bluuebunny/crossref_metadata_2025 huggingface dataset:
Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice
Authors: Clément-Lacroix Philippe , Ai Minrong , Morvan Frederic , Roman-Roman Sergio , Vayssière Béatrice , Belleville Cecille , Estrera Kenneth , Warman Matthew L. , Baron Roland , Rawadi Georges
Published: November 2005

One of the well characterized cell biologic actions of lithium is the inhibition of glycogen synthase kinase-3β and the consequent activation of canonical Wnt signaling. Because deficient Wnt signaling has been implicated in disorders of reduced bone mass, we tested whether lithium could improve bone mass in mice. We gavage-fed lithium chloride to 8-week-old mice from three different strains (
Lrp5
-/-
, SAMP6, and C57BL/6) and assessed the effect on bone metabolism after 4 weeks of therapy.
Lrp5
-/-
mice lack the Wnt coreceptor low-density lipoprotein receptor-related protein 5 and have markedly reduced bone mass. Lithium, which is predicted to act downstream of this receptor, restored bone metabolism and bone mass to near wild-type levels in these mice. SAMP6 mice have accelerated osteoporosis due to inadequate osteoblast renewal. Lithium significantly improved bone mass in these mice and in wild-type C57BL/6 mice. We found that lithium activated canonical Wnt signaling in cultured calvarial osteoblasts from
Lrp5
-/-
mice
ex vivo
and that lithium-treated mice had increased expression of Wnt-responsive genes in their bone marrow cells
in vivo
. These data lead us to conclude that lithium enhances bone formation and improves bone mass in mice and that it may do so via activation of the canonical Wnt pathway. Lithium has been used safely and effectively for over half a century in the treatment of bipolar illness. Prospective studies in patients receiving lithium should determine whether it also improves bone mass in humans.
Leukotriene B4signaling through NF-κB-dependent BLT1receptors on vascular smooth muscle cells in atherosclerosis and intimal hyperplasia
Authors: Bäck Magnus , Bu De-xiu , Bränström Robert , Sheikine Yuri , Yan Zhong-Qun , Hansson Göran K.
Published: November 2005

Leukotriene B4(LTB4), a potent leukocyte chemoattractant derived from the 5-lipoxygenase metabolism of arachidonic acid, exerts its action by means of specific cell surface receptors, denoted BLT1and BLT2. In this study, BLT1receptor proteins were detected in human carotid artery atherosclerotic plaques, colocalizing with markers for macrophages, endothelial cells, and vascular smooth muscle cells (SMC). Challenge of human coronary artery SMC with either LTB4or U75302, a partial agonist that is selective for the BLT1receptor, induced an ≈4-fold increase of whole-cell currents by using the patch-clamp technique, indicating that these cells express functional BLT1receptors. LTB4induced migration and proliferation of SMCin vitro, and treatment with the BLT receptor antagonist BIIL 284 (10 mg/kg, once daily) for 14 days after carotid artery balloon injuryin vivoinhibited intimal hyperplasia in rats. In the latter model, SMC derived from the intima exhibited increased levels of BLT1receptor mRNA compared with medial SMC. BLT receptor up-regulation in the intimain vivo, as well as that induced by IL-1βin vitro, were prevented by transfection with a dominant-negative form of Iκ kinase β carried by adenovirus, indicating that BLT1receptor expression depends on NF-κΒ. These results show that LTB4activates functional BLT1receptors on vascular SMC, inducing chemotaxis and proliferation, and that BLT1receptors were up-regulated through an Iκ kinase β/NF-κB-dependent pathway. Inhibition of LTB4/BLT1signaling during the response to vascular injury reduced intimal hyperplasia, suggesting this pathway as a possible target for therapy.
Burning down the brewery: Establishing and evacuating an ancient imperial colony at Cerro Baúl, Peru
Authors: Moseley Michael E. , Nash Donna J. , Williams Patrick Ryan , deFrance Susan D. , Miranda Ana , Ruales Mario
Published: November 2005

Before the Inca reigned, two empires held sway over the central Andes fromanno Domini600 to 1000: the Wari empire to the north ruled much of Peru, and Tiwanaku to the south reigned in Bolivia. Face-to-face contact came when both colonized the Moquegua Valley sierra in southern Peru. The state-sponsored Wari incursion, described here, entailed large-scale agrarian reclamation to sustain the occupation of two hills and the adjacent high mesa of Cerro Baúl. Monumental buildings were erected atop the mesa to serve an embassy-like delegation of nobles and attendant personnel that endured for centuries. Final evacuation of the Baúl enclave was accompanied by elaborate ceremonies with brewing, drinking, feasting, vessel smashing, and building burning.
Visualization of a primary anti-tumor immune response by positron emission tomography
Authors: Shu Chengyi J. , Guo Shuling , Kim Young J. , Shelly Stephanie M. , Nijagal Amar , Ray Pritha , Gambhir Sanjiv S. , Radu Caius G. , Witte Owen N.
Published: November 2005

Current methodologies that monitor immune responses rely on invasive techniques that sample tissues at a given point in time. New technologies are needed to elucidate the temporal patterns of immune responses and the spatial distribution of immune cells on a whole-body scale. We describe a noninvasive, quantitative, and tomographic approach to visualize a primary anti-tumor immune response by using positron emission tomography (PET). Bone marrow chimeric mice were generated by engraftment of hematopoietic stem and progenitor cells transduced with a trifusion reporter gene encoding synthetic
Renilla
luciferase (hRluc), EGFP, and Herpes virus thymidine kinase (sr39TK). Mice were challenged with the Moloney murine sarcoma and leukemia virus complex (M-MSV/M-MuLV), and the induced immune response was monitored by using PET. Hematopoietic cells were visualized by using 9-[4-[
18
F]fluoro-3-(hydroxymethyl)butyl]guanine ([
18
F]FHBG), a radioactive substrate specific for the sr39TK PET reporter protein. Immune cell localization and expansion were seen at the tumor and draining lymph nodes (DLNs). 2-[
18
F]fluoro-2-deoxy-
d
-glucose ([
18
F]FDG), which is sequestered in metabolically active cells, was used to follow tumor growth and regression. Elevated glucose metabolism was also seen in activated lymphocytes in the DLNs by using the [
18
F]FDG probe. When M-MSV/M-MuLV-challenged mice were treated with the immunosuppressive drug dexamethasone, activation and expansion of immune cell populations in the DLNs could no longer be detected with PET imaging. The method we describe can be used to kinetically measure the induction and therapeutic modulations of cell-mediated immune responses.
Experience induces structural and biochemical changes in the adult primate brain
Authors: Kozorovitskiy Yevgenia , Gross Charles G. , Kopil Catherine , Battaglia Lisa , McBreen Meghan , Stranahan Alexis M. , Gould Elizabeth
Published: November 2005

Primates exhibit complex social and cognitive behavior in the wild. In the laboratory, however, the expression of their behavior is usually limited. A large body of literature shows that living in an enriched environment alters dendrites and synapses in the brains of adult rodents. To date, no studies have investigated the influence of living in a complex environment on brain structure in adult primates. We assessed dendritic architecture, dendritic spines, and synaptic proteins in adult marmosets housed in either a standard laboratory cage or in one of two differentially complex habitats. A month-long stay in either complex environment enhanced the length and complexity of the dendritic tree and increased dendritic spine density and synaptic protein levels in the hippocampus and prefrontal cortex. No differences were detected between the brains of marmosets living in the two differentially complex environments. Our results show that the structure of the adult primate brain remains highly sensitive even to modest levels of experiential complexity. For adult primates, living in standard laboratory housing may induce reversible dendritic spine and synapse decreases in brain regions important for cognition.
Glyphosate inhibits rust diseases in glyphosate-resistant wheat and soybean
Authors: Feng Paul C. C. , Baley G. James , Clinton William P. , Bunkers Greg J. , Alibhai Murtaza F. , Paulitz Timothy C. , Kidwell Kimberlee K.
Published: November 2005

Glyphosate is a broad-spectrum herbicide used for the control of weeds in glyphosate-resistant crops. Glyphosate inhibits 5-enolpyruvyl shikimate 3-phosphate synthase, a key enzyme in the synthesis of aromatic amino acids in plants, fungi, and bacteria. Studies with glyphosate-resistant wheat have shown that glyphosate provided both preventive and curative activities against
Puccinia striiformis
f. sp.
tritici
and
Puccinia triticina
, which cause stripe and leaf rusts, respectively, in wheat. Growth-chamber studies demonstrated wheat rust control at multiple plant growth stages with a glyphosate spray dose typically recommended for weed control. Rust control was absent in formulation controls without glyphosate, dependent on systemic glyphosate concentrations in leaf tissues, and not mediated through induction of four common systemic acquired resistance genes. A field test with endemic stripe rust inoculum confirmed the activities of glyphosate pre- and postinfestation. Preliminary greenhouse studies also demonstrated that application of glyphosate in glyphosate-resistant soybeans suppressed Asian soybean rust, caused by
Phakopsora pachyrhizi
.
Wonderful varieties of type 𝐷
Authors: Bravi Paolo , Pezzini Guido
Published: November 2005

Let

G
G

be a connected semisimple group over

C

\mathbb C

, whose simple components have type

A

\mathsf A

or

D

\mathsf D

. We prove that wonderful

G
G

-varieties are classified by means of combinatorial objects called spherical systems. This is a generalization of a known result of Luna for groups of type

A

\mathsf A

; thanks to another result of Luna, this implies also the classification of all spherical

G
G

-varieties for the groups

G
G

we are considering. For these

G
G

we also prove the smoothness of the embedding of Demazure.
Spinal Anesthesia with an Indwelling Catheter Reduces the Stress Response in Pediatric Open Heart Surgery
Authors: Humphreys Nigel , Bays Simon M. , Parry Andrew J. , Pawade Ashwinikumar , Heyderman Robert S. , Wolf Andrew R.
Published: November 2005

Background

Extreme stress and inflammatory responses to open heart surgery are associated with increased morbidity and mortality. Based on both animal and adult human data, it was hypothesized that spinal anesthesia would be more effective at attenuating these responses than conventional high dose intravenous opioid techniques in infants and young children undergoing open heart surgery.

Methods

A prospective randomized controlled clinical trial was performed in 60 children aged up to 24 months undergoing open heart surgery. Patients were randomly assigned to receive either high-dose intravenous opioid or high-dose intravenous opioid plus spinal anesthesia. Spinal anesthesia was administered via an indwelling intrathecal catheter.

Results

Spinal anesthesia significantly reduced the stress responses as measured by plasma norepinephrine and epinephrine concentrations (both P < 0.05). Spinal anesthesia reduced plasma lactate concentrations (P < 0.05), but increased fluid requirements during the first postoperative day (P < 0.05). There were no differences in other cardiovascular parameters.

Conclusions

Continuous spinal anesthesia reduces stress responses in infants and young children undergoing cardiac surgery with cardiopulmonary bypass more effectively than high-dose intravenous opioids alone.
Validity of Unplanned Admission to an Intensive Care Unit as a Measure of Patient Safety in Surgical Patients
Authors: Haller Guy , Myles Paul S. , Wolfe Rory , Weeks Anthony M. , Stoelwinder Johannes , McNeil John
Published: November 2005

Background

An unplanned admission to the intensive care unit within 24 h of a procedure (UIA) is a recommended clinical indicator in surgical patients. Often regarded as a surrogate marker of adverse events, it has potential as a direct measure of patient safety. Its true validity for such use is currently unknown.

Methods

The authors validated UIA as an indicator of safety in surgical patients in a prospective cohort study of 44,130 patients admitted to their hospital. They assessed the association of UIA with intraoperative incidents and near misses, increased hospital length of stay, and 30-day mortality as three constructs of patient safety.

Results

The authors identified 201 patients with a UIA; 104 (52.2%) had at least one incident or near miss. After adjusting for confounders, these incidents were significantly associated with UIA in all categories of surgical procedures analyzed; odds ratios were 12.21 (95% confidence interval [CI], 6.33-23.58), 4.06 (95% CI, 2.74-6.03), and 2.13 (95% CI, 1.02-4.42), respectively. The 30-day mortality for patients with UIA was 10.9%, compared with 1.1% in non-UIA patients. After risk adjustment, UIA was associated with excess mortality in several types of surgical procedures (odds ratio, 3.89; 95% CI, 2.14-7.04). The median length of stay was increased if UIA occurred: 16 days (interquartile range, 10-31) versus 2 days (interquartile range, 0.5-9) (P < 0.001). For patients with a UIA, the likelihood of discharge from hospital was significantly decreased in most surgical categories analyzed, with adjusted hazard ratios of 0.41 (95% CI, 0.23-0.77) to 0.58 (95% CI, 0.37-0.93).

Conclusions

These findings provide strong support for the construct validity of UIA as a measure of patient safety.
Behavioral Interactions in the Perioperative Environment
Authors: Caldwell-Andrews Alison A. , Blount Ronald L. , Mayes Linda C. , Kain Zeev N.
Published: November 2005

Background

The authors suggest that research in the area of parental presence during induction of anesthesia should shift to emphasize what parents actually do during induction, rather than focusing simply on their presence. As a first step, the authors aimed to develop a behavioral coding system that would measure child and adult interactions in the perioperative environment.

Methods

The authors enrolled 45 parents and children (aged 2-12 yr) undergoing elective surgery and general anesthesia. A multidisciplinary team examined videotapes and transcriptions of interactions between children, parents, and medical personnel in the holding room and operating room. The team used an existing scale, the Child-Adult Medical Procedure Interaction Scale, as the prototype for the development of a new perioperative behavioral coding system. The research team conducted extensive revisions to the original scale and added multiple codes to the original scale, including nonverbal codes. Interrater reliability was assessed using weighted kappa statistics. Construct validity was also examined.

Results

The final Perioperative Child-Adult Medical Procedure Interaction Scale contains 40 codes in four domains. Analyses showed excellent reliability overall for verbal and nonverbal codes. Kappa values averaged 0.87 for verbal codes characterizing adult vocalizations, 0.92 for verbal codes characterizing child vocalizations, and 0.88 for nonverbal codes. Construct validity was demonstrated by finding the hypothesized associations between certain scale codes and children's anxiety (P = 0.0001).

Conclusion

Showing excellent reliability, the Perioperative Child-Adult Medical Procedure Interaction Scale is an appropriate tool for assessing child-adult behavioral interaction during the perioperative period. When sequential analyses are conducted and target behaviors are identified, empirically based parent preparation programs can be developed.
Optimal Puncture Site of the Right Internal Jugular Vein after Laryngeal Mask Airway Placement
Authors: Takeyama Kazuhide , Kobayashi Hiroyuki , Suzuki Toshiyasu
Published: November 2005

Background

Puncturing of the internal jugular vein (IJV) after placement of a laryngeal mask airway (LMA) is difficult. Overlapping of the right internal jugular vein (IJV) and common carotid artery (CCA) after placement of an LMA-Classic (Laryngeal Mask Company, Henley-on-Thames, United Kingdom) was investigated using an ultrasound scanner. A study was conducted to determine the optimal puncture site in the case of puncturing the right IJV after LMA-Classic placement.

Methods

The subjects in this study consisted of 114 patients (60 men and 54 women) scheduled to undergo LMA-Classic placement (size 4 for men and size 3 for women). Overlapping between the IJV and CCA was investigated at three points (high, middle, and low points) on the right side of the neck after LMA-Classic placement. A test puncture was also made at the right low (supraclavicular) point after LMA-Classic placement.

Results

(1) The degree of overlapping of the right IJV and CCA after LMA-Classic placement was clearly greater than before LMA placement. (2) With the exception of some measurements, there were many cases in which the right IJV and CCA were completely overlapping after LMA-Classic placement. Furthermore, the CCA was not observed in the vicinity of the right IJV at the right low point. (3) There were no complications (including pneumothorax and accidental arterial puncture) during supraclavicular IJV puncture after LMA-Classic placement.

Conclusion

After placement of the LMA-Classic, overlapping of the IJV and CCA increased at the high and middle puncture points of the IJV; however, at the lower puncture point, the position of the vessels remained unaffected. Therefore, during IJV puncture at high or middle points, ultrasound guidance is advisable to avoid CCA puncture.
Respiratory Reflex Responses of the Larynx Differ between Sevoflurane and Propofol in Pediatric Patients
Authors: Oberer Christine , von Ungern-Sternberg Britta S. , Frei Franz J. , Erb Thomas O.
Published: November 2005

Background

The effects of anesthetics on airway protective reflexes have not been extensively characterized in children. The aim of this study was to compare the laryngeal reflex responses in children anesthetized with either sevoflurane or propofol under two levels of hypnosis using the Bispectral Index score (BIS). The authors hypothesized that the incidence of apnea with laryngospasm evoked by laryngeal stimulation would not differ between sevoflurane and propofol when used in equipotent doses and that laryngeal responsiveness would be diminished with increased levels of hypnosis.

Methods

Seventy children, aged 2-6 yr, scheduled to undergo elective surgery were randomly allocated to undergo propofol or sevoflurane anesthesia while breathing spontaneously through a laryngeal mask airway. Anesthesia was titrated to achieve the assigned level of hypnosis (BIS 40 +/- 5 or BIS 60 +/- 5) in random order. Laryngeal and respiratory responses were elicited by spraying distilled water on the laryngeal mucosa, and a blinded reviewer assessed evoked responses.

Results

Apnea with laryngospasm occurred more often during anesthesia with sevoflurane compared with propofol independent of the level of hypnosis: episodes lasting longer than 5 s, 34% versus 19% at BIS 40 and 34% versus 16% at BIS 60; episodes lasting longer than 10 s, 26% versus 10% at BIS 40 and 26% versus 6% at BIS 60 (group differences P < 0.04 and P < 0.01, respectively). In contrast, cough and expiration reflex occurred significantly more frequently in children anesthetized with propofol.

Conclusion

Laryngeal and respiratory reflex responses in children aged 2-6 yr were different between sevoflurane and propofol independent of the levels of hypnosis examined in this study.
Intercellular Adhesion Molecule-1 Inhibition Attenuates Neurologic and Hepatic Damage after Resuscitation in Mice
Authors: Larmann Jan , Schmidt Christoph , Gammelin Harald , Van Aken Hugo K. , Frenzel Tim , Lanckohr Christian , Lox Marleen , Boese Nadine , Jurk Kerstin , Theilmeier Gregor
Published: November 2005

Background

Cardiac arrest and cardiopulmonary resuscitation may result in multiorgan damage after global hypoxia due to neutrophil recruitment. Patients display all signs of a systemic inflammatory response syndrome. Reducing neutrophil recruitment may thus preserve organ function.

Methods

Mice were subjected to cardiac arrest and resuscitation. CD18/CD11b expression on circulating neutrophils was assessed by flow cytometry. Intercellular adhesion molecule-1 expression was analyzed by Western blot and immunofluorescence. Neutrophil recruitment was quantified by immunohistochemistry. Neurologic function was assessed by a balance test. For liver and kidney function, plasma alanine aminotransferase activity and creatinine concentrations were determined. To reduce neutrophil recruitment, mice received 100 microg anti-intercellular adhesion molecule-1 antibody intraperitoneally.

Results

Resuscitation led to severe hypoxia, acidosis, and hypercarbia. Adhesion molecule expression and neutrophil recruitment were increased in the liver, kidney, and brain. Neurologic performance was impaired 24 h after cardiac arrest. Creatinine and alanine aminotransferase concentrations were significantly increased. Immunoneutralization of intercellular adhesion molecule-1 attenuated neutrophil influx in the liver along with alanine aminotransferase activity, whereas creatinine concentrations and neutrophil influx in the kidney remained unchanged. Neurologic function was improved in the treatment group.

Conclusions

Global hypoxia induces activation of the endothelium in the brain, liver, and kidney. The resulting damage to the brain and liver are due to infiltration of neutrophils, whereas kidney damage is not, because reduction of neutrophil recruitment after cardiopulmonary resuscitation improves recovery of neurologic and hepatic but not renal function. Inhibition of intercellular adhesion molecule-1 after global hypoxia may be beneficial in patients experiencing cardiac arrest and resuscitation.
Memory Enhancing Effect of Low-dose Sevoflurane Does Not Occur in Basolateral Amygdala–lesioned Rats
Authors: Alkire Michael T. , Nathan Sheila V. , McReynolds Jayme R.
Published: November 2005

Background

Certain anesthetics might enhance aversive memory at doses around 0.1 minimum alveolar concentration. This issue was investigated in a rat model of learning and memory. In addition, evidence for basolateral amygdala (BLA) involvement in mediating memory enhancement was sought.

Methods

First, the memory-enhancing potential of various anesthetics was determined. Rats underwent single-trial inhibitory avoidance training (0.3 mA shock/1 s) during exposure to air, 0.11% sevoflurane, 0.10% halothane, 0.77% desflurane, or 0.12% isoflurane. Memory was assessed at 24 h. Second, the BLA contribution to sevoflurane memory enhancement was determined. Rats received bilateral excitotoxic N-methyl-D-aspartate (12.5 mg in 0.2 microl per BLA) lesions of the BLA 1 week before training. Memory of lesioned and control rats was compared 24 h after training in air or sevoflurane.

Results

Sevoflurane exposure during training significantly enhanced 24-h retention performance for both nonoperated and sham-operated rats (P < 0.005 for both vs. their respective controls). Halothane, but not desflurane or isoflurane, also enhanced retention performance (P < 0.05). However, halothane-induced hyperalgesia during learning clouds interpreting enhanced retention performance solely as a memory consolidation effect. BLA lesions significantly reduced and equalized retention performance for both sevoflurane- and air-exposed animals. Lesions blocked memory enhancement without also causing a generalized inability to learn, because additional training revealed essentially normal task acquisition and 24-h memory.

Conclusions

Sevoflurane enhances aversive memory formation in the rat. The BLA likely contributes to this effect. The risk of aversive memory formation may be enhanced during exposure to low-dose sevoflurane.
Effects of Nitrous Oxide on the Rat Heart In Vivo
Authors: Weber Nina C. , Toma Octavian , Awan Saqib , Fräßdorf Jan , Preckel Benedikt , Schlack Wolfgang
Published: November 2005

Background

For nitrous oxide, a preconditioning effect on the heart has yet not been investigated. This is important because nitrous oxide is commonly used in combination with volatile anesthetics, which are known to precondition the heart. The authors aimed to clarify (1) whether nitrous oxide preconditions the heart, (2) how it affects protein kinase C (PKC) and tyrosine kinases (such as Src) as central mediators of preconditioning, and (3) whether isoflurane-induced preconditioning is influenced by nitrous oxide.

Methods

For infarct size measurements, anesthetized rats were subjected to 25 min of coronary artery occlusion followed by 120 min of reperfusion. Rats received nitrous oxide (60%), isoflurane (1.4%) or isoflurane-nitrous oxide (1.4%/60%) during three 5-min periods before index ischemia (each group, n = 7). Control animals remained untreated for 45 min. Additional hearts (control, 60% nitrous oxide alone%, and isoflurane-nitrous oxide [0.6%/60%, in equianesthetic doses]) were excised for Western blot of PKC-epsilon and Src kinase (each group, n = 4).

Results

Nitrous oxide had no effect on infarct size (59.1 +/- 15.2% of the area at risk vs. 51.1 +/- 10.9% in controls). Isoflurane (1.4%) and isoflurane-nitrous oxide (1.4%/60%) reduced infarct size to 30.9 +/- 10.6 and 28.7 +/- 11.8% (both P < 0.01). Nitrous oxide (60%) had no effect on phosphorylation (2.3 +/- 1.8 vs. 2.5 +/- 1.7 in controls, average light intensity, arbitrary units) and translocation (7.0 +/- 4.3 vs. 7.4 +/- 5.2 in controls) of PKC-epsilon. Src kinase phosphorylation was not influenced by nitrous oxide (4.6 +/- 3.9 vs. 5.0 +/- 3.8; 3.2 +/- 2.2 vs. 3.5 +/- 3.0). Isoflurane-nitrous oxide (0.6%/60%, in equianesthetic doses) induced PKC-epsilon phosphorylation (5.4 +/- 1.9 vs. 2.8 +/- 1.5; P < 0.001) and translocation to membrane regions (13.8 +/- 13.0 vs. 6.7 +/- 2.0 in controls; P < 0.05).

Conclusions

Nitrous oxide is the first inhalational anesthetic without preconditioning effect on the heart. However, isoflurane-induced preconditioning and PKC-epsilon activation are not influenced by nitrous oxide.
Influence of Sevoflurane on the Metabolism and Renal Effects of Compound A in Rats
Authors: Kharasch Evan D. , Schroeder Jesara L. , Sheffels Pam , Liggitt H Denny
Published: November 2005

Background

The sevoflurane degradation product compound A is nephrotoxic in rats. In contrast, patient exposure to compound A during sevoflurane anesthesia has no clinically significant renal effects. The mechanism for this difference is incompletely understood. One possibility is that the metabolism and toxicity of compound A in humans is prevented by sevoflurane. However, the effect of sevoflurane on compound A metabolism and nephrotoxicity is unknown. Thus, the purpose of this investigation was to determine the effect of sevoflurane on the metabolism and renal toxicity of compound A in rats.

Methods

Male rats received 0.25 mmol/kg intraperitoneal compound A, alone and during sevoflurane anesthesia (3%, 1.3 minimum alveolar concentration, for 3 h). Compound A metabolites in urine were quantified, and renal function was evaluated by serum creatinine and urea nitrogen, urine volume, osmolality, protein excretion, and renal tubular histology.

Results

Sevoflurane coadministration with compound A inhibited compound A defluorination while increasing relative metabolism through pathways of sulfoxidation and beta-lyase-catalyzed metabolism, which mediate toxicity. Sevoflurane coadministration with compound A increased some (serum creatinine and urea nitrogen, and necrosis) but not other (urine volume, osmolality, and protein excretion) indices of renal toxicity.

Conclusions

Sevoflurane does not suppress compound A nephrotoxicity in rats in vivo. These results do not suggest that lack of nephrotoxicity in surgical patients exposed to compound A during sevoflurane anesthesia results from an inhibitory effect of sevoflurane on compound A metabolism and toxicity. Rather, these results are consistent with differences between rats and humans in compound A exposure and inherent susceptibility to compound A nephrotoxicity.
Influence of Hemorrhagic Shock and Subsequent Fluid Resuscitation on the Electroencephalographic Effect of Isoflurane in a Swine Model
Authors: Kurita Tadayoshi , Morita Koji , Fukuda Kazushige , Uraoka Masahiro , Takata Kotaro , Sanjo Yoshimitsu , Sato Shigehito
Published: November 2005

Background

The authors have previously reported that hemorrhage does not alter the electroencephalographic effect of isoflurane under conditions of compensated hemorrhagic shock. Here, they have investigated the influence of decompensated hemorrhagic shock and subsequent fluid resuscitation on the electroencephalographic effect of isoflurane.

Methods

Twelve swine were anesthetized through inhalation of 2% isoflurane. The inhalational concentration was then decreased to 0.5% and maintained for 25 min, before being returned to 2% and maintained for 25 min (control period). Hemorrhagic shock was then induced by removing 28 ml/kg blood over 30 min. After a 30-min stabilization period, the inhalational concentration was varied as in the control period. Finally, fluid infusion was performed over 30 min using a volume of hydroxyethyl starch equivalent to the blood withdrawn. After a 30-min stabilization period, the inhalational concentration was again varied as in the control period. End-tidal isoflurane concentrations and spectral edge frequency were recorded throughout the study. The pharmacodynamics were characterized using a sigmoidal inhibitory maximal effect model for spectral edge frequency versus effect site concentration.

Results

Decompensated hemorrhagic shock slightly but significantly shifted the concentration-effect relation to the left, demonstrating a 1.12-fold decrease in the effect site concentration required to achieve 50% of the maximal effect in the spectral edge frequency. Fluid resuscitation reversed the onset of isoflurane, which was delayed by hemorrhage, but did not reverse the increase in end-organ sensitivity.

Conclusions

Although decompensated hemorrhagic shock altered the electroencephalographic effect of isoflurane regardless of fluid resuscitation, the change seemed to be minimal, in contrast to several intravenous anesthetics.
Rapacuronium Augments Acetylcholine-induced Bronchoconstriction via Positive Allosteric Interactions at the M3 Muscarinic Receptor
Authors: Jooste Edmund H. , Sharma Amit , Zhang Yi , Emala Charles W.
Published: November 2005

Background

Neuromuscular blocking agents' detrimental airway effects may occur as a result of interactions with muscarinic receptors, allergic reactions, or histamine release. Rapacuronium, a nondepolarizing muscle relaxant, was withdrawn from clinical use because of its association with fatal bronchospasm. Despite its withdrawal from clinical use, it is imperative that the mechanism by which bronchospasm occurred is understood so that new muscle relaxants introduced to clinical practice do not share these same detrimental airway effects.

Methods

Airway smooth muscle force was measured in guinea pig tracheal rings in organ baths exposed to muscle relaxants with or without subthreshold concentrations of acetylcholine. Antagonism of muscarinic, histamine, neurokinin, leukotriene receptors, or blockade of L-type calcium channels or depletion of nonadrenergic, noncholinergic neurotransmitters was performed. Muscle relaxants' potentiation of acetylcholine-stimulated inositol phosphate synthesis and allosteric interactions on the kinetics of atropine-induced [3H]N-methylscopolamine dissociation were measured in cells expressing recombinant human M3 muscarinic receptors.

Results

Rapacuronium, within clinically achieved concentrations, contracted tracheal rings in the presence but not in the absence of subthreshold concentrations of acetylcholine. This effect was prevented or reversed only by atropine. The allosteric action of rapacuronium was demonstrated by the slowing of atropine-induced dissociation of [3H]N-methylscopolamine, and positive cooperativity was demonstrated by potentiation of acetylcholine-induced inositol phosphate synthesis.

Conclusion

Many muscle relaxants have allosteric properties at muscarinic receptors; however, positive cooperativity at the M3 muscarinic receptor within clinically relevant concentrations is unique to rapacuronium. These findings establish novel parameters that should be considered in the evaluation of airway safety of any newly synthesized neuromuscular blocking agents considered for clinical practice.
Surfactants Reduce Platelet–Bubble and Platelet–Platelet Binding Induced by In Vitro Air Embolism
Authors: Eckmann David M. , Armstead Stephen C. , Mardini Feras
Published: November 2005

Background

The effect of gas bubbles on platelet behavior is poorly characterized. The authors assessed platelet-bubble and platelet-platelet binding in platelet-rich plasma in the presence and absence of bubbles and three surface-active compounds.

Methods

Platelet-rich plasma was prepared from blood drawn from 16 volunteers. Experimental groups were surfactant alone, sparging (microbubble embolization) alone, sparging with surfactant, and neither sparging nor surfactant. The surfactants were Pluronic F-127 (Molecular Probes, Eugene, OR), Perftoran (OJSC SPC Perftoran, Moscow, Russia), and Dow Corning Antifoam 1510US (Dow Corning, Midland, MI). Videomicroscopy images of specimens drawn through rectangular glass microcapillaries on an inverted microscope and Coulter counter measurements were used to assess platelet-bubble and platelet-platelet binding, respectively, in calcium-free and recalcified samples. Histamine-induced and adenosine diphosphate-induced platelet-platelet binding were measured in unsparged samples. Differences between groups were considered significant for P < 0.05 using analysis of variance and the Bonferroni correction.

Results

Sixty to 100 platelets adhered to bubbles in sparged, surfactant-free samples. With sparging and surfactant, few platelets adhered to bubbles. Numbers of platelet singlets and multimers not adherent to bubbles were different (P < 0.05) compared both with unsparged samples and sparged samples without surfactant. No significant platelet-platelet binding occurred in uncalcified, sparged samples, although 20-30 platelets adhered to bubbles. Without sparging, histamine and adenosine diphosphate provoked platelet-platelet binding with and without surfactants present.

Conclusions

Sparging causes platelets to bind to air bubbles and each other. Surfactants added before sparging attenuate platelet-bubble and platelet-platelet binding. Surfactants may have a clinical role in attenuating gas embolism-induced platelet-bubble and platelet-platelet binding.
Comparison of Morphine, Ketorolac, and Their Combination for Postoperative Pain
Authors: Cepeda Maria Soledad , Carr Daniel B. , Miranda Nelcy , Diaz Adriana , Silva Claudia , Morales Olga
Published: November 2005

Background

Meta-analyses report similar numbers needed to treat for nonsteroidal antiinflammatory drugs (NSAIDs) and opioids. Differences in baseline pain intensity among the studies from which these numbers needed to treat were derived may have confounded the results. NSAIDs have an opioid-sparing effect, but the importance of this effect is unclear. Therefore, the authors sought to compare the proportions of subjects who obtain pain relief with ketorolac versus morphine after surgery and to determine whether the opioid-sparing effect of an NSAID reduces the magnitude of opioid side effects.

Methods

The study was a double-blind, randomized controlled trial. The authors randomly assigned 1,003 adult patients to receive 30 mg ketorolac or 0.1 mg/kg morphine intravenously. They calculated the proportion of subjects who achieved at least 50% reduction in pain intensity 30 min after analgesic administration. Further, so long as pain intensity 30 min after analgesic administration was 5 or more out of 10, patients received 2.5 mg morphine every 10 min until pain intensity was 4 or less out of 10. The authors assessed the presence of opioid-related side effects.

Results

Five hundred patients received morphine and 503 received ketorolac. Fifty percent of patients in the morphine group achieved pain relief, compared with 31% in the ketorolac group (difference, 19%; 95% confidence interval, 13-25%). The ketorolac-morphine group required less morphine (difference, 6.5 mg; 95% confidence interval, -5.8 to -7.2) and had a lower incidence of side effects (difference, 11%; 95% confidence interval, 5-16%) than the morphine group.

Conclusions

Opioids are more efficacious analgesics than NSAIDs, although historic data for these two drugs yield similar numbers needed to treat. Adding NSAIDs to the opioid treatment reduces morphine requirements and opioid-related side effects in the early postoperative period.
Minimum Local Analgesic Dose
Authors: Parpaglioni Raffaella , Frigo Maria Grazia , Lemma Anna , Sebastiani Massimo , Barbati Giulia , Celleno Danilo
Published: November 2005

Background

This double-blind, randomized study was aimed at detecting the effect of three different volumes of intrathecal levobupivacaine on the minimum local analgesic dose in early labor.

Methods

Ninety-three nulliparous women requesting combined spinal-epidural analgesia, at more than 37 weeks gestation, with spontaneous onset of labor, cervical dilatation from 2 to 5 cm, were enrolled. Parturients received 10 ml (group 10), 5 ml (group 5), or 2.5 ml (group 2.5) of the spinal solution containing plain levobupivacaine diluted with 0.9% wt/vol saline to achieve the desired dose and volume at room temperature. A lumbar epidural catheter was then placed. The initial dose for each group was 2.0 mg, and the following doses were determined by the response of the previous patient using up-down sequential allocation. The authors required the test solution to achieve a visual analog pain score of 10 mm or less to be considered effective. The up-down sequences were analyzed using the Dixon and Massey formula and regression logistic model.

Results

The minimum local analgesic dose of spinal levobupivacaine in spontaneously laboring women was 1.35 mg (95% confidence interval, 1.25-1.45 mg) in group 10, 1.63 mg (95% confidence interval, 1.51-1.76 mg) in group 5, and 1.97 mg (95% confidence interval, 1.89-2.05 mg) in group 2.5. A unit change in volume increased the odds of an effective response multiplicatively by a factor of 1.8.

Conclusions

Analgesia can be achieved using lower doses and higher volumes even in subarachnoid space. The important role of the volume should be considered not only in epidural but also in spinal analgesia.
Ephedrine Blocks Rat Sciatic Nerve In Vivo and Sodium Channels In Vitro
Authors: Hung Yu-Chun , Kau Yi-Chuan , Zizza Anthony M. , Edrich Thomas , Zurakowski David , Myers Robert R. , Wang Ging Kuo , Gerner Peter
Published: November 2005

Background

The sympathomimetic drug ephedrine has been used intrathecally as the sole local anesthetic for labor and delivery. Because ephedrine may be a useful adjuvant to local anesthetics, the authors investigated the local anesthetic properties of ephedrine in a rat sciatic nerve block model and the underlying mechanism in cultured cells stably expressing Na channels.

Methods

After approval of the animal protocol, the sciatic nerves of anesthetized rats were exposed by lateral incision of the thighs, 0.2 ml ephedrine at 0.25, 1, 2.5, or 5% and/or bupivacaine at 0.125% was injected, and the wound was closed. Motor and sensory/nociceptive functions were evaluated by the force achieved by pushing against a balance and the reaction to pinch, respectively. The whole cell configuration of the patch clamp technique was used to record Na currents from human embryonal kidney cells stably transfected with Nav1.4 channels.

Results

The nociception blockade was significantly longer than the motor blockade at test doses of 2.5 and 5% of ephedrine, or when 1% ephedrine was combined with 0.125% bupivacaine (analysis of variance with repeated measures, P < 0.001, n = 8/group). In vitro, the 50% inhibitory concentrations of ephedrine at -150 and -60 mV were 1,043 +/- 70 and 473 +/- 13 mum, respectively. High-frequency stimulation revealed a use-dependent block of 18%, similar to most local anesthetics.

Conclusions

Because ephedrine's properties are at least partly due to Na channel blockade, detailed histopathologic investigations are justified to determine the potential of ephedrine as an adjuvant to clinically used local anesthetics.
Spinal Muscarinic and Nicotinic Subtypes Activated by Clonidine in Postincisional Pain
Authors: Duflo Frédéric , Boselli Emmanuel , Ryvlin Philippe , Chassard Dominique
Published: November 2005

Background

A recent model of acute incisional pain has been characterized that strongly parallels the postoperative period in patients experiencing evoked pain. In that setting, abundant literature has revealed antihypersensitive effects produced by intrathecally administered alpha2-adrenergic receptor agonists, such as clonidine, in both animals and humans. Recent reports have suggested an obligatory role of spinal acetylcholine receptors in the analgesic action of intrathecal clonidine. The authors sought to determine the involvement of spinal muscarinic and nicotinic receptor subpopulations in the antihypersensitivity effect of intrathecal clonidine in a rodent model for human postoperative pain.

Methods

After intrathecal catheterization, rats underwent superficial plantar incision. Clonidine or a combination of clonidine and muscarinic receptor subtype antagonists (M1, M2, M3, and M4) or nicotinic receptor subtype antagonists (alpha4beta2 and alpha7) were intrathecally administered, and withdrawal thresholds to mechanical stimuli were examined.

Results

Spinal clonidine maximally reduced hypersensitivity adjacent to the wound 30 min after its injection. When animals were intrathecally pretreated with the M1 muscarinic antagonist toxin MT-7, the M3 muscarinic antagonist 4-diphenylacetoxy-N-methylpiperidine, and the M4 muscarinic antagonist toxin MT-3, clonidine lost its antihypersensitive action. When animals were intrathecally pretreated with the alpha4beta2 nicotinic receptor antagonist dihydro-beta-erythroidine, but not with the alpha7 nicotinic receptor antagonist methyllycaconitine, the antihypersensitivity action of clonidine was abolished.

Conclusions

These data indicate for the first time that the clonidine-induced increase in punctuate mechanical threshold is mediated via the activation of all but M2 muscarinic receptor subtypes, and via the activation of alpha4beta2 but not alpha7 nicotinic receptor subtypes in a rodent model for human postoperative pain.
Sleep, Anesthesiology, and the Neurobiology of Arousal State Control
Authors: Lydic Ralph , Baghdoyan Helen A.
Published: November 2005

Sleep, like breathing, is a biologic rhythm that is actively generated by the brain. Neuronal networks that have evolved to regulate naturally occurring sleep preferentially modulate traits that define states of sedation and anesthesia. Sleep is temporally organized into distinct stages that are characterized by a unique constellation of physiologic and behavioral traits. Sleep and anesthetic susceptibility are genetically modulated, heritable phenotypes. This review considers 40 yr of research regarding the cellular and molecular mechanisms contributing to arousal state control. Clinical and preclinical data have debunked and supplanted the primitive view that sleep need is a weakness. Sleep deprivation and restriction diminish vigilance, alter neuroendocrine control, and negatively impact immune function. There is overwhelming support for the view that decrements in vigilance can negatively impact performance. Advances in neuroscience provide a foundation for the sea change in public and legal perspectives that now regard a sleep-deprived individual as impaired.
Does Multimodal Analgesia with Acetaminophen, Nonsteroidal Antiinflammatory Drugs, or Selective Cyclooxygenase-2 Inhibitors and Patient-controlled Analgesia Morphine Offer Advantages over Morphine Alone?
Authors: Elia Nadia , Lysakowski Christopher , Tramèr Martin R.
Published: November 2005

The authors analyzed data from 52 randomized placebo-controlled trials (4,893 adults) testing acetaminophen, nonsteroidal antiinflammatory drugs, or selective cyclooxygenase-2 inhibitors given in conjunction with morphine after surgery. The median of the average 24-h morphine consumption in controls was 49 mg (range, 15-117 mg); it was significantly decreased with all regimens by 15-55%. There was evidence of a reduction in pain intensity at 24 h (1 cm on the 0- to 10-cm visual analog scale) only with nonsteroidal antiinflammatory drugs. Nonsteroidal antiinflammatory drugs also significantly reduced the incidence of nausea/vomiting from 28.8% to 22.0% (number needed to treat, 15) and of sedation from 15.4% to 12.7% (number needed to treat, 37) but increased the risk of severe bleeding from 0% to 1.7% (number needed to harm, 59). Selective cyclooxygenase-2 inhibitors increased the risk of renal failure in cardiac patients from 0% to 1.4% (number needed to harm, 73). A decrease in morphine consumption is not a good indicator of the usefulness of a supplemental analgesic. There is evidence that the combination of nonsteroidal antiinflammatory drugs with patient-controlled analgesia morphine offers some advantages over morphine alone.
Fluorescently tagged canine adenovirus via modification with protein IX–enhanced green fluorescent protein
Authors: Le Long P. , Li Jing , Ternovoi Vladimir V. , Siegal Gene P. , Curiel David T.
Published: November 2005

Canine adenovirus type 2 (CAV2) has become an attractive vector for gene therapy because of its non-pathogenicity and the lack of pre-existing neutralizing antibodies against this virus in the human population. Additionally, this vector has been proposed as a conditionally replicative adenovirus agent under the control of an osteocalcin promoter for evaluation in a syngeneic, immunocompetent canine model with spontaneous osteosarcoma. In this study, a CAV2 vector labelled with the fluorescent capsid fusion protein IX–enhanced green fluorescent protein (pIX–EGFP) was developed. Expression of the fluorescent fusion-protein label in infected cells with proper nuclear localization, and incorporation into virions, could be detected. The labelled virions could be visualized by fluorescence microscopy; this was applicable to the tracking of CAV2 infection, as well as localizing the distribution of the vector in tissues. Expression of pIX–EGFP could be exploited to detect the replication and spread of CAV2. These results indicate that pIX can serve as a platform for incorporation of heterologous proteins in the context of a canine adenovirus xenotype. It is believed that capsid-labelled CAV2 has utility for vector-development studies and for monitoring CAV2-based oncolytic adenovirus replication.