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Biomedical subjects

C M Gray

Publications and source records attributed to C M Gray.

At least 19 recordsLinked to original sources
PubMed2000

Highly active antiretroviral therapy results in HIV type 1 suppression in lymph nodes, increased pools of naive T cells, decreased pools of activated T cells, and diminished frequencies of peripheral activated HIV type 1-specific CD8+ T cells.

This study examines sequential lymph nodes from 13 drug-naive patients before and after 24 weeks of highly active antiretroviral therapy (HAART). A multipronged approach was used to study changes in HIV-1 RNA in each paired lymph node in relation to tissue architecture and frequency of naive T cells. After 24 weeks, all patients showed significant suppression of plasma viral load and 12 of 13 showed concordant viral suppression in the lymph node (p = 0.001). Using in situ hybridization and quantitative image analysis, we showed that HIV-1 RNA was reduced to below detectable levels (two copies per cell) in follicular dendritic cell (FDC) and mononuclear cell pools. Independent immunohistochemical analysis of lymph node sections revealed that 5 of 13 patients displayed increased FDC networks and 6 of 13 showed no change and all patients showed increases in tissue-resident CD4+ cells. All lymph node biopsies at 24 weeks showed increased proportions of CD4+ and CD8+ cells coexpressing the naive markers CD45RA and CD62L when compared with baseline values. Significant correlations existed between viral load suppression and loss of activated CD8+ T cells after 24 weeks in both lymph node and blood, which was mirrored by significantly lowered frequencies of activated peripheral Gag peptide/MHC tetramer+ CD8+ cells. Overall, these data show that a potent and successful treatment strategy that significantly suppresses and removes FDC-resident HIV-1 results in improvements in lymphoid architecture and by so doing provides the structures available for increased numbers of naive cells to interact with cognate antigen. In addition, our article shows that suppression of HIV-1 replication results in diminished frequencies of peripherally activated antigen-specific CD8+ cells.

Antiretroviral Therapy, Highly Active↗
PubMed2000

Dynamic spike threshold reveals a mechanism for synaptic coincidence detection in cortical neurons in vivo.

Cortical neurons are sensitive to the timing of their synaptic inputs. They can synchronize their firing on a millisecond time scale and follow rapid stimulus fluctuations with high temporal precision. These findings suggest that cortical neurons have an enhanced sensitivity to synchronous synaptic inputs that lead to rapid rates of depolarization. The voltage-gated currents underlying action potential generation may provide one mechanism to amplify rapid depolarizations. We have tested this hypothesis by analyzing the relations between membrane potential fluctuations and spike threshold in cat visual cortical neurons recorded intracellularly in vivo. We find that visual stimuli evoke broad variations in spike threshold that are caused in large part by an inverse relation between spike threshold and the rate of membrane depolarization preceding a spike. We also find that spike threshold is inversely related to the rate of rise of the action potential upstroke, suggesting that increases in spike threshold result from a decrease in the availability of Na(+) channels. By using a simple neuronal model, we show that voltage-gated Na(+) and K(+) conductances endow cortical neurons with an enhanced sensitivity to rapid depolarizations that arise from synchronous excitatory synaptic inputs. Thus, the basic mechanism responsible for action potential generation also enhances the sensitivity of cortical neurons to coincident synaptic inputs.

Animals↗
PubMed2000

Inter- and intralimb oscillator coupling in parkinsonian tremor.

This study reports the findings of an analysis of temporal correlation between tremor of different muscles of the same and different limbs in four patients with Parkinson's disease. Spectral coherence methods were used for determining whether simultaneously occurring oscillations in the electromyograms of different muscles are statistically coupled. The incidence of significant coherence was considerably higher for muscle pairs in the same limb than for pairs in different limbs; Parkinson's disease tremor is coupled within but not between limbs. Because the characteristics of tremor are known to vary under different behavioral situations, the intralimb coupling was examined for different tasks. A mental arithmetic task resulted in an increase in the coherence between muscles of the same limb, whereas the finger-to-nose task decreased the coherence. No significant change in coherence was found for a postural task. The amplitude and regularity of tremor electromyography showed changes analogous to those in coherence. These results support the hypothesis that tremor in different limbs results from the activity of several neural circuits oscillating independently. The results also emphasize the value of these methods for rigorously characterizing tremor, in relation to disease state, behavioral conditions, and the selection of treatment strategies.

Aged↗
PubMed2000

Dynamics of striate cortical activity in the alert macaque: I. Incidence and stimulus-dependence of gamma-band neuronal oscillations.

Using single and multiunit recordings in the striate cortex of alert macaque monkeys, we find that gamma-band (20-70 Hz) oscillations in neuronal firing are a prominent feature of V1 neuronal activity. The properties of this rhythmic activity are very similar to those previously observed in the cat. Gamma-band activity is strongly dependent on visual stimulation, largely absent during spontaneous activity and, under the conditions of our experiment, not time-locked to the vertical refresh of the computer monitor (80 Hz) used to present the stimuli. In our sample, 61% of multiunit activity (MUA) and 46% of single-unit activity (SUA) was significantly oscillatory, with mean frequencies of 48+/-9 and 42+/-13 Hz, respectively. Gamma-band activity was most likely to occur when cells were activated by their optimal stimuli, but still occurred, although less often and with lower amplitude, in response to nonoptimal stimuli. The frequency of gamma-band activity also reflected stimulus properties, with drifting gratings evoking higher-frequency oscillations than stationary gratings. As in the cat, the spike trains of single cells showing gamma-band oscillations often displayed a pattern of repetitive burst firing, with intraburst firing rates of 300-800 Hz. The overall similarity of rhythmic neuronal activity in the primary visual cortex of cats and monkeys suggests that the phenomenon is not species-specific. The stimulus-dependence of the rhythmic activity is consistent with a functional role in visual perception.

Action Potentials↗
PubMed2000

Dynamics of striate cortical activity in the alert macaque: II. Fast time scale synchronization.

Synchronous neuronal activity with millisecond precision has been postulated to contribute to the process of visual perceptual grouping. We have performed multineuron recordings in striate cortex of two alert macaque monkeys to determine if the occurrence and properties of this form of activity are consistent with the minimal requirements of this theory. We find that neuronal synchronization with millisecond precision is a prevalent and robust feature of stimulus-evoked activity in striate cortex. It occurs among adjacent cells recorded by the same electrode (<120 microm), among cells recorded at separate but nearby sites (300-400 microm) and between cells recorded at locations separated by 3-4 mm. The magnitude and probability of synchronous firing is inversely related to the spatial separation between the cells and it occurs within and between groups of cells that are both tuned and untuned for stimulus orientation and direction. Among those tuned for orientation, cell pairs separated by <400 microm showed no clear dependence of correlated firing on orientation preference. The occurrence of gamma-band (20-70 Hz) oscillations in the cellular firing patterns was a strong predictor of synchronous firing at each of the spatial scales. Nearly 90% of the cell pairs showing significant correlation also showed oscillatory firing in one or both cells of the pair. These results are consistent with some, but not all, of the previous reports of synchronous activity in striate cortex of both cat and primates. The similarities in the properties of synchronous oscillations in the monkey and cat suggest that this form of neuronal activity is a general property of mammalian striate cortex. The relation between correlation and oscillation suggests that neuronal rhythmicity is an important mechanism contributing to synchronization.

Action Potentials↗
PubMed2000

Rethinking globally relevant vaccine strategies to human immunodeficiency virus type-1.

According to the latest UNAIDS figures for 1999 there were an estimated 30.6 million people living with HIV-1, with 16,000 new HIV infections per day. The only global strategy of combating new HIV infections is to make a vaccine that is affordable to developing countries, where greater than 90% of new infections occur, and that has enough efficacy to interrupt high rates of transmission. This review critically examines: 1) important immune parameters that should be considered which will allow an understanding of preventative vaccine design and 2) the mechanisms underlying immune destruction during HIV-1 infection that will facilitate design of therapeutic vaccines. A realistic goal of a preventative vaccine is to elicit protective immune responses in vaccinees that would prevent HIV-1 from replicating extensively in the host. Components of protective immunity are thought to include neutralizing antibodies (NAB) and cytotoxic T lymphocytes (CTL). Rethinking vaccine strategies has to take into account that HIV-1 vaccines must elicit primary cellular and humoral immunity via dendritic cell and Langerhan cell priming. It is only under these conditions that boosting immunity with subsequent vaccinations will allow high enough CTL effector cells and NAB titres to impede or to prevent HIV-1 replication. Success of therapeutic vaccine strategies, has to take into consideration the pathology of persistent immune stimulation by chronic HIV-1 infection. To re-stimulate immunity and re-direct immune responses, chronic immune stimulation by HIV-1 has to be alleviated by reducing high levels of viral antigen presentation by suppressing virus with antiretroviral agents. Such treatment courses may only have to be transient, long enough for immunity to respond to an immunogenic stimulus. Short-course drug therapy may then be an affordable option for many countries already carrying a high burden of HIV-1/AIDS.

AIDS Vaccines↗
PubMed1999

Cellular mechanisms contributing to response variability of cortical neurons in vivo.

Cortical neurons recorded in vivo exhibit highly variable responses to the repeated presentation of the same stimulus. To further understand the cellular mechanisms underlying this phenomenon, we performed intracellular recordings from neurons in cat striate cortex in vivo and examined the relationships between spontaneous activity and visually evoked responses. Activity was assessed on a trial-by-trial basis by measuring the membrane potential (Vm) fluctuations and spike activity during brief epochs immediately before and after the onset of an evoked response. We found that the response magnitude, expressed as a change in Vm relative to baseline, was linearly correlated with the preceding spontaneous Vm. This correlation was enhanced when the cells were hyperpolarized to reduce the activation of voltage-gated conductances. The output of the cells, expressed as spike counts and latencies, was only moderately correlated with fluctuations in the preceding spontaneous Vm. Spike-triggered averaging of Vm revealed that visually evoked action potentials arise from transient depolarizations having a rise time of approximately 10 msec. Consistent with this, evoked spike count was found to be linearly correlated with the magnitude of Vm fluctuations in the gamma (20-70 Hz) frequency band. We also found that the threshold of visually evoked action potentials varied over a range of approximately 10 mV. Examination of simultaneously recorded intracellular and extracellular activity revealed a correlation between Vm depolarization and spike discharges in adjacent cells. Together these results demonstrate that response variability is attributable largely to coherent fluctuations in cortical activity preceding the onset of a stimulus, but also to variations in action potential threshold and the magnitude of high-frequency fluctuations evoked by the stimulus.

Action Potentials↗
PubMed1999

Dynamics of tremor-related oscillations in the human globus pallidus: a single case study.

Physiological evidence indicates that the resting tremor of Parkinson's disease originates in oscillatory neural activity in the forebrain, but it is unknown whether that activity is globally synchronized or consists of parallel, independently oscillating circuits. In the present study, we used dual microelectrodes to record tremor-related neuronal activity from eight sites in the internal segment of the globus pallidus (GPi) from an awake Parkinson's disease patient undergoing stereotaxic pallidotomy. We utilized spectral analysis to evaluate the temporal correlations between multiunit activity at spatially separated sites and between neural and limb electromyographic activity. We observed that some GPi neural pairs oscillated synchronously at the tremor frequency, whereas other neural pairs oscillated independently. Additionally, we found that GPi tremor-related activity at a given site could fluctuate between states of synchronization and independence with respect to upper limb tremor. Consistent with this finding, some paired recording sites within GPi showed periods of transient synchronization. These observations support the hypothesis of independent tremor-generating circuits whose coupling can fluctuate over time.

Brain Mapping↗
PubMed1999

Frequency of class I HLA-restricted anti-HIV CD8+ T cells in individuals receiving highly active antiretroviral therapy (HAART).

Peptide/MHC tetrameric complexes were used to enumerate the frequency of HLA class I-restricted epitope-specific CD8+ T cells in 18 HLA-A*0201 HIV type 1-infected asymptomatic patients. HLA-A*0201 molecules were complexed to HIV Gag p17 (amino acids 77-85) and reverse transcriptase (amino acids 464-472) peptides, biotinylated, and bound to streptavidin-phycoerythrin to form tetramers. We show in this study that 17 of 18 HIV-1-infected asymptomatic patients have circulating frequencies of 1/50-1/1000 CD8+ T cells that recognize both Gag and Pol CTL epitopes or either epitope alone. The functional nature of these cells is open to interpretation, as we show that despite relatively high frequencies of fresh epitope-specific CD8+ T cells, variant epitope sequences in viral plasma progeny were rare. In addition, the majority of tetramer-positive cells did not display discernible fresh CTL activity; only after restimulation with specific peptide in culture was there an expansion of epitope-specific CD8+ cells, correlating with high CTL activity. These data suggest that fresh tetramer-stained cells probably represent memory precursors; we demonstrate, with the application of highly active antiretroviral therapy, that the interruption of chronic antigenic stimulation causes significant reductions in the frequency of these cells in five of six patients. In conclusion, this study provides evidence that persistently replicating viral populations are probably required to maintain high frequencies of HIV-1 epitope-specific CD8+ T cells in asymptomatic chronically infected individuals

Amino Acid Sequence↗
PubMed1998

Changes in CD4+ and CD8+ T cell subsets in response to highly active antiretroviral therapy in HIV type 1-infected patients with prior protease inhibitor experience.

This study explores whether previous failures on antiretroviral drug regimens preclude the possibility of immune restoration. This was assessed by evaluating T cell subset changes in individuals who received a salvage regimen of highly active antiretroviral therapy (HAART) after initially failing protease inhibitor monotherapy. Ten HIV-1-infected asymptomatic patients received a regimen of indinavir, zidovudine, and 3TC after failing saquinavir monotherapy. Changes in absolute numbers of naive, memory, and activated CD4+ and CD8+ T cells expressing a selection of CD45RA, CD62L, CD45RO, HLA-DR, and CD38 markers were monitored prospectively over 6 months. These measurements were correlated with plasma viral load along with alterations in a selected CD8+ V alpha/Vbeta T cell receptor (TCR) repertoire. Over 6 months there was a progressive increase in numbers of CD4+ memory (CD45RA-CD62L+) and naive (CD45RA+CD62L+) T cells, which displayed a modest inverse correlation with viral load. Two phases of CD8+ memory cell changes were identified, consisting of a transient increase in CD45RA+CD62L- numbers after 2 months and thereafter a progressive rise in CD45RA-CD62L+ cells until 6 months. A strong correlation existed between reduced viral load and loss of activated CD8+CD38+HLA-DR+ cell numbers. There was also a temporary broadening of the CD8+ V alpha/Vbeta TCR repertoire at 8 weeks, which became skewed after 6 months in parallel with reduced viral suppression. Closer analysis of naive and memory cell subset proportions in individual patients revealed that enlarged pools of naive subsets were evident in those patients with rebounds in viral load. Overall, drug-experienced patients responding to HAART displayed increased numbers of naive and memory CD4+ subsets, and reduced CD8+ cell activation with a loss of TCR skewing.

Adult↗
PubMed1998

Depressed phagocytosis and oxidative burst in polymorphonuclear leukocytes from individuals with pulmonary tuberculosis with or without human immunodeficiency virus type 1 infection.

Phagocytosis and oxidative burst in whole-blood granulocytes were assessed by flow cytometry with Phagotest and Bursttest kits, respectively. Seventy individuals were included in this study: 15 healthy, normal donors, 18 human immunodeficiency virus (HIV) type 1 (HIV-1)-seropositive patients, 19 patients with pulmonary tuberculosis (TB), and 18 patients co-infected with Mycobacterium tuberculosis and HIV-1 (TB-HIV). Granulocyte phagocytosis was assessed by incubating whole blood with fluorescence-labelled Escherichia coli and measuring the proportion of granulocytes with ingested bacteria and the capacity (fluorescence intensity) of each cell to phagocytose E. coli. The percentage of granulocytes converting nonfluorescent dihydrorhodamine to fluorescent rhodamine 123 on production of reactive oxygen intermediates (ROIs) and the mean channel shift were assessed as a measure of oxidative burst. No differences in the proportion of granulocytes that were capable of phagocytosing or producing ROIs in response to E. coli were observed between any of the study groups. Phagocytosis was significantly enhanced in granulocytes from HIV-1-infected individuals. On the other hand, granulocytes from individuals infected with M. tuberculosis alone or in combination with HIV-1 had a significantly reduced capacity to phagocytose E. coli and to produce ROIs in response to E. coli as an agonist. These results provide evidence that granulocytes from individuals with pulmonary TB with or without concomitant infection with HIV-1 have an impaired ability to phagocytose and to undergo oxidative burst, possibly contributing to the enhanced susceptibility to opportunistic infections in these patients.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Orientation selectivity in pinwheel centers in cat striate cortex.

In primary visual cortex of higher mammals neurons are grouped according to their orientation preference, forming "pinwheels" around "orientation centers." Although the general structure of orientation maps is largely resolved, the microscopic arrangement of neuronal response properties in the orientation centers has remained elusive. The tetrode technique, enabling multiple single-unit recordings, in combination with intrinsic signal imaging was used to reveal the fine-grain structure of orientation maps in these locations. The results show that orientation centers represent locations where orientation columns converge containing normal, sharply tuned neurons of different orientation preference lying in close proximity.

Action Potentials↗
PubMed1997

Stimulus-dependent neuronal oscillations and local synchronization in striate cortex of the alert cat.

Neuronal responses to visual stimuli that are correlated on a millisecond time scale are well documented in several areas of the mammalian visual cortex. This coherent activity often takes the form of synchronous rhythmic discharges ranging in frequency from 20 to 70 Hz. We performed experiments to determine the incidence and properties of this rhythmic activity in the striate cortex of alert cats and to compare this activity to similar data collected in the striate cortex of anesthetized cats. The results demonstrate that optimal visual stimuli evoke robust, locally synchronous, 20-70 Hz oscillatory responses in the striate cortex of cats that are fully alert and performing a visual fixation task. The oscillatory activity is stimulus dependent, largely absent during periods of spontaneous activity, and shows a systematic increase in frequency with increasing stimulus velocity. Thus, the synchronous oscillatory activity observed in this and earlier studies cannot be explained as an artifact of anesthesia nor as a phenomenon that occurs independent of visual stimulation. Rather, it is a robust process that is present in the alert state and is dependent on the presence and specific properties of visual stimuli.

Animals↗
PubMed1997

Physiological properties of inhibitory interneurons in cat striate cortex.

Physiological and morphological properties of identified interneurons in the striate cortex of the cat were studied in vivo by intracellular recording and staining with biocytin. In conformity with in vitro studies, these non-pyramidal fast spiking cells have very brief action potentials associated with a high rate of fall, and a large hyperpolarizing afterpotential. These cells show high discharge rates, little or no spike frequency adaptation in response to depolarizing current injection, as well as a diverse range of firing patterns. Three of the cells were labeled and were found to be aspiny or sparsely spiny basket cells, with bitufted or radial dendritic arrangements, in layers II-IV. Their axonal arborizations were more dense near their somata and extended horizontally or vertically. Of 13 visually responsive cells tested, the receptive field properties of six cells and the orientation and direction preferences of eight cells were determined. Five of the successfully mapped cells had simple receptive fields while one had a complex receptive field type. The orientation and direction tuning properties of the overlapping set of eight cells showed a broad spectrum ranging from unselective to tightly tuned. The majority exhibited a clear preference for orientation and none of the cells were clearly direction selective. Quantitative analysis of the temporal properties of the spike trains during visual stimulation and spontaneous activity revealed that these cells do not exhibit any significant periodic activity, and fired at rates that were well below their maximum in response to depolarizing current pulses.

Action Potentials↗
PubMed1996

Preemptive cadaveric renal transplantation--clinical outcome.

Preemptive cadaveric renal transplantation (PCRT) maximizes the chance of maintaining high quality of life and may avoid the morbidity of dialysis and the associated financial costs. These benefits are offset by disadvantages, which include the possibility of transplantation many months before the need for dialysis, resulting in wasted organ function; an immediate risk of graft failure with conversion to a dialysis-dependent state; and uncertainty of the safety of PCRT. Patients who underwent PCRT between June 1976 and December 1994 at the Oxford Transplant Centre were compared with a matched cohort of first cadaveric transplant recipients who were dialysis-dependent when transplanted. The 116 patients in the PCRT cohort were well matched to the control group with respect to sex, age, blood group, HLA match, degree of sensitization, donor age, immunosuppression, and year of transplantation. Patient and graft survival were significantly better in the PCRT group. The difference in graft survival did not appear to be completely explained by better patient survival, as suggested by a trend toward better graft survival after excluding death with a functioning graft as a cause of failure. Among surviving grafts there were no significant differences in graft function as assessed by 1, 2, and 3 year plasma creatinine levels. In conclusion, PCRT appears to be safe and may even be associated with superior graft survival when compared with conventional transplantation. Early inclusion on a transplant waiting list with a view to PCRT can be justified with respect to the clinical outcome but the financial costs and implications for the utilization of cadaveric donor kidneys must also be considered.

Adolescent↗
PubMed1996

Chattering cells: superficial pyramidal neurons contributing to the generation of synchronous oscillations in the visual cortex.

In response to visual stimulation, a subset of neurons in the striate and prestriate cortex displays synchronous rhythmic firing in the gamma frequency band (20 to 70 hertz). This finding has raised two fundamental questions: What is the functional significance of synchronous gamma-band activity and how is it generated? This report addresses the second of these two questions. By means of intracellular recording and staining of single cells in the cat striate cortex in vivo, a biophysically distinct class of pyramidal neuron termed "chattering cells" is described. These neurons are located in the superficial layers of the cortex, intrinsically generate 20- to 70-hertz repetitive burst firing in response to suprathreshold depolarizing current injection, and exhibit pronounced oscillations in membrane potential during visual stimulation that are largely absent during periods of spontaneous activity. These properties suggest that chattering cells may make a substantial intracortical contribution to the generation of synchronous cortical oscillations and thus participate in the recruitment of large populations of cells into synchronously firing assemblies.

Action Potentials↗