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Effects of intraportal exenatide on hepatic glucose metabolism in the conscious dog.
Edgerton DS, An Z, Johnson KM, Farmer T, Farmer B, Neal D, Cherrington AD
(2013) Am J Physiol Endocrinol Metab 305: E132-9
MeSH Terms: Animals, Consciousness, Dogs, Exenatide, Female, Glucose, Hyperglycemia, Hypoglycemic Agents, Infusions, Intravenous, Insulin, Lactic Acid, Liver, Male, Peptides, Portal Vein, Venoms
Show Abstract · Added July 21, 2014
Incretins improve glucose metabolism through multiple mechanisms. It remains unclear whether direct hepatic effects are an important part of exenatide's (Ex-4) acute action. Therefore, the objective of this study was to determine the effect of intraportal delivery of Ex-4 on hepatic glucose production and uptake. Fasted conscious dogs were studied during a hyperglycemic clamp in which glucose was infused into the hepatic portal vein. At the same time, portal saline (control; n = 8) or exenatide was infused at low (0.3 pmol·kg⁻¹·min⁻¹, Ex-4-low; n = 5) or high (0.9 pmol·kg⁻¹·min⁻¹, Ex-4-high; n = 8) rates. Arterial plasma glucose levels were maintained at 160 mg/dl during the experimental period. This required a greater rate of glucose infusion in the Ex-4-high group (1.5 ± 0.4, 2.0 ± 0.7, and 3.7 ± 0.7 mg·kg⁻¹·min⁻¹ between 30 and 240 min in the control, Ex-4-low, and Ex-4-high groups, respectively). Plasma insulin levels were elevated by Ex-4 (arterial: 4,745 ± 428, 5,710 ± 355, and 7,262 ± 1,053 μU/ml; hepatic sinusoidal: 14,679 ± 1,700, 15,341 ± 2,208, and 20,445 ± 4,020 μU/ml, 240 min, area under the curve), whereas the suppression of glucagon was nearly maximal in all groups. Although glucose utilization was greater during Ex-4 infusion (5.92 ± 0.53, 6.41 ± 0.57, and 8.12 ± 0.54 mg·kg⁻¹·min⁻¹), when indices of hepatic, muscle, and whole body glucose uptake were expressed relative to circulating insulin concentrations, there was no indication of insulin-independent effects of Ex-4. Thus, this study does not support the notion that Ex-4 generates acute changes in hepatic glucose metabolism through direct effects on the liver.
1 Communities
4 Members
1 Resources
16 MeSH Terms
Suppression of thalamocortical oscillations following traumatic brain injury in rats.
Kao C, Forbes JA, Jermakowicz WJ, Sun DA, Davis B, Zhu J, Lagrange AH, Konrad PE
(2012) J Neurosurg 117: 316-23
MeSH Terms: Animals, Brain Injuries, Cerebral Cortex, Consciousness, Cortical Synchronization, Disease Models, Animal, Electric Stimulation, Electroencephalography, Evoked Potentials, Male, Nerve Net, Rats, Rats, Sprague-Dawley, Reference Values, Signal Processing, Computer-Assisted, Somatosensory Cortex, Thalamus, Tissue Culture Techniques
Show Abstract · Added August 14, 2014
OBJECT - Traumatic brain injury (TBI) often causes an encephalopathic state, corresponding amplitude suppression, and disorganization of electroencephalographic activity. Clinical recovery in patients who have suffered TBI varies, and identification of patients with a poor likelihood of functional recovery is not always straightforward. The authors sought to investigate temporal patterns of electrophysiological recovery of neuronal networks in an animal model of TBI. Because thalamocortical circuit function is a critical determinant of arousal state, as well as electroencephalography organization, these studies were performed using a thalamocortical brain slice preparation.
METHODS - Adult rats received a moderate parietal fluid-percussion injury and were allowed to survive for 1 hour, 2 days, 7 days, or 15 days prior to in vitro electrophysiological recording. Thalamocortical brain slices, 450-μm thick, were prepared using a cutting angle that preserved reciprocal connections between the somatosensory cortex and the ventrobasal thalamic complex.
RESULTS - Extracellular recordings in the cortex of uninjured control brain slices revealed spontaneous slow cortical oscillations (SCOs) that are blocked by (2R)-amino-5-phosphonovaleric acid (50 μM) and augmented in low [Mg2+]o. These oscillations have been shown to involve simultaneous bursts of activity in both the cortex and thalamus and are used here as a metric of thalamocortical circuit integrity. They were absent in 84% of slices recorded at 1 hour postinjury, and activity slowly recovered to approximate control levels by Day 15. The authors next used electrically evoked SCO-like potentials to determine neuronal excitability and found that the maximum depression occurred slightly later, on Day 2 following TBI, with only 28% of slices showing evoked activity. In addition, stimulus intensities needed to create evoked SCO activity were elevated at 1 hour, 2 days, and 7 days following TBI, and eventually returned to control levels by Day 15. The SCO frequency remained low throughout the 15 days following TBI (40% of control by Day 15).
CONCLUSIONS - The suppression of cortical oscillatory activity following TBI observed in the rat model suggests an injury-induced functional disruption of thalamocortical networks that gradually recovers to baseline at approximately 15 days postinjury. The authors speculate that understanding the processes underlying disrupted thalamocortical circuit function may provide important insights into the biological basis of altered consciousness following severe head injury. Moreover, understanding the physiological basis for this process may allow us to develop new therapies to enhance the rate and extent of neurological recovery following TBI.
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18 MeSH Terms
Prevention of intraoperative awareness.
Wilson SH, McEvoy MD
(2011) N Engl J Med 365: 2032-3; author reply 2034
MeSH Terms: Anesthesia, General, Anesthetics, Inhalation, Consciousness Monitors, Female, Humans, Intraoperative Awareness, Male, Monitoring, Intraoperative, Pulmonary Alveoli
Added October 17, 2015
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1 Members
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9 MeSH Terms
Effects of the α₂-adrenergic agonist clonidine on the pharmacodynamics and pharmacokinetics of 3,4-methylenedioxymethamphetamine in healthy volunteers.
Hysek CM, Brugger R, Simmler LD, Bruggisser M, Donzelli M, Grouzmann E, Hoener MC, Liechti ME
(2012) J Pharmacol Exp Ther 340: 286-94
MeSH Terms: 3,4-Methylenedioxyamphetamine, Adrenergic alpha-2 Receptor Agonists, Adult, Affect, Blood Pressure, Body Temperature, Brain, Clonidine, Consciousness, Cross-Over Studies, Double-Blind Method, Drug Interactions, Emotions, Epinephrine, Female, Heart Rate, Humans, Male, Mental Processes, N-Methyl-3,4-methylenedioxyamphetamine, Norepinephrine, Young Adult
Show Abstract · Added August 3, 2013
The mechanism of action of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) involves the carrier-mediated and potentially vesicular release of monoamines. We assessed the effects of the sympatholytic α₂-adrenergic receptor agonist clonidine (150 μg p.o.), which inhibits the neuronal vesicular release of norepinephrine, on the cardiovascular and psychotropic response to MDMA (125 mg p.o.) in 16 healthy subjects. The study used a randomized, double-blind, placebo-controlled crossover design with four experimental sessions. The administration of clonidine 1 h before MDMA reduced the MDMA-induced increases in plasma norepinephrine concentrations and blood pressure but only to the extent that clonidine lowered norepinephrine levels and blood pressure compared with placebo. Thus, no interaction was found between the cardiovascular effects of the two drugs. Clonidine did not affect the psychotropic effects or pharmacokinetics of MDMA. The lack of an interaction of the effects of clonidine and MDMA indicates that vesicular release of norepinephrine, which is inhibited by clonidine, does not critically contribute to the effects of MDMA in humans. Although clonidine may be used in the treatment of stimulant-induced hypertensive reactions, the present findings do not support a role for α₂-adrenergic receptor agonists in the prevention of psychostimulant dependence.
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22 MeSH Terms
Impaired consciousness in temporal lobe seizures: role of cortical slow activity.
Englot DJ, Yang L, Hamid H, Danielson N, Bai X, Marfeo A, Yu L, Gordon A, Purcaro MJ, Motelow JE, Agarwal R, Ellens DJ, Golomb JD, Shamy MC, Zhang H, Carlson C, Doyle W, Devinsky O, Vives K, Spencer DD, Spencer SS, Schevon C, Zaveri HP, Blumenfeld H
(2010) Brain 133: 3764-77
MeSH Terms: Adult, Behavior, Beta Rhythm, Cerebral Cortex, Consciousness Disorders, Delta Rhythm, Electrodes, Implanted, Electroencephalography, Epilepsies, Partial, Epilepsy, Complex Partial, Epilepsy, Temporal Lobe, Female, Humans, Male, Middle Aged, Neocortex, Seizures, Young Adult
Show Abstract · Added August 12, 2016
Impaired consciousness requires altered cortical function. This can occur either directly from disorders that impair widespread bilateral regions of the cortex or indirectly through effects on subcortical arousal systems. It has therefore long been puzzling why focal temporal lobe seizures so often impair consciousness. Early work suggested that altered consciousness may occur with bilateral or dominant temporal lobe seizure involvement. However, other bilateral temporal lobe disorders do not impair consciousness. More recent work supports a 'network inhibition hypothesis' in which temporal lobe seizures disrupt brainstem-diencephalic arousal systems, leading indirectly to depressed cortical function and impaired consciousness. Indeed, prior studies show subcortical involvement in temporal lobe seizures and bilateral frontoparietal slow wave activity on intracranial electroencephalography. However, the relationships between frontoparietal slow waves and impaired consciousness and between cortical slowing and fast seizure activity have not been directly investigated. We analysed intracranial electroencephalography recordings during 63 partial seizures in 26 patients with surgically confirmed mesial temporal lobe epilepsy. Behavioural responsiveness was determined based on blinded review of video during seizures and classified as impaired (complex-partial seizures) or unimpaired (simple-partial seizures). We observed significantly increased delta-range 1-2 Hz slow wave activity in the bilateral frontal and parietal neocortices during complex-partial compared with simple-partial seizures. In addition, we confirmed prior work suggesting that propagation of unilateral mesial temporal fast seizure activity to the bilateral temporal lobes was significantly greater in complex-partial than in simple-partial seizures. Interestingly, we found that the signal power of frontoparietal slow wave activity was significantly correlated with the temporal lobe fast seizure activity in each hemisphere. Finally, we observed that complex-partial seizures were somewhat more common with onset in the language-dominant temporal lobe. These findings provide direct evidence for cortical dysfunction in the form of bilateral frontoparietal slow waves associated with impaired consciousness in temporal lobe seizures. We hypothesize that bilateral temporal lobe seizures may exert a powerful inhibitory effect on subcortical arousal systems. Further investigations will be needed to fully determine the role of cortical-subcortical networks in ictal neocortical dysfunction and may reveal treatments to prevent this important negative consequence of temporal lobe epilepsy.
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18 MeSH Terms
An evaluation of remifentanil-sevoflurane response surface models in patients emerging from anesthesia: model improvement using effect-site sevoflurane concentrations.
Johnson KB, Syroid ND, Gupta DK, Manyam SC, Pace NL, LaPierre CD, Egan TD, White JL, Tyler D, Westenskow DR
(2010) Anesth Analg 111: 387-94
MeSH Terms: Adult, Analgesics, Anesthesia Recovery Period, Anesthetics, Combined, Anesthetics, Inhalation, Anesthetics, Intravenous, Computer Simulation, Consciousness, Dose-Response Relationship, Drug, Drug Synergism, Elective Surgical Procedures, Female, Fentanyl, Humans, Male, Methyl Ethers, Middle Aged, Models, Biological, Pain Measurement, Pain Threshold, Piperidines, Predictive Value of Tests, Pulmonary Alveoli, Recovery of Function, Remifentanil, Sevoflurane
Show Abstract · Added February 12, 2015
INTRODUCTION - We previously reported models that characterized the synergistic interaction between remifentanil and sevoflurane in blunting responses to verbal and painful stimuli. This preliminary study evaluated the ability of these models to predict a return of responsiveness during emergence from anesthesia and a response to tibial pressure when patients required analgesics in the recovery room. We hypothesized that model predictions would be consistent with observed responses. We also hypothesized that under non-steady-state conditions, accounting for the lag time between sevoflurane effect-site concentration (Ce) and end-tidal (ET) concentration would improve predictions.
METHODS - Twenty patients received a sevoflurane, remifentanil, and fentanyl anesthetic. Two model predictions of responsiveness were recorded at emergence: an ET-based and a Ce-based prediction. Similarly, 2 predictions of a response to noxious stimuli were recorded when patients first required analgesics in the recovery room. Model predictions were compared with observations with graphical and temporal analyses.
RESULTS - While patients were anesthetized, model predictions indicated a high likelihood that patients would be unresponsive (> or = 99%). However, after termination of the anesthetic, models exhibited a wide range of predictions at emergence (1%-97%). Although wide, the Ce-based predictions of responsiveness were better distributed over a percentage ranking of observations than the ET-based predictions. For the ET-based model, 45% of the patients awoke within 2 min of the 50% model predicted probability of unresponsiveness and 65% awoke within 4 min. For the Ce-based model, 45% of the patients awoke within 1 min of the 50% model predicted probability of unresponsiveness and 85% awoke within 3.2 min. Predictions of a response to a painful stimulus in the recovery room were similar for the Ce- and ET-based models.
DISCUSSION - Results confirmed, in part, our study hypothesis; accounting for the lag time between Ce and ET sevoflurane concentrations improved model predictions of responsiveness but had no effect on predicting a response to a noxious stimulus in the recovery room. These models may be useful in predicting events of clinical interest but large-scale evaluations with numerous patients are needed to better characterize model performance.
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26 MeSH Terms
Consciousness and epilepsy: why are complex-partial seizures complex?
Englot DJ, Blumenfeld H
(2009) Prog Brain Res 177: 147-70
MeSH Terms: Animals, Brain Mapping, Consciousness, Consciousness Disorders, Electroencephalography, Epilepsy, Temporal Lobe, Humans, Magnetic Resonance Imaging, Nerve Net, Rats, Seizures, Temporal Lobe
Show Abstract · Added August 12, 2016
Why do complex-partial seizures in temporal lobe epilepsy (TLE) cause a loss of consciousness? Abnormal function of the medial temporal lobe is expected to cause memory loss, but it is unclear why profoundly impaired consciousness is so common in temporal lobe seizures. Recent exciting advances in behavioral, electrophysiological, and neuroimaging techniques spanning both human patients and animal models may allow new insights into this old question. While behavioral automatisms are often associated with diminished consciousness during temporal lobe seizures, impaired consciousness without ictal motor activity has also been described. Some have argued that electrographic lateralization of seizure activity to the left temporal lobe is most likely to cause impaired consciousness, but the evidence remains equivocal. Other data correlates ictal consciousness in TLE with bilateral temporal lobe involvement of seizure spiking. Nevertheless, it remains unclear why bilateral temporal seizures should impair responsiveness. Recent evidence has shown that impaired consciousness during temporal lobe seizures is correlated with large-amplitude slow EEG activity and neuroimaging signal decreases in the frontal and parietal association cortices. This abnormal decreased function in the neocortex contrasts with fast polyspike activity and elevated cerebral blood flow in limbic and other subcortical structures ictally. Our laboratory has thus proposed the "network inhibition hypothesis," in which seizure activity propagates to subcortical regions necessary for cortical activation, allowing the cortex to descend into an inhibited state of unconsciousness during complex-partial temporal lobe seizures. Supporting this hypothesis, recent rat studies during partial limbic seizures have shown that behavioral arrest is associated with frontal cortical slow waves, decreased neuronal firing, and hypometabolism. Animal studies further demonstrate that cortical deactivation and behavioral changes depend on seizure spread to subcortical structures including the lateral septum. Understanding the contributions of network inhibition to impaired consciousness in TLE is an important goal, as recurrent limbic seizures often result in cortical dysfunction during and between epileptic events that adversely affects patients' quality of life.
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12 MeSH Terms
Inhibition of dipeptidyl peptidase-4 by vildagliptin during glucagon-like Peptide 1 infusion increases liver glucose uptake in the conscious dog.
Edgerton DS, Johnson KM, Neal DW, Scott M, Hobbs CH, Zhang X, Duttaroy A, Cherrington AD
(2009) Diabetes 58: 243-9
MeSH Terms: Adamantane, Animals, Consciousness, Dipeptidyl Peptidase 4, Dipeptidyl-Peptidase IV Inhibitors, Dogs, Glucagon, Glucagon-Like Peptide 1, Glucose, Insulin, Liver, Nitriles, Pyrrolidines, Vildagliptin
Show Abstract · Added February 13, 2015
OBJECTIVE - This study investigated the acute effects of treatment with vildagliptin on dipeptidyl peptidase-4 (DPP-4) activity, glucagon-like peptide 1 (GLP-1) concentration, pancreatic hormone levels, and glucose metabolism. The primary aims were to determine the effects of DPP-4 inhibition on GLP-1 clearance and on hepatic glucose uptake.
RESEARCH DESIGN AND METHODS - Fasted conscious dogs were studied in the presence (n = 6) or absence (control, n = 6) of oral vildagliptin (1 mg/kg). In both groups, GLP-1 was infused into the portal vein (1 pmol . kg(-1) . min(-1)) for 240 min. During the same time, glucose was delivered into the portal vein at 4 mg . kg(-1) . min(-1) and into a peripheral vein at a variable rate to maintain the arterial plasma glucose level at 160 mg/dl.
RESULTS - Vildagliptin fully inhibited DPP-4 over the 4-h experimental period. GLP-1 concentrations were increased in the vildagliptin-treated group (50 +/- 3 vs. 85 +/- 7 pmol/l in the portal vein in control and vildagliptin-treated dogs, respectively; P < 0.05) as a result of a 40% decrease in GLP-1 clearance (38 +/- 5 and 22 +/- 2 ml . kg(-1) . min(-1), respectively; P < 0.05). Although hepatic insulin and glucagon levels were not significantly altered, there was a tendency for plasma insulin to be greater (hepatic levels were 73 +/- 10 vs. 88 +/- 15 microU/ml, respectively). During vildagliptin treatment, net hepatic glucose uptake was threefold greater than in the control group. This effect was greater than that predicted by the change in insulin.
CONCLUSIONS - Vildagliptin fully inhibited DPP-4 activity, reduced GLP-1 clearance by 40%, and increased hepatic glucose disposal by means beyond the effects of GLP-1 on insulin and glucagon secretion.
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14 MeSH Terms
Considerations in the design of hyperinsulinemic-euglycemic clamps in the conscious mouse.
Ayala JE, Bracy DP, McGuinness OP, Wasserman DH
(2006) Diabetes 55: 390-7
MeSH Terms: Animals, Catheterization, Consciousness, Dose-Response Relationship, Drug, Food Deprivation, Glucose, Glucose Clamp Technique, Hyperinsulinism, Insulin, Male, Mice, Mice, Inbred C57BL, Time Factors
Show Abstract · Added December 10, 2013
Despite increased use of the hyperinsulinemic-euglycemic clamp to study insulin action in mice, the effects of experimental parameters on the results obtained have not been addressed. In our studies, we determined the influences of sampling sites, fasting duration, and insulin delivery on results obtained from clamps in conscious mice. Carotid artery and jugular vein catheters were implanted in C57BL/6J mice (n = 6-10/group) fed a normal diet for sampling and infusions. After a 5-day recovery period, mice underwent a 120-min clamp (2.5-mU . kg(-1) . min(-1) insulin infusion; approximately 120-130 mg/dl glucose) while receiving [3-(3)H]glucose to determine glucose appearance (endoR(a)) and disappearance (R(d)). Sampling large volumes (approximately 100 mul) from the cut tail resulted in elevated catecholamines and basal glucose compared with artery sampling. Catecholamines were not elevated when taking small samples ( approximately 5 mul) from the cut tail. Overnight (18-h) fasting resulted in greater loss of total body, lean, and fat masses and hepatic glycogen but resulted in enhanced insulin sensitivity compared with 5-h fasting. Compared with a 16-mU/kg insulin prime, a 300-mU/kg prime resulted in hepatic insulin resistance and slower acquisition of steady-state glucose infusion rates (GIR) after a 5-h fast. The steady-state GIR was expedited after the 300-mU/kg prime in 18-h-fasted mice. The GIR and R(d) rose with increasing insulin infusions (0.8, 2.5, 4, and 20 mU . kg(-1) . min(-1)), but endoR(a) was fully suppressed with doses higher than 0.8 mU . kg(-1) . min(-1). Thus, common variations in experimental factors yield different results and should be considered in designing and interpreting clamps.
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13 MeSH Terms
Control of muscle glucose uptake: test of the rate-limiting step paradigm in conscious, unrestrained mice.
Fueger PT, Shearer J, Bracy DP, Posey KA, Pencek RR, McGuinness OP, Wasserman DH
(2005) J Physiol 562: 925-35
MeSH Terms: Adaptation, Physiological, Animals, Blood Glucose, Consciousness, Female, Glucose, Glucose Transporter Type 4, Hexokinase, Humans, Hyperinsulinism, Insulin, Male, Metabolic Clearance Rate, Mice, Mice, Inbred C57BL, Mice, Transgenic, Monosaccharide Transport Proteins, Muscle Proteins, Muscle, Skeletal
Show Abstract · Added July 21, 2014
The aim of this study was to test whether in fact glucose transport is rate-limiting in control of muscle glucose uptake (MGU) under physiological hyperinsulinaemic conditions in the conscious, unrestrained mouse. C57Bl/6J mice overexpressing GLUT4 (GLUT4(Tg)), hexokinase II (HK(Tg)), or both (GLUT4(Tg) + HK(Tg)), were compared to wild-type (WT) littermates. Catheters were implanted into a carotid artery and jugular vein for sampling and infusions at 4 month of age. After a 5-day recovery period, conscious mice underwent one of two protocols (n = 8-14/group) after a 5-h fast. Saline or insulin (4 mU kg(-1) min(-1)) was infused for 120 min. All mice received a bolus of 2-deoxy[(3)H]glucose (2-(3)HDG) at 95 min. Glucose was clamped at approximately 165 mg dl(-1) during insulin infusion and insulin levels reached approximately 80 microU ml(-1). The rate of disappearance of 2-(3)HDG from the blood provided an index of whole body glucose clearance. Gastrocnemius, superficial vastus lateralis and soleus muscles were excised at 120 min to determine 2-(3)HDG-6-phosphate levels and calculate an index of MGU (R(g)). Results show that whole body and tissue-specific indices of glucose utilization were: (1) augmented by GLUT4 overexpression, but not HKII overexpression, in the basal state; (2) enhanced by HKII overexpression in the presence of physiological hyperinsulinaemia; and (3) largely unaffected by GLUT4 overexpression during insulin clamps whether alone or combined with HKII overexpression. Therefore, while glucose transport is the primary barrier to MGU under basal conditions, glucose phosphorylation becomes a more important barrier during physiological hyperinsulinaemia in all muscles. The control of MGU is distributed rather than confined to a single rate-limiting step such as glucose transport as glucose transport and phosphorylation can both become barriers to skeletal muscle glucose influx.
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19 MeSH Terms