bluuebunny/crossref_metadata_2025 huggingface dataset:
Reduction of Thermodynamics: A Few Problems
Authors: Yi Sang Wook
Published: February 2004

Lawrence Sklar in his book,Physics and Chance(1993), proposes a sophisticated account of reduction of thermodynamics (TD) by statistical mechanics (SM). I argue that Sklar's analysis of the alleged reduction of TD by SM is problematic in several respects. I consider a few counterexamples to show that none of what Sklar takes to be the central features of successful reduction in science (unification and identification) holds in the case of TD and SM. I suggest the broader conclusion that a more useful way of understanding the relationship between TD and SM is as collaboration and competition among alternative methodologies rather than reduction of one theory to another.
Einstein Algebras and the Hole Argument
Authors: Bain Jonathan
Published: February 2004

Einstein algebras have been suggested (Earman 1989) and rejected (Rynasiewicz 1992) as a way to avoid the hole argument against spacetime substantivalism. In this article, I debate their merits and faults. In particular, I suggest that a gauge-invariant interpretation of Einstein algebras that avoids the hole argument can be associated with one approach to quantizing gravity, and, for this reason, is at least as well motivated as sophisticated substantivalist and relationalist interpretations of the standard tensor formalism.
Time Travel and Consistency Constraints
Authors: Kutach Douglas N.
Published: February 2004

The possibility of time travel, as permitted in General Relativity, is responsible for constraining physical fields beyond what laws of nature would otherwise require. In the special case where time travel is limited to a single object returning to the past and interacting with itself, consistency constraints can be avoided if the dynamics is continuous and the object's state space satisfies a certain topological requirement: that all null-homotopic mappings from the state-space to itself have some fixed point. Where consistency constraints do exist, no new physics is needed to enforce them. One needs only to accept certain global topological constraints as laws, something that is reasonable in any case.
Francis Bacon's Philosophy of Science: Machina intellectus and Forma indita
Authors: Muntersbjorn Madeline M.
Published: February 2004

Francis Bacon (1561–1626) wrote that good scientists are not like ants (mindlessly gathering data) or spiders (spinning empty theories). Instead, they are like bees, transforming nature into a nourishing product. This essay examines Bacon's “middle way” by elucidating the means he proposes to turn experience and insight into understanding. The human intellect relies on “machines” to extend perceptual limits, check impulsive imaginations, and reveal nature's latent causal structure, or “forms.” This constructivist interpretation is not intended to supplant inductivist or experimentalist interpretations, but is designed to explicate Bacon's account of science as a collaborative project with several interdependent methodological goals.
Defending Conventions as Functionally a Priori Knowledge
Authors: Stump David J.
Published: February 2004

Recent defenses of a priori knowledge can be applied to the idea of conventions in science in order to indicate one important sense in which conventionalism is correct—some elements of physical theory have a unique epistemological status as a functionally a priori part of our physical theory. I will argue that the former a priori should be treated as empirical in a very abstract sense, but still conventional. Though actually coming closer to the Quinean position than recent defenses of a priori knowledge, the picture of science developed here is very different from that developed in Quinean holism in that categories of knowledge can be differentiated.
The Use of Race in Medicine as a Proxy for Genetic Differences
Authors: Root Michael
Published: February 2004

Race is a prominent category in medicine. Epidemiologists describe how rates of morbidity and mortality vary with race, and doctors consider the race of their patients when deciding whether to test them for sickle-cell anemia or what drug to use to treat their hypertension. At the same time, critics of racial classification say that race is not real but only an illusion or that race is scientifically meaningless. In this paper, I explain how race is used in medicine as a proxy for genes that encode drug metabolizing enzymes and how a proper understanding of race calls into doubt the practice of treating race as a marker of any medically relevant genetic trait.
When Is Biology Destiny? Biological Determinism and Social Responsibility
Authors: de Melo-Martín Inmaculada
Published: February 2004

I argue here that critics of biological explanations of human nature are mistaken when they maintain that the truth of genetic determinism implies the end of critical evaluation and reform of our social institutions. Such a claim erroneously presupposes that our social values, practices, and institutions have nothing to do with what makes biological explanations troublesome. What constitutes a problem for those who are concerned with social justice is not the fact that particular behaviors might be genetically determined, but the fact that our value system and social institutions create the conditions that make such behaviors problematic.
AIC and Large Samples
Authors: Kieseppä I. A.
Published: February 2004

I discuss the behavior of the Akaike Information Criterion in the limit when the sample size grows. I show the falsity of the claim made recently by Stanley Mulaik in Philosophy of Science that AIC would not distinguish between saturated and other correct factor analytic models in this limit. I explain the meaning and demonstrate the validity of the familiar, more moderate criticism that AIC is not a consistent estimator of the number of parameters of the smallest correct model. I also give a short explanation why this feature of AIC is compatible with the motives for using it.
Random Boolean Networks and Evolutionary Game Theory
Authors: Alexander J. McKenzie
Published: February 2004

Recent years have seen increased interest in the question of whether it is possible to provide an evolutionary game-theoretic explanation for certain kinds of social norms. I sketch a proof of a general representation theorem for a large class of evolutionary game-theoretic models played on a social network, in hope that this will contribute to a greater understanding of the long-term evolutionary dynamics of such models, and hence the evolution of social norms.
Interpretations of Probability in Evolutionary Theory
Authors: Millstein Roberta L.
Published: February 2004

The ubiquitous probabilities of evolutionary theory (ET) spark the question: Which interpretation of probability is the most appropriate for ET? There is reason to think that, whatever we take probabilities in ET to be, they must be consistent with both determinism and indeterminism. I argue that the probabilities used in ET are objective in a realist sense, if not in an indeterministic sense. Furthermore, there are a number of interpretations of probability that are objective and would be consistent with deterministic evolution and indeterministic evolution. However, I suggest that evolutionary probabilities are best understood as propensities of population-level kinds.
For Fundamentalism
Authors: Hoefer Carl
Published: February 2004

In this paper I defend fundamental physical laws from the arguments mounted by Nancy Cartwright in her (1999) book The Dappled World (and other publications). I argue, positively, that we have a good deal of evidence for mathematical laws—not just causal capacities—underlying many natural phenomena. I also argue, negatively, that Cartwright's main arguments unfairly demand that a fundamentalist be a strong reductionist.
Is It Possible to Nominalize Quantum Mechanics?
Authors: Bueno Otávio
Published: February 2004

Hartry Field (1980) has developed an interesting nominalization strategy for Newtonian gravitation theory—a strategy that reformulates the theory without quantification over abstract entities. According to David Malament (1982), Field's strategy cannot be extended to quantum mechanics (QM), and so it only has a limited scope. In a recent work, Mark Balaguer has responded to Malament's challenge by indicating how QM can be nominalized, and by “doing much of the work needed to provide the nominalization” (Balaguer 1998, 114). In this paper, I critically assess Balaguer's proposal, and argue that it ultimately fails. Balaguer's strategy is incompatible with a number of interpretations of QM, in particular with Bas van Fraassen's version of the modal interpretation. And given that Balaguer's strategy invokes physically real propensities, it is unclear whether it is even compatible with nominalism. I conclude that the nominalization of QM remains a major problem for the nominalist.
Quantum Mechanics and Ordinary Language: The Fuzzy Link
Authors: Lewis Peter J.
Published: February 2004

It is widely acknowledged that the link between quantum language and ordinary language must be “fuzzier” than the traditional eigenstate-eigenvalue link. In the context of spontaneous-collapse theories, Albert and Loewer (1996) argue that the form of this fuzzy link is a matter of convention, and can be freely chosen to minimize anomalies for those theories. I defend the position that the form of the link is empirical, and could be such as to render collapse theories idle. This means that defenders of spontaneous-collapse theories must gamble that the actual form of the link renders such theories tenable.
Trigger-dependent Gene Expression Profiles in Cardiac Preconditioning
Authors: Sergeev Pavel , da Silva Rafaela , Lucchinetti Eliana , Zaugg Kathrin , Pasch Thomas , Schaub Marcus C. , Zaugg Michael
Published: February 2004

Background

DNA chips facilitate genomic-wide exploration of gene expression. The authors hypothesized that ischemic (IPC) and anesthetic preconditioning (APC) would differentially modulate gene expression in hearts.

Methods

Affymetrix rat U34A gene chips were used to explore the transcriptional response to IPC and APC, sustained ischemia (110 min) without reperfusion, and time-matched perfusion in isolated rat hearts. IPC was induced by three cycles of 5 min of ischemia, and APC was induced by 1.5 minimum alveolar concentration isoflurane (110 min). For each heart, a separate chip was used for hybridization. Data were analyzed for significant > or = 2.0-fold changes in gene expression. Microarray results were confirmed by quantitative real-time reverse-transcription polymerase chain reaction.

Results

Of the 8,799 genes represented on U34A, 217 transcripts in the APC group, 234 in the IPC group, and 29 in the ischemia group displayed significant > or = 2.0-fold up-regulation in messenger RNA levels, and 185 transcripts in the APC group, 55 in the IPC group, and 49 in the ischemia group displayed significant > or = 2.0-fold down-regulation. Many of these transcripts were unknown genes. A high number of commonly regulated genes were found in IPC and APC (39 up-regulated, 17 down-regulated). Genes commonly regulated included those associated with cell defense (heat shock protein 10, aldose reductase, Bcl-xS). Conversely, a pool of protective and antiprotective genes was differentially regulated in APC versus IPC (heat shock protein 27/70, programmed cell death 8), suggesting trigger-dependent transcriptome variability.

Conclusions

The novel microarray technology provides evidence for distinct cardioprotective phenotypes in IPC and APC. The observed transcriptional changes raise the possibility of a second window of protection by volatile anesthetics. The authors' molecular portraits are the first global genomic comparison between IPC and APC.
Attenuation of Mitochondrial Respiration by Sevoflurane in Isolated Cardiac Mitochondria Is Mediated in Part by Reactive Oxygen Species
Authors: Riess Matthias L. , Eells Janis T. , Kevin Leo G. , Camara Amadou K. S. , Henry Michele M. , Stowe David F.
Published: February 2004

Background

Anesthetic preconditioning protects against cardiac ischemia/reperfusion injury. Increases in reduced nicotinamide adenine dinucleotide and reactive oxygen species during sevoflurane exposure suggest attenuated mitochondrial electron transport as a trigger of anesthetic preconditioning. The authors investigated the effects of sevoflurane on respiration in isolated cardiac mitochondria.

Methods

Mitochondria were isolated from fresh guinea pig hearts, and mitochondrial oxygen consumption was measured in the presence of complex I (pyruvate) or complex II (succinate) substrates. The mitochondria were exposed to 0, 0.13, 0.39, 1.3, or 3.9 mM sevoflurane. State 3 respiration was determined after adenosine diphosphate addition. The reactive oxygen species scavengers manganese(III) tetrakis (4-benzoic acid) porphyrin chloride and N-tert-Butyl-a-(2-sulfophenyl)nitrone sodium (10 microM each), or the K(ATP) channel blockers glibenclamide (2 microM) or 5-hydroxydecanoate (300 microM), were given alone or before 1.3 mM sevoflurane.

Results

Sevoflurane attenuated respiration for both complex I and complex II substrates, depending on the dose. Glibenclamide and 5-hydroxydecanoate had no effect on this attenuation. Both scavengers, however, abolished the sevoflurane-induced attenuation for complex I substrates, but not for complex II substrates.

Conclusion

The findings suggest that sevoflurane-induced attenuation of complex I is mediated by reactive oxygen species, whereas attenuation of other respiratory complexes is mediated by a different mechanism. The opening of mitochondrial K(ATP) channels by sevoflurane does not seem to be involved in this effect. Thus, reactive oxygen species formation may not only result from attenuated electron transport by sevoflurane, but it may also contribute to complex I attenuation, possibly leading to a positive feedback and amplification of sevoflurane-induced reactive oxygen species formation in triggering anesthetic preconditioning.
Adenosine and a Nitric Oxide Donor Enhances Cardioprotection by Preconditioning with Isoflurane through Mitochondrial Adenosine Triphosphate-sensitive K+Channel-dependent and -independent Mechanisms
Authors: Wakeno-Takahashi Mayu , Otani Hajime , Nakao Shinichi , Uchiyama Yuka , Imamura Hiroji , Shingu Koh
Published: February 2004

Background

Preconditioning with isoflurane has been shown to confer cardioprotection via activation of mitochondrial adenosine triphosphate-sensitive K+ (mito K(ATP)) channels. However, the relative contribution of mito K(ATP) channel and non-mito K(ATP) channel mechanisms to isoflurane-mediated cardioprotection has not been investigated.

Methods

Isolated and buffer-perfused rat hearts were used. Flavoprotein fluorescence was monitored as an index for mito K(ATP) channel activity. Isovolumic left ventricular function and infarct size were measured as indices for cardioprotection.

Results

Flavoprotein fluorescence, which was monitored as an index for mito K(ATP) channel activity, was increased by isoflurane and a known mito K(ATP) channel opener, diazoxide, in a 5-hydroxydecanoate-sensitive manner. Although flavoprotein oxidation induced by diazoxide was dissipated soon after its removal from the buffer, flavoprotein oxidation induced by isoflurane was sustained after cessation of the treatment. The sustained increase in flavoprotein oxidation was associated with a significant reduction in infarct size after 30 min of ischemia followed by 120 min of reperfusion. Although adenosine and S-nitroso-N-acetyl-penicillamine each alone did not increase flavoprotein fluorescence, nor did they confer significant cardioprotection, coadministration of adenosine and S-nitroso-N-acetyl-penicillamine with isoflurane conferred a highly significant reduction of infarct size and improvement of left ventricular function without increasing flavoprotein oxidation over isoflurane alone. The early treatment with 5-hydroxydecanoate before and during preconditioning completely reversed flavoprotein oxidation and inhibited the infarct-sparing effect of isoflurane and combined preconditioning with isoflurane, adenosine, and S-nitroso-N-acetyl-penicillamine. The late treatment with 5-hydroxydecanoate after preconditioning abolished flavoprotein oxidation and the infarct-sparing effect of isoflurane but only partially inhibited cardioprotection conferred by the combined preconditioning, despite complete abrogation of flavoprotein oxidation.

Conclusions

Mito K(ATP) channel activation is the essential trigger of both preconditioning with isoflurane and combined preconditioning with isoflurane, adenosine, and S-nitroso-N-acetyl-penicillamine. Mito K(ATP) channel activation is also a crucial mediator of cardioprotection afforded by preconditioning with isoflurane. However, enhanced cardioprotection conferred by combined preconditioning is mediated through both mito K(ATP) channel-dependent and -independent mechanisms.
Protein Kinase C Translocation and Src Protein Tyrosine Kinase Activation Mediate Isoflurane-induced Preconditioning In Vivo
Authors: Ludwig Lynda M. , Weihrauch Dorothee , Kersten Judy R. , Pagel Paul S. , Warltier David C.
Published: February 2004

Background

The authors tested the hypotheses that protein kinase C (PKC)-specific isoform translocation and Src protein tyrosine kinase (PTK) activation play important roles in isoflurane-induced preconditioning in vivo.

Methods

Rats (n = 125) instrumented for measurement of hemodynamics underwent 30 min of coronary artery occlusion followed by 2 h of reperfusion and received 0.9% saline (control); PKC inhibitors chelerythrine (5 mg/kg), rottlerin (0.3 mg/kg), or PKC-epsilonV1-2 peptide (1 mg/kg); PTK inhibitors lavendustin A (1 mg/kg) or 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1; 1 mg/kg); mitochondrial adenosine triphosphate-sensitive potassium channel antagonist 5-hydroxydecanote (10 mg/kg); or reactive oxygen species scavenger N-acetylcysteine (150 mg/kg) in the absence and presence of a 30-min exposure to isoflurane (1.0 minimum alveolar concentration) in separate groups. Isoflurane was discontinued 15 min before coronary occlusion (memory period). Infarct size was determined using triphenyltetrazolium staining. Immunohistochemistry and confocal microscopic imaging were performed to examine PKC translocation in separate groups of rats.

Results

Isoflurane significantly (P < 0.05) reduced infarct size (40 +/- 3% [n = 13]) as compared with control experiments (58 +/- 2% [n = 12]). Chelerythrine, rottlerin, PKC-epsilonV1-2 peptide, lavendustin A, PP1, 5-hydroxydecanote, and N-acetylcysteine abolished the anti-ischemic actions of isoflurane (58 +/- 2% [n = 8], 50 +/- 3% [n = 9], 53 +/- 2% [n = 9], 59 +/- 3% [n = 6], 57 +/- 3% [n = 7], 60 +/- 3% [n = 7], and 53 +/- 3% [n = 6], respectively). Isoflurane stimulated translocation of the delta and epsilon isoforms of PKC to sarcolemmal and mitochondrial membranes, respectively.

Conclusions

Protein kinase C-delta, PKC-epsilon, and Src PTK mediate isoflurane-induced preconditioning in the intact rat heart. Opening of mitochondrial adenosine triphosphate-sensitive potassium channels and generation of reactive oxygen species are upstream events of PKC activation in this signal transduction process.
Cyclooxygenase-2 Mediates Ischemic, Anesthetic, and Pharmacologic Preconditioning In Vivo
Authors: Alcindor Dunbar , Krolikowski John G. , Pagel Paul S. , Warltier David C. , Kersten Judy R.
Published: February 2004

Background

Cyclooxygenase-2 (COX-2) mediates the late phase of ischemic preconditioning (IPC), but whether this enzyme modulates early IPC, anesthetic-induced preconditioning (APC), or other forms of pharmacologic preconditioning (PPC) is unknown. The authors tested the hypothesis that COX-2 is an essential mediator of IPC, APC, and PPC in vivo.

Methods

Barbiturate-anesthetized dogs (n = 91) were instrumented for measurement of hemodynamics and randomly assigned to receive IPC (four 5-min coronary occlusions interspersed with 5-min reperfusions), APC (1.0 minimum alveolar concentration of isoflurane for 30 min), or PPC (selective mitochondrial K(ATP) channel opener diazoxide, 2.5 mg/kg intravenous) in the presence or absence of pretreatment with oral aspirin (650 mg), the selective COX-2 inhibitor celecoxib (200 mg), or acetaminophen (500 mg) administered 24, 12, and 2 h before experimentation in 12 separate experimental groups. All dogs were subjected to a 60-min coronary artery occlusion followed by 3 h of reperfusion. Myocardial infarct size and coronary collateral blood flow were quantified with triphenyltetrazolium staining and radioactive microspheres, respectively. Myocardial 6-keto-prostaglandin F1alpha, a stable metabolite of prostacyclin, was measured (enzyme immunoassay) in separate experiments (n = 8) before and after isoflurane administration, in the presence or absence of celecoxib.

Results

No significant differences in baseline hemodynamics or the left ventricular area at risk for infarction were observed between groups. IPC, isoflurane, and diazoxide all decreased myocardial infarct size (9 +/- 1, 12 +/- 2, and 11 +/- 1%, respectively) as compared with control (30 +/- 1%). Celecoxib alone had no effect on infarct size (26 +/- 3%) but abolished IPC (30 +/-3%), APC (30 +/- 3%), and PPC (26 +/- 1%). Aspirin (24 +/- 3%) and acetaminophen alone (29 +/- 2%) did not alter infarct size or abolish APC-induced protection (18 +/- 1 and 19 +/- 1%, respectively). Isoflurane increased myocardial 6-keto-prostaglandin F1alpha to 463 +/- 267% of baseline in the absence but not in the presence (94 +/- 13%) of celecoxib.

Conclusions

The results indicate that COX-2 is a critical mediator of IPC, APC, and PPC in dogs. The role of cyclooxygenase enzymes as obligatory mediators of myocardial protection produced by diverse preconditioning stimuli may have implications for the clinical use of COX-2 inhibitors.
Role of Tyrosine Kinase in Desflurane-induced Preconditioning
Authors: Ebel Dirk , Müllenheim Jost , Südkamp Hendrik , Bohlen Thomas , Ferrari Jan , Huhn Ragnar , Preckel Benedikt , Schlack Wolfgang
Published: February 2004

Background

Short administration of volatile anesthetics preconditions myocardium and protects the heart against the consequences of subsequent ischemia. Activation of tyrosine kinase is implicated in ischemic preconditioning. The authors investigated whether desflurane-induced preconditioning depends on activation of tyrosine kinase.

Methods

Sixty-four rabbits were instrumented for measurement of left ventricular pressure, cardiac output, and myocardial infarct size (IS). All rabbits were subjected to 30 min of occlusion of a major coronary artery and 2 h of subsequent reperfusion. Rabbits underwent a treatment period consisting of either no intervention for 35 min (control group, n = 12) or 15 min of 1 minimum alveolar concentration desflurane inhalation followed by a 10-min washout period (desflurane group, n = 12). Four additional groups received the tyrosine kinase inhibitor genistein (5 mg/kg) or lavendustin A (1.3 mg/kg) at the beginning of the treatment period with (desflurane-genistein group, n = 11; desflurane-lavendustin A group, n = 12) or without desflurane inhalation (genistein group, n = 9; lavendustin A group, n = 8).

Results

Hemodynamic values were similar in all groups during baseline (left ventricular pressure, 87 +/- 14 mmHg (mean +/- SD]; cardiac output, 198 +/- 47 ml/min), during coronary artery occlusion (left ventricular pressure, 78 +/- 12 mmHg; cardiac output, 173 +/- 39 ml/min), and after 2 h of reperfusion (left ventricular pressure, 59 +/- 17; cardiac output, 154 +/- 43 ml/min). IS in the control group was 55 +/- 10% of the area at risk. The tyrosine inhibitors had no effect on IS (genistein group, 56 +/- 13%; lavendustin A group, 49 +/- 13%; each P = 1.0 vs. control group). Desflurane preconditioning reduced IS to 40 +/- 15% (P = 0.04 vs. control group). Tyrosine kinase inhibitor administration had no effect on IS reduction (desflurane-genistein group, 44 +/- 13%; desflurane-lavendustin A group, 44 +/- 16%; each P = 1.0 vs. desflurane group).

Conclusion

Desflurane-induced preconditioning does not depend on tyrosine kinase activation.
Contribution of Reactive Oxygen Species to Isoflurane-induced Sensitization of Cardiac Sarcolemmal Adenosine Triphosphate–sensitive Potassium Channel to Pinacidil
Authors: An Jianzhong , Stadnicka Anna , Kwok Wai-Meng , Bosnjak Zeljko J.
Published: February 2004

Background

Myocardial protection by volatile anesthetics involves activation of cardiac adenosine triphosphate-sensitive potassium (K(ATP)) channels. The authors have previously shown that isoflurane enhances sensitivity of the sarcolemmal K(ATP) channel to the opener, pinacidil. Because reactive oxygen species seem to be mediators in anesthetic preconditioning, the authors investigated whether they contribute to the mechanism of the sensitization effect by isoflurane.

Methods

Ventricular myocytes were isolated from guinea pig hearts for the whole cell patch clamp recordings of the sarcolemmal K(ATP) channel current (I(KAPT)). Free radical scavengers N-acetyl-L-cysteine, carnosine, superoxide dismutase, and catalase were used to investigate whether reactive oxygen species mediate isoflurane facilitation of the channel opening by pinacidil. A possible role of the mitochondrial K(ATP) channels was tested using a blocker of these channels, 5-hydroxydecanoate.

Results

The mean density (+/- SEM) of I(KAPT) elicited by pinacidil (20 microM) was 18.9 +/- 1.8 pA/pF (n = 11). In the presence of isoflurane (0.55 mM), the density of pinacidil-activated I(KAPT) increased to 38.5 +/- 2.4 pA/pF (n = 9). Concurrent application of isoflurane and N-acetyl-L-cysteine decreased the sensitization effect by isoflurane in a concentration-dependent manner, whereby the densities of I(KAPT) were 32.6 +/- 1.4 (n = 6), 26.2 +/- 2.3 (n = 6), and 19.4 +/- 2.1 pA/pF (n = 8) at 100, 250, and 500 microM N-acetyl-L-cysteine, respectively. Concurrent application of isoflurane and carnosine (100 microM), superoxide dismutase (100 U/ml), or catalase (100 U/ml) attenuated the densities of I(KAPT) to 27.9 +/- 2.6, 27.2 +/- 2.9, and 25.9 +/- 2.2 pA/pF, respectively. None of the scavengers affected activation of I(KAPT) by pinacidil alone. 5-Hydroxydecanoate (100 microM) did not alter the sensitization effect by isoflurane, and the density of I(KAPT) in this group was 37.1 +/- 3.8 pA/pF (n= 6).

Conclusion

These results suggest that reactive oxygen species contribute to the mechanism by which isoflurane sensitizes the cardiac sarcolemmal K(ATP) channel to the opener, pinacidil.
Remifentanil Induces Systemic Arterial Vasodilation in Humans with a Total Artificial Heart
Authors: Ouattara Alexandre , Boccara Gilles , Köckler Uwe , Lecomte Patrick , Leprince Pascal , Léger Philippe , Riou Bruno , Rama Akthar , Coriat Pierre
Published: February 2004

Background

To assess intrinsic vascular effects of remifentanil, increased concentrations were infused in critically ill patients with a total artificial heart.

Methods

In the early postoperative period after implantation of a total artificial heart, nine ventilated patients requiring short general anesthesia were included in this study. After anesthesia was induced with 0.3 mg/kg intravenous etomidate, the artificial heart settings were modified to render cardiac output "preload-independent." While maintenance of anesthesia was ensured by a continuous infusion of etomidate, increased concentrations of remifentanil (from 0.1 to 1 microg x kg(-1) x min(-1)) were infused in steps of 5 min under hemodynamic monitoring, including left and right atrial pressures, systemic and pulmonary arterial pressures, and left and right cardiac indices. The invasive procedure was started under the highest concentration of remifentanil tolerated by the patient. Infusion of remifentanil was stopped at the end of the invasive procedure, while etomidate infusion was maintained. New hemodynamic measurements were performed at the end of the 12-min recovery period.

Results

Remifentanil produced a dose-dependent and significant decrease in systemic arterial pressure and vascular resistances (n = 9) from a concentration of 0.25 microg x kg(-1) x min(-1). No significant changes were observed on pulmonary vascular resistances (n = 6). Neither right (n = 9) nor left (n = 6) atrial pressures were affected by remifentanil infusion. Hemodynamic variables returned to baseline value over the 12-min recovery period.

Conclusions

In humans with a total artificial heart, remifentanil induces a systemic arterial vasodilation without significant effect on the capacitance vessels.
Variable Ventilation Improves Perioperative Lung Function in Patients Undergoing Abdominal Aortic Aneurysmectomy
Authors: Boker Abdulaziz , Haberman Craig J. , Girling Linda , Guzman Randy P. , Louridas George , Tanner John R. , Cheang Mary , Maycher Bruce W. , Bell Dean D. , Doak Greg J.
Published: February 2004

Background

Optimizing perioperative mechanical ventilation remains a significant clinical challenge. Experimental models indicate that "noisy" or variable ventilation (VV)--return of physiologic variability to respiratory rate and tidal volume--improves lung function compared with monotonous control mode ventilation (CV). VV was compared with CV in patients undergoing abdominal aortic aneurysmectomy, a patient group known to be at risk of deteriorating lung function perioperatively.

Methods

After baseline measurements under general anesthesia (CV with a tidal volume of 10 ml/kg and a respiratory rate of 10 breaths/min), patients were randomized to continue CV or switch to VV (computer control of the ventilator at the same minute ventilation but with 376 combinations of respiratory rate and tidal volume). Lung function was measured hourly for the next 6 h during surgery and recovery.

Results

Forty-one patients for aneurysmectomy were studied. The characteristics of the patients in the two groups were similar. Repeated-measures analysis of variance (group x time interaction) revealed greater arterial oxygen partial pressure (P = 0.011), lower arterial carbon dioxide partial pressure (P = 0.012), lower dead space ventilation (P = 0.011), increased compliance (P = 0.049), and lower mean peak inspiratory pressure (P = 0.013) with VV.

Conclusions

The VV mode of ventilation significantly improved lung function over CV in patients undergoing abdominal aortic aneurysmectomy.
Effect of Amino Acid Infusion on Central Thermoregulatory Control in Humans
Authors: Nakajima Yasufumi , Takamata Akira , Matsukawa Takashi , Sessler Daniel I. , Kitamura Yoshihiro , Ueno Hiroshi , Tanaka Yoshifumi , Mizobe Toshiki
Published: February 2004

Background

Administration of protein or amino acids enhances thermogenesis, presumably by stimulating oxidative metabolism. However, hyperthermia results even when thermoregulatory responses are intact, suggesting that amino acids also alter central thermoregulatory control. Therefore, the authors tested the hypothesis that amino acid infusion increases the thermoregulatory set point.

Methods

Nine male volunteers each participated on 4 study days in randomized order: (1) intravenous amino acids infused at 4 kJ x kg(-1) x h(-1) for 2.5 h combined with skin-surface warming, (2) amino acid infusion combined with cutaneous cooling, (3) saline infusion combined with skin-surface warming, and (4) saline infusion combined with cutaneous cooling.

Results

Amino acid infusion increased resting core temperature by 0.3 +/- 0.1 degrees C (mean +/- SD) and oxygen consumption by 18 +/- 12%. Furthermore, amino acid infusion increased the calculated core temperature threshold (triggering core temperature at a designated mean skin temperature of 34 degrees C) for active cutaneous vasodilation by 0.3 +/- 0.3 degrees C, for sweating by 0.2 +/- 0.2 degrees C, for thermoregulatory vasoconstriction by 0.3 +/- 0.3 degrees C, and for thermogenesis by 0.4 +/- 0.5 degrees C. Amino acid infusion did not alter the incremental response intensity (i.e., gain) of thermoregulatory defenses.

Conclusions

Amino acid infusion increased the metabolic rate and the resting core temperature. However, amino acids also produced a synchronous increase in all major autonomic thermoregulatory defense thresholds; the increase in core temperature was identical to the set point increase, even in a cold environment with amble potential to dissipate heat. In subjects with intact thermoregulatory defenses, amino acid-induced hyperthermia seems to result from an increased set point rather than increased metabolic rate per se.
Effect of Propofol on Hypotonic Swelling-induced Membrane Depolarization in Human Coronary Artery Smooth Muscle Cells
Authors: Masuda Takako , Tomiyama Yoshinobu , Kitahata Hiroshi , Kuroda Yasuhiro , Oshita Shuzo
Published: February 2004

Background

Stretch (mechanical stress)-induced membrane depolarization of smooth muscle may contribute to basal vascular tone and myogenic control. Propofol induces vasodilation and inhibits myogenic control. Hypotonic swelling was used as a model of mechanical stress. The authors investigated the effects of propofol and 5-nitro-2-(3-phenylpropylamino)benzoic acid, a chloride channel and nonselective cation channel blocker, on hypotonicity-induced membrane depolarization in cultured human coronary artery smooth muscle cells.

Methods

A voltage-sensitive fluorescent dye, bis-(1,3-diethylthiobarbiturate)trimethine oxonol, was used to assess relative changes in membrane potential semiquantitatively. The cells were continuously perfused with Earle's balanced salt solution containing 200 nM bis-(1,3-diethylthiobarbiturate)trimethine oxonol and exposed sequentially to isotonic and hypotonic medium. In a second series of experiments, the cells were exposed to hypotonic media in the presence and absence of 5-nitro-2-(3-phenylpropylamino)benzoic acid or propofol.

Results

The relative fluorescence values at 10, 20, and 30% hypotonicity were 147 +/- 29, 214 +/- 74, and 335 +/- 102% of baseline, respectively. The changes were all significantly different from the isotonic time control group. In the presence of 200 microM 5-nitro-2-(3-phenylpropylamino)benzoic acid or 0.1, 1, 10, or 100 microg/ml propofol, the relative fluorescence values at 30% hypotonicity were 87 +/- 17, 194 +/- 27, 160 +/- 18, 130 +/- 18, and 84 +/- 15%, respectively. These changes were significantly less than the 30% for the hypotonic control (246 +/- 23%).

Conclusion

These results suggest that volume-sensitive chloride channels and nonselective cation channels may participate in hypotonicity-induced membrane depolarization and that propofol inhibits hypotonicity-induced membrane depolarization in coronary artery smooth muscle.
Single Amino Acid Residue in the Extracellular Portion of Transmembrane Segment 2 in the Nicotinic α7 Acetylcholine Receptor Modulates Sensitivity to Ketamine
Authors: Ho Kenny K. , Flood Pamela
Published: February 2004

Background

Ketamine inhibits the activation of both heteromeric and homomeric nicotinic acetylcholine receptors. The site of molecular interaction is unknown.

Methods

The inhibition of alpha7 nicotinic acetylcholine receptors by ketamine was compared to that of 5-hydroxytryptamine-3A (5HT3A) receptors that are resistant to ketamine inhibition in Xenopus laevis oocytes. To determine whether the region of transmembrane segments 2 and 3 is relevant for ketamine inhibition of nicotinic receptors, the authors identified single amino acid residues that differ in the sequence alignment of the two proteins. They created 22 mutant alpha7 nicotinic receptors that contain the single homologous amino acid residue in the 5HT3A sequence.

Results

Of the 22 mutant alpha7 nicotinic receptors tested, only one (alpha7 A258S) was significantly resistant to 20 microM ketamine. The ketamine concentration response relationship for the alpha7 A258S mutant was shifted to the right with the IC50 for ketamine increased from 17 +/- 2 for wild type to 30 +/- 3 microM in the mutant (P < 0.001). Agonist activation was unchanged by the mutation. The homologous amino acid residue in the 5HT3A receptor was mutated to the alanine that occurs in the wild-type nicotinic receptor. This mutation made the previously insensitive 5HT3A receptor sensitive to ketamine (P < 0.001).

Conclusions

Conservative mutation of a single amino acid in the extracellular transmembrane segment 2 domain induces resistance to ketamine inhibition in the alpha7 nicotinic receptor and sensitivity to inhibition in the 5HT3A receptor. This region may represent a ketamine binding site in the alpha7 nicotinic receptor, or it may be an important transduction site for ketamine action.
Isoflurane Inhibits Transmitter Release and the Presynaptic Action Potential
Authors: Wu Xin-Sheng , Sun Jian-Yuan , Evers Alex S. , Crowder Michael , Wu Ling-Gang
Published: February 2004

Background

Isoflurane inhibits the excitatory postsynaptic current (EPSC) at many synapses. Accumulated evidence suggests the involvement of a presynaptic mechanism. However, the extent of the presynaptic contribution has not been quantitatively studied. Furthermore, the mechanism underlying the presynaptic contribution remains unclear.

Methods

To estimate the presynaptic contribution, the authors compared the effects of isoflurane on the presynaptic capacitance jump, which is proportional to vesicle release, and the postsynaptic glutamate receptor-mediated EPSC at a calyx-type synapse in rat brainstem. The authors determined whether isoflurane affects the waveform of the action potential recorded from nerve terminals. By studying the relation between the EPSC and the presynaptic action potential at the same synapse, the authors determined whether isoflurane inhibits the EPSC by decreasing the presynaptic action potential.

Results

Isoflurane at 0.35-1.05 mM reduced the EPSC and the presynaptic capacitance jump to a similar degree without affecting the miniature EPSC (an indicator of quantal size), suggesting that isoflurane inhibits the EPSC predominantly by reducing glutamate release. Isoflurane reduced the presynaptic action potential by approximately 3-8%. The EPSC was proportional to the presynaptic action potential amplitude raised to a power of 10.2. Based on this relation, inhibition of the presynaptic action potential contributed to 62-78% of isoflurane-induced inhibition of the EPSC.

Conclusions

Isoflurane inhibits the EPSC predominantly by inhibition of transmitter release. Isoflurane reduces the presynaptic action potential amplitude, which may contribute significantly to its inhibitory effect on the EPSC.
Peripheral Nerve Injury Sensitizes the Response to Visceral Distension but Not Its Inhibition by the Antidepressant Milnacipran
Authors: Shin Sang-Wook , Eisenach James C.
Published: February 2004

Background

Manipulations that cause hypersensitivity to visceral stimuli have been shown to also result in hypersensitivity to somatic stimuli coming from convergent dermatomes, but the converse has not been examined. The authors tested whether lumbar spinal nerve ligation in rats, a common model of neuropathic pain that results in hypersensitivity to somatic stimuli, also leads to hypersensitivity to visceral stimuli coming from convergent dermatomes and whether pharmacology of inhibition differed between these two sensory modalities.

Methods

Female Sprague-Dawley rats were anesthetized, and the left L5 and L6 spinal nerves were ligated. Animals received either intrathecal saline or milnacipran (0.1-3 microg), and withdrawal thresholds to mechanical testing in the left hind paw, using von Frey filaments, and visceral testing, using balloon colorectal distension, were determined.

Results

Nerve ligation resulted in decreases in threshold to withdrawal to somatic mechanical stimulation (from 13 +/- 1.8 g to 2.7 +/- 0.7 g) and also in decreases in threshold to reflex response to visceral stimulation (from 60 mmHg to 40 mmHg). Intrathecal milnacipran increased withdrawal threshold to somatic stimulation in a dose-dependent manner but failed to alter the response to noxious visceral stimulation.

Conclusions

Injury of nerves innervating somatic structures enhances nociception from stimulation of viscera with convergent input from nearby dermatomes, suggesting that somatic neuropathic pain could be accompanied by an increased likelihood of visceral pain. Lack of efficacy of the antidepressant milnacipran against visceral stimuli suggests that visceral hypersensitivity may not share the same pharmacology of inhibition as somatic hypersensitivity after nerve injury.
Synergistic Antinociceptive Effect of Amitriptyline and Morphine in the Rat Orofacial Formalin Test
Authors: Luccarini Philippe , Perrier Laurent , Dégoulange Céline , Gaydier Anne-Marie , Dallel Radhouane
Published: February 2004

Background

Combination therapy is often used to increase the clinical utility of analgesic agents. The coadministration of two compounds may achieve analgesia at doses lower than those required for either compound alone, leading to enhanced pain relief and reduction of adverse effects. Herein, the authors describe the effect of coadministration of morphine and amitriptyline on cutaneous orofacial inflammatory pain in rats.

Methods

Amitriptyline, morphine, or the combination of amitriptyline and morphine was administered systemically to rats, and antinociceptive effects were determined by means of the rat orofacial formalin test. Isobolographic analysis was used to define the nature of the interactions between morphine and amitriptyline.

Results

Amitriptyline as well as morphine produced a dose-related inhibition in the first phase and the second phase of rubbing activity. ED50 values against rubbing behavior were 14.6 mg/kg (95% confidence interval, 10.2-33.5 mg/kg) and 1.3 mg/kg (95% confidence interval, 1.0-1.7 mg/kg) for amitriptyline and morphine, respectively. Combinations of increasing fractional increments of amitriptyline and morphine ED50 doses produced a synergistic effect against rubbing behavior, as revealed by isobolographic analysis.

Conclusions

The current study suggests that systemic amitriptyline and morphine synergistically inhibit cutaneous orofacial inflammatory pain in rats.
Human β‐defensin‐2 functions as a chemotactic agent for tumour necrosis factor‐α‐treated human neutrophils
Authors: Niyonsaba François , Ogawa Hideoki , Nagaoka Isao
Published: February 2004

Neutrophils are the effector cells in both innate and adaptive immunity, where they perform the functions of phagocytosis and killing of bacteria. They respond to a large number of chemoattractants, but their response to epithelial cell‐derived human β‐defensins (hBD) has not been investigated. Here we report that hBD‐2, but not hBD‐1, is a specific chemoattractant for tumour necrosis factor (TNF)‐α‐treated human neutrophils. The optimal concentration required for maximal chemotactic activity was 5 µg/ml. The effect of hBD‐2 on neutrophils was dependent on the G‐protein‐phospholipase C pathway, as demonstrated by inhibition by pertussis toxin and U‐73122. In addition, ligand‐receptor analysis indicated that the binding of hBD‐2 was markedly inhibited by macrophage inflammatory protein (MIP)‐3α, a specific and unique ligand for CCR6. Furthermore, anti‐CCR6 antibody could almost completely suppress the cell migration induced by hBD‐2, suggesting that hBD‐2 mainly utilizes CCR6 as a functional receptor. Thus, our finding that hBD‐2 is a potent chemoattractant for human neutrophils through specific receptors provides a novel mechanism by which this peptide contributes to the host defence system by recruiting neutrophils to inflammation/infection sites. This also suggests an important link between epithelial cell‐derived antibacterial peptides and neutrophils during infection or inflammation.
Expression of matrix metalloproteinases and their inhibitors during the resorption of schistosome egg‐induced fibrosis in praziquantel‐treated mice
Authors: Singh Kameshwar P. , Gerard Herve C. , Hudson Alan P. , Boros Dov L.
Published: February 2004

Schistosomiasis mansoni is a tropical helminthic disease characterized by parasite egg‐induced granulomatous inflammation and cumulative fibrosis. Because fibrosis is influenced by the imbalance between degradative matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), we analysed the resorption of fibrous tissue and MMP/TIMP expression in the livers of S. mansoni‐infected and praziquantel‐cured mice. Worm elimination significantly enhanced survival rate, ameliorated the granulomatous pathology and reduced collagen I, III and IV gene expression at 6 and 12 months post‐treatment. Compared to 6 months infected, untreated controls, liver fibrous tissue was resorbed by 71·4% at 12 months after treatment. At 3 months post‐treatment, expression of the MMP‐2, ‐3, ‐8, ‐10, ‐13, ‐14 and ‐16 genes decreased compared with untreated controls. By 6 months, a highly significant increase in MMP‐10 gene expression was manifest. At 12 months, messages for all MMP genes decreased in relation to untreated controls. TIMP‐1, ‐2 and ‐3 gene expression drastically decreased between 3 and 6 months. At 1 year, only TIMP‐1 expression was significantly diminished. Overall, profibrogenic tumour necrosis factor (TNF)‐α, transforming growth factor (TGF)‐β and inducible nitric oxide synthase (iNOS) gene expression decreased. Antigen‐stimulated splenocytes secreted significantly higher levels of interleukin (IL)‐4, IL‐5, IL‐10 and IL‐13 cytokines between 3 and 12 months after treatment. Production of interferon (IFN)‐γ was higher than in untreated controls 3 and 6 months after treatment. In conclusion, praziquantel‐treated mice showed a slow resorption of liver fibrous tissue. Resorption is attributed to the precipitous drop in TIMP‐1 gene expression level, which shifted the balance in favour of MMP message expression and presumed enhanced collagenase activity.
Early delayed‐type hypersensitivity eosinophil infiltrates depend on T helper 2 cytokines and interferon‐γ via CXCR3 chemokines
Authors: Akahira‐Azuma Moe , Szczepanik Marian , Tsuji Ryohei F. , Campos Regis A. , Itakura Atsuko , Mobini Narciss , McNiff Jennifer , Kawikova Ivana , Lu Bao , Gerard Craig , Pober Jordan S. , Askenase Philip W.
Published: February 2004

We investigated the role of T helper (Th)1‐ and Th2‐type cytokines in delayed‐type hypersensitivity to soluble protein antigens elicited early postimmunization. Mice were sensitized by intradermal injection without adjuvants, or subcutaneously with complete Freund's adjuvant, and subsequently ear challenged intradermally. As soon as day 3, antigen‐specific eosinophil‐rich responses were elicited in wild‐type mice, but not in T‐cell receptor‐α–/– mice without adjuvant. Draining lymph node T cells stimulated with antigen secreted interleukin (IL)‐4, IL‐5 and interferon‐γ (IFN‐γ). IFN‐γ‐dependent specific immunoglobulin G (IgG)2a and IL‐4‐dependent IgG1 were also generated. Delayed‐type hypersensitivity ear swelling and local eosinophil recruitment were decreased in IL‐5–/–, IL‐4–/– and signal transducer and activator of transcription‐6 (STAT‐6)–/– mice, and with anti‐IL‐4 treatment of wild‐type mice, suggesting Th2 mechanisms. Interestingly, responses were also decreased in IFN‐γ–/– mice, and IFN‐γ protein and the IFN‐γ‐inducible CXC chemokine, IP‐10, were present in 24‐hr ear tissue extracts, suggesting Th1 effects. Finally, ear swelling, total histology and eosinophils were decreased in mice deficient in CXCR3, the chemokine receptor for IP‐10. These results suggest that both a Th2‐like (IL‐5, IL‐4 and STAT‐6) and a Th1‐like (IFN‐γ, IP‐10, CXCR3) pathway contribute to eosinophil recruitment in early delayed‐type hypersensitivity.