bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficient acquisition of dual metastasis organotropism to bone and lung through stable spontaneous fusion between MDA-MB-231 variants
Authors: Lu Xin , Kang Yibin
Published: May 2009

Cell fusion is involved in many critical developmental processes, including zygote formation and organogenesis of placenta, bone, and skeletal muscle. In adult tissues, cell fusion has been shown to play an active role in tissue regeneration and repair, and its frequency of occurrence is significantly increased during chronic inflammation. Fusion between tumor cells and normal cells, or among tumor cells themselves, has also been speculated to contribute to tumor initiation, as well as phenotypic evolution during cancer progression and metastasis. Here, we show that dual metastasis organotropisms can be acquired in the same cell through in vitro or in vivo spontaneous fusion between bone- and lung-tropic sublines of the MDA-MB-231 human breast cancer cell line. The synkaryonic hybrids assimilate organ-specific metastasis gene signatures from both parental cells and are genetically and phenotypically stable. Our study suggests cell fusion as an efficient means of phenotypic evolution during tumor progression and additionally demonstrates the compatibility of different metastasis organotropisms.
Neural activity in the visual thalamus reflects perceptual suppression
Authors: Wilke Melanie , Mueller Kai-Markus , Leopold David A.
Published: May 2009

To examine the role of the visual thalamus in perception, we recorded neural activity in the lateral geniculate nucleus (LGN) and pulvinar of 2 macaque monkeys during a visual illusion that induced the intermittent perceptual suppression of a bright luminance patch. Neural responses were sorted on the basis of the trial-to-trial visibility of the stimulus, as reported by the animals. We found that neurons in the dorsal and ventral pulvinar, but not the LGN, showed changes in spiking rate according to stimulus visibility. Passive viewing control sessions showed such modulation to be independent of the monkeys' active report. Perceptual suppression was also accompanied by a marked drop in low-frequency power (9–30 Hz) of the local field potential (LFP) throughout the visual thalamus, but this modulation was not observed during passive viewing. Our findings demonstrate that visual responses of pulvinar neurons reflect the perceptual awareness of a stimulus, while those of LGN neurons do not.
Erbin regulates NRG1 signaling and myelination
Authors: Tao Yanmei , Dai Penggao , Liu Yu , Marchetto Sylvie , Xiong Wen-Cheng , Borg Jean-Paul , Mei Lin
Published: May 2009

Neuregulin 1 (NRG1) plays a critical role in myelination. However, little is known about regulatory mechanisms of NRG1 signaling. We show here that Erbin, a protein that contains leucine-rich repeats (LRR) and a PSD95-Dlg-Zol (PDZ) domain and that interacts specifically with ErbB2, is necessary for NRG1 signaling and myelination of peripheral nervous system (PNS). In Erbin null mice, myelinated axons were hypomyelinated with reduced expression of P0, a marker of mature myelinating Schwann cells (SCs), whereas unmyelinated axons were aberrantly ensheathed in Remak bundles, with increased numbers of axons in the bundles and in pockets. The morphological deficits were associated with decreased nerve conduction velocity and increased sensory threshold to mechanistic stimulation. These phenotypes were duplicated in
erbin
ΔC/ΔC
mice, in which Erbin lost the PDZ domain to interact with ErbB2. Moreover, ErbB2 was reduced at protein levels in both Erbin mutant sciatic nerves, and ErbB2 became unstable and NRG1 signaling compromised when Erbin expression was suppressed. These observations indicate a critical role of Erbin in myelination and identify a regulatory mechanism of NRG1 signaling. Our results suggest that Erbin, via the PDZ domain, binds to and stabilizes ErbB2, which is necessary for NRG1 signaling that has been implicated in tumorigenesis, heart development, and neural function.
Carboxylation mechanism and stereochemistry of crotonyl-CoA carboxylase/reductase, a carboxylating enoyl-thioester reductase
Authors: Erb Tobias J. , Brecht Volker , Fuchs Georg , Müller Michael , Alber Birgit E.
Published: May 2009

Chemo- and stereoselective reductions are important reactions in chemistry and biology, and reductases from biological sources are increasingly applied in organic synthesis. In contrast, carboxylases are used only sporadically. We recently described crotonyl-CoA carboxylase/reductase, which catalyzes the reduction of (
E
)-crotonyl-CoA to butyryl-CoA but also the reductive carboxylation of (
E
)-crotonyl-CoA to ethylmalonyl-CoA. In this study, the complete stereochemical course of both reactions was investigated in detail. The pro-(4
R
) hydrogen of NADPH is transferred in both reactions to the
re
face of the C3 position of crotonyl-CoA. In the course of the carboxylation reaction, carbon dioxide is incorporated in anti fashion at the C2 atom of crotonyl-CoA. For the reduction reaction that yields butyryl-CoA, a solvent proton is added in
anti
fashion instead of the CO
2
. Amino acid sequence analysis showed that crotonyl-CoA carboxylase/reductase is a member of the medium-chain dehydrogenase/reductase superfamily and shares the same phylogenetic origin. The stereospecificity of the hydride transfer from NAD(P)H within this superfamily is highly conserved, although the substrates and reduction reactions catalyzed by its individual representatives differ quite considerably. Our findings led to a reassessment of the stereospecificity of enoyl(-thioester) reductases and related enzymes with respect to their amino acid sequence, revealing a general pattern of stereospecificity that allows the prediction of the stereochemistry of the hydride transfer for enoyl reductases of unknown specificity. Further considerations on the reaction mechanism indicated that crotonyl-CoA carboxylase/reductase may have evolved from enoyl-CoA reductases. This may be useful for protein engineering of enoyl reductases and their application in biocatalysis.
One in Singapore English
Authors: Bao Zhiming
Published: May 2009

This paper investigates the grammar and usage of one in Singapore English, which exhibits the influence of both Chinese and English, the two dominant languages in the multilingual ecology of Singapore English, as well as the influence of relevant linguistic universals. The grammar of one is essentially the grammar of Chinese de filtered through the morphosyntax of English one. The corpus data show that some one forms which are judged acceptable by native-speaker informants have nevertheless low frequency of use. I argue that usage plays an important role in the success of contact-induced grammatical innovation, and propose an exemplar-based model of relexification that provides a satisfactory explanation of the grammatical properties and usage patterns of one in Singapore English.
A twice-mixed creole?
Authors: Good Jeff
Published: May 2009

Saramaccan, a maroon creole of Suriname, shows evidence of having a split lexicon where the majority of its words are marked for pitch accent but an important minority are marked for tone. The basic origins of this split would appear to be clear: pitch-accented words represent transfer of a European-like accent system, while tonal words represent transfer of an African-like tone system. If this is the right account, its apparent simplicity raises an important question: Why didn’t it happen more often? While a definitive answer cannot yet be given, it is suggested that a likely explanation is that the split lexicon was not a product of creolization but, rather, the result of a restricted kind of language mixing, which took place after marronage, and that this mixing was employed as a means of establishing a distinct speech variety for the nascent Saramaccan community.
The Development of Specialized Processing of Own‐Race Faces in Infancy
Authors: Ferguson Kim T. , Kulkofsky Sarah , Cashon Cara H. , Casasola Marianella
Published: May 2009

In this study, we examined developmental changes in infants' processing of own‐ versus other‐race faces. Caucasian American 8‐month‐olds (Experiment 1) and 4‐month‐olds (Experiment 2) were tested in a habituation‐switch procedure designed to assess holistic (attending to the relationship between internal and external features of the face) versus featural (attending to individual features of the face) processing of faces. Eight‐month‐olds demonstrated holistic processing of upright own‐race (Caucasian) faces, but featural processing of upright other‐race (African) faces. Inverted faces were processed featurally, regardless of ethnicity. Four‐month‐olds, however, demonstrated holistic processing of both Caucasian and African upright faces. These results demonstrate that infants' processing of own‐ versus other‐race faces becomes specialized between 4 and 8 months.
Eigenmode analysis of the ITER ICRF antenna plug and electrical solution to the grounding of the antenna
Authors: Louche F. , Messiaen A. , Dumortier P. , Durodié F. , Koch R. , Lamalle P.
Published: May 2009

The excitation of non-TEM modes around the ITER ICRF (ion cyclotron range of frequency) antenna plug can considerably increase the level of RF currents and voltages on the ITER plug. We report on a study of these modes and a solution to avoid them in the ITER ion cyclotron range of frequencies. From a transmission line approach we show that resonances can be avoided if the distance between the mouth of the line and an added short-circuit is sufficiently small. We therefore propose to position short-circuits at about 1 m from the antenna mouth, constituted by rows of closely spaced non-capacitive contacts all around the plug. These conclusions are further validated with Microwave Studio® simulations. A simplified model of the ITER ICRF array is used for comparing various grounding solutions and it is proved that the solution already inferred from transmission line approximation suppresses the resonances from the frequency domain relevant for ICRH in ITER. The MWS calculations predict that the proposed solution also avoids large RF currents in the blanket modules and in their connectors. Their amplitude barely exceeds 5% of the strap RF currents. This solution avoids perturbation of the antenna array impedance matrix by the coaxial gap. We also discuss resonances appearing at harmonic frequencies which could be excited by various non-linear effects due to the plasma or the generator. This kind of excitation should not lead to large voltage build-up.
Long-pulse hybrid scenario development in JT-60U
Authors: Oyama N. , Isayama A. , Matsunaga G. , Suzuki T. , Takenaga H. , Sakamoto Y. , Nakano T. , Kamada Y. , Ide S.
Published: May 2009

The performance and sustained duration of long-pulse discharges for the ‘ITER hybrid scenario’ have been improved in JT-60U. The modification of power supply systems for three perpendicular neutral beam (NB) injections provides a long period of central NB heating up to 30 s, which is important for keeping the internal transport barrier (ITB). The peaked density profile in the core plasma can be maintained even when the density at the pedestal increased in the latter phase of the discharge due to the increase in the divertor recycling. Then, the peaked pressure profile attributed to the ITB can be kept constant through the discharge with the peaked power deposition profile. In these long-pulse discharges, MHD activity with toroidal mode number n = 1 is observed even when neoclassical tearing modes (NTMs) are suppressed. When the amplitude of the mode in the peripheral region becomes large, the pedestal pressure is degraded. The mode amplitude is sensitive to the toroidal magnetic field (or edge safety factor) and heating power. After the adjustment of the toroidal magnetic field so as to reduce the mode amplitude, a high normalized beta (βN) of 2.6 and a high thermal confinement enhancement factor (H
H98(y,2) > 1) are sustained for 25 s (∼14τR, where τR is the current diffusion time) under the ITER relevant small toroidal rotation condition. The peaked pressure profile in low safety factor plasma (safety factor at 95% flux surface q
95 ∼ 3.2) is stable against NTMs up to βN ∼ 3. A high βN
H
H98(y,2) of 2.6 gives a high G-factor (
) of 0.25 and a peaked pressure profile gives a large bootstrap current fraction (f
BS > 0.43).
Localized tungsten deposition in divertor region in JT-60U
Authors: Ueda Y. , Fukumoto M. , Watanabe J. , Ohtsuka Y. , Arai T. , Asakura N. , Nobuta Y. , Sato M. , Nakano T. , Yagyu J. , Ochiai K. , Takakura K. , Tanabe T.
Published: May 2009

Tungsten local transport in the diverter region emitted from the outer divertor was studied in JT-60U. Tungsten-coated CFC tiles were installed in the outer divertor position, on which outer strike points did not normally sit. A neutron activation method to measure tungsten surface density was used for the first time. On the outer wing tile, W existed only in the top surface, while on the inner divertor tile W was embedded in the thick carbon deposition layer. Poloidal distribution in the same toroidal section as the tungsten tiles showed dense W deposition near the inner strike points, the dome top and outer wing of the dome. Carbon ions by puffing 13CH4 at the same toroidal position of the W-tiles were also deposited near the inner strike points. Toroidal distribution on the outer wing showed significant localization of W deposition near the W tile array. In addition, toroidal asymmetry of W deposition on the outer wing probably due to the plasma parallel flow was observed.
Regulation of Cell Polarity through Phosphorylation of Bni4 by Pho85 G1 Cyclin-dependent Kinases inSaccharomyces cerevisiae
Authors: Zou Jian , Friesen Helena , Larson Jennifer , Huang Dongqing , Cox Mike , Tatchell Kelly , Andrews Brenda
Published: May 2009

In the budding yeast Saccharomyces cerevisiae, the G1-specific cyclin-dependent kinases (Cdks) Cln1,2-Cdc28 and Pcl1,2-Pho85 are essential for ensuring that DNA replication and cell division are properly linked to cell polarity and bud morphogenesis. However, the redundancy of Cdks and cyclins means that identification of relevant Cdk substrates remains a significant challenge. We used array-based genetic screens (synthetic genetic array or SGA analysis) to dissect redundant pathways associated with G1 cyclins and identified Bni4 as a substrate of the Pcl1- and Pcl2-Pho85 kinases. BNI4 encodes an adaptor protein that targets several proteins to the bud neck. Deletion of BNI4 results in severe growth defects in the absence of the Cdc28 cyclins Cln1 and Cln2, and overexpression of BNI4 is toxic in yeast cells lacking the Pho85 cyclins Pcl1 and Pcl2. Phosphorylation of Bni4 by Pcl-Pho85 is necessary for its localization to the bud neck, and the bud neck structure can be disrupted by overexpressing BNI4 in pcl1Δpcl2Δ mutant cells. Our data suggest that misregulated Bni4 may bind in an uncontrolled manner to an essential component that resides at the bud neck, causing catastrophic morphogenesis defects.
Stress-Induced Phenotypic Switching inCandida albicans
Authors: Alby Kevin , Bennett Richard J.
Published: May 2009

Candida albicans is both a common commensal and an opportunistic pathogen, being a prevalent cause of mucosal and systemic infections in humans. Phenotypic switching between white and opaque forms is a reversible transition that influences virulence, mating behavior, and biofilm formation. In this work, we show that a wide range of factors induces high rates of switching from white to opaque. These factors include different forms of environmental stimuli such as genotoxic and oxidative stress, as well as intrinsic factors such as mutations in DNA repair genes. We propose that these factors increase switching to the opaque phase via a common mechanism—inhibition of cell growth. To confirm this hypothesis, growth rates were artificially manipulated by varying expression of the CLB4 cyclin gene; slowing cell growth by depleting CLB4 resulted in a concomitant increase in white-opaque switching. Furthermore, two clinical isolates of C. albicans, P37005 and L26, were found to naturally exhibit both slow growth and high rates of white-opaque switching. Notably, suppression of the slow growth phenotype suppressed hyperswitching in the P37005 isolate. Based on the sensitivity of the switch to levels of the master regulator Wor1, we propose a model for how changes in cellular growth modulate white-opaque switching frequencies.
Plasma Membrane Area Increases with Spread Area by Exocytosis of a GPI-anchored Protein Compartment
Authors: Gauthier Nils C. , Rossier Olivier M. , Mathur Anurag , Hone James C. , Sheetz Michael P.
Published: May 2009

The role of plasma membrane (PM) area as a critical factor during cell motility is poorly understood, mainly due to an inability to precisely follow PM area dynamics. To address this fundamental question, we developed static and dynamic assays to follow exocytosis, endocytosis, and PM area changes during fibroblast spreading. Because the PM area cannot increase by stretch, spreading proceeds by the flattening of membrane folds and/or by the addition of new membrane. Using laser tweezers, we found that PM tension progressively decreases during spreading, suggesting the addition of new membrane. Next, we found that exocytosis increases the PM area by 40–60% during spreading. Reducing PM area reduced spread area, and, in a reciprocal manner, reducing spreadable area reduced PM area, indicating the interconnection between these two parameters. We observed that Golgi, lysosomes, and glycosylphosphatidylinositol-anchored protein vesicles are exocytosed during spreading, but endoplasmic reticulum and transferrin receptor-containing vesicles are not. Microtubule depolymerization blocks lysosome and Golgi exocytosis but not the exocytosis of glycosylphosphatidylinositol-anchored protein vesicles or PM area increase. Therefore, we suggest that fibroblasts are able to regulate about half of their original PM area by the addition of membrane via a glycosylphosphatidylinositol-anchored protein compartment.
Intrinsic Conformational Determinants Signal Protein Misfolding to the Hrd1/Htm1 Endoplasmic Reticulum–associated Degradation System
Authors: Xie Wei , Kanehara Kazue , Sayeed Ayaz , Ng Davis T.W.
Published: May 2009

Endoplasmic reticulum (ER) quality control mechanisms monitor the folding of nascent polypeptides of the secretory pathway. These are dynamic processes that retain folding proteins, promote the transport of conformationally mature proteins, and target misfolded proteins to ER-associated degradation (ERAD) pathways. Aided by the identification of numerous ERAD factors, late functions that include substrate extraction, ubiquitination, and degradation are fairly well described. By contrast, the mechanisms of substrate recognition remain mysterious. For some substrates, a specific N-linked glycan forms part of the recognition code but how it is read is incompletely understood. In this study, systematic analysis of model substrates revealed such glycans mark structural determinants that are sensitive to the overall folding state of the molecule. This strategy effectively generates intrinsic folding sensors that communicate with high fidelity to ERAD. Normally, these segments fold into the mature structure to pass the ERAD checkpoint. However, should a molecule fail to fold completely, they form a bipartite signal that comprises the unfolded local structure and adjacent enzymatically remodeled glycan. Only if both elements are present will the substrate be targeted to the ERAD pathway for degradation.
Intermittent Hypoxia and the Practice of Anesthesia
Authors: Brown Karen A.
Published: May 2009

Intermittent hypoxia, a powerful and unique stimulus, leads to physiologic changes that are distinct from those associated with either single or continuous hypoxic exposure. There is an accumulating body of evidence that the neurocognitive, inflammatory and cardiovascular symptoms that characterize the syndrome of obstructive sleep apnea are linked to the stimulus of intermittent hypoxia. In addition, altered sensitivities to opiates in children with obstructive sleep apnea have been linked to recurrent hypoxia during sleep. Therefore anesthesiologists should have an understanding of this important stimulus.
Obstructive Sleep Apnea of Obese Adults
Authors: Isono Shiroh , Warner David S. , Warner Mark A.
Published: May 2009

Collapsible pharyngeal airway size is determined by interaction between structural properties of the pharyngeal airway and neural regulation of the pharyngeal dilating muscles. Obesity seems to have two distinct mechanical influences on the pharyngeal airway collapsibility. First, obesity increases soft tissue surrounding the pharyngeal airway within limited maxillomandible enclosure occupying and narrowing its space (pharyngeal anatomical imbalance). Second, obesity, particularly central obesity, increases visceral fat volume decreasing lung volume. Pharyngeal wall collapsibility is increased by the lung volume reduction, possibly through decreased longitudinal tracheal traction (lung volume hypothesis). Neural compensation for functioning structural abnormalities operating during wakefulness is lost during sleep, leading to pharyngeal obstruction. Instability of the negative feedback of the respiratory system may accelerate cycling of pharyngeal closure and opening. Improvement of the pharyngeal anatomical imbalance and maintenance of lung volume are the keys for safe perioperative airway managements of obese patients with obstructive sleep apnea.
Reversal of Profound Neuromuscular Block by Sugammadex Administered Three Minutes after Rocuronium
Authors: Lee Chingmuh , Jahr Jonathan S. , Candiotti Keith A. , Warriner Brian , Zornow Mark H. , Naguib Mohamed
Published: May 2009

Background

Rocuronium in intubation doses provides similar intubation conditions as succinylcholine, but has a longer duration of action. This study compared time to sugammadex reversal of profound rocuronium-induced neuromuscular block with time to spontaneous recovery from succinylcholine.

Methods

One hundred and fifteen adult American Society of Anesthesiologists Class I-II surgical patients were randomized to this multicenter, safety-assessor-blinded, parallel group, active-controlled, Phase IIIa trial. Anesthesia was induced and maintained with propofol and an opioid. Neuromuscular transmission was blocked and tracheal intubation facilitated with 1.2 mg/kg rocuronium or 1 mg/kg succinylcholine. Sugammadex (16 mg/kg) was administered 3 min after rocuronium administration. Neuromuscular function was monitored by acceleromyography. The primary efficacy endpoint was the time from the start of relaxant administration to recovery of the first train-of-four twitch (T(1)) to 10%.

Results

One hundred and ten patients received study treatment. Mean times to recovery of (T(1)) to 10% and (T(1)) to 90% were significantly faster in the rocuronium-sugammadex group (4.4 and 6.2 min, respectively), as compared with the succinylcholine group (7.1 and 10.9 min, respectively; all P < 0.001). Timed from sugammadex administration, the mean time to recovery of (T(1)) to 10%, (T(1)) to 90%, and the train-of-four (T(4)/T(1)) ratio to 0.9 was 1.2, 2.9, and 2.2 min, respectively. Reoccurrence of the block was not observed. There were no serious adverse events related to study treatments.

Conclusion

Reversal of profound high-dose rocuronium-induced neuromuscular block (1.2 mg/kg) with 16 mg/kg sugammadex was significantly faster than spontaneous recovery from 1 mg/kg succinylcholine.
Lidocaine Protects from Myocardial Damage due to Ischemia and Reperfusion in Mice by Its Antiapoptotic Effects
Authors: Kaczmarek Dominik J. , Herzog Christine , Larmann Jan , Gillmann Hans-Jörg , Hildebrand Reinhard , Schmitz Martina , Westermann Anik , Harendza Thomas , Werdehausen Robert , Osthaus Alexander W. , Echtermeyer Frank , Hahnenkamp Klaus , Wollert Kai C. , Theilmeier Gregor
Published: May 2009

Background

Perioperative myocardial ischemia poses a vital threat to surgical patients. Means to protect postischemic myocardium are clinically not available. Lidocaine has been demonstrated to exert antiinflammatory pleiotropic effects. The authors set out to test if lidocaine protects ischemic myocardium from reperfusion injury.

Method

A mouse model of transient coronary artery ligation (30 min) and reperfusion (24 h) was used with animal care committee approval. Infarct size and area-at-risk were determined. Leukocyte recruitment was quantified on immunohistochemical stainings. Apoptosis was assessed using enzyme-linked immunosorbent assay to detect histone modifications and terminal deoxynucleotidyl transferase dUTP nick end labeling assays. Lidocaine effects on leukocyte-endothelial interactions were assessed in vitro by using a parallel-plate flow chamber or static adhesion assays.

Results

Infarct size per area-at-risk was reduced by 27% in mice treated with a lidocaine bolus (1 mg/kg) before a continuous infusion (0.6 mg . kg(-1) . h(-1)) during ischemia (P < 0.005). Neutrophil density in the infarct and periinfarct zone was not reduced by lidocaine, although the size of the infiltrated area was. Terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cardiomyocytes and endothelial cells were significantly reduced in the periinfarct zone by lidocaine. In vitro, no effect on leukocyte rolling or firm adhesion to resting or activated endothelium was demonstrable. In vitro, lidocaine reduced cardiomyocyte apoptosis induced by hypoxia and reoxygenation (3h/1h) significantly. Infarct size and in vitro cardiomyocyte apoptosis were likewise reduced when lidocaine bolus and infusion were administered after the ischemic insult.

Conclusion

Lidocaine exerts cardioprotective effects when administered before or after the ischemic insult. This effect is mediated through an antiapoptotic and not through an antiinflammatory pathway and may be therapeutically exploitable.
Neuronal Preconditioning by Inhalational Anesthetics
Authors: Bantel Carsten , Maze Mervyn , Trapp Stefan
Published: May 2009

Background

Ischemic preconditioning is an important intrinsic mechanism for neuroprotection. Preconditioning can also be achieved by exposure of neurons to K+ channel-opening drugs that act on adenosine triphosphate-sensitive K+ (K(ATP)) channels. However, these agents do not readily cross the blood-brain barrier. Inhalational anesthetics which easily partition into brain have been shown to precondition various tissues. Here, the authors explore the neuronal preconditioning effect of modern inhalational anesthetics and investigate their effects on K(ATP) channels.

Methods

Neuronal-glial cocultures were exposed to inhalational anesthetics in a preconditioning paradigm, followed by oxygen-glucose deprivation. Increased cell survival due to preconditioning was quantified with the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide reduction test. Recombinant plasmalemmal K(ATP) channels of the main neuronal type (Kir6.2/SUR1) were expressed in HEK293 cells, and the effects of anesthetics were evaluated in whole cell patch clamp recordings.

Results

Both sevoflurane and the noble gas xenon preconditioned neurons at clinically used concentrations. The effect of sevoflurane was independent of K(ATP) channel activation, whereas the effect of xenon required the opening of plasmalemmal K(ATP) channels. Recombinant K(ATP) channels were activated by xenon but inhibited by halogenated volatiles. Modulation of mitochondrial K-ATP channels did not affect the activity of K(ATP) channels, thus ruling out an indirect effect of volatiles via mitochondrial channels.

Conclusions

The preconditioning properties of halogenated volatiles cannot be explained by their effect on K(ATP) channels, whereas xenon preconditioning clearly involves the activation of these channels. Therefore, xenon might mimic the intrinsic mechanism of ischemic preconditioning most closely. This, together with its good safety profile, might suggest xenon as a viable neuroprotective agent in the clinical setting.
Dexmedetomidine Attenuates Isoflurane-induced Neurocognitive Impairment in Neonatal Rats
Authors: Sanders Robert D. , Xu Jing , Shu Yi , Januszewski Adam , Halder Sunil , Fidalgo Antonio , Sun Pamela , Hossain Mahmuda , Ma Daqing , Maze Mervyn
Published: May 2009

Background

Neuroapoptosis is induced by the administration of anesthetic agents to the young. As alpha2 adrenoceptor signaling plays a trophic role during development and is neuroprotective in several settings of neuronal injury, the authors investigated whether dexmedetomidine could provide functional protection against isoflurane-induced injury.

Methods

Isoflurane-induced injury was provoked in organotypic hippocampal slice cultures in vitro or in vivo in postnatal day 7 rats by a 6-h exposure to 0.75% isoflurane with or without dexmedetomidine. In vivo, the alpha2 adrenoceptor antagonist atipamezole was used to identify if dexmedetomidine neuroprotection involved alpha2 adrenoceptor activation. The gamma-amino-butyric-acid type A antagonist, gabazine, was also added to the organotypic hippocampal slice cultures in the presence of isoflurane. Apoptosis was assessed using cleaved caspase-3 immunohistochemistry. Cognitive function was assessed in vivo on postnatal day 40 using fear conditioning.

Results

In vivo dexmedetomidine dose-dependently prevented isoflurane-induced injury in the hippocampus, thalamus, and cortex; this neuroprotection was attenuated by treatment with atipamezole. Although anesthetic treatment did not affect the acquisition of short-term memory, isoflurane did induce long-term memory impairment. This neurocognitive deficit was prevented by administration of dexmedetomidine, which also inhibited isoflurane-induced caspase-3 expression in organotypic hippocampal slice cultures in vitro; however, gabazine did not modify this neuroapoptosis.

Conclusion

Dexmedetomidine attenuates isoflurane-induced injury in the developing brain, providing neurocognitive protection. Isoflurane-induced injury in vitro appears to be independent of activation of the gamma-amino-butyric-acid type A receptor. If isoflurane-induced neuroapoptosis proves to be a clinical problem, administration of dexmedetomidine may be an important adjunct to prevent isoflurane-induced neurotoxicity.
Prediction of Neurological Outcome Using Bispectral Index Monitoring in Patients with Severe Ischemic-Hypoxic Brain Injury Undergoing Emergency Surgery
Authors: Myles Paul S. , Daly David , Silvers Andrew , Cairo Sesto
Published: May 2009

Background

Predicting outcome from ischemic-hypoxic brain injury can be difficult in patients rushed to the operating room for time-critical emergency surgery. The authors chose to evaluate the prognostic ability of bispectral index (BIS) in this setting.

Methods

Twenty-five critically ill, unconscious patients with ischemic-hypoxic brain injury undergoing emergency surgery were prospectively studied. Clinical evaluation, laboratory investigations, BIS, and burst suppression ratio were recorded before and during surgery. Neurologic outcome of the patients was measured according to the Glasgow outcome scale at 30 days after injury, with poor neurologic outcome defined as severe disability or death.

Results

The incidence of poor neurologic outcome was 68%. Neither clinical judgment (P = 0.40) nor pupillary responses (P = 0.21) were predictive of neurologic outcome after surgery. An abnormal BIS trace was strongly associated with poor neurologic outcome, positive likelihood ratio 6.6 (95% CI 1.7-36.4; exact test P = 0.002). Some BIS values were significantly different when comparing patients with and without poor outcome: c-statistics for the average BIS and maximal electroencephalographic burst-suppression were 0.80 (95% CI 0.62-0.98; P = 0.017) and 0.84 (95% CI 0.68-0.99; P = 0.007), respectively. A normal BIS (P < 0.0005) but not clinical judgment (P = 0.16) could identify a group of patients more likely to survive with a good neurologic outcome.

Conclusions

BIS, when compared with clinical judgment and routine laboratory tests, provides useful information that may identify patients with a good chance of recovery after ischemic-hypoxic brain injury requiring emergency surgery.
Lidocaine Concentration in Cerebrospinal Fluid after Epidural Administration
Authors: Kamiya Yoshinori , Kikuchi Tatsuaki , Inagawa Gaku , Miyazaki Hiroshi , Miura Masashi , Morita Satoshi , Goto Takahisa
Published: May 2009

Background

In this study, lidocaine concentrations in cerebrospinal fluid (CSF) at different interspaces were measured with or without preceding spinal anesthesia, 10 min after epidural injection of lidocaine, to investigate the effects of preceding meningeal puncture on CSF concentrations of epidurally administered local anesthetic.

Methods

Sixty patients scheduled to receive combined spinal-epidural anesthesia were randomly allocated to receive either spinal anesthesia first (group CSEA) or epidural lidocaine first (group Epi). Each group was divided into three subgroups in which the site of epidural cannulation and spinal tap were separated by one, three, or five interspaces (sets I, II, and III, respectively). CSF was collected from the L4-L5 interspace 10 min after 10 ml lidocaine, 1%, was administered epidurally. In group Epi, CSF was collected after epidural administration of lidocaine and before spinal anesthesia. In group CSEA, spinal anesthesia was performed at the L3-L4 interspace after epidural cannulation and epidural lidocaine was administered postoperatively, after which CSF was sampled.

Results

Lidocaine concentrations in CSF were significantly higher with increasing proximity of epidural injection site to CSF collection site in both groups. There were no significant differences in CSF lidocaine concentrations between group CSEA and group Epi in set I, although lidocaine concentrations were significantly higher in group CSEA set II and III patients.

Conclusion

Lidocaine concentration in CSF was similar with or without preceding meningeal puncture beneath the epidural administration site.
Influence of Disease Progression on the Neuromuscular Blocking Effect of Mivacurium in Children and Adolescents with Duchenne Muscular Dystrophy
Authors: Ihmsen Harald , Schmidt Joachim , Schwilden Helmut , Schmitt Hubert J. , Muenster Tino
Published: May 2009

Background

Studies with nondepolarizing neuromuscular blocking agents showed a delayed onset and prolonged recovery in patients with Duchenne muscular dystrophy. The objective of this study was to investigate if these alterations depend on disease progression.

Methods

The authors studied 11 children (6-9 yr) with moderate Duchenne muscular dystrophy, 11 adolescents (12-16 yr) with advanced Duchenne muscular dystrophy, and 2 age-matched control groups of 8 patients each (5-9 and 10-17 yr). Anesthesia was performed with propofol and remifentanil. Patients received a single intravenous dose of 0.2 mg/kg mivacurium. Neuromuscular transmission was monitored by acceleromyography. The time course of neuromuscular blockade was characterized by the onset time and the times to different levels of recovery.

Results

Onset and duration of neuromuscular blockade were significantly prolonged in adolescent Duchenne muscular dystrophy patients (onset time, 4.0 min; recovery index, 12.3 min; median), as compared with Duchenne muscular dystrophy children (onset time, 2.3 min; recovery index, 6.8 min), and also as compared with young controls (onset time, 2.0 min; recovery index, 4.4 min) and adolescent controls (onset time, 2.5 min; recovery index, 4.8 min). Within the Duchenne muscular dystrophy patients, onset time and recovery index increased significantly with age. In the control group, age had no effect.

Conclusions

The neuromuscular blocking effects of mivacurium showed a significant age dependency in Duchenne muscular dystrophy patients, which was most probably caused by the progression of the disease.
Influence of Respiratory Rate on Stroke Volume Variation in Mechanically Ventilated Patients
Authors: De Backer Daniel , Taccone Fabio Silvio , Holsten Roland , Ibrahimi Fayssal , Vincent Jean-Louis
Published: May 2009

Background

Heart-lung interactions are used to evaluate fluid responsiveness in mechanically ventilated patients, but these indices may be influenced by ventilatory conditions. The authors evaluated the impact of respiratory rate (RR) on indices of fluid responsiveness in mechanically ventilated patients, hypothesizing that pulse pressure variation and respiratory variation in aortic flow would decrease at high RRs.

Methods

In 17 hypovolemic patients, thermodilution cardiac output and indices of fluid responsiveness were measured at a low RR (14-16 breaths/min) and at the highest RR (30 or 40 breaths/min) achievable without altering tidal volume or inspiratory/expiratory ratio.

Results

An increase in RR was accompanied by a decrease in pulse pressure variation from 21% (18-31%) to 4% (0-6%) (P < 0.01) and in respiratory variation in aortic flow from 23% (18-28%) to 6% (5-8%) (P < 0.01), whereas respiratory variations in superior vena cava diameter (caval index) were unaltered, i.e., from 38% (27-43%) to 32% (22-39%), P = not significant. Cardiac index was not affected by the changes in RR but did increase after fluids. Pulse pressure variation became negligible when the ratio between heart rate and RR decreased below 3.6.

Conclusions

Respiratory variations in stroke volume and its derivates are affected by RR, but caval index was unaffected. This suggests that right and left indices of ventricular preload variation are dissociated. At high RRs, the ability to predict the response to fluids of stroke volume variations and its derivate may be limited, whereas caval index can still be used.
Effect of Flumazenil on Bispectral Index Monitoring in Unpremedicated Patients
Authors: Dahaba Ashraf A. , Bornemann Helmar , Rehak Peter H. , Wang Geng , Wu Xin Min , Metzler Helfried
Published: May 2009

Background

Flumazenil is an imidazobenzodiazepine that promptly reverses via competitive inhibition the hypnotic/sedative effects of benzodiazepines on gamma-aminobutyric acid receptors. Endogenous benzodiazepine ligands (endozepines) were isolated in urine, cerebrospinal fluid, and breast milk of women who had not received benzodiazepines. The bispectral index (BIS), an electroencephalographically derived parameter widely used for monitoring the effects of anesthetic/hypnotic drugs, was shown to correlate to various conditions that could influence electroencephalography. The authors examined the hypothesis that 0.5 mg of flumazenil administered to healthy unpremedicated patients during deep surgical remifentanil/propofol anesthesia would increase the BIS value and might expedite recovery from anesthesia.

Methods

Sixty healthy unpremedicated patients were randomly allocated to the flumazenil or control groups. After study drug administration, the authors compared BIS values and various recovery parameters in the flumazenil and control groups.

Results

BIS baseline values in the flumazenil group (38.7 +/- 3.8) increased 15 min after flumazenil administration (53.2 +/- 4.7), with a significant difference over time (P < 0.0001) between the two groups. Mean recovery parameters time, comprising time to spontaneous breathing, eye opening/hand squeezing on verbal command, extubation, and date of birth recollection, was significantly shorter (P = 0.0002) in the flumazenil group (6.9 +/- 2.6 min) compared with the control group (9.8 +/- 2.9 min).

Conclusions

This study demonstrates that flumazenil given to healthy unpremedicated patients during propofol/remifentanil anesthesia significantly increased the BIS value and allowed earlier emergence from anesthesia. This may indicate that flumazenil could be used on a case-by-case basis to reverse endogenous or exogenous endozepines that might play a role during anesthesia.
Individual Probability of Allogeneic Erythrocyte Transfusion in Elective Spine Surgery
Authors: Lenoir Brigitte , Merckx Paul , Paugam-Burtz Catherine , Dauzac Cyril , Agostini Marie-Madeleine , Guigui Pierre , Mantz Jean
Published: May 2009

Background

The aim of this study was to generate a score based on preoperative characteristics and predictive of the individual probability of allogeneic erythrocyte transfusion in patients undergoing elective thoracolumbar spine surgery.

Methods

Two hundred thirty consecutive patients were retrospectively included over a 15-month period (derivation set). Preoperative independent predictors of erythrocyte transfusion from the day of surgery until postoperative day 5 were determined by multivariable analysis, from which a model of individual probability of transfusion was derived and prospectively validated in 125 additional patients (validation set).

Results

Four preoperative independent predictors were associated with transfusion: age older than 50 yr (adjusted odds ratio = 4.9 [2-13.5]), preoperative hemoglobin level less than 12 g/dl (adjusted odds ratio = 6.9 [3.1-17.2]), fusion of more than two levels (adjusted odds ratio = 6.7 [3.1-15.2]), and transpedicular osteotomy (adjusted odds ratio = 19.9 [5.6-98.2]). A 0-4 score (0 = no risk, 4 = maximum risk) predictive of allogeneic transfusion was derived by weighting estimate parameters for each variable in a multivariable logistic regression model. Discriminating capacity of the score was 0.86 [0.81-0.92] in the receiver operating characteristics in the derivation sample and 0.83 [0.75-0.91] in the validation sample. The observed transfusion rates in the validation set and the individual probabilities of erythrocyte transfusion from the score were well correlated (y = 0.98x + 0.04; P < 0.0001), and the observed differences were not statistically different (goodness-of-fit chi-square, P = 0.125). The score was also correlated with the number of erythrocyte units transfused (Spearman rho = 0.61; P < 0.0001).

Conclusion

The Predictive Model of Transfusion in Spine Surgery may be useful in clinical practice to identify patients undergoing spine surgery at risk of massive bleeding and encourage erythrocyte-saving strategies in these patients.
Ampakine CX717 Protects against Fentanyl-induced Respiratory Depression and Lethal Apnea in Rats
Authors: Ren Jun , Ding Xiuqing , Funk Gregory D. , Greer John J.
Published: May 2009

Background

The use of fentanyl as a potent analgesic is contradicted by marked respiratory depression among a subpopulation of patients. The commonly used approach of reversing fentanyl-induced respiratory depression with mu-opiate receptor antagonists such as naloxone has the undesirable effect of blocking analgesia. Here, the authors report a clinically feasible pharmacological solution for countering fentanyl-induced respiratory depression via a mechanism that does not interfere with analgesia. Specifically, to determine if the ampakine CX717, which has been proven metabolically stable and safe for human use, can prevent and rescue from severe fentanyl-induced apnea.

Methods

Plethsymographic recordings were performed from young and adult rats. Varying doses of fentanyl were administered either intraperitoneally or intravenously to induce moderate to life-threatening apneas. CX717 was administered either before or after fentanyl administration. In addition, phrenic nerve recordings were performed from in situ working heart brainstem preparations from juvenile rats.

Results

Preadministration of CX717 markedly attenuated fentanyl-induced respiratory depression. Postadministration of CX717 rescued animals from a lethal dose of fentanyl. Significantly, CX717 countered fentanyl-induced depression of respiratory frequency without suppressing analgesia. The effective dose of CX717 was in the range deemed safe on the basis of clinical trials examining its efficacy for cognitive disorders. In situ, fentanyl-induced depression in respiratory frequency and amplitude was alleviated by CX717.

Conclusions

CX717 is an agent that enhances the safety of using opiate drugs while preserving the analgesic effects. This advancement could significantly improve pain management in a variety of clinical settings.
Rifampin Greatly Reduces the Plasma Concentrations of Intravenous and Oral Oxycodone
Authors: Nieminen Tuija H. , Hagelberg Nora M. , Saari Teijo I. , Pertovaara Antti , Neuvonen Mikko , Laine Kari , Neuvonen Pertti J. , Olkkola Klaus T.
Published: May 2009

Background

Oxycodone is a mu-opioid receptor agonist that is metabolized mainly in the liver by cytochrome P450 3A and 2D6 enzymes. Rifampin is a strong inducer of several drug-metabolizing enzymes. The authors studied the interaction of rifampin with oxycodone. Their hypothesis was that rifampin enhances the CYP3A-mediated metabolism of oxycodone and attenuates its pharmacologic effect.

Methods

The protocol was a four-session, paired crossover. Twelve volunteers were given 600 mg oral rifampin or placebo once daily for 7 days. Oxycodone was given on day 6. In the first part of the study, 0.1 mg/kg oxycodone hydrochloride was given intravenously. In the second part of the study, 15 mg oxycodone hydrochloride was given orally. Concentrations of oxycodone and its metabolites noroxycodone, oxymorphone, and noroxymorphone were determined for 48 h. Psychomotor effects were characterized for 12 h by several visual analog scales. Analgesic effects were characterized by measuring the heat pain threshold and cold pain sensitivity.

Results

Rifampin decreased the area under the oxycodone concentration-time curve of intravenous and oral oxycodone by 53% and 86%, respectively (P < 0.001). Oral bioavailability of oxycodone was decreased from 69% to 21% (P < 0.001). Rifampin greatly increased the plasma metabolite-to-parent drug ratios for noroxycodone and noroxymorphone (P < 0.001). Pharmacologic effects of oral oxycodone were attenuated.

Conclusions

Induction of cytochrome P450 3A by rifampin reduced the area under the oxycodone concentration-time curve of intravenous and oral oxycodone. The pharmacologic effects of oxycodone were modestly attenuated. To maintain adequate analgesia, dose adjustment of oxycodone may be necessary, when used concomitantly with rifampin.
Impaired Upper Airway Integrity by Residual Neuromuscular Blockade: Increased Airway Collapsibility and Blunted Genioglossus Muscle Activity in Response to Negative Pharyngeal Pressure
Authors: Herbstreit Frank , Peters Jürgen , Eikermann Matthias
Published: May 2009

Background

Residual neuromuscular blockade increases the risk to develop postoperative complications. The authors hypothesized that minimal neuromuscular blockade (train-of-four [TOF] ratio 0.5-1) increases upper airway collapsibility and impairs upper airway dilator muscle compensatory responses to negative pharyngeal pressure challenges.

Methods

Epiglottic and nasal mask pressures, genioglossus electromyogram, respiratory timing, and changes in lung volume were measured in awake healthy volunteers (n = 15) before, during (TOF = 0.5 and 0.8 [steady state]), and after recovery of TOF to unity from rocuronium-induced partial neuromuscular blockade. Passive upper airway closing pressure (negative pressure drops, random order, range +2 to -30 cm H2O) and pressure threshold for flow limitation were determined.

Results

Upper airway closing pressure increased (was less negative) significantly from baseline by 54 +/- 4.4% (means +/- SEM), 37 +/- 4.2%, and 16 +/- 4.1% at TOF ratios of 0.5, 0.8, and 1.0, respectively (P < 0.01 vs. baseline for any level). Phasic genioglossus activity almost quadrupled in response to negative (-20 cm H2O) pharyngeal pressure at baseline, and this increase was significantly impaired by 57 +/- 44% and 32 +/- 6% at TOF ratios of 0.5 and 0.8, respectively (P < 0.01 vs. baseline). End-expiratory lung volume, respiratory rate, and tidal volume did not change.

Conclusion

Minimal neuromuscular blockade markedly increases upper airway closing pressure, partly by impairing the genioglossus muscle compensatory response. Increased airway collapsibility despite unaffected values for resting ventilation may predispose patients to postoperative respiratory complications, particularly during airway challenges.