Biomedical subjects

Gary Rogers

Publications and source records attributed to Gary Rogers.

9 recordsLinked to original sources

PubMed2005

The effects of L-dopa on the functional magnetic resonance imaging response of patients with amblyopia: a pilot study.

PURPOSE: We investigated the effects of a single dose of levodopa (L-dopa) on the level and extent of visual cortex activation of subjects with amblyopia and normal subjects using blood oxygenation level-dependent functional magnetic resonance imaging (fMRI). SUBJECTS AND METHODS: Six patients with amblyopia and 9 control patients were recruited. A baseline fMRI session was followed by a second session 90 minutes after the dose of L-dopa. Visual stimuli included vertical sinusoidal gratings with spatial frequencies of 1 and 2 cpd that were counterphased at 4 Hz. Stimuli were presented monocularly and binocularly. The fMRI response was characterized by the total volume and the average level of activation within the occipital cortex. An interocular absolute difference (IDIF) was defined in terms of said measures for between-population analysis of monocular data. RESULTS: After the administration of L-dopa, visual acuity improved significantly ( P = 0.026) from 0.72 +/- 0.21 (mean +/- SD) to 0.64 +/- 0.24 LogMAR in the amblyopic eye, although remaining the same in the dominant eye and in the eyes of control subjects. The response to L-dopa was found to be population-specific, as indicated by a significant treatment-by-population interaction for the volume of activation IDIF ( P = 0.018) measure: subjects with amblyopia exhibited a post-treatment increase in the volume of activation IDIF whereas control subjects showed a less prominent decrease. This post-treatment increase of IDIF in subjects with amblyopia may be explained by the decrease in the volume of activation found for the amblyopic eye after L-dopa ( P = 0.038). No L-dopa-related activation changes were detected for dominant eye or binocular stimulation in the amblyopic group, and no change was detected in control subjects. CONCLUSION: L-dopa elicits a population-specific modulation of the fMRI response, namely, a reduced total volume of activation from the amblyopic eye despite improvement in visual acuity.

Adolescent↗

PubMed2004

No effect of rosiglitazone for treatment of HIV-1 lipoatrophy: randomised, double-blind, placebo-controlled trial.

BACKGROUND: Lipodystrophy commonly complicates antiretroviral therapy of HIV-1 infection. Thiazolidinediones such as rosiglitazone promote subcutaneous fat growth in type 2 diabetics and adults with congenital lipodystrophy, and can prevent HIV-1 protease inhibitor toxicity to adipocytes in vitro. We postulated that rosiglitazone would improve HIV lipoatrophy. METHODS: 108 HIV-1-infected lipoatrophic adults on antiretroviral therapy were randomised to rosiglitazone 4 mg twice daily (n=53) or matching placebo (n=55) for 48 weeks. The study had 80% power to detect a 0.5 kg difference in changes in limb fat (using dual-energy X-ray absorptiometry) between groups at week 48 by intention-to-treat analysis, and a 0.7 kg difference within each protease inhibitor stratum. FINDINGS: Limb fat increased by 0.14 kg in the rosiglitazone group and 0.18 kg in the placebo group (mean difference -0.04 kg [95%CI -0.29 to 0.21]; p=0.74 by t test), with three participants (one on rosiglitazone and two controls), lost to follow-up. Rosiglitazone had no significant benefit on any other measure of lipodystrophy, despite large relative increases in plasma adiponectin (4.2 mmol/L [102%]; p<0.0001) and in three markers of insulin sensitivity (p=0.01 to 0.02). Six participants ceased study drug in each group, four participants (three on rosiglitazone and one control) for related adverse events. The main adverse effects, which seem to be almost unique to this population, were asymptomatic hypertriglyceridaemia (mean relative increase 0.9 mmol/L at week 48; p=0.04) and hypercholesterolaemia (1.5 mmol/L; p=0.001). INTERPRETATION: Rosiglitazone for 48 weeks did not improve lipoatrophy in HIV-1-infected adults receiving antiretroviral therapy. Use of less toxic antiretroviral treatment is necessary to prevent lipoatrophy.

Anemia↗

PubMed2003

Enhancement of therapeutic protein in vivo activities through glycoengineering.

Delivery of protein therapeutics often requires frequent injections because of low activity or rapid clearance, thereby placing a burden on patients and caregivers. Using glycoengineering, we have increased and prolonged the activity of proteins, thus allowing reduced frequency of administration. Glycosylation analogs with new N-linked glycosylation consensus sequences introduced into the protein were screened for the presence of additional N-linked carbohydrates and retention of in vitro activity. Suitable consensus sequences were combined in one molecule, resulting in glycosylation analogs of rHuEPO, leptin, and Mpl ligand. All three molecules had substantially increased in vivo activity and prolonged duration of action. Because these proteins were of three different classes (rHuEPO is an N-linked glycoprotein, Mpl ligand an O-linked glycoprotein, and leptin contains no carbohydrate), glycoengineering may be generally applicable as a strategy for increasing the in vivo activity and duration of action of proteins. This strategy has been validated clinically for glycoengineered rHuEPO (darbopoetin alfa).

Anemia↗

PubMed2003

Specificity of the rat vesicular acetylcholine transporter.

The protein kinase A-deficient PC12 cell line PC12A123.7 lacks both choline acetyltransferase and the vesicular acetylcholine transporter. This cell line has been used to establish a stably transfected cell line expressing recombinant rat vesicular acetylcholine transporter that is appropriately trafficked to small synaptic vesicles. Acetylcholine is transported by the rat vesicular acetylcholine transporter at a maximal rate of 1.45 nmol acetylcholine/min/mg protein and exhibits a Km for transport of 2.5 mM. The transporter binds vesamicol with a Kd of 7.5 nM. The ability of structural analogs of acetylcholine to inhibit both acetylcholine uptake and vesamicol binding was measured. The results demonstrate that like Torpedo vesicular acetylcholine transporter, the mammalian transporter can bind a diverse group of acetylcholine analogs.

Acetylcholine↗

PubMed2002

Positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors elicits neuroprotection after trimethyltin exposure in hippocampus.

The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamatergic receptors have been linked to survival signaling, especially when the receptors are allosterically modulated by members of the Ampakine family. While increased glutamatergic communication through AMPA receptors has been shown to protect against toxic conditions that target hippocampal subfield CA1, protection in other subfields has not been shown. Accordingly, positive modulation of AMPA receptors by Ampakine compounds CX727 and CX516 was tested for effects on trimethyltin (TMT) neurotoxicity in rat hippocampal slice cultures. TMT was applied for 4 h followed by a rapid washout and antagonistic quenching of AMPA and N-methyl-D-aspartate (NMDA) receptors. After a 24-h period, the TMT-exposed slices exhibited increased levels of calpain-mediated spectrin breakdown as well as synaptic deterioration. TMT selectively targeted CA3 pyramidal neurons and dentate gyrus (DG) granule cells as evidenced by degeneration and neuronal loss. The cytoskeletal and synaptic damage was reduced when Ampakine modulation was initiated during the postinsult period. Furthermore, the extent of protection was comparable to that produced by the NMDA receptor antagonist AP5. The above results were substantiated by histological experiments, revealing that Ampakine treatment prevented TMT-induced cell loss in CA3 and DG. These results indicate that AMPA receptor signals are part of cellular repair responses following exposure to an environmental toxin.

Animals↗

PubMed2002

Survival signaling and selective neuroprotection through glutamatergic transmission.

In the brain, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors mediate glutamatergic neurotransmission and, when intensely activated, can induce excitotoxic cell death. In addition to their ionotropic properties, however, AMPA receptors have been functionally coupled to a variety of signal transduction events involving Src-family kinases, G-proteins, and the mitogen-activated protein kinase (MAPK). In the present study, we tested whether AMPA receptors are linked to appropriate signaling events in order to prevent neuronal injury and/or enhance recovery. AMPA stimulation in hippocampal slice cultures caused the selective activation of MAPK through the upstream activator MAPK kinase (MEK). Inhibition of either component of the AMPA receptor--MAPK pathway potentiated cellular damage due to serum deprivation, suggesting that this pathway facilitates compensatory signals in response to injury. Correspondingly, positive modulation of AMPA receptors with the Ampakine 1-(quinoxalin-6-ylcarbonyl)piperidine (CX516) enhanced MAPK activation and reduced the extent of synaptic and neuronal degeneration resulting from excitotoxic episodes. CX516 was neuroprotective when infused into slices either before or after the insult. The Ampakine derivative also elicited neuroprotection in an in vivo model of excitotoxicity as evidenced by reduction in lesion size and preservation of two different types of neurons. Interestingly, the AMPA receptor--MAPK pathway selectively protects against excitotoxicity since enhancing the pathway did not protect against the nonexcitotoxic, slow pathology initiated by lysosomal dysfunction. The results indicate that glutamatergic communication is important for cellular maintenance and that AMPA receptors activate survival signals to counterpoise their own excitotoxic potential.

Allosteric Regulation↗

PubMed2002

Functional magnetic resonance imaging as a tool for investigating amblyopia in the human visual cortex: a pilot study.

PURPOSE: This study investigates interocular differences in the level and extent of cortical activation in amblyopic and normal subjects. SUBJECTS AND METHODS: Blood oxygenation level dependent functional magnetic resonance imaging (FMRI) was performed at 1.5 T. A total of 5 subjects with amblyopia and 6 control subjectswere recruited. Visual stimuli included a homogeneous field flickering at 8 Hz and vertical sinusoidal gratings with spatial frequencies of 0.5, 1, and 2 cycles per degree of visual angle (counterphased at 8 Hz). Baseline images were taken in darkness. Stimuli were presented monocularly and binocularly. Data analysis was constrained to the occipital cortex, including striate and extrastriate areas. An absolute percent difference measure defined interocular differences in terms of total area, average level of activation, and a pooled activation parameter. RESULTS: Subjects with amblyopia exhibited a significantly larger (P <.05) interocular activation difference compared to controls. The level of activation driven by monocular stimulation of the amblyopic eye was reduced by 8.25% +/- 1.3% relative to the dominant eye. Controls showed an interocular difference in level of activation of 4.82% +/- 0.74%. The total area of activation driven by the amblyopic eye was reduced by 34.86% +/- 6.25% relative to the dominant eye. Controls showed an interocular difference in total area of activation of 20.80% +/- 3.67%. Subjects with amblyopia also manifested significantly greater (P <.05) cortical area and level of activation differences between the binocular and monocular states; the dominant eye response differed less from the binocular response than did the amblyopic eye response. CONCLUSION: FMRI is sensitive to amblyopia-related deficits in the human occipital cortex and, therefore, has potential as a tool for basic amblyopia research.

Adolescent↗

PubMed2002

Benzamide-type AMPA receptor modulators form two subfamilies with distinct modes of action.

CX516 (BDP-12) and CX546, two first-generation benzamide-type AMPA receptor modulators, were compared with regard to their influence on AMPA receptor-mediated currents, autaptic responses in cultured hippocampal neurons, hippocampal excitatory postsynaptic currents, synaptic field potentials, and agonist binding. The two drugs exhibited comparable potencies in most tests but differed in their efficacy and in their relative impact on various response parameters. CX546 greatly prolonged the duration of synaptic responses, and it slowed 10-fold the deactivation of excised-patch currents following 1-ms pulses of glutamate. The effects of CX516 on those measures were, by comparison, small; however, the drug was equally or more efficacious than CX546 in increasing the amplitude of synaptic responses. This double dissociation suggests that amplitude and duration of synaptic responses are governed by different aspects of receptor kinetics, which are differentially modified by the two drugs. These effects can be reproduced in receptor simulations if one assumes that CX516 preferentially accelerates channel opening while CX546 slows channel closing. In binding tests, CX546 caused an approximately 2-fold increase in the affinity for radiolabeled agonists, whereas CX516 was ineffective. More importantly, even millimolar concentrations of CX516 did not influence the dose-response relation for CX546, suggesting the possibility that they bind to different sites. Taken together, the evidence suggests that benzamide modulators from the Ampakine family form two subgroups with different modes and sites of action. Of these, CX516-type drugs may have the greater therapeutic utility because of their limited efficacy in prolonging synaptic responses and in attenuating receptor desensitization.

Allosteric Regulation↗

PubMedDate not supplied

Ectopia lentis.

Explore the source record for details and available documents.

Ectopia Lentis↗