application of 100 microM cyclothiazide (a specific AMPA receptor desensitization blocker) enhanced the glutamate-induced current by about 5 fold. In contrast, 300 microgram ml-1 Co nA (a specific kainate receptor desensitization blocker), had no effect. GYKI 52466 (a specific AMPA receptor antagonist) at 30 microM almost completely suppressed the glutamate-induced inward current in HCs. Cyclothiazide at 100 microM depolarized the HC dark membrane potential by about 5 mV and reduced the amplitudes of the voltage responses to dim lights, but enhanced the voltage responses to bright lights. Cyclothiazide had no effect on either the dark potential or the light responses of rods and cones. Con A at 300 microgram ml-1 had no effect on either the dark potential or the light responses of the HC. GYKI 52466 (30 microM) hyperpolarized the HC dark membrane potential by about 55 mV and almost completely suppressed the light responses. We conclude from these results that the postsynaptic glutamate- and light-induced responses in the tiger salamander retinal horizontal cells are mediated by AMPA-preferring, and not kainate-preferring glutamate receptors. The functional roles of AMPA receptors and their desensitization kinetics in visual information processing are discussed.

Ambystoma↗
PubMed1998

Actin cytoskeleton regulates ion channel activity in retinal neurons.

The actin cytoskeleton is an important contributor to the integrity of cellular shape and responses in neurons. However, the molecular mechanisms associated with functional interactions between the actin cytoskeleton and neuronal ion channels are largely unknown. Whole-cell and single channel recording techniques were thus applied to identified retinal bipolar neurons of the tiger salamander (Ambystoma tigrinum) to assess the role of acute changes in actin-based cytoskeleton dynamics in the regulation of voltage-gated ion channels. Disruption of endogenous actin filaments after brief treatment (20-30 min) with cytochalasin D (CD) activated voltage-gated K+ currents in bipolar cells, which were largely prevented by intracellular perfusion with the actin filament-stabilizer agent, phalloidin. Either CD treatment under cell-attached conditions or direct addition of actin to excised, inside-out patches of bipolar cells activated and/or increased single K+ channels. Thus, acute changes in actin-based cytoskeleton dynamics regulate voltage-gated ion channel activity in bipolar cells.

Actins↗
PubMed1998

Transport-mediated release of endogenous glutamate in the vertebrate retina.

In the present study we measured calcium-dependent, vesicular glutamate release, and calcium-independent, transport-mediated glutamate release patterns in the vertebrate retina to better understand the sources of elevated glutamate in neural tissue under ischemic conditions. A potassium concentration of 40 mM, which mimics the extracellular potassium concentration in the central nervous system during ischemia, was applied to the bathing medium of a retinal slice prepared from zebrafish. High external potassium evoked release of endogenous glutamate that was measured using a glutamate-specific fluorometric assay applied to the bath. The slice was visualized under 668 nm light using Normarski optics and fluorescent images were captured using a cooled charge-coupled device (CCD) camera. Following the elevation of external potassium to 40 mM several bands of glutamate fluorescence, reflecting the spatial distribution of glutamate release, were observed. A calcium-dependent cloud of glutamate was observed in the inner plexiform layer, that was antagonized by bath-applied nifedipine. A relatively dense glutamate cloud (1-10 microM) was observed over the ganglion cell layer, which was blocked by dihydrokainate, a glutamate transport antagonist. In contrast, nifedipine, an inhibitor of calcium-dependent neurotransmitter release in the retina, failed to block the cloud of released glutamate in the ganglion cell layer. These data suggest that under pathological conditions in the eye where glutamate levels are elevated surrounding retinal ganglion cells, such as observed in some forms of glaucoma, a possible source of the elevated glutamate is through a glutamate transporter operating in a reversed direction. A likely candidate for mediating this reversed transport of glutamate is the retinal Muller cell.

ATP-Binding Cassette Transporters↗
PubMed1998

Differential expression of voltage-gated K+ and Ca2+ currents in bipolar cells in the zebrafish retinal slice.

Whole-cell voltage-gated currents were recorded from bipolar cells in the zebrafish retinal slice. Two physiological populations of bipolar cells were identified. In the first, depolarizing voltage steps elicited a rapidly activating A-current that reached peak amplitude < or = 5 ms of step onset. IA was antagonized by external tetraethylammonium or 4-aminopyridine, and by intracellular caesium. The second population expressed a delayed rectifying potassium current (IK) that reached peak amplitude > or = 10 ms after step onset and did not inactivate. IK was antagonized by internal caesium and external tetraethylammonium. Bipolar cells expressing IK also expressed a time-dependent h-current at membrane potentials < -50 mV. Ih was sensitive to external caesium and barium, and was also reduced by Na+-free Ringer. In both groups, a calcium current (ICa) and a calcium-dependent potassium current (IK(Ca)) were identified. Depolarizing voltage steps > -50 mV activated ICa, which reached peak amplitude between -20 and -10 mV. ICa was eliminated in Ca+2-free Ringer and blocked by cadmium and cobalt, but not tetrodotoxin. In most cells, Ica was transient, activating rapidly at -50 mV. This current was antagonized by nickel. The remaining bipolar cells expressed a nifedipine-sensitive sustained current that activated between -40 and -30 mV, with both slower kinetics and smaller amplitude than transient ICa. IK(Ca) was elicited by membrane depolarizations > -20 mV. Bipolar cells in the zebrafish retinal slice preparation express an array of voltage-gated currents which contribute to non-linear I-V characteristics. The zebrafish retinal slice preparation is well-suited to patch clamp analyses of membrane mechanisms and provides a suitable model for studying genetic defects in visual system development.

Animals↗
PubMed1997

Increased dopamine activity associated with stuttering.

Position emission tomography using 6-FDOPA as a marker of presynaptic dopaminergic activity was used to investigate the role of the dopamine system in stuttering. Three patients with moderate to severe developmental stuttering were compared with six normal controls. Stuttering subjects showed significantly higher 6-FDOPA uptake than normal controls in medial prefrontal cortex, deep orbital cortex, insular cortex, extended amygdala, auditory cortex and caudate tail. Elevated 6-FDOPA uptake in ventral limbic cortical and subcortical regions is compatible with the hypothesis that stuttering is associated with an overactive presynaptic dopamine system in brain regions that modulate verbalization.

Adult↗
PubMed1995

A positron emission tomography [18F]deoxyglucose study of developmental stuttering.

Positron emission tomography using [18F]deoxyglucose (FDG) as a marker of regional brain metabolism was used to investigate the neural substrate of stuttering. Four patients with severe developmental stuttering were studied while reading aloud to another person (stuttering condition) and while reading aloud in unison with someone else (non-stuttering condition). The patients were also compared with four normal controls reading aloud by themselves. In the stuttering condition, significant decreases in regional glucose metabolism in Broca's area, Wernicke's area and frontal pole were seen compared with themselves while not stuttering. These differences were also seen in stuttering condition compared with normal controls. Significantly lower left caudate metabolism was seen in patients during both stuttering and non-stuttering conditions compared with normal controls. A circuit for stuttering is proposed based on these findings.

Adult↗
PubMed1995

Quality of life on home parenteral nutrition: a single centre study of 37 patients.

Quality of life was assessed in 37 patients receiving home parenteral nutrition (HPN) for intestinal failure. A questionnaire was developed specifically for this purpose and the results were compared with those obtained by subjective assessment using a simple linear scale. The majority of patients (n = 26, 70.3%) had a good objective quality of life and most (n = 16, 53.3%) of those eligible (n = 30, 81.1%) did not express an interest in intestinal transplantation. Despite the apparent good quality of life enjoyed by patients receiving HPN, there were numerous areas in which patients with intestinal failure felt that their quality of life left much to be desired: many patients reported significant psychological symptoms (n = 15, 40.5%) sexual (n = 10, 27.0%) and social dysfunction (n = 19, 51.3%) and most patients with intestinal failure were unable to return to work (n = 24, 88.9%). Detailed quality of life assessment reveals that there is much still to be done to ensure that provision of care for patients with intestinal failure involves not only prolongation of life but also an improvement in quality of life.

Journal Article↗
PubMed1994

The retinal dopamine network alters the adaptational properties of retinal ganglion cells in the cat.

1. Single-unit extracellular recordings of optic tract fibers were used to study ganglion cell (GC) response properties of the intact cat eye before and after the intravitreal injection of haloperidol or SCH23390, dopamine-specific antagonists. Nearly all of the dopaminergic cells in the cat retina are amacrine cells (ACs); thus the dopamine antagonists are thought to primarily block the postsynaptic effects of these dopaminergic amacrine cells. All GCs encountered were subjected to a battery of receptive-field (RF) tests, including classification as X or Y, and as ON or OFF. 2. The effects of haloperidol were greatest in the light-adapted OFF-center pathways and especially in the OFF-center Y-cell. Within 30 min of haloperidol injection, both the spontaneous and light-evoked activity of the OFF-center Y-cell fell to zero, but when the same cell was exposed to lower levels of steady-state background illumination (scotopic levels), the response of the cell once again became robust. 3. OFF-Center Y-cells that had partially recovered from the drug effects and OFF-center X-cells recorded when the drug effect was maximal both possessed intensity-response curves that were shifted to the right of normal. 4. Recovery from the drug effects reflect supranormal responses after the initial response reductions and may be due to haloperidol's action on the dopamine autoreceptor. 5. Of the ON-center cells, only the Y-cells showed response alterations; possessing higher spontaneous activities and slightly reduced amplitudes to RF center (RFC) illumination. 6. The effects of SCH23390 paralleled those of haloperidol except that the onset was faster and the duration of the action of SCH23390 was much shorter, and no supranormal responses followed the initial effects. 7. Dark-adaptation functions of OFF-center GCs revealed a normal rod-cone shift; however, SCH23390 eliminated the rod-cone break, and threshold quickly fell to that of the rod mechanism. 8. The dopaminergic neurons of the cat retina appear to play an important role in regulating the activity of retinal OFF-center pathways in the photopically adapted eye, and one of its functions may be to control the relative contributions of the rod and cone systems to the response properties of light-adapted OFF-center GCs. 9. It is argued that dopamine is released in the light and enhances cone pathway activity, perhaps in the outer retina at bipolar and horizontal cells, and suppresses rod pathway activity, perhaps in the inner retina at amacrine cells.

Adaptation, Ocular↗
PubMed1994

Dopamine enhances a glutamate-gated ionic current in OFF bipolar cells of the tiger salamander retina.

The transmitter glutamate is thought to be used by all vertebrate photoreceptors to drive the second-order neurons of the retina, horizontal and bipolar neurons. Dopamine, an endogenous retinal neurotransmitter localized to amacrine and interplexiform cells, has previously been shown to enhance glutamate-gated currents in retinal horizontal cells. In the present study we demonstrate that bipolar cells, like horizontal cells, possess glutamate receptors that are modulated by dopamine. We then identify some components of the pathway through which dopamine acts. We used whole-cell patch recording to measure how bath-applied dopamine modulated the currents elicited by puffs of transmitter solutions at bipolar cell dendrites. Excitatory amino acid-gated currents were evoked by pressure ejecting 1 mM glutamate or 10 microM kainate for 40 msec through a micropipette positioned at the dendrites of bipolar cells. Bath-applied dopamine (20 microM) enhanced the response to glutamate in OFF bipolar cells in the retinal slice by 40% and in isolated OFF bipolar cells by 65%. We also explored the components of the intracellular pathway mediating this modulation. Response enhancement was blocked by the D1 receptor antagonist SCH23390, but not by the D2 receptor antagonist spiperone, suggesting that the enhancement by dopamine is mediated by a D1 receptor. GDP-beta-S, a G-protein inactivator, blocked the enhancing action of dopamine, suggesting that the D1 receptor activated a G-protein to enhance the glutamate-gated current. Both 8-(4-chlorophenylthio)adenosine, a cAMP analog, and the addition of the catalytic subunit of protein kinase A (PKA) to the recording pipette enhanced glutamate-gated currents, while H-7, a PK inactivator, and PKI20amide, a PKA-specific inhibitor, blocked the enhancing action of dopamine. These data suggest that dopamine acts at D1 receptors in the dendrites of bipolar cells to activate adenyl cyclase, which through cAMP enhances a glutamate-gated current in bipolar cell dendrites. Thus, dopamine may modulate synaptic transmission from photoreceptors to OFF bipolar cells.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1993

Localized pleural microdeposition of type A amyloid in a patient with rheumatoid pleuritis. Histologic distinction from pleural involvement in systemic amyloidosis.

Decorticated pleural tissue from a 74-year-old man with rheumatoid arthritis, an exudative pleural effusion, and normal left ventricular function contained microscopic deposits of amyloid A protein, localized to the interface between a deep layer of dense fibrocollagen and a layer of granulation tissue beneath a surface fibrin exudate. Previously reported instances of pleural amyloid deposition have occurred in patients with presumed systemic amyloidosis, and most such effusions are the result of congestive heart failure. This patient had no evidence of systemic amyloidosis, and this case appeared to be an example of an unusual form of localized amyloidosis, so-called periinflammatory amyloidosis A. These observations suggest that amyloid in a pleural biopsy should not be construed per se to be diagnostic of systemic amyloidosis.

Aged↗