Barbiturate reduction of calcium-dependent action potentials: Correlation with anesthetic action

Calcium-dependent action potentials were recorded from mouse spinal cord neurons in primary dissociated cell culture following addition of the potassium channel blockers tetraethylammonium ion and 3-aminopyridine. The pharmacologically active barbiturates, pentobarbital and phenobarbital, but not the pharmacologically inactive barbiturate, barbituric acid, produced reversible, dose-dependent reduction of action potential duration at sedative-hypnotic and anesthetic concentrations. Pentobarbital reduced action potential duration at concentrations from 25 to 600 [mu]M (50% reduction at 170 [mu]M) while phenobarbital reduced action potential duration at concentrations from 100 to 5000 [mu]M (50% reduction at 900 [mu]M). The barbiturate concentrations which reduced calcium-dependent action potential duration in this study correlate with reduction of neurotransmitter release from other neuronal preparations and with reduction of calcium uptake by synaptosomes. The results suggest that barbiturates may produce anesthesia in part by reduction of presynaptic calcium entry and consequent reduction of neurotransmitter release in addition to postsynaptic increase of membrane chloride ion conductance. Barbiturate anticonvulsant actions are probably due to postsynaptic augmentation of GABA-mediated inhibition and depression of excitatory synaptic transmission. The major difference between anticonvulsant (phenobarbital) and anesthetic (pentobarbital) barbiturates was the dose-dependency of these actions. Phenobarbital produced postsynaptic modulation of neurotransmitter responses at low concentrations and decreased calcium-dependent action potential duration and increased chloride ion conductance at high concentrations. In contrast, pentobarbital produced all actions at low concentrations. Thus for phenobarbital there would be a large therapeutic index for anticonvulsant activity compared to anesthetic activity but for pentobarbital there would be a small therapeutic index.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24032/1/0000281.pd

Takotsubo cardiomyopathy associated with anesthesia: three case reports

Takotsubo cardiomyopathy is a form of transient, reversible left ventricular dysfunction that can mimic an acute coronary event. However, cardiac catheterization often reveals normal coronary arteries. Patients are often postmenopausal women who experience acute physical or emotional distress. The prognosis for this entity is quite favorable. In this report, we present three cases of Takotsubo cardiomyopathy in patients having procedures involving anesthesia. Each case illustrates a different etiology for the syndrome: Patient, procedure, and anesthetic management

Isotropically Driven versus Outflow Driven Turbulence: Observational Consequences for Molecular Clouds

Feedback from protostellar outflows can influence the nature of turbulence in star forming regions even if they are not the primary source of velocity dispersion for all scales of molecular clouds. For the rate and power expected in star forming regions, we previously (Carroll et al. 2009) demonstrated that outflows could drive supersonic turbulence at levels consistent with the scaling relations from Matzner 2007 although with a steeper velocity power spectrum than expected for an isotropically driven supersonic turbulent cascade. Here we perform higher resolution simulations and combine simulations of outflow driven turbulence with those of isotropically forced turbulence. We find that the presence of outflows within an ambient isotropically driven turbulent environment produces a knee in the velocity power spectrum at the outflow scale and a steeper slope at sub-outflow scales than for a purely isotropically forced case. We also find that the presence of outflows flattens the density spectrum at large scales effectively reducing the formation of large scale turbulent density structures. These effects are qualitatively independent of resolution. We have also carried out Principal Component Analysis (PCA) for synthetic data from our simulations. We find that PCA as a tool for identifying the driving scale of turbulence has a misleading bias toward low amplitude large scale velocity structures even when they are not necessarily the dominant energy containing scales. This bias is absent for isotropically forced turbulence but manifests strongly for collimated outflow driven turbulence.Comment: 30 pages, 10 figures, Submitted to Ap

Membrane depolarization and prolongation of calcium-dependent action potentials of mouse neurons in cell culture by two convulsants: Bicuculline and penicillin

The convulsant compounds bicuculline (BICUC) and penicillin (PCN) are antagonists of GABA-mediated synaptic inhibition. In addition, we have shown that BICUC and PCN produced membrane depolarization of mouse spinal cord neurons in primary dissociated cell culture by blocking a potassium conductance, a non-synaptic direct effect. Both compounds also prolonged calcium-dependent action potentials of mouse dorsal root ganglion and spinal cord neurons in cell culture. Thus, BICUC and PCN had both synaptic and non-synaptic actions. The possibility that both synaptic and non-synaptic actions of BICUC and PCN are involved in their convulsant mechanism of action is discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24075/1/0000328.pd

Does Cognitive Dysfunction after Carotid Endarterectomy Vary by Statin Type or Dose?

Abstract Our prev ious work demonstrates that asymptomatic carotid endarterectomy (CEA ) patients demonstrate less perioperative neurologic in jury, defined as stroke and early cognitive dysfunction (eCD) observed within 24h r of CEA, when taking statins pre-operatively. This study examines whether the incidence of eCD observed 24hr after asympto matic CEA varies as a function of statin type or dose. Patients with asymptomatic carotid stenosis scheduled for CEA consented to participate in an observational IRB-approved study (N=324). Pat ients were evaluated with an extensive battery of neuropsychometric tests pre-operatively and 24hr post-operatively. Of the 324 consented patients, 200 were taking statins. Patients taking pravastatin and fluvastatin exhib ited no eCD, while patients taking lovastatin (17.7%) and rosuvastatin (16.7%) exh ib ited incidences of eCD similar to those not taking statins (20.2%). Patients taking simvastatin exhib ited a significantly lower incidence of eCD than those taking atorvastatin (3.0% vs. 16.0%, P=0.005). Patients taking a maximal dose of any statin exhib ited a significantly lower incidence of eCD than patients taking sub-maximal doses (2.7% vs. 15.9%, P=0.002). These observations suggest that the incidence of eCD may in fact vary as a function of statin type and that maximal doses may be the optimal dose for patients undergoing CEA. This variation may be due to the physico-chemical properties of statins such as lipophilicity, molecu lar size, and b lood brain barrier penetrability. These findings should be used to inspire randomized prospective work to determine the safety, feasibility, and outcomes of optimizing statin use prior to CEA

Calcium-dependent action potentials in mouse spinal cord neurons in cell culture

Following blockade of membrane potassium conductance with tetraethylammonium ions or 3-aminopyridine, long-duration action potentials were recorded from mouse spinal cord neurons in primary dissociated cell culture. The action potentials were calcium-dependent since they: (1) were not blocked by the sodium-channel blocker tetrodotoxin, (2) could be recorded in sodium-free, calcium-containing medium (3) could not be evoked in sodium-containing, calcium-free medium, (4) were blocked by calcium channel blockers manganese and cobalt and (5) had overshot amplitudes that varied linearly with the log of the extracellular calcium concentration (slope of 27.5 mV/decade change in calcium concentration).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24258/1/0000521.pd

Post-carotid endarterectomy neurocognitive decline is associated with cerebral blood flow asymmetry on post-operative magnetic resonance perfusion brain scans

Objective: Up to 25% of patients experience subtle declines in post-operative neurocognitive function following, otherwise uncomplicated, carotid endarterectomy (CEA). We sought to determine if post-CEA neurocognitive deficits are associated with cerebral blood flow (CBF) abnormalities on post-operative MR perfusion brain scans. Methods: We enrolled 22 CEA patients to undergo a battery of neuropsychometric tests pre-operatively and on post-operative day 1 (POD 1). Neurocognitive dysfunction was defined as a two standard deviation decline in performance in comparison to a similarly aged control group of lumbar laminectomy patients. All patients received MR perfusion brain scans on POD 1 that were analysed for asymmetries in CBF distribution. One patient experienced a transient ischemic attack within 24 hours before the procedure and was excluded from our analysis. Results: Twenty-nine percent of CEA patients demonstrated neurocognitive dysfunction on POD 1. One hundred percent of those patients with cognitive deficits demonstrated CBF asymmetry, in contrast to only 27% of those patients without cognitive impairment. Post-CEA cognitive dysfunction was significantly associated with CBF abnormalities (RR=3.75, 95% CI: 1.62-8.67, p=0.004). Conclusion: Post-CEA neurocognitive dysfunction is significantly associated with post-operative CBF asymmetry. These results support the hypothesis that post-CEA cognitive impairment is caused by cerebral hemodynamic changes. Further work exploring the relationship between CBF and post-CEA cognitive dysfunction is needed

Protostellar Outflow Evolution in Turbulent Environments

The link between turbulence in star formatting environments and protostellar jets remains controversial. To explore issues of turbulence and fossil cavities driven by young stellar outflows we present a series of numerical simulations tracking the evolution of transient protostellar jets driven into a turbulent medium. Our simulations show both the effect of turbulence on outflow structures and, conversely, the effect of outflows on the ambient turbulence. We demonstrate how turbulence will lead to strong modifications in jet morphology. More importantly, we demonstrate that individual transient outflows have the capacity to re-energize decaying turbulence. Our simulations support a scenario in which the directed energy/momentum associated with cavities is randomized as the cavities are disrupted by dynamical instabilities seeded by the ambient turbulence. Consideration of the energy power spectra of the simulations reveals that the disruption of the cavities powers an energy cascade consistent with Burgers'-type turbulence and produces a driving scale-length associated with the cavity propagation length. We conclude that fossil cavities interacting either with a turbulent medium or with other cavities have the capacity to sustain or create turbulent flows in star forming environments. In the last section we contrast our work and its conclusions with previous studies which claim that jets can not be the source of turbulence.Comment: 24 pages, submitted to the Astrophysical Journa

An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques

Chronic unresolved inflammation plays a causal role in the development of advanced atherosclerosis, but the mechanisms that prevent resolution in atherosclerosis remain unclear. Here, we use targeted mass spectrometry to identify specialized pro-resolving lipid mediators (SPM) in histologically-defined stable and vulnerable regions of human carotid atherosclerotic plaques. The levels of SPMs, particularly resolvin D1 (RvD1), and the ratio of SPMs to pro-inflammatory leukotriene B4 (LTB₄), are significantly decreased in the vulnerable regions. SPMs are also decreased in advanced plaques of fat-fed Ldlr⁻/⁻ mice. Administration of RvD1 to these mice during plaque progression restores the RvD1:LTB₄ ratio to that of less advanced lesions and promotes plaque stability, including decreased lesional oxidative stress and necrosis, improved lesional efferocytosis, and thicker fibrous caps. These findings provide molecular support for the concept that defective inflammation resolution contributes to the formation of clinically dangerous plaques and offer a mechanistic rationale for SPM therapy to promote plaque stability

Outflow Driven Turbulence in Molecular Clouds

In this paper we explore the relationship between protostellar outflows and turbulence in molecular clouds. Using 3-D numerical simulations we focus on the hydrodynamics of multiple outflows interacting within a parsec scale volume. We explore the extent to which transient outflows injecting directed energy and momentum into a sub-volume of a molecular cloud can be converted into random turbulent motions. We show that turbulence can readily be sustained by these interactions and show that it is possible to broadly characterize an effective driving scale of the outflows. We compare the velocity spectrum obtained in our studies to that of isotropically forced hydrodynamic turbulence finding that in outflow driven turbulence a power law is indeed achieved. However we find a steeper spectrum (beta ~ 3) is obtained in outflow driven turbulence models than in isotropically forced simulations (beta ~ 2). We discuss possible physical mechanisms responsible for these results as well and their implications for turbulence in molecular clouds where outflows will act in concert with other processes such as gravitational collapse.Comment: 12 pages, 3 figure