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Biomedical subjects

R S Turner

Publications and source records attributed to R S Turner.

At least 37 records · Page 2Linked to original sources
PubMed1998

GABAA receptor pharmacology and subtype mRNA expression in human neuronal NT2-N cells.

Human NT2 teratocarcinoma cells differentiate into neuron-like NT2-N cells when treated with retinoic acid. GABA evoked concentration-dependent whole-cell currents in NT2-N cells with an EC50 of 21.8 microM and a Hill slope of 1.2. GABAA receptor (GABAR) currents reversed at ECl- and did not display voltage-dependent rectification. GABAR single channels opened in bursts to a 23 pS main conductance level and a 19 pS subconductance level, with infrequent openings to a 27 pS conductance level. Kinetic properties of the main conductance level were similar to other native and recombinant GABAR channels. Diazepam and zolpidem enhanced GABAR currents with moderate affinity, whereas methyl-6, 7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate inhibited GABAR currents. Loreclezole enhanced GABAR currents with high affinity, but furosemide antagonized GABAR currents with low affinity. The neurosteroids alphaxalone and pregnenolone sulfate appropriately modulated GABAR currents. Zinc blocked GABAR currents with low affinity, but lanthanum did not significantly alter NT2-N GABAR currents. Reverse transcription PCR (RT-PCR) performed on RNA from NT2-N cells clearly detected transcripts encoding human alpha2, alpha3, alpha5, beta3, gamma3, and pi subtypes. The combined pharmacological and RT-PCR results are most consistent with a single or predominant GABAR isoform composed of an alpha2 and/or alpha3 subtype combined with the beta3 and gamma3 subtypes. The data do not rule out receptors containing combinations of alpha2 and/or alpha3 subtypes with the alpha5 subtype or receptors with both beta1 and beta3 subtypes. The presence or absence or the pi subunit in functionally expressed receptors could not be determined.

Anticonvulsants↗
PubMed1998

The X11alpha protein slows cellular amyloid precursor protein processing and reduces Abeta40 and Abeta42 secretion.

Constitutive amyloid precursor protein (APP) metabolism results in the generation of soluble APP (APPs) and Abeta peptides, including Abeta40 and Abeta42-the major component of amyloid plaques in Alzheimer's disease brain. The phosphotyrosine binding (PTB) domain of X11 binds to a peptide containing a YENPTY motif found in the carboxyl terminus of APP. We have cloned the full-length X11 gene now referred to as X11alpha. Coexpression of X11alpha with APP results in comparatively greater levels of cellular APP and less APPs, Abeta40, and Abeta42 recovered in conditioned medium of transiently transfected HEK 293 cells. These effects are impaired by a single missense mutation of either APP (Y682G within the YENPTY motif) or X11alpha (F608V within the PTB domain), which diminishes their interaction, thus demonstrating specificity. The inhibitory effect of X11alpha on Abeta40 and Abeta42 secretion is amplified by coexpression with the Swedish mutation of APP (K595N/M596L), which promotes its amyloidogenic processing. Pulse-chase analysis demonstrates that X11alpha prolongs the half-life of APP from approximately 2 h to approximately 4 h. The effects of X11alpha on cellular APP and APPs recovery were confirmed in a 293 cell line stably transfected with APP. The specific binding of the PTB domain of X11alpha to the YENPTY motif-containing peptide of APP appears to slow cellular APP processing and thus reduces recovery of its soluble fragments APPs, Abeta40, and Abeta42 in conditioned medium of transfected HEK 293 cells. X11alpha may be involved in APP trafficking and metabolism in neurons and thus may be implicated in amyloidogenesis in normal aging and Alzheimer's disease brain.

Alzheimer Disease↗
PubMed1998

Motor subcircuits mediating the control of movement velocity: a PET study.

The influence of changes in the mean velocity of movement on regional cerebral blood flow (rCBF) was studied using positron emission tomography (PET) in nine healthy right-handed adults while they performed a smooth pursuit visuomanual tracking task. Images of relative rCBF were obtained while subjects moved a hand-held joystick to track the movement of a target at three different rates of a sinusoidal displacement (0.1, 0.4, and 0.7 Hz). Significant changes in rCBF between task conditions were detected using analysis of variance and weighted linear contrasts. The kinematics of arm and eye movements indicated that subjects performed tasks in a similar manner, particularly during the faster two tracking conditions. Significant increases in rCBF during arm movement (relative to an eye tracking only control condition) were detected in a widespread network of areas known for their involvement in motor control. The activated areas included primary sensorimotor (M1S1), dorsal and mesial premotor, and dorsal parietal cortices in the left hemisphere and to a lesser extent the sensorimotor and superior parietal cortices in the right hemisphere. Subcortically, activations were found in the left putamen, globus pallidus (GP), and thalamus, in the right basal ganglia, and in the right anterior cerebellum. Within the cerebral volume activated with movement, three areas had changes in rCBF that correlated positively with the rate of movement: left M1S1, left GP, and right anterior cerebellum. No movement-related sites had rCBF that correlated negatively with the rate of movement. Regressions of mean percent change (MPC) in rCBF onto mean hand velocity yielded two nonoverlapping subpopulations of movement-related loci, the three sites with significant rate effects and regression slopes steeper than 0.17 MPC.cm-1.s-1 and all other sites with nonsignificant rate effects and regression slopes below 0.1 MPC.cm-1. s-1. Moreover, the effects of movement per se and of movement velocity varied in magnitude independently. These results confirm previous reports that movement-related activations of M1S1 and cerebellum are sensitive to movement frequency or some covarying parameter of movement. The activation of GP with increasing movement velocity, not described in previous functional-imaging studies, supports the hypothesis that the basal ganglia motor circuit may be involved preferentially in controlling or monitoring the scale and/or dynamics of arm movements. The remaining areas that were activated equally for all movement rates may be involved in controlling higher level aspects of motor control that are independent of movement dynamics.

Aged↗
PubMed1997

Pallidal discharge related to the kinematics of reaching movements in two dimensions.

Movement-related discharge of neurons in the internal and external segments of the globus pallidus (GPi and GPe, respectively) of two monkeys was studied during reaching movements in a two-dimensional work-space. Discharge was studied during movements to targets in eight directions and at three distances from the starting position under three behavioral conditions that manipulated target visibility and movement triggering. A total of 73 neurons (57 in GPe and 18 in GPi) with changes in discharge in concert with arm movements were included in a quantitative analysis. Of these, 83% also changed their discharge during manipulation of the contralateral arm outside of the task. Although 73% of changes in discharge began before the initiation of movement, they seldom preceded the initial activity of the antagonist muscles. Decreases in discharge were more common than reported previously, constituting 40% of the changes in discharge detected. In GPi neurons, decreases also tended to begin earlier than increases. Changes in discharge in GPe neurons were of larger magnitude than those in GPi, and increases in discharge were larger than decreases. Onsets of changes in discharge were temporally linked to movement onset in 69% of neurons. Time locking of neural onset to trigger presentation and movement termination was found in only 30 and 1% of neurons, respectively. Direction of movement influenced the magnitude of changes in discharge in 78% of cells. Directional modulations were broadly tuned and preferred directions were uniformly distributed across the range of directions. When directional modulations were large, preferred directions were consistent for different amplitudes of movement and for different behavioral conditions. Amplitude of movement influenced the magnitude of changes in discharge in 78% of cells, and in 80% of cases that relation had a significant linear component. Amplitude effects were not more common or stronger for movements in directions close to a cell's preferred direction. Linear relations to movement amplitude were more common and accounted for more of the trial-to-trial variance in discharge rate than relations to either average velocity or movement duration. The relation to movement amplitude was consistent for two behavioral conditions when the change in discharge was scaled strongly with movement amplitude. Movement-related changes in discharge of neurons in the skeletomotor portions of both pallidal segments reflect the kinematics of movement. This information, encoded in combination with sensory and contextual information, may play an on-line role in the selective facilitation and suppression of different frontal thalamocortical circuits.

Action Potentials↗
PubMed1997

Probable diffuse Lewy body disease presenting as REM sleep behavior disorder.

Rapid eye movement sleep behavior disorder may herald several neurodegenerative disorders associated with parkinsonism, including Parkinson's disease. A 72-year-old man with a 17-year history of rapid eye movement sleep behavior disorder confirmed by polysomnography developed a progressive dementia that met operational clinical criteria for diffuse Lewy body disease. The differential diagnosis of progressive neurodegenerative disorders heralding as rapid eye movement sleep behavior disorder should now include diffuse Lewy body disease.

Aged↗
PubMed1996

Vaccinia virus serves as an efficient vector for expressing heterologous proteins in human NTera 2 neurons.

The human teratocarcinoma cell line NTera 2 (NT2) can be induced to differentiate into post-mitotic neurons possessing well-defined axonal and dendritic morphology. Highly enriched neurons (NT2-N cells) can be prepared in large numbers, thus combining many of the advantages of both primary and continuous cell culture systems. Unfortunately, it has proven difficult to express foreign genes in NT2-N cells. We examined whether vaccinia virus (VV) can express heterologous proteins in NT2-N cells and characterized the response of NT2-N cells to VV infection. NT2-N cells were infected with VV vectors expressing the envelope glycoprotein (gp160) from the human immunodeficiency type 1 virus (HIV 1). These vectors were chosen because VV-directed synthesis and post-translational processing of gp160 have been well characterized in many cell types. Approximately 85% of the neurons expressed gp160 which underwent native post-translational cleavage. The rate of gp160 synthesis was maximal at 5-48 hours postinfection, but was detectable for as long as 4 days. Surprisingly, NT2-N cells showed no VV-induced alterations in morphology, downregulation of host protein synthesis, or cytotoxicity, as measured by lactate dehydrogenase release. These results indicate that VV can serve as an efficient vector for introducing foreign genes in NT2-N cells without the cytotoxic effects often associated with VV infection. These properties, in conjunction with the advantages provided by NT2-N cells, provide new options for analyzing the cellular and molecular functions of human neurons.

Cell Death↗
PubMed1996

Amyloids beta40 and beta42 are generated intracellularly in cultured human neurons and their secretion increases with maturation.

Previous studies have demonstrated the presence of amyloid beta (Abeta) in neurons (NT2N) derived from a human embryonal carcinoma cell line (NT2) by steady state metabolic radiolabeling and immunoprecipitation. We show here that Abeta is present intracellularly since trypsin digestion of intact NT2N cells at 4 degrees C did not eliminate the Abeta recovered in cell lysates. To determine whether both Abeta40 and Abeta42 are produced intracellularly, quantitative sandwich enzyme-linked immunosorbent assay (ELISA) was performed using COOH-terminal end-specific anti-Abeta monoclonal antibodies. Sandwich ELISA detected intracellular Abeta40 and A++beta42 in NT2N cell lysates at a ratio of 3:1, whereas secreted Abeta40 and Abeta42 were recovered in medium conditioned by NT2N cells at a ratio of approximately 20:1. Metabolic steady state and pulse-chase labeling studies demonstrated a 2-h delay in the detection of cell-associated Abeta40/Abeta42 in the medium, suggesting that Abeta is generated at a slow rate intracellularly prior to its secretion. Finally, as NT2N cells mature over time in culture, the secretion of Abeta40 and Abeta42 increases more than 5-fold over 7 weeks. This increase in the secretion of Abeta40/Abeta42 in NT2N cells as a function of time may recapitulate a similar phenomenon in the aging brain.

Amyloid beta-Peptides↗
PubMed1996

Clinical, neuroimaging, and pathologic features of progressive nonfluent aphasia.

We report the clinical, neuroimaging, and neuropathologic features of progressive nonfluent aphasia (PNFA), a rare neurodegenerative syndrome most notable for its distinct language disturbance. Longitudinal observations of 3 patients revealed progressively telegraphic speech and writing, followed by gradual deterioration of sentence comprehension, and finally, preterminal mutism and dementia. Magnetic resonance imaging revealed cortical atrophy most pronounced in anterior regions of the left hemisphere. Functional neuroimaging demonstrated reduced cerebral activity most prominently in left frontal and temporal regions. At necropsy, microscopic pathology of brain was most consistent with the diagnosis of "dementia lacking distinctive histology" (DLDH). A review of published primary progressive aphasia cases with adequate clinical and histopathological descriptions reveals that the most common pathology underlying PNFA is DLDH. PNFA is one example of a family of clinical syndromes with similar underlying histopathology that affects different regions of the frontal lobe.

Adult↗
PubMed1996

Treatment of advanced Parkinson's disease by posterior GPi pallidotomy: 1-year results of a pilot study.

The effects of posterior internal pallidal ablation (GPi pallidotomy) on parkinsonian signs and symptoms were studied in 15 patients with medically intractable Parkinson's disease (PD). The sensorimotor territory of the internal portion of the globus pallidus and the adjacent optic tract and internal capsule were identified with microelectrode recording and stimulation. Radiofrequency lesions were then created in the identified sensorimotor territory. Pallidotomy significantly improved all cardinal parkinsonian motor signs (tremor, rigidity, akinesia/bradykinesia, and gait dysfunction) and reduced drug-induced motor fluctuations and dyskinesias. The improvements occurred predominately contralateral to the lesion, but were also present ipsilaterally. Early postoperative (3-month), mean total United Parkinson's Disease Rating Scale scores improved by 30.1% from preoperative values. Mean combined "on/off" Schwab and England Scale scores, a measure of functional independence, increased from 48.8% to 73.0% postoperatively. The mean total United Parkinson's Disease Rating Scale and Schwab and England scores did not show a statistically significant decline over the 1-year postoperative period. Surgery resulted in little morbidity, including a lack of significant deficits on neuropsychological and psychiatric testing. Physical and social functioning and vitality measures on the Medical Outcome Scale also showed significant improvement over the postoperative period. The findings of this pilot study demonstrate that ablation of the sensorimotor portion of the internal pallidum is a highly effective treatment for advanced PD, with benefits sustained at 1 year.

Adult↗
PubMed1995

Directional variation of spatial and temporal characteristics of limb movements made by monkeys in a two-dimensional work space.

1. The directional variation of kinematic and electromyographic (EMG) characteristics of two-joint arm movements made to targets in a two-dimensional work space was studied in monkeys trained to make targeted arm movements under different behavioral conditions. 2. In each animal, kinematic measures of movement (movement amplitude, movement time, peak velocity, and trajectory curvature) and endpoint spatial position within the target zone varied as a function of the direction of the target from the starting position. Movements made toward the body into the ipsilateral hemispace generally had the smallest amplitude, lowest peak velocity, and longest movement time. 3. Although the directional variation in peak velocity could partially be accounted for by predicted anisotropies in the inertial load imposed by the arm, deviations from these predictions suggest that movement amplitude is controlled more rigorously by the CNS. Adjustments in movement time may be used to compensate for inertial anisotropies. 4. The spatial characteristics of movements (amplitude, trajectory curvature, or endpoint error) were influenced little by the visibility of the target during movement, the advanced knowledge of target location, or the presence or absence of an external trigger cue. However, temporal characteristics (movement time, peak velocity, and for some animals, reaction time) varied more as sensory cues were changed. 5. The time of initial EMG activity in muscles acting around the shoulder varied systematically as a function of target direction. A cosine model accounted for a large fraction of the variability in initial onset time, as determined in a trial-by-trial analysis. The amplitude of the EMG activity was more narrowly tuned, however. Muscles acting at the elbow showed less activity and more variable directional tuning. 6. We conclude that directional variations in the kinematic characteristics of movement, and thus, the dynamic force requirements of the task, must be taken into consideration as contributors to the apparent directional coding described for neuronal populations in different portions of the CNS.

Animals↗
PubMed1994

Postoperative total hip prosthetic femoral head dislocations. Incidence, etiologic factors, and management.

Twenty-five dislocations occurred after 561 total hip arthroplasties performed by the author from 1971 to 1992. Acetabular shell and liner loosening must be differentiated from true dislocations. The dislocation rate of 5.49% in female patients was higher than the 2.8% rate in male patients. The 4.76% rate after 84 total hip revisions was slightly higher than the 3.98% rate after 477 primary replacements. No dislocations occurred using the anterolateral approach for 53 patients. Dislocation rates varied using different prosthetic systems for 508 patients who had the posterolateral approach used. Femoral prostheses with larger neck diameters were more prone to dislocation. These differences were not statistically significant with the sample sizes used, according to the chi square test for equality of proportions. Fluoroscopy aided reduction of one multiplanar recurrent case. Single hip spica abduction casts with and without knee hinges used for three to four months, along with abduction isometric exercises, led to stability in six recurrent cases.

Aged↗
PubMed1993

Human neurons derived from a teratocarcinoma cell line express solely the 695-amino acid amyloid precursor protein and produce intracellular beta-amyloid or A4 peptides.

The beta-amyloid or beta/A4 peptides that accumulate as filamentous aggregates in the extracellular space of Alzheimer disease (AD) brains are derived from one or more alternatively spliced amyloid precursor proteins (APPs). The more abundant APPs in the central nervous system are the 695-(APP695), 751- (APP751), and 770- (APP770) amino acid isoforms, and each could be the source of beta/A4 peptide that accumulates in the AD brain. It is plausible that altered metabolism of these APPs by central nervous system neurons could lead to the release and deposition of beta/A4 peptide in brain parenchyma. Thus, we examined the expression and processing of the three major brain APPs in nearly pure human neurons (NT2N cells) derived from a teratocarcinoma cell line (NTera2/c1.D1 or NT2 cells) after retinoic acid treatment. NT2N neurons expressed almost exclusively APP695, whereas NT2 cells expressed predominantly APP751/770. Furthermore, the processing of the APPs in NT2N cells was distinct from NT2 and nonneuronal cells. Most significantly, the NT2N neurons but not the NT2 cells constitutively generated intracellular beta/A4 peptide and released it into the culture medium. This work demonstrates the intracellular production of beta/A4 peptide and suggests that cultured NT2N cells may provide a unique model system for understanding the contribution of neurons and APP695 to amyloidogenesis in the AD brain.

Amyloid beta-Peptides↗
PubMed1993

The incidence of deep-vein thrombosis after upper tibial osteotomy. A venographic study.

We performed postoperative venography on 84 consecutive patients who had undergone upper tibial osteotomy for medial compartment osteoarthritis of the knee. Deep-vein thrombosis was demonstrated in 41%. Only 15% of the cases were diagnosed clinically, all in the calf veins. Cases of proximal thromboses (3) and mixed-vein thromboses (12) were only revealed by venography.

Adult↗
PubMed1992

Use of historical assessment for evaluation of process-based model projections of future environmental change: Lake acidification in the Adirondack mountains, New York, USA.

Because of the considerable uncertainties associated with modeling complex ecosystem processes, it is essential that every effort be made to test model performance prior to relying on model projections for assessment of future surface water chemical response to environmental perturbation. Unfortunately, long-term chemical data with which to validate model performance are seldom available. The authors present here an evaluation of historical acidification of lake waters in the northeastern United States, and compare historical changes in a set of lakes to hindcasts from the same watershed model (MAGIC) used to estimate future changes in response to acidic deposition. The historical analyses and comparisons with MAGIC model hindcasts and forecasts of acid-base response demonstrate that the acidic and low-ANC lakes in this region are responsive to strong acid inputs. However, the model estimates suggest lakewater chemistry is more responsive to atmospheric inputs of sulfur than do the estimates based on paleolimnological historical analyses. A 'weight-of-evidence approach' that incorporates all available sources of information regarding acid-base response provides a more reasonable estimate of future change than an approach based on model projections alone. The results of these analyses have important implications for predicting future surface water chemical change in response to acidic deposition, establishing critical loads of atmospheric pollutants, and other environmental assessment activities where natural variation often exceeds the trends under investigation (high noise-to-signal ratio). Under these conditions, it is particularly important to evaluate future model projections in light of historical trends data.

Journal Article↗
PubMed1992

Sensitivity to change for low-ANC eastern US lakes and streams and brook trout populations under alternative sulfate deposition scenarios.

A weight-of-evidence approach was used by the US National Acid Precipitation Assessment Program (NAPAP) to assess the sensitivity of chemistry and biology of lakes and streams to hypothesized changes in sulfate deposition over the next 50 years. The analyses focused on projected effects in response to differences in the magnitude and the timing of changes in sulfate deposition in the north-eastern United States, the Mid-Appalachian Highlands, and the Southern Blue Ridge Province. A number of tools was used to provide the weight of evidence that is required to have confidence in an assessment that has many uncertainties because of the complexity of the systems for which the projections of future conditions were made and because of limited historical data. The MAGIC model provided the projections of chemical changes in response to alternative deposition scenarios. Projected chemical conditions were input into biological models that evaluate effects on fish populations. The sensitivity of water chemistry and brook trout resources to the hypothesized changes in deposition was found to be greatest in the Adirondacks and Mid-Atlantic Highlands. Under the hypothesized sulfur deposition reduction scenarios, chemical conditions suitable for fish were projected to improve 20-30 years sooner than with the scenario that assumed no new legislated controls. Other lines of evidence, e.g. other models, field observations, and paleolimnological findings, were used to evaluate uncertainty in the projections. Model parameter/calibration uncertainty for the chemical models and population sampling uncertainty were explicitly quantified. Model structural uncertainties were bracketed using model comparisons, recent measured changes, and paleolimnological reconstructions of historical changes in lake chemistry.

Journal Article↗
PubMed1991

A quantitative analysis of pallidal discharge during targeted reaching movement in the monkey.

Neurons in the globus pallidus have been studied during reaching movements of the arm made at varying speeds. The reaching task is similar to one used in earlier experiments, in which disruption of normal pallidal output caused changes in movement time. The pallidal cells studied were those that showed task-related changes in activity and a modification of discharge when the arm was manipulated outside of the task. Neuronal discharge was assessed to evaluate two possible models, one in which the timing of task-related discharge varied as a function of movement time and the other in which the amplitude (mean firing rate) of the change in discharge varied as movement time varied. The relation between neuronal discharge and movement time was examined quantitatively on a trial-by-trial basis using a statistical algorithm that identified each phase of the change in neuronal discharge on each trial. A non-parametric statistic was used to determine the correlation between movement time and the duration or latency of changes in neural firing or the mean discharge during each phase of the cell's response. For fifty-five percent of the 40 neurons studied, the timing of the cell's response (duration or latency) varied as a function of movement time. For only 10 cells (25%) was there a significant correlation between movement time and the mean firing rate during one or more phases of the cell's response. Both timing and frequency modulation with movement time were limited to cells responsive to manipulation at the wrist or the shoulder.

Animals↗
PubMed1991

Aspects of 'safe' surgery.

The differing concern among surgeons regarding the blood-borne transmissible infections HIV and hepatitis B virus (HBV), has prompted a confidential questionnaire of 250 consultant orthopaedic surgeons on some aspects of their current practice of 'safe' surgery. Only 154 replied. Hepatitis B vaccine uptake by surgeons was 70 per cent in this sample. This compares favourably with two recently published figures (47 per cent and 24 per cent). Unfortunately, we do not fare as well on routine screening for HBV in known 'at risk' groups, although 92 per cent of surgeons felt confident that they would recognize the 'inoculation risk' categories. The response to sustaining a needlestick injury by the majority of surgeons (87 per cent), was to change the affected glove. Only 7 per cent reported the incident as recommended to the Occupational Health Department and 6 per cent took no action at all. Current recommendations for 'safe' surgical practice as they apply to surgeons with regard to needlestick injury are discussed.

Adult↗