bluuebunny/crossref_metadata_2025 huggingface dataset:
Chromatin assembly factors Asf1 and CAF-1 have overlapping roles in deactivating the DNA damage checkpoint when DNA repair is complete
Authors: Kim Jung-Ae , Haber James E.
Published: January 2009

In response to a DNA double-strand break (DSB), chromatin is rapidly modified by the damage dependent checkpoint kinases. Also, disassembly of chromatin occurs at the break site. The damage-induced modification of chromatin structure is involved in the maintenance of the checkpoint. However, it has not been determined how chromatin is restored to its undamaged state when DSB repair is complete. Here, we show the involvement of two chromatin assembly factors (CAFs), Asf1 and CAF-1, in turning off the DNA damage checkpoint in budding yeast. DSB repair or formation of γ-H2AX does not depend on either the CAF-1 protein, Cac1, or Asf1. Absence of these proteins does not impair the ability of cells to resume cell cycle progression in the presence of an unrepaired DSB (adaptation). However, recovery from cell cycle checkpoint arrest when the DSB is repaired by gene conversion is substantially defective in the absence of both CAF-1 and Asf1, whereas deleting
CAC1
or
ASF1
individually had little effect. We suggest that CAF-1 and Asf1 function redundantly to deactivate the checkpoint by restoring chromatin structure on the completion of DSB repair.
Polymorphic mature microRNAs from passenger strand of pre-miR-146a contribute to thyroid cancer
Authors: Jazdzewski Krystian , Liyanarachchi Sandya , Swierniak Michal , Pachucki Janusz , Ringel Matthew D. , Jarzab Barbara , de la Chapelle Albert
Published: January 2009

Prior work has shown that heterozygosity G/C of single nucleotide polymorphism (SNP rs2910164) within the precursor of microRNA-146a predisposes to PTC (odds ratio = 1.62,
P
= 0.000007) although the mechanism was unclear. Here, we show that GC heterozygotes differ from both GG and CC homozygotes by producing 3 mature microRNAs: 1 from the leading strand (miR-146a), and 2 from the passenger strand (miR-146a*G and miR-146a*C), each with its distinct set of target genes. TaqMan analysis of paired tumor/normal samples revealed 1.5- to 2.6-fold overexpression of polymorphic miR-146a* in 7 of 8 tumors compared with the unaffected part of the same gland. The microarray data showed that widely different transcriptomes occurred in the tumors and in unaffected parts of the thyroid from GC and GG patients. The modulated genes are mainly involved in regulation of apoptosis leading to exaggerated DNA-damage response in heterozygotes potentially explaining the predisposition to cancer. We propose that contrary to previously held views transcripts from the passenger strand of miRs can profoundly affect the downstream effects. Heterozygosity for polymorphisms within the premiR sequence can cause epistasis through the production of additional mature miRs. We propose that mature miRs from the passenger strand may regulate many genetic processes.
Disulfide bond formation by exported glutaredoxin indicates glutathione's presence in the
E. coli
periplasm
Authors: Eser Markus , Masip Lluis , Kadokura Hiroshi , Georgiou George , Beckwith Jonathan
Published: January 2009

Organisms have evolved elaborate systems that ensure the homeostasis of the thiol redox environment in their intracellular compartments. In
Escherichia coli
, the cytoplasm is kept under reducing conditions by the thioredoxins with the help of thioredoxin reductase and the glutaredoxins with the small molecule glutathione and glutathione reductase. As a result, disulfide bonds are constantly resolved in this compartment. In contrast to the cytoplasm, the periplasm of
E. coli
is maintained in an oxidized state by DsbA, which is recycled by DsbB. Thioredoxin 1, when exported to the periplasm turns from a disulfide bond reductase to an oxidase that, like DsbA, is dependent on DsbB. In this study we set out to investigate whether a subclass of the thioredoxin superfamily, the glutaredoxins, can become disulfide bond-formation catalysts when they are exported to the periplasm. We find that glutaredoxins can promote disulfide bond formation in the periplasm. However, contrary to the behavior of thioredoxin 1 in this environment, the glutaredoxins do so independently of DsbB. Furthermore, we show that glutaredoxin 3 requires the glutathione biosynthesis pathway for its function and can oxidize substrates with only a single active-site cysteine. Our data provides in vivo evidence suggesting that oxidized glutathione is present in the
E. coli
periplasm in biologically significant concentrations.
Framing ideas in aphasia: the need for thinking therapy*
Authors: Marshall Jane
Published: January 2009

This paper argues that some of the patterns seen in aphasia may reflect difficulties in the cognitive preparations for language. In particular, some individuals might be unable to carry out processes of ‘Thinking for Speaking’ (Slobin 1996), which frame thoughts for language production. Evidence to support this proposal is presented, together with signs that such thinking can be assisted with cues and therapy. It is argued that these preliminary data need to be pursued via a more comprehensive investigation of thinking therapy.
Neural correlates of inference-driven attention in perceptual and symbolic tasks: An event-related potential study
Authors: Vallesi Antonino , Mapelli Daniela , Cherubini Paolo
Published: January 2009

The inferential system anticipates the external environment by building up internal representations of its regularities. To that purpose, two sources of information are especially important and attract attentional resources: expected and unexpected events, which are useful for checking the accuracy of internal representations. In the present study, we investigated the behavioural properties and the neural mechanisms underlying the strategic allocation of attention triggered by those events. To that end, event-related potentials (ERPs) were recorded during the performance of two tasks requiring detection of predictable and unpredictable response events embedded in a visuospatial or numeric sequence. The behavioural results in the two tasks mirror each other, suggesting the recruitment of similar attentional allocation processes between the two domains. The ERPs showed partially similar effects. In both tasks, a P3a-like component signalled the capture of attention by events clashing with previous expectations, whilst a P3b-like component marked the focusing of attention on predicted events and its redistribution among all possible response events occurring after the detection of an unexpected event.
Short article: People think about what is true for conditionals, not what is false: Only true possibilities prime the comprehension of “if”
Authors: Espino Orlando , Santamaría Carlos , Byrne Ruth M. J.
Published: January 2009

We report the results of two priming experiments that examine the comprehension of conditionals—for example, “if there are apples then there are oranges”—and biconditionals—for example, “if and only if there are apples then there are oranges”. The first experiment showed that participants read a biconditional faster when it was primed by a true possibility, “there were apples and there were oranges” than when it was primed by a false possibility, “there were no apples and there were oranges”; a conditional was primed equally by both possibilities. The second experiment showed that participants read the negated-antecedent conjunction faster when it was primed by a conditional than when it was primed by a biconditional; the affirmative conjunction was primed equally by both connectives. The experiments show that (a) when people understand “if A then B”, they access the true possibilities, “A and B”, and “not-A and B”, and (b) when they understand “if and only if A then B” they access “A and B”, but they do not access “not-A and B”. We discuss their implications for current theories of reasoning.
Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation
Authors: Wang Yanming , Li Ming , Stadler Sonja , Correll Sarah , Li Pingxin , Wang Danchen , Hayama Ryo , Leonelli Lauriebeth , Han Hyunsil , Grigoryev Sergei A. , Allis C. David , Coonrod Scott A.
Published: January 2009

Peripheral blood neutrophils form highly decondensed chromatin structures, termed neutrophil extracellular traps (NETs), that have been implicated in innate immune response to bacterial infection. Neutrophils express high levels of peptidylarginine deiminase 4 (PAD4), which catalyzes histone citrullination. However, whether PAD4 or histone citrullination plays a role in chromatin structure in neutrophils is unclear. In this study, we show that the hypercitrullination of histones by PAD4 mediates chromatin decondensation. Histone hypercitrullination is detected on highly decondensed chromatin in HL-60 granulocytes and blood neutrophils. The inhibition of PAD4 decreases histone hypercitrullination and the formation of NET-like structures, whereas PAD4 treatment of HL-60 cells facilitates these processes. The loss of heterochromatin and multilobular nuclear structures is detected in HL-60 granulocytes after PAD4 activation. Importantly, citrullination of biochemically defined avian nucleosome arrays inhibits their compaction by the linker histone H5 to form higher order chromatin structures. Together, these results suggest that histone hypercitrullination has important functions in chromatin decondensation in granulocytes/neutrophils.
Word maps and Waring type problems
Authors: Larsen Michael , Shalev Aner
Published: January 2009

Waring’s classical problem deals with expressing every natural number as a sum ofg(k)g(k)kkth powers. Recently there has been considerable interest in similar questions for nonabelian groups and simple groups in particular. Here thekkth power word is replaced by an arbitrary group wordw≠1w \ne 1, and the goal is to express group elements as short products of values ofww.

We give a best possible and somewhat surprising solution for this Waring type problem for various finite simple groups, showing that a product of length two suffices to express all elements. We also show that the set of values ofwwis very large, improving various results obtained so far.

Along the way we also obtain new results of independent interest on character values and class squares in symmetric groups.

Our methods involve algebraic geometry, representation theory, probabilistic arguments, as well as results from analytic number theory, including three primes theorems (approximating Goldbach’s Conjecture).
Smale’s 17th problem: Average polynomial time to compute affine and projective solutions
Authors: Beltrán Carlos , Pardo Luis
Published: January 2009

Smale’s 17th problem asks: “Can a zero of

n
n

complex polynomial equations in

n
n

unknowns be found approximately, on the average, in polynomial time with a uniform algorithm?” We give a positive answer to this question. Namely, we describe a uniform probabilistic algorithm that computes an approximate zero of systems of polynomial equations

f
:

C

n

⟶

C

n

f:\mathbb {C}^n\longrightarrow \mathbb {C}^n

, performing a number of arithmetic operations which is polynomial in the size of the input, on the average.
Visualization of Distinct Entities of the SecYEG Translocon during Translocation and Integration of Bacterial Proteins
Authors: Boy Diana , Koch Hans-Georg
Published: January 2009

The universally conserved SecYEG/Sec61 translocon constitutes the major protein-conducting channel in the cytoplasmic membrane of bacteria and the endoplasmic reticulum membrane of eukaryotes. It is engaged in both translocating secretory proteins across the membrane as well as in integrating membrane proteins into the lipid phase of the membrane. In the current study we have detected distinct SecYEG translocon complexes in native Escherichia coli membranes. Blue-Native-PAGE revealed the presence of a 200-kDa SecYEG complex in resting membranes. When the SecA-dependent secretory protein pOmpA was trapped inside the SecYEG channel, a smaller SecY-containing complex of ∼140-kDa was observed, which probably corresponds to a monomeric SecYEG–substrate complex. Trapping the SRP-dependent polytopic membrane protein mannitol permease in the SecYEG translocon, resulted in two complexes of 250 and 600 kDa, each containing both SecY and the translocon-associated membrane protein YidC. The appearance of both complexes was correlated with the number of transmembrane domains that were exposed during targeting of mannitol permease to the membrane. These results suggest that the assembly or the stability of the bacterial SecYEG translocon is influenced by the substrate that needs to be transported.
Nbl1p: A Borealin/Dasra/CSC-1-like Protein Essential for Aurora/Ipl1 Complex Function and Integrity inSaccharomyces cerevisiae
Authors: Nakajima Yuko , Tyers Randall G. , Wong Catherine C.L. , Yates John R. , Drubin David G. , Barnes Georjana
Published: January 2009

The Aurora kinase complex, also called the chromosomal passenger complex (CPC), is essential for faithful chromosome segregation and completion of cell division. In Fungi and Animalia, this complex consists of the kinase Aurora B/AIR-2/Ipl1p, INCENP/ICP-1/Sli15p, and Survivin/BIR-1/Bir1p. A fourth subunit, Borealin/Dasra/CSC-1, is required for CPC targeting to centromeres and central spindles and has only been found in Animalia. Here we identified a new core component of the CPC in budding yeast, Nbl1p. NBL1 is essential for viability and nbl1 mutations cause chromosome missegregation and lagging chromosomes. Nbl1p colocalizes and copurifies with the CPC, and it is essential for CPC localization, stability, integrity, and function. Nbl1p is related to the N-terminus of Borealin/Dasra/CSC-1 and is similarly involved in connecting the other CPC subunits. Distant homology searching identified nearly 200, mostly unannotated, Borealin/Dasra/CSC-1–related proteins from nearly 150 species within Fungi and Animalia. Analysis of the sequence of these proteins, combined with comparative protein structure modeling of Bir1p-Nbl1p-Sli15p using the crystal structure of the human Survivin–Borealin–INCENP complex, revealed a striking structural conservation across a broad range of species. Our biological and computational analyses therefore establish that the fundamental design of the CPC is conserved from Fungi to Animalia.
Kinesin-5–dependent Poleward Flux and Spindle Length Control inDrosophilaEmbryo Mitosis
Authors: Brust-Mascher Ingrid , Sommi Patrizia , Cheerambathur Dhanya K. , Scholey Jonathan M.
Published: January 2009

We used antibody microinjection and genetic manipulations to dissect the various roles of the homotetrameric kinesin-5, KLP61F, in astral, centrosome-controlled Drosophila embryo spindles and to test the hypothesis that it slides apart interpolar (ip) microtubules (MT), thereby controlling poleward flux and spindle length. In wild-type and Ncd null mutant embryos, anti-KLP61F dissociated the motor from spindles, producing a spatial gradient in the KLP61F content of different spindles, which was visible in KLP61F-GFP transgenic embryos. The resulting mitotic defects, supported by gene dosage experiments and time-lapse microscopy of living klp61f mutants, reveal that, after NEB, KLP61F drives persistent MT bundling and the outward sliding of antiparallel MTs, thereby contributing to several processes that all appear insensitive to cortical disruption. KLP61F activity contributes to the poleward flux of both ipMTs and kinetochore MTs and to the length of the metaphase spindle. KLP61F activity maintains the prometaphase spindle by antagonizing Ncd and another unknown force-generator and drives anaphase B, although the rate of spindle elongation is relatively insensitive to the motor's concentration. Finally, KLP61F activity contributes to normal chromosome congression, kinetochore spacing, and anaphase A rates. Thus, a KLP61F-driven sliding filament mechanism contributes to multiple aspects of mitosis in this system.
Myosin 2 Maintains an Open Exocytic Fusion Pore in Secretory Epithelial Cells
Authors: Bhat Purnima , Thorn Peter
Published: January 2009

Many studies have implicated F-actin and myosin 2 in the control of regulated secretion. Most recently, evidence suggests a role for the microfilament network in regulating the postfusion events of vesicle dynamics. This is of potential importance as postfusion behavior can influence the loss of vesicle content and may provide a new target for drug therapy. We have investigated the role of myosin 2 in regulating exocytosis in secretory epithelial cells by using novel assays to determine the behavior of the fusion pore in individual granules. We immunolocalize myosin 2A to the apical region of pancreatic acinar cells, suggesting it is this isoform that plays a role in granule exocytosis. We further show myosin 2 phosphorylation increased on cell stimulation, consistent with a regulatory role in secretion. Importantly, in a single-cell, single-granule secretion assay, neither the myosin 2 inhibitor (−)-blebbistatin nor the myosin light chain kinase inhibitor ML-9 had any effect on the numbers of granules stimulated to fuse after cell stimulation. These data indicate that myosin 2, if it has any action on secretion, must be targeting postfusion granule behavior. This interpretation is supported by direct study of fusion pore opening in which we show that (−)-blebbistatin and ML-9 promote fusion pore closure and decrease fusion pore lifetimes. Our work now adds to a growing body of evidence showing that myosin 2 is an essential regulator of postfusion granule behavior. In particular, in the case of the secretory epithelial cells, myosin 2 activity is necessary to maintain fusion pore opening.
Disperse—a software system for design of selector probes for exon resequencing applications
Authors: Stenberg J. , Zhang M. , Ji H.
Published: January 2009

Summary:Selector probes enable the amplification of many selected regions of the genome in multiplex. Disperse is a software pipeline that automates the procedure of designing selector probes for exon resequencing applications.

Availability:Software and documentation is available at http://bioinformatics.org/disperse

Contact:  genomics_ji@stanford.edu
Detecting gene clusters under evolutionary constraint in a large number of genomes
Authors: Ling Xu , He Xin , Xin Dong
Published: January 2009

Motivation: Spatial clusters of genes conserved across multiple genomes provide important clues to gene functions and evolution of genome organization. Existing methods of identifying these clusters often made restrictive assumptions, such as exact conservation of gene order, and relied on heuristic algorithms.

Results: We developed a very efficient algorithm based on a ‘gene teams’ model that allows genes in the clusters to appear in different orders. This allows us to detect conserved gene clusters under flexible evolutionary constraints in a large number of genomes. Our statistical evaluation incorporates the evolutionary relationship among genomes, a key aspect that has been missing in most previous studies. We conducted a large-scale analysis of 133 bacterial genomes. Our results confirm that our approach is an effective way of uncovering functionally related genes. The comparison with known operons and the analysis of the structural properties of our predicted clusters suggest that operons are an important source of constraint, but there are also other forces that determine evolution of gene order and arrangement. Using our method, we predicted functions of many poorly characterized genes in bacterial. The combined algorithmic and statistical methods we present here provide a rigorous framework for systematically studying evolutionary constraints of genomic contexts.

Availability: The software, data and the full results of this article are available online at http://www.ews.uiuc.edu/~xuling/mcmusec.

Contact:  xuling@uiuc.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
Gclust: trans-kingdom classification of proteins using automatic individual threshold setting
Authors: Sato Naoki
Published: January 2009

Motivation:  Trans-kingdom protein clustering remained difficult because of large sequence divergence between eukaryotes and prokaryotes and the presence of a transit sequence in organellar proteins. A large-scale protein clustering including such divergent organisms needs a heuristic to efficiently select similar proteins by setting a proper threshold for homologs of each protein. Here a method is described using two similarity measures and organism count.

Results: The Gclust software constructs minimal homolog groups using all-against-all BLASTP results by single-linkage clustering. Major points include (i) estimation of domain structure of proteins; (ii) exclusion of multi-domain proteins; (iii) explicit consideration of transit peptides; and (iv) heuristic estimation of a similarity threshold for homologs of each protein by entropy-optimized organism count method. The resultant clusters were evaluated in the light of power law. The software was used to construct protein clusters for up to 95 organisms.

Availability: Software and data are available at http://gclust.c.u-tokyo.ac.jp/Gclust_Download.html.

Contact:  naokisat@bio.c.u-tokyo.ac.jp

Supplementary information:  Supplementary data are available at Bioinformatics online.
Geographic variability of sardine dynamics in the Iberian Biscay region
Authors: Silva A. , Skagen D. W. , Uriarte A. , Massé J. , Santos M. B. , Marques V. , Carrera P. , Beillois P. , Pestana G. , Porteiro C. , Stratoudakis Y.
Published: January 2009

Silva, A., Skagen, D. W., Uriarte, A., Massé, J., Santos, M. B., Marques, V., Carrera, P., Beillois, P., Pestana, G., Porteiro, C., and Stratoudakis, Y. 2009. Geographic variability of sardine dynamics in the Iberian Biscay region. – ICES Journal of Marine Science, 66: 495–508. The spatio-temporal variability in the distribution, demographic structure, recruitment, and mortality of sardine within the Iberian Biscay region is described using area-disaggregated data collected during acoustic surveys and at ports since the mid-1980s. Multiple regression models were used to describe log numbers-at-age obtained annually in ten areas covered by three surveys to test the existence of geographic differences in selectivity-at-age, recruitment strength, and mortality and to infer plausible migration routes. Within Iberian waters, sardine biomass was mainly concentrated off western Portugal and the Gulf of Cadiz. In the Bay of Biscay, biomass levels were comparable with those off western Portugal. Recruitment was localized in a few areas (northern Portugal and the Gulf of Cadiz and Bay of Biscay), intermingling with areas dominated by older fish. Recruitment was generally asynchronous among areas, although some recruitment peaks were noticeable across wider regions. Spatial patterns related to strong and weak year classes and year-class slopes were also noted. Clearly distinct dynamics were not evidenced within the Atlanto–Iberian sardine stock area, but the validity of the northern limit was questioned by the connection between sardine dynamics in the Bay of Biscay and the Cantabrian Sea. The results provided some evidence consistent with the hypothesis of sardine movement from recruiting grounds to areas farther along the coast as they grow.
Behavior and Cellular Evidence for Propofol-induced Hypnosis Involving Brain Glycine Receptors
Authors: Nguyen Hai T. , Li Ke-yong , daGraca Ralph L. , Delphin Ellise , Xiong Ming , Ye Jiang H.
Published: January 2009

Background

It is well documented that several general anesthetics, including propofol, potentiate glycine receptor function. Furthermore, glycine receptors exist throughout the central nervous system, including areas of the brain thought to be involved in sleep. However, the role of glycine receptors in anesthetic-induced hypnosis has not been determined.

Methods

Experiments were conducted in rats where the loss of righting reflex (LORR) was used as a marker of the hypnotic state. Propofol-induced LORR was examined in the presence and absence of strychnine (a glycine receptor antagonist), GABAzine (a gamma-aminobutyric acid A receptor antagonist), as well as ketamine (an antagonist of N-methyl-D-aspartic acid subtype of glutamate receptors). Furthermore, the effects of propofol on the currents elicited by glycine and gamma-aminobutyric acid were analyzed in neurons isolated from the posterior hypothalamus of rats. The effects of strychnine and GABAzine on propofol-induced currents were also evaluated.

Results

Strychnine and GABAzine dose-dependently reduced the percentage of rats exhibiting LORR induced by propofol. Furthermore, strychnine significantly increased the onset time and reduced the duration of LORR induced by propofol. In contrast, strychnine did not affect the LORR induced by ketamine. In addition, propofol markedly increased the currents elicited by glycine and GABA of hypothalamic neurons. Conversely, strychnine and GABAzine both profoundly attenuated the current induced by propofol.

Conclusion

Strychnine, the glycine receptor antagonist, dose-dependently reduced propofol-induced LORR in rats and propofol-induced current of rat hypothalamic neurons. These results suggest that neuronal glycine receptors partially contribute to propofol-induced hypnosis.
Neurocognitive Performance in Hypertensive Patients after Spine Surgery
Authors: Yocum Gene T. , Gaudet John G. , Teverbaugh Lauren A. , Quest Donald O. , McCormick Paul C. , Connolly E Sander , Heyer Eric J.
Published: January 2009

Background

Cognitive dysfunction is fairly common after noncardiac surgery and may be related to intraoperative blood pressure management. The authors present an analysis of risk factors for cognitive deterioration after spine surgery in older patients, with particular emphasis on intraoperative blood pressure in normotensive and hypertensive patients.

Methods

This is a post hoc cohort analysis of 45 patients enrolled before undergoing lumbar laminectomy or microdiscectomy. The patients underwent a battery of 5 neuropsychometric tests preoperatively, and 1 day and 1 month postoperatively. Computerized anesthesia records were used to obtain intraoperative mean arterial pressure (MAP) data. Simple linear regressions between intraoperative MAP and postoperative cognitive performance were performed, and multivariate linear regression models of postoperative cognitive performance were constructed to analyze potential risk factors for cognitive decline after surgery.

Results

Twenty-one normotensive patients (mean age, 62.4 yr) and 24 hypertensive patients (mean age, 67.9 yr) were included in this analysis. There was a significant positive relationship between minimum intraoperative MAP values and 1-day cognitive performance by simple linear regression in hypertensive (P = 0.003), but not normotensive, patients. In multivariate linear regression analysis of cognitive performance, there was a significant interaction between hypertension and minimum intraoperative MAP at 1 day and 1 month.

Conclusions

In hypertensive patients, there was a significant relationship between minimum intraoperative MAP and decline in cognitive function 1 day and 1 month after surgery. A prospective controlled trial of intraoperative blood pressure control, especially during induction of anesthesia when MAP values typically drop, is needed to confirm these findings.
Critical Closing Pressure as the Arterial Downstream Pressure with the Heart Beating and during Circulatory Arrest
Authors: Kottenberg-Assenmacher Eva , Aleksic Ivan , Eckholt Mareike , Lehmann Nils , Peters Jürgen
Published: January 2009

Background

Calculation of systemic vascular resistance, used for hemodynamic decision-making, is based on central venous pressure taken as the downstream pressure. However, during circulatory arrest, arterial pressure decreases to a plateau higher than central venous pressure, the critical closing pressure (Pcrit). The authors assessed in humans undergoing arrest whether two-compartment and pressure-dependent conductivity models better estimate arterial pressure decay and Pcrit than a single-compartment model, and whether Pcrit corresponds to Pcrit calculated with the heart beating.

Methods

Aortic pressure decay was fitted to single-compartment, two-compartment, and pressure-dependent conductivity models using specified time intervals during arrest and natural diastole in 10 patients during defibrillator implantation.

Results

Although all models closely predicted Pcrit with an arrest of > or = 7s, both two-compartment and pressure-dependent conductivity models better estimated pressure decay than a single-compartment model. However, Pcrit calculated from natural diastolic pressure decay was greater (53 mmHg +/- 15.6) than Pcrit 15 s (26.6 mmHg +/- 7.8, P = 0.001) and 30 s (23.9 mmHg +/- 7.1, P = 0.001) during arrest, and also greater than Pcrit calculated for the same time interval during initial arrest.

Conclusions

Thus, during arrest, Pcrit can be closely predicted after > or = 7 s, regardless of the model; two-compartment and pressure-dependent conductivity models provide a better fit than a single-compartment model, and actual Pcrit is much less than Pcrit calculated with the heart beating. Irrespective of uncertainties in whether Pcrit calculated with the heart beating or during arrest is the "true" Pcrit prevailing physiologically, linear vascular resistance is markedly less when substituting Pcrit for central venous pressure as the downstream pressure.
Role of Heat Shock Protein 90 and Endothelial Nitric Oxide Synthase during Early Anesthetic and Ischemic Preconditioning
Authors: Amour Julien , Brzezinska Anna K. , Weihrauch Dorothee , Billstrom Amie R. , Zielonka Jacek , Krolikowski John G. , Bienengraeber Martin W. , Warltier David C. , Pratt Philip F. , Kersten Judy R.
Published: January 2009

Background

Nitric oxide is known to be essential for early anesthetic preconditioning (APC) and ischemic preconditioning (IPC) of myocardium. Heat shock protein 90 (Hsp90) regulates endothelial nitric oxide synthase (eNOS) activity. In this study, the authors tested the hypothesis that Hsp90-eNOS interactions modulate APC and IPC.

Methods

Myocardial infarct size was measured in rabbits after coronary occlusion and reperfusion in the absence or presence of preconditioning within 30 min of isoflurane (APC) or 5 min of coronary artery occlusion (IPC), and with or without pretreatment with geldanamycin or radicicol, two chemically distinct Hsp90 inhibitors, or N-nitro-L-arginine methyl ester, a nonspecific nitric oxide synthase NOS inhibitor. Isoflurane-dependent nitric oxide production was measured (ozone chemiluminescence) in human coronary artery endothelial cells or mouse cardiomyocytes, in the absence or presence of Hsp90 inhibitors or N-nitro-L-arginine methyl ester. Interactions between Hsp90 and eNOS, and eNOS activation, were assessed with immunoprecipitation, immunoblotting, and confocal microscopy.

Results

APC and IPC decreased infarct size (by 50% and 59%, respectively), and this action was abolished by Hsp90 inhibitors. N-nitro-L-arginine methyl ester blocked APC but not IPC. Isoflurane increased nitric oxide production in human coronary artery endothelial cells concomitantly with an increase in Hsp90-eNOS interaction (immunoprecipitation, immunoblotting, and immunohistochemistry). Pretreatment with Hsp90 inhibitors abolished isoflurane-dependent nitric oxide production and decreased Hsp90-eNOS interactions. Isoflurane did not increase nitric oxide production in mouse cardiomyocytes, and eNOS was below the level of detection.

Conclusion

The results indicate that Hsp90 plays a critical role in mediating APC and IPC through protein-protein interactions, and suggest that endothelial cells are important contributors to nitric oxide-mediated signaling during APC.
Propofol and Midazolam Inhibit Conscious Memory Processes Very Soon after Encoding: An Event-related Potential Study of Familiarity and Recollection in Volunteers
Authors: Veselis Robert A. , Pryor Kane O. , Reinsel Ruth A. , Li Yuelin , Mehta Meghana , Johnson Ray
Published: January 2009

Background

Intravenous drugs active via gamma-aminobutyric acid receptors to produce memory impairment during conscious sedation. Memory function was assessed using event-related potentials (ERPs) while drug was present.

Methods

The continuous recognition task measured recognition of photographs from working (6 s) and long-term (27 s) memory while ERPs were recorded from Cz (familiarity recognition) and Pz electrodes (recollection recognition). Volunteer participants received sequential doses of one of placebo (n = 11), 0.45 and 0.9 microg/ml propofol (n = 10), 20 and 40 ng/ml midazolam (n = 12), 1.5 and 3 microg/ml thiopental (n = 11), or 0.25 and 0.4 ng/ml dexmedetomidine (n = 11). End-of-day yes/no recognition 225 min after the end of drug infusion tested memory retention of pictures encoded on the continuous recognition tasks.

Results

Active drugs increased reaction times and impaired memory on the continuous recognition task equally, except for a greater effect of midazolam (P < 0.04). Forgetting from continuous recognition tasks to end of day was similar for all drugs (P = 0.40), greater than placebo (P < 0.001). Propofol and midazolam decreased the area between first presentation (new) and recognized (old, 27 s later) ERP waveforms from long-term memory for familiarity (P = 0.03) and possibly for recollection processes (P = 0.12). Propofol shifted ERP amplitudes to smaller voltages (P < 0.002). Dexmedetomidine may have impaired familiarity more than recollection processes (P = 0.10). Thiopental had no effect on ERPs.

Conclusion

Propofol and midazolam impaired recognition ERPs from long-term memory but not working memory. ERP measures of memory revealed different pathways to end-of-day memory loss as early as 27 s after encoding.
α-1-Adrenergic Receptor Agonist Activity of Clinical α-Adrenergic Receptor Agonists Interferes with α-2-Mediated Analgesia
Authors: Gil Daniel W. , Cheevers Cynthia V. , Kedzie Karen M. , Manlapaz Cynthia A. , Rao Sandhya , Tang Elaine , Donello John E.
Published: January 2009

Background

The use of alpha-2 adrenergic agonists for analgesia is limited due to a narrow therapeutic window. Definition of the role of alpha receptor subtypes in alpha agonist mediated analgesia may identify strategies to separate the analgesic from sedative and cardiovascular effects.

Methods

Analgesic activity of brimonidine, clonidine, and tizanidine was investigated in wild-type C57B/6, alpha-2A, and alpha-2C knockout mice with allodynia induced by N-methyl-D-aspartate or sulprostone. The alpha receptor selectivity of the alpha agonists was assessed using functional in vitro recombinant assays.

Results

Brimonidine, clonidine, and tizanidine reduced N-methyl-D-aspartate- and sulprostone-induced allodynia in wild-type mice, but not alpha-2A knockout mice. In alpha-2C knockout mice, brimonidine and tizanidine reduced allodynia in both models, whereas clonidine only reduced N-methyl-D-aspartate-induced allodynia. In vitro, clonidine and tizanidine activated alpha-1 and alpha-2 receptors with similar potencies, whereas brimonidine was selective for alpha-2 receptors. In alpha-2C knockout mice with sulprostone-induced allodynia, blockade of clonidine's alpha-1 receptor agonist activity restored clonidine's analgesic efficacy. In wild-type mice, the analgesic potency of intrathecal clonidine and tizanidine was increased 3- to 10-fold by coadministration with the alpha-1A-selective antagonist 5-methylurapidil without affecting sedation. Following intraperitoneal administration, the therapeutic window was negligible for clonidine and tizanidine, but greater for brimonidine. 5-Methylurapidil enhanced the therapeutic window of intraperitoneal clonidine and tizanidine approximately 10-fold.

Conclusions

Alpha-1A receptor agonist activity can counterbalance alpha-2 receptor agonist-induced analgesia. Greater alpha-2 selectivity may enhance the therapeutic window of alpha-2 agonists in the treatment of pain.
Perioperative Glycemic Control
Authors: Lipshutz Angela K. M. , Gropper Michael A. , Warner David S. , Warner Mark A.
Published: January 2009

Hyperglycemia in perioperative patients has been identified as a risk factor for morbidity and mortality. Intensive insulin therapy (IIT) has been shown to reduce morbidity and mortality among the critically ill, decrease infection rates and improve survival after cardiac surgery, and improve outcomes in acute neurologic injury and acute myocardial infarction. However, recent evidence of severe hypoglycemia and adverse events associated with IIT brings its safety and efficacy into question. In this article, we summarize the mechanisms and rationale of hyperglycemia and IIT, review the evidence behind the use of IIT in the perioperative period, and discuss the implications of including glycemic control in national quality benchmarks. We conclude that while avoidance of hyperglycemia is clearly beneficial, the appropriate glucose target and specific subpopulations who might benefit from IIT have yet to be identified. Given the potential for harm, inclusion of glucose targets in national quality benchmarks is premature.
Factor XIII Substitution in Surgical Cancer Patients at High Risk for Intraoperative Bleeding
Authors: Korte Wolfgang C. , Szadkowski Christine , Gähler Anita , Gabi Konrad , Kownacki Edward , Eder Monika , Degiacomi Priska , Zoller Norbert , Devay Jan , Lange Jochen , Schnider Thomas
Published: January 2009

Background

Excessive intraoperative bleeding is associated with significant morbidity and mortality. The authors and others have shown that fibrin monomer allows preoperative risk stratification for intraoperative blood loss, likely due to an imbalance between available factor XIII and prothrombin conversion. The authors hypothesized that the use of factor XIII would delay the decrease of clot firmness in high-risk patients.

Methods

The concept was tested in a prospective, randomized, double-blind, placebo-controlled trial in elective gastrointestinal cancer surgery. Patients were randomized to receive factor XIII (30 U/kg) or placebo in addition to controlled standard therapy.

Results

Twenty-two patients were evaluable for a planned interim analysis. For the primary outcome parameter maximum clot firmness, patients receiving factor XIII showed a nonsignificant 8% decrease, and patients receiving placebo lost 38%, a highly significantly difference between the two groups (P = 0.004). A reduction in the nonprimary outcome parameters fibrinogen consumption (-28%, P = 0.01) and blood loss (-29%, P = 0.041) was also observed in the factor XIII group. Three patients experienced adverse events that seemed unrelated to factor XIII substitution. The trial was stopped early after a planned interim analysis with the primary endpoint reached.

Conclusions

This proof of concept study confirms the hypothesis that patients at high risk for intraoperative blood loss show reduced loss of clot firmness when factor XIII is administered early during surgery. Further clinical trials are needed to assess relevant clinical endpoints such as blood loss, loss of other coagulation factors, and use of blood products.
Perioperative Ischemic Optic Neuropathy
Authors: Holy Sarah E. , Tsai Jonathan H. , McAllister Russell K. , Smith Kyle H.
Published: January 2009

Background

Ischemic optic neuropathy is the most common cause of perioperative vision loss. The authors sought to determine its incidence and identify risk factors that may contribute to perioperative ischemic optic neuropathy associated with nonophthalmologic surgical procedures at their institution.

Methods

Seventeen patients who experienced perioperative ischemic optic neuropathy were included in a retrospective chart review case-control study. The authors matched each patient with two control patients who had a similar surgical procedure but did not lose vision. They analyzed multiple perioperative variables for the case and control groups.

Results

From among 126,666 surgical procedures performed during the study period, the authors identified 17 patients with perioperative ischemic optic neuropathy, yielding an overall incidence of 0.013%. There were no hemodynamic variables that differed significantly between the ischemic optic neuropathy patients and the matched control patients.

Conclusion

The authors conclude that perioperative ischemic optic neuropathy can occur in the absence of atypical fluctuations in hemodynamic variables during the perioperative period.
Binding of Long-lasting Local Anesthetics to Lipid Emulsions
Authors: Mazoit Jean-Xavier , Le Guen Régine , Beloeil Hélène , Benhamou Dan
Published: January 2009

Background

Rapid infusion of lipid emulsion has been proposed to treat local anesthetic toxicity. The authors wanted to test the buffering properties of two commercially available emulsions made of long- and of long- and medium-chain triglycerides.

Methods

Using the shake-flask method, the authors measured the solubility and binding of racemic bupivacaine, levobupivacaine, and ropivacaine to diluted Intralipid (Fresenius Kabi, Paris, France) and Medialipide (B-Braun, Boulogne, France).

Results

The apparent distribution coefficient expressed as the ratio of mole fraction was 823 +/- 198 and 320 +/- 65 for racemic bupivacaine and levobupivacaine, and ropivacaine, respectively, at 500 mg in the Medialipide/buffer emulsion; and 1,870 +/- 92 and 1,240 +/- 14 for racemic bupivacaine and levobupivacaine, and ropivacaine, respectively, in the Intralipid/buffer emulsion. Decreasing the pH from 7.40 to 7.00 of the Medialipide/buffer emulsion led to a decrease in ratio of molar concentration from 121 +/- 3.8 to 46 +/- 2.8 for bupivacaine, and to a lesser extent from 51 +/- 4.0 to 31 +/- 1.6 for ropivacaine. The capacity of the 1% emulsions was 871 and 2,200 microM for the 1% Medialipide and Intralipid emulsions, respectively. The dissociation constant was 818 and 2,120 microM for racemic bupivacaine and levobupivacaine, and ropivacaine, respectively. Increasing the temperature from 20 to 37 degrees C led to a greater increase in affinity for ropivacaine (55%) than for bupivacaine (27%). When the pH of the buffer was decreased from 7.40 to 7.00, the affinity was decreased by a factor of 1.68, similar for both anesthetics.

Conclusions

The solubility of long-acting local anesthetics in lipid emulsions and the high capacity of binding of these emulsions most probably explain their clinical efficacy in case of toxicity. The long-chain triglyceride emulsion Intralipid appears to be about 2.5 times more efficacious than the 50/50 medium-chain/long-chain Medialipide emulsion. Also, because of their higher hydrophobicity, racemic bupivacaine and levobupivacaine seem to clear more rapidly than ropivacaine.
Perioperative Acute Ischemic Stroke in Noncardiac and Nonvascular Surgery
Authors: Bateman Brian T. , Schumacher H Christian , Wang Shuang , Shaefi Shahzad , Berman Mitchell F.
Published: January 2009

Background

Perioperative acute ischemic stroke (AIS) is a recognized complication of noncardiac, nonvascular surgery, but few data are available regarding incidence and effect on outcome. This study examines the epidemiology of perioperative AIS in three common surgeries: hemicolectomy, total hip replacement, and lobectomy/segmental lung resection.

Methods

Discharges for patients aged 18 yr or older who underwent any of the surgical procedures listed above were extracted from the Nationwide Inpatient Sample, an administrative database that contains 20% of all discharges from non-Federal hospitals each year, for years 2000 to 2004. Using appropriate International Classification of Diseases, 9th revision, Clinical Modification codes, patients with perioperative AIS were identified, as were comorbid conditions that may be risk factors for perioperative AIS. Multivariate logistic regression was performed to identify independent predictors of perioperative AIS and to ascertain the effect of AIS on outcome.

Results

A total of 0.7% of 131,067 hemicolectomy patients, 0.2% of 201,235 total hip replacement patients, and 0.6% of 39,339 lobectomy/segmental lung resection patients developed perioperative AIS. For patients older than 65 yr, AIS rose to 1.0% for hemicolectomy, 0.3% for hip replacement, and 0.8% for pulmonary resection. Multivariate logistic regression analysis revealed renal disease (odds ratio, 3.0), atrial fibrillation (odds ratio, 2.0), history of stroke (odds ratio, 1.6), and cardiac valvular disease (odds ratio, 1.5) to be the most significant risk factors for perioperative AIS.

Conclusions

Perioperative AIS is an important source of morbidity and mortality associated with noncardiac, nonvascular surgery, particularly in elderly patients and patients with atrial fibrillation, valvular disease, renal disease, or previous stroke.
Reversal of Rocuronium-induced Neuromuscular Blockade with Sugammadex in Pediatric and Adult Surgical Patients
Authors: Plaud Benoît , Meretoja Olli , Hofmockel Rainer , Raft Julien , Stoddart Peter A. , van Kuijk Jacqueline H. M. , Hermens Yvonne , Mirakhur Rajinder K.
Published: January 2009

Background

Sugammadex reverses neuromuscular blockade by chemical encapsulation of rocuronium. This phase IIIA study explored efficacy and safety of sugammadex in infants (28 days to 23 months), children (2-11 yr), adolescents (12-17 yr), and adults (18-65 yr).

Methods

Anesthetized patients (American Society of Anesthesiologists class 1-2) received 0.6 mg/kg rocuronium and were randomized to receive sugammadex (0.5, 1.0, 2.0, or 4.0 mg/kg) or placebo at reappearance of T2. Neuromuscular monitoring was performed using acceleromyography. Primary endpoint was time from sugammadex/placebo administration to recovery of the train-of-four ratio to 0.9. Adverse events and electrocardiograms were recorded, and blood samples were collected for safety and determination of sugammadex and rocuronium plasma concentrations.

Results

A dose-response relation was demonstrated in children (n = 22), adolescents (n = 28), and adults (n = 26), but not infants because of the small sample size (n = 8). After placebo, median recovery time of train-of-four to 0.9 was 21.0, 19.0, 23.4, and 28.5 min in infants, children, adolescents, and adults, respectively. After 2.0 mg/kg sugammadex train-of-four 0.9 was attained in 0.6, 1.2, 1.1, and 1.2 min, respectively. The sugammadex plasma concentrations were similar for the children, adolescent, and adult age groups across the dose range. Sugammadex was well tolerated: No reoccurrence of blockade, inadequate reversal, significant QT prolongation, or other abnormalities were observed.

Conclusions

Sugammadex is a new reversal agent that rapidly, effectively, safely, and with similar recovery times reverses rocuronium-induced neuromuscular blockade in children, adolescents, adults, and the small number of infants studied.