bluuebunny/crossref_metadata_2025 huggingface dataset:
Exogeneity within the M2 Demand Function: Evidence from a Large Macroeconomic System
Authors: Schmidt Martin B.
Published: August 2004

A large body of literature investigates whether a stable and predictable long‐run association between money and its arguments exists. One point of variation between models is whether to include an interest rate measure directly within the long‐run relationship. Several recent studies indicate that empirical findings are sensitive to the choice. Therefore, the present article reexamines the empirical significance of the interest rate within a four‐equation macroeconomic system. The results suggest that the interest rate (1) may be excluded from the M2 demand function, (2) is strongly exogenous to most of the system's remaining variables, and (3) may represent a common trend.
Does Asymmetry of International Shocks Matter for the U.S. Business Cycle?
Authors: Gamber Edward N. , Hung Juann H.
Published: August 2004

This article proposes and investigates the asymmetry hypothesis, which predicts that an international asymmetric shock tends to have a stronger and longer effect on the U.S. business cycle than a symmetric shock. The hypothesis finds empirical support in the impulse responses of U.S. output and inflation to symmetric and asymmetric shocks; those responses are estimated in a four‐variable structural vector autoregression. The hypothesis also finds support in stylized facts: The longest U.S. expansions have tended to occur when the rest of the world was growing below potential.
Time Preference and Life Cycle Consumption with Endogenous Survival
Authors: Acharya Arnab K. , Balvers Ronald J.
Published: August 2004

We provide a structural theory of time preference and derive a functional form of intertemporal preferences by postulating that individuals make their life‐cycle consumption choices as if to maximize expected lifetime. This yields a nontime‐separable expected utility representation where the inverse of the coefficient of intertemporal substitution exceeds the coefficient of relative risk aversion. The rate of time preference depends on the inverse of expected remaining lifetime and the effect of age on the productivity of consumption in affecting health. The preference formulation is applied in a standard intertemporal consumption model to illustrate the implied life‐cycle consumption choices (JEL D91, B41).
Two‐Player Asymmetric Contests with Ratio‐Form Contest Success Functions
Authors: Baik Kyung Hwan
Published: August 2004

I examine players' equilibrium effort levels in two‐player asymmetric contests with ratio‐form contest success functions. I first characterize the Nash equilibrium of the simultaneous‐move game. I show that the equilibrium effort ratio is equal to the valuation ratio, and that the prize dissipation ratios for the players are the same. I also show that the prize dissipation ratio for each player is less than or equal to the minimum of the players' probabilities of winning at the Nash equilibrium and thus never exceeds a half. Then I examine how the equilibrium effort ratio, the prize dissipation ratios, and the players' equilibrium effort levels respond when the players' valuations for the prize or their abilities change.
The Economics of the Counter‐Reformation: Incumbent‐Firm Reaction to Market Entry
Authors: Ekelund Robert B. , Hebert Robert F. , Tollison Robert D.
Published: August 2004

The Catholic Church reacted to the Protestant Reformation by taking on the defensive posture of an incumbent‐firm monopoly fighting to survive in the face of new competition. Contemporary firms typically respond to rival entry by rewriting their corporate charter. So did the medieval Catholic Church. But the Council of Trent failed as a reorganization plan because to keep economic rents flowing as before, it left intact the distribution of powers and property rights among the governing body of pope and cardinals—thus demonstrating that entrenched economic interests are powerful inducements to behavior, even in spiritual institutions.
On the Internal Contradictions of the Law of One Price
Authors: McChesney Fred S. , Shughart William F. , Haddock David D.
Published: August 2004

As stated originally, the venerable law of one price succinctly describes long‐run equilibrium in a perfectly competitive market. The law was later amended, defining a market as the geographic area within which the same thing sells for the same price at the same time, allowance being made for transportation costs. Modified in that way, the law has two plausible interpretations. By one interpretation, every production site is a market. By the other, prices in fact do not differ by transportation costs. The transportation‐cost amendment thus introduces internal contradictions that render the revised law of one price either useless or wrong.
Introduction to the Special Issue
Authors: Gill Jeff
Published: August 2004

Welcome to the special issue ofPolitical Analysisdedicated to Bayesian methods. We hope that you enjoy the varied and interesting contributions herein featuring Bayesian statistical methods. For many people in empirical political science, Bayesian statistics seems like a weird offshoot of probability that surfaces occasionally in journals and books but does not occupy a particularly central role. This perception appears to be changing. In fact, it appears to be changing quite rapidly. The purpose of this issue is to support and accelerate this momentum by further demonstrating the full flexibility and power of Bayesian methodology.
Bayesian Factor Analysis for Mixed Ordinal and Continuous Responses
Authors: Quinn Kevin M.
Published: August 2004

Many situations exist in which a latent construct has both ordinal and continuous indicators. This presents a problem for the applied researcher because standard measurement models are not designed to accommodate mixed ordinal and continuous data. I address this problem by formulating a measurement model that is appropriate for such mixed multivariate responses. This model unifies standard normal theory factor analysis and item response theory models for ordinal data. I detail a Markov chain Monte Carlo algorithm for model fitting. I apply the model to cross-national data on political-economic risk and find that the model works well. Software for fitting this model is publicly available in theMCMCpack(Martin and Quinn 2004, “MCMCpack 0.4–8”)Rpackage.
Bayesian Multilevel Estimation with Poststratification: State-Level Estimates from National Polls
Authors: Park David K. , Gelman Andrew , Bafumi Joseph
Published: August 2004

We fit a multilevel logistic regression model for the mean of a binary response variable conditional on poststratification cells. This approach combines the modeling approach often used in small-area estimation with the population information used in poststratification (see Gelman and Little 1997,Survey Methodology23:127–135). To validate the method, we apply it to U.S. preelection polls for 1988 and 1992, poststratified by state, region, and the usual demographic variables. We evaluate the model by comparing it to state-level election outcomes. The multilevel model outperforms more commonly used models in political science. We envision the most important usage of this method to be not forecasting elections but estimating public opinion on a variety of issues at the state level.
Simple Bayesian Inference for Qualitative Political Research
Authors: Buckley Jack
Published: August 2004

In political science and related disciplines in the social and behavioral sciences, there exists an unfortunate de facto divide between qualitative and quantitative empirical research. Sometimes this divide is purely a function of training and disciplinary socialization, but often it reflects a valid dispute over the philosophical foundations of inquiry. I argue here that the Bayesian approach to quantitative empirical modeling is an amenable starting point for building a rapprochement between qualitative and quantitative research, and I introduce as an example a straightforward model that allows for the Bayesian estimation of the difference between means of very small samples with unknown and possibly unequal variances. I then extend this approach to consider nonnormal variates, informative priors, and a multivariate test of the difference of means useful for the researcher who is interested in determining whether two small samples are different on several dimensions simultaneously.
Effects of Short-term Fenoldopam Infusion on Gastric Mucosal Blood Flow in Septic Shock
Authors: Morelli Andrea , Rocco Monica , Conti Giorgio , Orecchioni Alessandra , De Gaetano Andrea , Coluzzi Flaminia , Vernaglione Enrico , Pelaia Paolo , Pietropaoli Paolo
Published: August 2004

Background

Inadequate splanchnic perfusion in septic shock is associated with increased morbidity and mortality. As result of splanchnic ischemia, mucosal permeability increases. Considering the implication of improved mucosal perfusion in terms of maintenance of mucosal barrier integrity, dopamine-1 receptor stimulation could be helpful in septic shock. The goal of the current study was to determine the effects of fenoldopam on systemic hemodynamic parameters and gastric mucosal perfusion in patients with septic shock. Furthermore, the authors tested the hypothesis that the addition of fenoldopam (0.1 microg x kg(-1) x min(-1)) to a combination of norepinephrine and dobutamine (5 microg x kg(-1) x min(-1)) may improve gastric mucosal perfusion in septic shock.

Methods

Patients with septic shock were randomized to a double-blind 2-h infusion of fenoldopam (n = 20) or placebo (n = 20). Each group received dobutamine (5 microg x kg(-1) x min(-1)), and the dosage of norepinephrine was adjusted to achieve a mean arterial pressure between 70 and 80 mmHg. A laser-Doppler probe and tonometer were introduced into the gastric lumen.

Results

A significant increase in gastric mucosal perfusion, detected by laser-Doppler flowmetry, was observed in the group treated with fenoldopam (P < 0.05). In addition, this increase in microcirculatory flow occurred despite the fact that systemic flow remained unchanged. Differences in gastroarterial partial pressure of carbon dioxide values were not statistically significant in the fenoldopam and placebo groups.

Conclusions

The study showed that, for the same mean arterial pressure, short-term fenoldopam infusion increased gastric mucosal perfusion in patients with septic shock.
A New Closed-Loop Control System for Isoflurane Using Bispectral Index Outperforms Manual Control
Authors: Locher Stephan , Stadler Konrad S. , Boehlen Thomas , Bouillon Thomas , Leibundgut Daniel , Schumacher Peter M. , Wymann Rolf , Zbinden Alex M.
Published: August 2004

Background

Automatic control of depth of hypnosis using the Bispectral Index (BIS) can help to reduce phases of inadequate control. Automated BIS control with propofol or isoflurane administration via an infusion system has recently been described, a comparable study with isoflurane administration via a vaporizer had not been conducted yet. Our hypothesis was that our new model based closed-loop control system can safely be applied clinically and maintains the BIS within a defined target range better than manual control.

Methods

Twenty-three patients, American Society of Anesthesiologists risk class I-III, scheduled for decompressive spinal surgery were randomized into groups with either closed-loop or manual control of BIS using isoflurane. An alfentanil target-controlled infusion was adjusted according to standard clinical practice. The BIS target was set to 50 during the operation. The necessity of human intervention in the control system and events of inadequate sedation (BIS <40 or BIS >60) were counted. The number of phases of inadequate control, defined as BIS >/=65 for more than 3 min, were recorded. The performance of the controller was assessed by several indicators (mean absolute deviation and median absolute performance error) and measured during the skin incision phase, the subsequent low flow phase, and the wound closure phase. Recovery profiles of both groups were compared.

Results

No human intervention was necessary in the closed-loop control group. The occurrence of inadequate BIS was quantified with the mean and median values of the area under the curve and amounted to 0.360 and 0.088 for the manual control group and 0.049 and 0.017 for the closed-loop control group, respectively. In the manual control group nine phases of inadequate control were recorded, compared with one in the closed-loop control group, 10.3% to 0.5% of all observed anesthesia time. During all phases the averages of the performance parameters (mean absolute deviation and median absolute performance error) were more than 30% smaller in closed-loop control than in manual control (P < 0.05 between groups).

Conclusions

Closed-loop control with BIS using isoflurane can safely be applied clinically and performs significantly better than manual control, even in phases with abrupt changes of stimulation that cannot be foreseen by the control system.
Retrograde Air Embolization during Routine Radial Artery Catheter Flushing in Adult Cardiac Surgical Patients
Authors: Murphy Glenn S. , Szokol Joseph W. , Marymont Jesse H. , Avram Michael J. , Vender Jeffery S.
Published: August 2004

Background

Rapid flushing of radial artery catheters may result in retrograde embolization of air into the cerebral circulation. This study examined the incidence of central air embolization during and after flushing of an arterial pressure monitoring system.

Methods

One hundred adult patients undergoing cardiac surgical procedures were enrolled in this study. Ten ml of saline and blood were withdrawn into a syringe in the arterial flushing-sampling pressure system and then readministered to the patient through a 20-gauge radial artery catheter over 3-12 s. The right carotid artery, left carotid artery, and aortic arch were visualized using ultrasound imaging techniques during three manual flushes of the system. The left and right common carotid arteries were examined for the presence of macrobubbles or microbubbles using a linear array ultrasound transducer. The aortic arch was imaged using transesophageal echocardiography to detect retrograde air emboli. The severity of air embolization was quantified using a modification of an established grading system.

Results

A total of 298 ultrasound studies in 100 patients were recorded and analyzed after radial artery catheter flushing. Two aortic arch images were not obtained because of an inability to place the probe. Most clinicians (54%) returned flush solution to patients at near-maximal injection rates (2-3 ml per second). No air emboli (macrobubbles or microbubbles) were detected in the carotid arteries or aortic arch of any subject.

Conclusion

Retrograde air embolization is a rare event after routine radial artery catheter flushing in adult patients with stable hemodynamic conditions.
Recruitment Maneuvers after a Positive End-expiratory Pressure Trial Do Not Induce Sustained Effects in Early Adult Respiratory Distress Syndrome
Authors: Oczenski Wolfgang , Hörmann Christoph , Keller Christian , Lorenzl Norbert , Kepka Anton , Schwarz Sylvia , Fitzgerald Robert D.
Published: August 2004

Background

Recruitment maneuvers performed in early adult respiratory distress syndrome remain a matter of dispute in patients ventilated with low tidal volumes and high levels of positive end-expiratory pressure (PEEP). In this prospective, randomized controlled study the authors evaluated the impact of recruitment maneuvers after a PEEP trial on oxygenation and venous admixture (Qs/Qt) in patients with early extrapulmonary adult respiratory distress syndrome.

Methods

After a PEEP trial 30 consecutive patients ventilated with low tidal volumes and high levels of PEEP were randomly assigned to either undergo a recruitment maneuver or not. Data were recorded at baseline, 3 min after the recruitment maneuver, and 30 min after baseline. Recruitment maneuvers were performed with a sustained inflation of 50 cm H2O maintained for 30 s.

Results

Compared with baseline the ratio of the arterial oxygen partial pressure to the fraction of inspired oxygen (Pao2/Fio2) and Qs/Qt improved significantly at 3 min after the recruitment maneuver (Pao2/Fio2, 139 +/- 46 mm Hg versus 246 +/- 111 mm Hg, P < 0.001; Qs/Qt, 30.8 +/- 5.8% versus 21.5 +/- 9.7%, P < 0.005), but baseline values were reached again within 30 min. No significant differences in Pao2/Fio2 and Qs/Qt were detected between the recruitment maneuver group and the control group at baseline and after 30 min (recruitment maneuver group [n = 15]: Pao2/Fio2, 139 +/- 46 mm Hg versus 138 +/- 39 mm Hg; Qs/Qt, 30.8 +/- 5.8% versus 29.2 +/- 7.4%; control group: [n = 15]: Pao2/Fio2, 145 +/- 33 mm Hg versus 155 +/- 52 mm Hg; Qs/Qt, 30.2 +/- 8.5% versus 28.1 +/- 5.4%).

Conclusion

In patients with early extrapulmonary adult respiratory distress syndrome who underwent a PEEP trial, recruitment maneuvers failed to induce a sustained improvement of oxygenation and venous admixture.
Remifentanil versus Morphine Analgesia and Sedation for Mechanically Ventilated Critically Ill Patients
Authors: Dahaba Ashraf A. , Grabner Tanja , Rehak Peter H. , List Werner F. , Metzler Helfried
Published: August 2004

Background

The rapid onset and offset of action of remifentanil could make it quickly adjustable to the required level of sedation in critically ill patients. The authors hypothesized that the efficacy of a remifentanil-based regimen was greater than that of a morphine-based regimen.

Methods

Forty intent-to-treat patients were randomly allocated to receive a blinded infusion of either remifentanil 0.15 microg x kg(-1) x min(-1) or morphine 0.75 microg x kg(-1) x min(-1). The opioid infusion was titrated, in the first intent, to achieve optimal sedation defined as Sedation Agitation scale of 4. A midazolam open-label infusion was started if additional sedation was required.

Results

The mean percentage hours of optimal sedation was significantly longer in the remifentanil group (78.3 +/- 6.2) than in the morphine group (66.5 +/- 8.5). This was achieved with less frequent infusion rate adjustments (0.34 +/- 0.25 changes/h) than in the morphine group (0.42 +/- 0.22 changes/h). The mean duration of mechanical ventilation and extubation time were significantly longer in the morphine group (18.1 +/- 3.4 h, 73 +/- 7 min) than in the remifentanil group (14.1 +/- 2.8 h, 17 +/- 6 min), respectively. Remifentanil mean infusion rate was 0.13 +/- 0.03 microg x kg(-1) x min(-1), whereas morphine mean infusion rate was 0.68 +/- 0.28 microg x kg(-1) x min(-1). More subjects in the morphine group (9 of 20) than in the remifentanil group (6 of 20) required midazolam. The incidence of adverse events was low and comparable across the two treatment groups.

Conclusions

A remifentanil-based regimen was more effective in the provision of optimal analgesia-sedation than a standard morphine-based regimen. The remifentanil-based regimen allowed a more rapid emergence from sedation and facilitated earlier extubation.
Inhibitory Effect of Glucocorticoids on Human-cloned 5-hydroxytryptamine3AReceptor Expressed in Xenopus Oocytes
Authors: Suzuki Takahiro , Sugimoto Masahiro , Koyama Hideki , Mashimo Takashi , Uchida Ichiro
Published: August 2004

Background

Methylprednisolone, dexamethasone, and other glucocorticoids have been found effective against nausea and vomiting induced by chemotherapy and surgery. Although the specific 5-hydroxytriptamine3 (5-HT3) receptor antagonists such as ondansetron and ramosetron are used as antiemetics, reports show that the use of 5-HT3 receptor antagonists with some glucocorticoids brings additional effects. Glucocorticoids are reported to be antiemetic. The effect of glucocorticoids on 5-HT3 receptor, however, has not been well characterized. This study was designed to examine whether dexamethasone and methylprednisolone had direct effects on human-cloned 5-HT3A receptor expressed in Xenopus oocytes.

Methods

Homomeric human-cloned 5-HT3A receptor was expressed in Xenopus oocytes. The authors used the two-electrode voltage-clamping technique to study the effect of methylprednisolone and dexamethasone on 5-HT-induced current.

Results

Both dexamethasone and methylprednisolone concentration-dependently attenuated 5-HT-induced current. Dexamethasone inhibited 2 microm 5-HT-induced current, which was equivalent to EC30 concentration for 5-HT3A receptor, with an inhibitory concentration 50% of 5.29 +/- 1.02 microm. Methylprednisolone inhibited 2 microm 5-HT-induced current with an inhibitory concentration 50% of 1.07 +/- 0.15 mm. The mode of inhibition with either dexamethasone or methylprednisolone was noncompetitive and voltage-independent. When administered together with the 5-HT3 receptor antagonists, ramosetron or metoclopramide, both glucocorticoids showed an additive effect on 5-HT3 receptor.

Conclusion

The glucocorticoids had a direct inhibitory effect on 5-HT3 receptors. The combined effect of glucocorticoids and the 5-HT3 receptor antagonists seems additive.
Effects of Isoflurane and Sevoflurane on Intracellular Calcium and Contractility in Pressure-overload Hypertrophy
Authors: Hannon James D. , Cody Mark J. , Sun David X. , Housmans Philippe R.
Published: August 2004

Background

Depression of myocardial contractility as a result of isoflurane appears to be greater in myocardial hypertrophy, and the cellular basis for this difference in susceptibility is not clear. In this study we examined the effects of isoflurane and sevoflurane on contractility and intracellular calcium in an animal model of pressure-overload hypertrophy.

Methods

Pressure-overload hypertrophy was established in young male ferrets by banding the main pulmonary artery for 1 month and the effects of isoflurane and sevoflurane on contractility and intracellular calcium ([Ca]i) were examined in isolated right ventricular papillary muscles, trabeculae, and myocytes. Intracellular calcium was measured with the bioluminescent photoprotein aequorin in isolated papillary muscles, and also with the fluorescent indicator fluo-3 in isolated ventricular myocytes. In addition, Ca sensitivity was assessed in isolated trabeculae after disruption of the surface membrane with a nonionic detergent (skinned fibers).

Results

In the presence of isoflurane and sevoflurane, papillary muscles from banded animals exhibited a greater depression of contractility and isolated ventricular myocytes showed a greater decrease in peak [Ca]i. Furthermore, baseline calcium sensitivity was decreased and the slope of the relationship between [Ca] and force was increased in skinned trabeculae from banded animals. Isoflurane decreased calcium sensitivity in trabeculae from both normal and banded animals.

Conclusions

These results suggest that changes in [Ca]i and altered calcium sensitivity are both responsible for the exaggerated effects of some volatile anesthetics on contractility in pressure-overload hypertrophy.
Inhibitory Effects of the Anesthetics Propofol and Sevoflurane on Spontaneous Lymphatic Vessel Activity in Rats
Authors: Hattori Jun-Ichi , Yamakage Michiaki , Seki Sumihiko , Okazaki Kayoko , Namiki Akiyoshi
Published: August 2004

Background

The effects of propofol and sevoflurane on lymphatic vessel activity are unknown. This study aimed to clarify the effects of these anesthetics on lymphatic vessel activity in rats by the use of a technique for mechanical removal of the endothelium.

Methods

The authors first examined the effects of propofol (8 mg/kg) and sevoflurane (2.0%) on in vivo lymphatic flow by injection of dye into the femoral regions of rats. In the in vitro study, the ends of the vessel segments of rat thoracic duct were connected to a syringe and stopcock, respectively. Spontaneous changes in diameter of each segment were monitored, and the extraluminal side of each segment was exposed to propofol (1 x 10(-6) approximately 3 x 10(-5) M) or sevoflurane (0.5 approximately 2.0%). Endothelial function was eliminated by perfusion of air into the lumen.

Results

In the dye uptake study, 80% of iliac lymphatic nodes were positively stained in a control group, whereas only 10% and 20% were positively stained in propofol and sevoflurane groups, respectively. In the in vitro study, both of the anesthetics significantly decreased the amplitude of spontaneous activity of lymphatic vessels with or without endothelial function. Sevoflurane inhibited the frequency of lymphatic vessel activity but propofol had no effect on it. When the endothelial function was eliminated, both anesthetics decreased the frequency of spontaneous activity of lymphatic vessels.

Conclusions

Propofol and sevoflurane seem to have some different effects on endothelial function, which regulates the pacemaking of spontaneous contraction of lymphatic vessels.
Isoflurane Preconditioning Induces Neuroprotection That Is Inducible Nitric Oxide Synthase–dependent in Neonatal Rats
Authors: Zhao Ping , Zuo Zhiyi
Published: August 2004

Background

Perinatal stroke is a common human disease. Neonatal brains are immature and engaged in active synaptogenesis. Preconditioning adult rats with the volatile anesthetic isoflurane induces neuroprotection. Whether isoflurane preconditioning induces neuroprotection in neonates is not known.

Methods

Seven-day-old Sprague-Dawley rats had left common carotid arterial ligation followed by hypoxia with 8% oxygen for 1, 2, or 2.5 h at 37 degrees C. Isoflurane preconditioning with 1 or 1.5% isoflurane for 30 min was performed at 24 h before the brain hypoxia/ischemia. The inducible nitric oxide synthase inhibitor aminoguanidine (200 mg/kg, intraperitoneally) was administered 30 min before the isoflurane pretreatment. The weight ratio of left to right cerebral hemispheres at 7 days after the brain hypoxia/ischemia was calculated. The mortality during the period from cerebral hypoxia/ischemia to 7 days afterwards was monitored. In another experiment, 6-day-old rats were exposed to 1.5% isoflurane for 30 min. The cerebral hemispheres were removed at various time points for Western analysis of inducible nitric oxide synthase.

Results

The mortality was about 40% in neonates with brain hypoxia/ischemia for 2 h or 2.5 h and was not altered by isoflurane preconditioning. The weight ratio of left/right cerebral hemispheres in the survivors was 0.99 +/- 0.02, 0.65 +/- 0.19, and 0.86 +/- 0.15 (n = 7-18) for the rats in control, brain hypoxia/ischemia for 2.5 h, and isoflurane preconditioning plus brain hypoxia/ischemia for 2.5 h groups, respectively (P < 0.05 for the comparisons between control versus brain hypoxia/ischemia and brain hypoxia/ischemia versus isoflurane preconditioning plus brain hypoxia/ischemia). This isoflurane preconditioning-induced neuroprotection was abolished by aminoguanidine (the weight ratio was 0.61 +/- 0.18, n = 12). Isoflurane induced a time-dependent increase in the inducible nitric oxide synthase proteins.

Conclusions

Isoflurane preconditioning induces neuroprotection in neonatal rats. This neuroprotection is inducible nitric oxide synthase-dependent.
Inhaled Anesthetic Enhancement of Amyloid-β Oligomerization and Cytotoxicity
Authors: Eckenhoff Roderic G. , Johansson Jonas S. , Wei Huafeng , Carnini Anna , Kang Baobin , Wei Wenlin , Pidikiti Ravindernath , Keller Jason M. , Eckenhoff Maryellen F.
Published: August 2004

Background

The majority of surgical patients receive inhaled anesthetics, principally small haloalkanes and haloethers. Long-term cognitive problems occur in the elderly subsequent to anesthesia and surgery, and previous surgery might also be a risk factor for neurodegenerative disorders like Alzheimer and Parkinson disease. The authors hypothesize that inhaled anesthetics contribute to these effects through a durable enhancement of peptide oligomerization.

Methods

Light scattering, filtration assays, electron microscopy, fluorescence spectroscopy and size-exclusion chromatography was used to characterize the concentration-dependent effects of halothane, isoflurane, propofol, and ethanol on amyloid beta peptide oligomerization. Pheochromocytoma cells were used to characterize cytotoxicity of amyloid oligomers with and without the above anesthetics.

Results

Halothane and isoflurane enhanced amyloid beta oligomerization rates and pheochromocytoma cytotoxicity in vitro through a preference for binding small oligomeric species. Ethanol and propofol inhibited oligomerization at low concentration but enhanced modestly at very high concentration. Neither ethanol nor propofol enhanced amyloid beta toxicity in pheochromocytoma cells.

Conclusions

Inhaled anesthetics enhance oligomerization and cytotoxicity of Alzheimer disease-associated peptides. In addition to the possibility of a general mechanism for anesthetic neurotoxicity, these results call for further evaluation of the interaction between neurodegenerative disorders, dementia, and inhalational anesthesia.
Sevoflurane Inhibits Phorbol-Myristate-Acetate-induced Activator Protein-1 Activation in Human T Lymphocytes in Vitro : Potential Role of the p38-Stress Kinase Pathway
Authors: Loop Torsten , Scheiermann Patrick , Doviakue David , Musshoff Frank , Humar Matjaz , Roesslein Martin , Hoetzel Alexander , Schmidt Rene , Madea Burkhard , Geiger Klaus K. , Pahl Heike L. , Pannen Benedikt H. J.
Published: August 2004

Background

Modulation of immune defense mechanisms by volatile anesthetics during general anesthesia may compromise postoperative immune competence and healing reactions and affect the infection rate and the rate of tumor metastases disseminated during surgery. Several mechanisms have been suggested to account for these effects. The current study was undertaken to examine the molecular mechanisms underlying these observations.

Methods

Effects of sevoflurane, isoflurane, and desflurane were studied in vitro in primary human CD3 T-lymphocytes. DNA-binding activity of the transcription factor activator protein-1 (AP-1) was assessed using an electrophoretic mobility shift assay. Phorbol-myristate-acetate-dependent effects of sevoflurane on the phosphorylation of the mitogen-activated protein kinases were studied using Western blots, the trans-activating potency of AP-1 was determined using reporter gene assays, and the cytokine release was measured using enzyme-linked immunosorbent assays.

Results

Sevoflurane inhibited activation of the transcription factor AP-1. This effect was specific, as the activity of nuclear factor kappabeta, nuclear factor of activated T cells, and specific protein-1 was not altered and several other volatile anesthetics studied did not affect AP-1 activation. Sevoflurane-mediated suppression of AP-1 could be observed in primary CD3 lymphocytes from healthy volunteers, was time-dependent and concentration-dependent, and occurred at concentrations that are clinically achieved. It resulted in an inhibition of AP-1-driven reporter gene activity and of the expression of the AP-1 target gene interleukin-3. Suppression of AP-1 was associated with altered phosphorylation of p38 mitogen-activated protein kinases.

Conclusion

The data demonstrate that sevoflurane is a specific inhibitor of AP-1 and may thus provide a molecular mechanism for the antiinflammatory effects associated with sevoflurane administration.
Influence of Hepatic and Intestinal Cytochrome P4503A Activity on the Acute Disposition and Effects of Oral Transmucosal Fentanyl Citrate
Authors: Kharasch Evan D. , Whittington Dale , Hoffer Christine
Published: August 2004

Background

Oral transmucosal fentanyl citrate (OTF) was developed to provide rapid analgesia and is specifically approved for treating breakthrough cancer pain. Fentanyl in OTF is absorbed across the oral mucosa, but a considerable portion is swallowed and absorbed enterally. Fentanyl metabolism is catalyzed by cytochrome P4503A4 (CYP3A). The role of intestinal or hepatic first-pass metabolism and CYP3A activity in OTF disposition is unknown. This investigation examined the influence of hepatic and intestinal CYP3A activity on the disposition and clinical effects of OTF.

Methods

Healthy volunteers (n = 12) were studied in an Institutional Review Board-approved, randomized, balanced, four-way crossover. They received OTF (10 microg/kg) after hepatic/intestinal CYP3A induction by rifampin, hepatic/intestinal CYP3A inhibition by troleandomycin, selective intestinal CYP3A inhibition by grapefruit juice, or nothing (control). Plasma fentanyl and norfentanyl concentrations were determined by mass spectrometry. Fentanyl effects were measured by dark-adapted pupil diameter and subjective self-assessments using visual analog scales.

Results

: Peak plasma fentanyl concentrations, time to peak, and maximum pupil diameter change from baseline were unchanged after rifampin, troleandomycin, and grapefruit juice. Fentanyl elimination, however, was significantly affected by CYP3A alterations. After control, rifampin, troleandomycin and grapefruit juice, respectively, area under the curve of plasma fentanyl versus time was 5.9 +/- 3.7, 2.2 +/- 0.8,* 10.4 +/- 8.9,* and 5.8 +/- 3.3 h x ng/ml; norfentanyl/fentanyl plasma area under the curve ratios were 0.92 +/- 0.63, 3.2 +/- 1.8,* 0.08 +/- 0.14,* and 0.67 +/- 0.33 (*P < 0.05 versus control).

Discussion

Peak fentanyl concentrations and clinical effects after OTF were minimally affected by altering both intestinal and hepatic CYP3A activity, whereas fentanyl metabolism, elimination, and duration of effects were significantly affected; selective intestinal CYP3A inhibition had minimal effects. This suggests that first-pass metabolism minimally influences OTF bioavailability. When treating breakthrough pain, with careful attention to maximal mucosal absorption and minimal swallowing, CYP3A variability and drug interactions are unlikely to affect the onset or magnitude of OTF analgesia; however, duration may be affected.
Influence of Age on the Pharmacokinetics and Pharmacodynamics of Oral Transmucosal Fentanyl Citrate
Authors: Kharasch Evan D. , Hoffer Christine , Whittington Dale
Published: August 2004

Background

Cancer pain is primarily a problem of older persons. Oral transmucosal fentanyl citrate (OTF) was developed to provide rapid analgesia and is the first drug specifically approved for treating breakthrough cancer pain. Fentanyl in OTF is absorbed across the oral mucosa but a considerable portion is swallowed and absorbed enterally. The effects of age on OTF pharmacokinetics and pharmacodynamics are unknown. This investigation evaluated OTF disposition and clinical effects in older (60-75 yr) compared with younger (18-40 yr) volunteers.

Methods

Healthy young (26 +/- 6 yr) and older (67 +/- 6 yr) volunteers (n = 12 each) were studied in an Institutional Review Board approved protocol. They received OTF (10 microg/kg). Plasma fentanyl and norfentanyl concentrations were determined by mass spectrometry. Fentanyl effects were measured by dark-adapted pupil diameter and by subjective self-assessments using visual analog scales.

Results

Plasma fentanyl and norfentanyl concentrations and pharmacokinetic parameters did not differ between younger and older subjects. Maximum pupil diameter change from baseline was significantly less in older (3.1 +/- 0.7 mm) compared with younger (4.5 +/- 1.1 mm) subjects (P < 0.05). OTF-dependent subjective assessments of alertness/sedation, energy level, confusion, clumsiness, anxiety, and nausea did not differ in the older subjects.

Discussion

The pharmacokinetics of OTF were not altered in older volunteers. In contrast, there was a somewhat diminished response to the miotic effects of fentanyl in older subjects. No change in OTF dosing in the elderly would appear necessary because of altered pharmacokinetics. If the response to OTF in older patients is similar to that in older volunteers and miosis is representative of analgesia and respiratory depression, then changes in OTF dosing with age alone do not appear indicated.
The Spinal Antinociceptive Effect of Nocistatin in Neuropathic Rats Is Blocked by D-Serine
Authors: Muth-Selbach Uta , Dybek Eva , Kollosche Katrin , Stegmann Jens-Ulrich , Holthusen Holger , Lipfert Peter , Zeilhofer Hanns Ulrich
Published: August 2004

Background

The neuropeptide nocistatin (NST) has been implicated in the modulation of nociceptive responses in the spinal cord. Depending on the dose, both pronociceptive and antinociceptive effects have repeatedly been reported. The pronociceptive effect is most likely attributable to inhibition of synaptic glycine and gamma-aminobutyric acid release and a subsequent reduction in the activation of inhibitory glycine and gamma-aminobutyric acid receptors, but the mechanisms of its antinociceptive action have hitherto remained elusive. It has recently been demonstrated that synaptically released glycine contributes to N-methyl-D-aspartate receptor activation. The authors therefore investigated whether a reduction in glycine release might also account for the antinociceptive action of NST in neuropathic rats.

Methods

The authors analyzed the effects of spinally applied NST in the chronic constriction injury model of neuropathic pain. NST was injected intrathecally from nanomolar to picomolar doses and its effects on thermal paw withdrawal latencies were monitored. Furthermore, we tested whether D-serine (100 microg per rat), a full agonist at the glycine binding site of the N-methyl-D-aspartate receptor, would interfere with the effects of NST.

Results

At high doses (10 nmol/rat), intrathecally injected NST was pronociceptive, whereas lower doses (1 pmol/rat) elicited antinociception. The antinociceptive, but not the pronociceptive, action was occluded by intrathecal pretreatment with D-serine. L-serine, which does not bind to N-methyl-D-aspartate receptors, affected neither the pronociceptive nor the antinociceptive effect.

Conclusions

These results demonstrate that NST produces a biphasic dose-dependent effect on neuropathic pain. The spinal antinociception by NST is most likely attributable to inhibition of glycine-dependent N-methyl-D-aspartate receptor activation.
Successful ageing: from cell to self
Authors: Lupien S. J. , Wan N.
Published: August 2004

Many people see ageing as a time of cognitive and physical decline. For the past three decades, most scientists and the general public have accepted this negative age–stereotype as the norm, but fortunately this view is now challenged. New findings show that well–being and a positive view of ageing are major protective factors against the effects of age on the organism. These results challenge the scientific studies that place emphasis on the negative side of ageing. This ageism view has been observed in each sphere of science, from genetics to social sciences. Perspectives from each domain are described, and new integrative views of successful ageing are summarized.
Organ Polarity in Arabidopsis. NOZZLE Physically Interacts with Members of the YABBY Family
Authors: Sieber Patrick , Petrascheck Michael , Barberis Alcide , Schneitz Kay
Published: August 2004

Plant lateral organs exhibit proximal-distal and adaxial-abaxial polarity. In Arabidopsis, abaxial cell fate is regulated in part by putative transcription factors of the YABBY family, such as FILAMENTOUS FLOWER (FIL) and INNER NO OUTER (INO), by a mechanism that currently is not fully understood. NOZZLE (NZZ) encodes a plant-specific nuclear protein. Genetic evidence has shown that NZZ is involved in the positive feedback regulation of INO, thereby acting both as a temporal and spatial repressor of INO transcription. This mechanism allows the ovule primordium to complete its proximal-distal organization, prior to the onset of adaxial-abaxial development in the chalaza. During our study, we isolated FIL in a yeast two-hybrid screen using NZZ as bait. In vitro pull-down experiments confirmed the NZZ-FIL interaction. NZZ also bound INO and YABBY3, suggesting that NZZ generally interacts with YABBY proteins in vitro. The polar-charged region of NZZ was necessary and sufficient to bind to the zinc finger of INO and to interact with its C terminus carrying the high mobility group-like domain. We suggest that NZZ coordinates proximal-distal patterning and adaxial-abaxial polarity establishment in the developing ovule by directly binding to INO.
Roles for Class III HD-Zip and KANADI Genes in Arabidopsis Root Development
Authors: Hawker Nathaniel P. , Bowman John L.
Published: August 2004

Meristems within the plant body differ in their structure and the patterns and identities of organs they produce. Despite these differences, it is becoming apparent that shoot and root apical and vascular meristems share significant gene expression patterns. Class III HD-Zip genes are required for the formation of a functional shoot apical meristem. In addition, Class III HD-Zip and KANADI genes function in patterning lateral organs and vascular bundles produced from the shoot apical and vascular meristems, respectively. We utilize both gain- and loss-of-function mutants and gene expression patterns to analyze the function of Class III HD-Zip and KANADI genes in Arabidopsis roots. Here we show that both Class III HD-Zip and KANADI genes play roles in the ontogeny of lateral roots and suggest that Class III HD-Zip gene activity is required for meristematic activity in the pericycle analogous to its requirement in the shoot apical meristem.
Graft Transmission of a Floral Stimulant Derived from CONSTANS
Authors: Ayre Brian G. , Turgeon Robert
Published: August 2004

Photoperiod in plants is perceived by leaves and in many species influences the transition to reproductive growth through long-distance signaling. CONSTANS (CO) is implicated as a mediator between photoperiod perception and the transition to flowering in Arabidopsis. To test the role of CO in long-distance signaling, CO was expressed from a promoter specific to the companion cells of the smallest veins of mature leaves. This expression in tissues at the inception of the phloem translocation stream was sufficient to accelerate flowering at the apical meristem under noninductive (short-day) conditions. Grafts that conjoined the vegetative stems of plants with different flower-timing phenotypes demonstrated that minor-vein expression of CO is able to substitute for photoperiod in generating a mobile flowering signal. Our results suggest that a CO-derived signal(s), or possibly CO itself, fits the definition of the hypothetical flowering stimulant, florigen.
Dynamic Changes in the Osmotic Water Permeability of Protoplast Plasma Membrane
Authors: Moshelion Menachem , Moran Nava , Chaumont François
Published: August 2004

The osmotic water permeability coefficient (Pf) of plasma membrane of maize (Zea mays) Black Mexican Sweet protoplasts changed dynamically during a hypoosmotic challenge, as revealed using a model-based computational approach. The best-fitting model had three free parameters: initial Pf, Pf rate-of-change (slopePf), and a delay, which were hypothesized to reflect changes in the number and/or activity of aquaporins in the plasma membrane. Remarkably, the swelling response was delayed 2 to 11 s after start of the noninstantaneous (but accounted for) bath flush. The Pf during the delay was ≤1 μm s−1. During the swelling period following the delay, Pf changed dynamically: within the first 15 s Pf either (1) increased gradually to approximately 8 μm s−1 (in the majority population of low-initial-Pf cells) or (2) increased abruptly to 10 to 20 μm s−1 and then decreased gradually to 3 to 6 μm s−1 (in the minority population of high-initial-Pf cells). We affirmed the validity of our computational approach by the ability to reproduce previously reported initial Pf values (including the absence of delay) in control experiments on Xenopus oocytes expressing the maize aquaporin ZmPIP2;5. Although mercury did not affect the Pf in swelling Black Mexican Sweet cells, phloretin, another aquaporin inhibitor, inhibited swelling in a predicted manner, prolonging the delay and slowing Pf increase, thereby confirming the hypothesis that Pf dynamics, delay included, reflected the varying activity of aquaporins.
Brassinosteroids Do Not Undergo Long-Distance Transport in Pea. Implications for the Regulation of Endogenous Brassinosteroid Levels
Authors: Symons Gregory M. , Reid James B.
Published: August 2004

It is widely accepted that brassinosteroids (BRs) are important regulators of plant growth and development. However, in comparison to the other classical plant hormones, such as auxin, relatively little is known about BR transport and its potential role in the regulation of endogenous BR levels in plants. Here, we show that end-pathway BRs in pea (Pisum sativum) occur in a wide range of plant tissues, with the greatest accumulation of these substances generally occurring in the young, actively growing tissues, such as the apical bud and young internodes. However, despite the widespread distribution of BRs throughout the plant, we found no evidence of long-distance transport of these substances between different plant tissues. For instance, we show that the maintenance of steady-state BR levels in the stem does not depend on their transport from the apical bud or mature leaves. Similarly, reciprocal grafting between the wild type and the BR-deficient lkb mutants demonstrates that the maintenance of steady-state BR levels in whole shoots and roots does not depend on either basipetal or acropetal transport of BRs between these tissues. Together, with results from 3H-BR feeding studies, these results demonstrate that BRs do not undergo long-distance transport in pea. The widespread distribution of end-pathway BRs and the absence of long-distance BR transport between different plant tissues provide significant insight into the mechanisms that regulate BR homeostasis in plants.
Rapid Regulation of the Methylerythritol 4-Phosphate Pathway during Isoprene Synthesis
Authors: Wolfertz Michael , Sharkey Thomas D. , Boland Wilhelm , Kühnemann Frank
Published: August 2004

More volatile organic carbon is lost from plants as isoprene than any other molecule. This flux of carbon to the atmosphere affects atmospheric chemistry and can serve as a substrate for ozone production in polluted air. Isoprene synthesis may help leaves cope with heatflecks and active oxygen species. Isoprene synthase, an enzyme related to monoterpene synthases, converts dimethylallyl diphosphate derived from the methylerythritol 4-phosphate pathway to isoprene. We used dideuterated deoxyxylulose (DOX-d2) to study the regulation of the isoprene biosynthetic pathway. Exogenous DOX-d2 displaced endogenous sources of carbon for isoprene synthesis without increasing the overall rate of isoprene synthesis. However, at higher concentrations, DOX-d2 completely suppressed isoprene synthesis from endogenous sources and increased the overall rate of isoprene synthesis. We interpret these results to indicate strong feedback control of deoxyxylulose-5-phosphate synthase. We related the emission of labeled isoprene to the concentration of labeled dimethylallyl diphosphate in order to estimate the in situ K  m of isoprene synthase. The results confirm that isoprene synthase has a K  m 10- to 100-fold higher for its allylic diphosphate substrate than related monoterpene synthases for geranyl diphosphate.