bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative Analysis of Apoptosis-inducing Activity of Codeine and Codeinone
Authors: Hitosugi Naoko , Hatsukari Ikusuke , Ohno Rie , Hashimoto Ken , Mihara Saori , Mizukami Satoshi , Nakamura Shinichi , Sakagami Hiroshi , Nagasaka Hiroshi , Matsumoto Isao , Kawase Masami
Published: November 2003

Background

There are relatively few studies about the antiproliferative effects of codeine-related compounds on human cancer cell lines, compared with those of morphine-related compounds. The authors previously found that codeinone, an oxidation metabolite of codeine, among 10 opioids, showed the highest cytotoxic activity (DNA fragmentation-inducing activity) against human promyelocytic leukemic cell lines (HL-60). This was counteracted by an antioxidant, N-acetyl-L-cysteine (NAC). These findings prompted us to perform a more detailed study of apoptosis induction after codeinone treatment.

Methods

Apoptosis was induced by treating HL-60 cells for 1-6 h with codeine or codeinone. DNA fragmentation was assessed by both agarose gel electrophoresis and fluorometric determination of the fragmented DNA after staining with diamidinophenylindole (DAPI). The appearance of apoptotic cells was monitored by microscopic observation after staining with Hoechst (H)-33342, and fluorescence activated cell sorter (FACS) after staining with Annexin. The release of cytochrome c and cytochrome oxidase from mitochondria and activation of caspase 3 were monitored by Western blot analysis. Intracellular caspase 3-like activity was confirmed by FACS, using cell permeable substrate. Mitochondrial manganese-containing superoxide dismutase (MnSOD) activity and mRNA expression were assayed by activity staining after separation on the polyacrylamide gel electrophoresis, and reverse transcriptase-polymerase chain reaction (RT-PCR), respectively.

Results

Codeinone induced internucleosomal DNA fragmentation and production of Annexin-positive apoptotic cells more potently than codeine in HL-60 cells. Codeinone stimulated the release of both cytochrome c and cytochrome oxidase, and cleavage of procaspase 3 without significant changes in both the activity and expression of MnSOD.

Conclusions

Codeinone was found to possess both apoptosis and necrosis-inducing activity, in addition to the reported antinociceptive activity, further substantiating its antitumor potential.
Xenon Attenuates Cardiopulmonary Bypass–induced Neurologic and Neurocognitive Dysfunction in the Rat
Authors: Ma Daqing , Yang Hong , Lynch John , Franks Nicholas P. , Maze Mervyn , Grocott Hilary P.
Published: November 2003

Background

With clinical data suggesting a role for excitatory amino acid neurotransmission in the pathogenesis of cardiopulmonary bypass (CPB)-associated brain injury, the current study was designed to determine whether xenon, an N-methyl-D-aspartate receptor antagonist, would attenuate CPB-induced neurologic and neurocognitive dysfunction in the rat.

Methods

Following surgical preparation, rats were randomly divided into four groups: (1) sham rats were cannulated but did not undergo CPB; (2) CPB rats were subjected to 60 min of CPB using a membrane oxygenator receiving a gas mixture of 30% O2, 65% N2, and 5% CO2; (3) CPB + MK801 rats received MK801 (0.15 mg/kg intravenous) 15 min prior to 60 min of CPB with the same gas mixture; and (4) CPB + xenon rats underwent 60 min of CPB using an oxygenator receiving 30% O2, 60% xenon, 5% N2, and 5% CO2. Following CPB, the rats recovered for 12 days, during which they underwent standardized neurologic and neurocognitive testing (Morris water maze).

Results

The sham and CPB + xenon groups had significantly better neurologic outcome compared to both the CPB and CPB + MK801 groups on postoperative days 1 and 3 (P < 0.05). Compared to the CPB group, the sham, CPB + MK801, and CPB + xenon groups had better neurocognitive outcome on postoperative days 3 and 4 (P < 0.001). By the 12th day, the neurocognitive outcome remained significantly better in the CPB + xenon group compared to the CPB group (P < 0.01).

Conclusion

These data indicate that CPB-induced neurologic and neurocognitive dysfunction can be attenuated by the administration of xenon, potentially related to its neuroprotective effect via N-methyl-D-aspartate receptor antagonism.
Dialysis Delivery of an Adenosine A1Receptor Agonist to the Pontine Reticular Formation Decreases Acetylcholine Release and Increases Anesthesia Recovery Time
Authors: Tanase Diana , Baghdoyan Helen A. , Lydic Ralph
Published: November 2003

Background

Adenosine modulates cell excitability, acetylcholine release, nociception, and sleep. Pontine cholinergic neurotransmission contributes to the generation and maintenance of electroencephalographic and behavioral arousal. Adenosine A(1) receptors inhibit arousal-promoting, pontine cholinergic neurons, and adenosine enhances sleep. No previous studies have determined whether pontine adenosine also modulates recovery from anesthesia. Therefore, the current study tested the hypotheses that dialysis delivery of the adenosine A(1) receptor agonist N6-p-sulfophenyladenosine (SPA) into the pontine reticular formation would decrease acetylcholine release and increase the time needed for recovery from halothane anesthesia.

Methods

A microdialysis probe was positioned in the pontine reticular formation of halothane-anesthetized cats. Probes were perfused with Ringer's solution (control) followed by the adenosine A(1) receptor agonist SPA (0.088 or 8.8 mm). Dependent measures included acetylcholine release and a numeric assessment of recovery from anesthesia. An intensive, within-subjects design and analysis of variance evaluated SPA's main effect on acetylcholine release and anesthetic recovery. The adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 100 microm) was coadministered with SPA to test for antagonist blocking of SPA's effects.

Results

SPA significantly (P < 0.0001) decreased acetylcholine release in the pontine reticular formation and significantly (P < 0.0001) delayed recovery from anesthesia. Coadministration of SPA and DPCPX caused no decrease in acetylcholine release or delay in postanesthetic recovery. Dialysis delivery of SPA into the cerebellar cortex confirmed that the SPA effects were site-specific to the pontine reticular formation.

Conclusion

The results provide a novel extension of the sleep-promoting effects of adenosine by showing that pontine delivery of an adenosine A(1) receptor agonist delays resumption of wakefulness following halothane anesthesia. This extension is consistent with a potentially larger relevance of the current findings for efforts to specify neurons and molecules causing physiologic and behavioral traits comprising anesthetic states. These data support the conclusion that adenosine A(1) receptors in medial regions of the pontine reticular formation, known to modulate sleep, also contribute to the generation and/or maintenance of halothane anesthesia.
Spinal Carbonic Anhydrase Contributes to Nociceptive Reflex Enhancement by Midazolam, Pentobarbital, and Propofol
Authors: Wang Bing , Samanani Naaznin , Roth Sheldon H. , Archer David P.
Published: November 2003

Background

Systemic administration of acetazolamide blocks nociceptive hyperreflexia induced by pentobarbital. The authors assessed the effect of intrathecal carbonic anhydrase inhibitors (CAIs) on nociceptive reflex enhancement by pentobarbital, propofol, and midazolam.

Methods

Twenty-seven rats with chronic indwelling subarachnoid catheters were studied. Nociceptive paw reflex latency (PWL) for paw withdrawal from radiant heat was measured in forelimbs and hind limbs. Measurements were obtained under control conditions, 15 min after lumbar intrathecal injection of 10 microl artificial cerebrospinal fluid containing the CAIs acetazolamide or ethoxyzolamide, and during the 55 min after intraperitoneal injection of three sedative drugs: 30 mg/kg pentobarbital, 50 mg/kg propofol, or 1.9 mg/kg midazolam.

Results

Control values of PWL averaged 10.9 +/- 1.5 s in the forelimbs and 11.1 +/- 1.6 s in the hind limbs (P = 0.18). Intrathecal injection of 50 microm ethoxyzolamide reduced PWL by 8% and 4% in the forelimbs and hind limbs, respectively (P = 0.01); all other CAI injections had no effect on PWL. Following anesthetic injection, PWL in the forelimbs was reduced by approximately 35-40% of control values; in the hind limbs, CAI treatment decreased the PWL reduction to 8-16% for pentobarbital (P < 0.001), 30-32% for propofol (P < 0.02), and 9-16% for midazolam (P < 0.001). The hind limb reduction of hyperreflexia by CAI was less for propofol than for midazolam or pentobarbital (P < 0.002).

Conclusion

Spinal carbonic anhydrase contributes to nociceptive hyperreflexia induced by pentobarbital and midazolam and to a lesser extent with propofol. These findings are consistent with a role for carbonic anhydrase in nociceptive signal enhancement by these drugs.
The Effects of Isoflurane and Desflurane on Intracranial Pressure, Cerebral Perfusion Pressure, and Cerebral Arteriovenous Oxygen Content Difference in Normocapnic Patients with Supratentorial Brain Tumors
Authors: Fraga Marcial , Rama-Maceiras Pablo , Rodiño Sara , Aymerich Humberto , Pose Pilar , Belda Javier
Published: November 2003

Background

Desflurane is a volatile anesthetic agent with low solubility whose use in neurosurgery has been debated because of its effect on intracranial pressure and cerebral blood flow. The purpose of this study was to determine the variations on intracranial pressure (ICP) and cerebral perfusion pressure (CPP) as well as on cerebral arteriovenous oxygen content difference (AVDo(2)) in normocapnic patients scheduled to undergo removal of supratentorial brain tumors with no evidence of mass effect during anesthesia with isoflurane or desflurane.

Methods

In 60 patients scheduled to undergo craniotomy and removal of supratentorial brain tumors with no evidence of midline shift, anesthesia was induced with intravenous fentanyl, thiopental, and vecuronium and was maintained with 60% nitrous oxide in oxygen. Patients were assigned to two groups randomized to receive 1 minimum alveolar concentration isoflurane or desflurane for 30 min. Heart rate, mean arterial pressure, intraparenchymal ICP, and CPP were monitored continuously. Before and after 30 min of continuous administration of the inhaled agents, AVDo(2) was calculated.

Results

There were no significant differences between groups in heart rate, mean arterial pressure, ICP, and CPP. ICP measurements throughout the study did not change within each group compared to baseline values. Mean arterial pressure decreased significantly in all patients compared to baseline values, changing from 105 +/- 14 mmHg (mean +/- SD) to 85 +/- 10 mmHg in the isoflurane group and from 107 +/- 11 mmHg to 86 +/- 10 mmHg in the desflurane group (P < 0.05 in both groups). CPP also decreased within each group compared with baseline values, changing from 95 +/- 15 mmHg to 74 +/- 11 mmHg in the isoflurane group and from 95 +/- 16 mmHg to 74 +/- 10 mmHg in the desflurane group (P < 0.05 in both groups). Cerebral AVDo(2) decreased significantly in both groups throughout the study, changing from 2.35 +/- 0.77 mm to 1.82 +/- 0.61 mm (mmol/l) in the isoflurane group (P < 0.05) and from 2.23 +/- 0.72 mm to 1.94 +/- 0.76 mm in the desflurane group (P < 0.05), without differences between groups.

Conclusions

The results of this study indicate that there are no variations on ICP in normocapnic patients undergoing removal of supratentorial brain tumors without midline shift, as they were anesthetized with isoflurane or desflurane. CPP and cerebral AVDo(2) decreased with both agents.
Midazolam Stimulates Vascular Endothelial Growth Factor Release in Aortic Smooth Muscle Cells
Authors: Tanabe Kumiko , Dohi Shuji , Matsuno Hiroyuki , Hirade Kouseki , Kozawa Osamu
Published: November 2003

Background

Intravenous anesthetics used during perioperative periods affect the vascular signaling molecules and the vascular reactivity. Vascular endothelial growth factor (VEGF), an angiogenesis factor produced in and secreted from aortic smooth muscle cells, is a specific mitogen for vascular endothelial cells. This study investigated the effects of various intravenous anesthetics on VEGF release, and the underlying mechanism, in a rat aortic smooth muscle cell line, A10 cells.

Methods

Intravenous anesthetics (midazolam and propofol) were continuously administered to rats by infusion. Cultured A10 cells were stimulated by intravenous anesthetics (midazolam, propofol, and ketamine). VEGF was evaluated by immunoassay. The phosphorylation of mitogen-activated protein (MAP) kinases was evaluated by Western blotting.

Results

Continuous infusion of midazolam, but not propofol, increased the VEGF concentration in rat plasma. In cultured cells, midazolam stimulated VEGF release, but propofol and ketamine did not. Midazolam induced phosphorylation of p44/p42 MAP kinase and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK), without affecting p38 MAP kinase. PD98059 and U0126, specific inhibitors of MAP kinase kinase, significantly reduced the midazolam-stimulated release of VEGF. SP600125, a specific inhibitor of SAPK/JNK, significantly reduced midazolam-stimulated VEGF release. Applied together, PD98059 and SP600125 produced an additive reduction in midazolam-stimulated VEGF release. Moreover, a bolus injection of PD98059 truly inhibited the midazolam-increased VEGF concentration in rat plasma in vivo.

Conclusions

Midazolam, but not propofol or ketamine, stimulates VEGF release in aortic smooth muscle cells. Its effect is mediated at least in part via activation of p44/p42 MAP kinase and SAPK/JNK.
Combinations of Morphine with Ketamine for Patient-controlled Analgesia
Authors: Sveticic Gorazd , Gentilini Andrea , Eichenberger Urs , Luginbühl Martin , Curatolo Michele
Published: November 2003

Background

According to previous studies, the addition of ketamine to morphine for intravenous patient-controlled analgesia (PCA) may be beneficial. The authors developed and applied a new model to optimize the combination of morphine, ketamine, and a lockout interval for PCA after lumbar spine and hip surgery.

Methods

One-hundred two patients undergoing lumbar spine or hip surgery participated in the study. The analgesic effect of PCA during 48 h after surgery was optimized under restrictions dictated by side effects. Initially, eight combinations of morphine, ketamine (expressed as drug concentration in the solution administered), and a lockout interval (i.e., minimal allowed time between two consecutive PCA boluses) were empirically chosen and investigated. To determine subsequent combinations, an optimization model was applied until three consecutive steps showed no decrease in pain score.

Results

The authors analyzed 12 combinations with an allowed morphine and ketamine range in a PCA solution of 0-2 mg/ml and a lockout interval range of 5-12 min. During the optimization procedure, a reduction in mean pain scores with a low incidence of side effects was observed. The procedure converged to a morphine-to-ketamine ratio of 1:1 and a lockout interval of 8 min.

Conclusions

Using a novel method to analyze drug combinations, the study supports combinations of morphine with ketamine in a ratio of 1:1 and a lockout interval of 8 min for postoperative PCA following spine and hip surgery.
Piriformis Syndrome
Authors: Benzon Honorio T. , Katz Jeffrey A. , Benzon Hubert A. , Iqbal Muhammad S.
Published: November 2003

Background

Piriformis syndrome can be caused by anatomic abnormalities. The treatments of piriformis syndrome include the injection of steroid into the piriformis muscle and near the area of the sciatic nerve. These techniques use either fluoroscopy and muscle electromyography to identify the piriformis muscle or a nerve stimulator to stimulate the sciatic nerve.

Methods

The authors performed a cadaver study and noted anatomic variations of the piriformis muscle and sciatic nerve. To standardize their technique of injection, they also noted the distance from the lower border of the sacroiliac joint (SIJ) to the sciatic nerve. They retrospectively reviewed the charts of 19 patients who had received piriformis muscle injections, noting the site of needle insertion in terms of the distance from the lower border of the SIJ and the depth of needle insertion at which the motor response of the foot was elicited. The authors tabulated the response of the patients to the injection, any associated diagnoses, and previous treatments that these patients had before the injection. Finally, they reviewed the literature on piriformis syndrome, a rare cause of buttock pain and sciatica.

Results

In the cadavers, the distance from the lower border of the SIJ to the sciatic nerve was 2.9 +/- 0.6 (1.8-3.7) cm laterally and 0.7 +/- 0.7 (0.0-2.5) cm caudally. In 65 specimens, the sciatic nerve passed anterior and inferior to the piriformis. In one specimen, the muscle was bipartite and the two components of the sciatic nerve were separate, with the tibial nerve passing below the piriformis and the peroneal nerve passing between the two components of the muscle. In the patients who received the injections, the site of needle insertion was 1.5 +/- 0.8 (0.4-3.0) cm lateral and 1.2 +/- 0.6 (0.5-2.0) cm caudal to the lower border of the SIJ as seen on fluoroscopy. The needle was inserted at a depth of 9.2 +/- 1.5 (7.5-13.0) cm to stimulate the sciatic nerve. Patients had comorbid etiologies including herniated disc, failed back surgery syndrome, spinal stenosis, facet syndrome, SIJ dysfunction, and complex regional pain syndrome. Sixteen of the 19 patients responded to the injection, their improvements ranged from a few hours to 3 months.

Conclusions

Anatomic abnormalities causing piriformis syndrome are rare. The technique used in the current study was successful in injecting the medications near the area of the sciatic nerve and into the piriformis muscle.
Large-dose Hydroxyethyl Starch 130/0.4 Does Not Increase Blood Loss and Transfusion Requirements in Coronary Artery Bypass Surgery Compared with Hydroxyethyl Starch 200/0.5 at Recommended Doses
Authors: Kasper Stefan-Mario , Meinert Philipp , Kampe Sandra , Görg Christoph , Geisen Christof , Mehlhorn Uwe , Diefenbach Christoph
Published: November 2003

Background

Hydroxyethyl starch (HES) 130/0.4 may impair blood coagulation less than other HES solutions and, thus, may be used at larger doses without increasing the risk of postoperative bleeding. This study tested the hypothesis that volume replacement with 6% HES 130/0.4 at a dose of up to 50 ml/kg does not increase blood loss and transfusion requirements in elective coronary artery bypass surgery compared with 6% HES 200/0.5 at a dose of up to 33 ml/kg.

Methods

One hundred twenty adult patients scheduled for elective coronary artery bypass surgery were randomized to receive up to 50 ml/kg of 6% HES 130/0.4 or up to 33 ml/kg of 6% HES 200/0.5 for volume replacement during surgery and until 24 h thereafter. Volume requirements in excess of the respective maximum dose of HES were treated with gelatin. Colloid use was at the discretion of the attending physicians and not dictated by protocol. The primary outcome variable was chest tube drainage volume during the first 24 h after surgery.

Results

The data from 117 patients (HES 130/0.4, 59 patients; HES 200/0.5, 58 patients) who completed the study according to protocol were analyzed. The median volumes of HES administered were 49 and 33 ml/kg in the HES 130/0.4 and HES 200/0.5 groups, respectively (P < 0.001). Consequently, patients in the HES 130/0.4 group required less gelatin in addition to HES than those in the HES 200/0.5 group (medians: 7 ml/kg vs. 20 ml/kg, P < 0.001). The combined volumes of HES and gelatin were similar for both groups (P = 0.21). The 24-h chest tube drainage (medians: 660 ml vs. 705 ml, P = 0.60) did not differ significantly between the groups, nor did transfusion outcome.

Conclusion

Six percent HES 130/0.4 at a median dose of 49 ml/kg did not increase blood loss and transfusion requirements in coronary artery bypass surgery compared with 6% HES 200/0.5 at a median dose of 33 ml/kg.
Translocation of Protein Kinase C Isoforms to Subcellular Targets in Ischemic and Anesthetic Preconditioning
Authors: Uecker Marina , da Silva Rafaela , Grampp Thomas , Pasch Thomas , Schaub Marcus C. , Zaugg Michael
Published: November 2003

Background

Translocation of protein kinase C (PKC) to subcellular targets is a pivotal signaling step in ischemic preconditioning (IPC). However, to date, it is unknown whether PKC isoforms translocate in anesthetic preconditioning (APC).

Methods

The PKC blockers chelerythrine and rottlerin and the adenosine triphosphate-dependent potassium (K(ATP)) channel blockers HMR-1098 and 5-hydroxydecanoate were used to assess the role of PKC and K(ATP) channels in isolated perfused rat hearts subjected to IPC or APC (1.5 minimum alveolar concentration isoflurane) followed by 40 min of ischemia and 30 min of reperfusion. Immunohistochemical techniques were used to visualize PKC translocation after preconditioning. In addition, the phosphorylation status of PKC isoforms was assessed.

Results

Chelerythrine, rottlerin, and 5-hydroxydecanoate blocked IPC and APC with respect to functional recovery, albeit IPC at higher concentrations. HMR-1098 did not affect IPC or APC. PKCdelta and PKCepsilon translocated to nuclei in both IPC and APC, which was inhibited by chelerythrine and rottlerin. PKCdelta translocated to mitochondria but not to the sarcolemma, and PKCepsilon translocated to the sarcolemma and intercalated disks but not to mitochondria. Interestingly, PKCepsilon was accumulated at the intercalated disks in control and preconditioned hearts. Phosphorylation of PKCdelta on serine643 was increased in IPC and APC and blocked by chelerythrine and rottlerin, whereas phosphorylation of PKCdelta on threonine505 was increased only in IPC and not blocked by chelerythrine or rottlerin. PKCepsilon on serine729 did not change its phosphorylation status.

Conclusions

This study indicates that translocation of PKCdelta plays a pivotal role in IPC and APC and suggests that phosphorylation of PKCdelta on serine643 may be of particular relevance in transferring the APC stimulus to mitochondrial K(ATP) channels.
Laryngeal Resistance before and after Minor Surgery
Authors: Tanaka Atsuko , Isono Shiroh , Ishikawa Teruhiko , Sato Jiro , Nishino Takashi
Published: November 2003

Background

The placement of an endotracheal tube (ETT) may promote laryngeal swelling, which is an important cause of upper airway obstruction after extubation. The authors hypothesized that laryngeal swelling after ETT placement increases laryngeal resistance and tested that hypothesis by comparing postoperative laryngeal patency between patients with ETT placement and those with a Laryngeal Mask Airway trade mark (LMA).

Methods

Fourteen adult patients who underwent elective minor surgeries were randomly allocated to two groups whose airway would be managed through ETTs (the ETT group) or LMAs (the LMA group) during the surgery. While maintaining at sevoflurane 1 minimum alveolar concentration, the authors measured laryngeal resistance before and after surgery, during both spontaneous breathing and mechanical ventilation under complete paralysis. In addition, they endoscopically measured the vocal cord angle under complete paralysis.

Results

In association with marked swelling of the vocal cords, the vocal cord angle significantly decreased after surgery in the ETT group, whereas the angle did not change in the LMA group. Laryngeal resistance during mechanical ventilation significantly increased only in the ETT group. Laryngeal resistance during spontaneous breathing significantly increased after surgeries in both groups.

Conclusions

Postoperative laryngeal resistance increases at least in part because of laryngeal swelling in patients with ETT placement, whereas alteration of laryngeal neural control mechanisms has been also indicated. The use of the LMA trade mark has an advantage over ETT placement in order to avoid postoperative laryngeal swelling.
Short- and Long-term Prognostic Value of Postoperative Cardiac Troponin I Concentration in Patients Undergoing Coronary Artery Bypass Grafting
Authors: Fellahi Jean-Luc , Gué Xavier , Richomme Xavier , Monier Emmanuel , Guillou Louis , Riou Bruno
Published: November 2003

Background

The value of postoperative cardiac troponin I (cTnI) has been shown to indicate a higher risk of in-hospital death after cardiac surgery. The authors therefore assessed the long-term prognostic value of cTnI in patients undergoing elective coronary artery bypass grafting.

Methods

Consecutive patients (n = 202) were included and divided into two groups according to the postoperative value of cTnI (< or >/= 13 ng/ml). In-hospital mortality and nonfatal cardiac events (delayed extubation > 24 h; postoperative requirement of inotropic agent; ventricular and supraventricular arrhythmia; postoperative myocardial infarction) were recorded. Survivors were then followed up over a 2-yr period. Data are median and odds ratio (95% confidence interval).

Results

Of all patients, 174 (86%) had a low cTnI (4.1 ng/ml; range, 1.1-12.6) and 28 (14%) had a high cTnI (23.8 ng/ml; range, 13.4-174.6). In-hospital mortality was not significantly different (4 vs. 2%), whereas long-term mortality (18 vs. 3%, P = 0.006) and mortality from cardiac cause (18 vs. 1%, P < 0.001) was greater in patients with a high cTnI. A high cTnI was a significant factor predicting death (odds ratio, 7.3 [2.0-27.1]) or death from cardiac causes (odds ratio, 37.4 [4.2-334.4]). Nonfatal cardiac events were also more frequent in the hospital (64 vs. 41%, P = 0.02) and within the 2-yr follow-up period (39% vs. 16%, P = 0.03) in patients with high cTnI.

Conclusion

A high postoperative peak of cTnI is associated with increased risk of death, death from cardiac causes, and nonfatal cardiac events within 2 yr after coronary artery bypass grafting.
Thiopental Inhibits Tumor Necrosis Factor α–induced Activation of Nuclear Factor κB through Suppression of IκB Kinase Activity
Authors: Loop Torsten , Humar Matjaz , Pischke Soeren , Hoetzel Alexander , Schmidt Rene , Pahl Heike L. , Geiger Klaus K. , Pannen Benedikt H. J.
Published: November 2003

Background

Thiopental is frequently used for the treatment of intracranial hypertension after severe head injury and is associated with immunosuppressive effects. The authors have recently reported that thiopental inhibits activation of nuclear factor (NF) kappaB, a transcription factor implicated in the expression of many inflammatory genes. Thus, it was the aim of the current study to examine the molecular mechanism of this inhibitory effect.

Methods

The authors tested gamma-aminobutyric acid (GABA), the GABA(A) antagonist bicuculline, and the GABA(B) antagonist dichlorophenyl-methyl-amino-propyl-diethoxymethyl-phosphinic acid (CGP 52432) in combination with thiopental for their influence on the activation of NF-kappaB. In addition, they investigated the direct effect of thiopental on activated NF-kappaB DNA binding activity. These experiments were conducted in Jurkat T lymphocytes using electrophoretic mobility shift assays. The presence of the phosphorylated and dephosphorylated NF-kappaB inhibitor IkappaBalpha (Western blotting) and IkappaB kinase activity were studied in Jurkat T cells and human CD3+ T lymphocytes. In addition, the authors tested the effect of the structural barbiturate analog pairs thiopental-pentobarbital and thiamylal-secobarbital and of thiopental in combination with the thio-group containing chemical dithiothreitol on the activation of NF-kappaB.

Results

GABA did not inhibit NF-kappaB activation, and the GABA(A) and GABA(B) antagonists bicuculline and CGP did not diminish the thiopental-mediated inhibitory effect on NF-kappaB activation. Thiopental did not inhibit activated NF-kappaB directly in a cell-free system. The phosphorylation of IkappaBalpha was prevented after incubation with 1,000 microg/ml thiopental. The same concentration of thiopental also inhibited IkappaB kinase activity in tumor necrosis factor-stimulated Jurkat T cells and human CD3+ T lymphocytes (60% suppression, P < 0.05 vs. tumor necrosis factor alpha alone). Thiobarbiturates (4 x 10(-3) m) inhibited NF-kappaB activity, whereas equimolar concentrations of the structural oxyanalogs did not. Preincubation of thiopental with dithiothreitol diminished the inhibitory effect.

Conclusion

Thiopental-mediated inhibition of NF-kappaB activation is due to the suppression of IkappaB kinase activity and depends at least in part on the thio-group of the barbiturate molecule.
Neuroprotective Effects of Propofol in a Model of Ischemic Cortical Cell Cultures
Authors: Velly Lionel J. , Guillet Benjamin A. , Masmejean Frederique M. , Nieoullon André L. , Bruder Nicolas J. , Gouin François M. , Pisano Pascale M.
Published: November 2003

Background

During cerebral ischemia, excess of glutamate release and dysfunction of its high affinity transport induce an accumulation of extracellular glutamate, which plays an important role in neuronal death. The authors studied the relationship among propofol neuroprotection, glutamate extracellular concentrations, and glutamate transporter activity in a model of ischemic cortical cell cultures.

Methods

Thirteen-day-old primary cortical neuronal-glial cultures were exposed to a 90-min combined oxygen-glucose deprivation (OGD) in an anaerobic chamber, followed by reoxygenation. Propofol was added only during the OGD period, and its effect was compared to that of the N-methyl-d-aspartate receptor antagonist dizocilpine (MK-801). Twenty-four hours after the injury, cell death was quantified by lactate dehydrogenase release and cell viability by reduction of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT). Extracellular concentrations of glutamate in culture supernatants and glutamate uptake were performed at the end of OGD period by high-performance liquid chromatography and incorporation of l-[3H]glutamate into cells, respectively.

Results

At clinically relevant concentrations (0.05-10 microm), propofol offered protection equivalent to that of MK-801. It significantly reduced lactate dehydrogenase release and increased the reduction of MTT. At the end of the ischemic injury, propofol was able to reverse the OGD-induced increase in glutamate extracellular concentrations and decrease of glutamate uptake. The inhibition of the glial GLT1 transporter by 3-methyl-glutamate did not further modify the effect of propofol on glutamate uptake, suggesting that GLT1 was not the major target of propofol.

Conclusion

Propofol showed a neuroprotective effect in this in vitro model of OGD, which was apparently mediated by a GLT1-independent restoration of the glutamate uptake impaired during the injury.
G-protein Activation Decreases Isoflurane Inhibition of N-type Ba2+Currents
Authors: Nikonorov Igor M. , Blanck Thomas J. J. , Recio-Pinto Esperanza
Published: November 2003

Background

G-protein activation mediates inhibition of N-type Ca2+ currents. Volatile anesthetics affect G-protein pathways at various levels, and activation of G-proteins has been shown to increase the volatile anesthetic potency for inhibiting the electrical-induced contraction in ileum. The authors investigated whether isoflurane inhibition of N-type Ba2+ currents was mediated by G-protein activation.

Methods

N-type Ba2+ currents were measured in the human neuronal SH-SY5Y cell line by using the whole cell voltage-clamp method.

Results

Isoflurane was found to have two effects on N-type Ba2+ currents. First, isoflurane reduced the magnitude of N-type Ba2+ currents to a similar extent (IC50 approximately 0.28 mm) in the absence and presence of GDPbetaS (a nonhydrolyzable GDP analog). Interestingly, GTPgammaS (a nonhydrolyzable GTP analog and G-protein activator) in a dose-dependent manner reduced the isoflurane block; 120 microm GTPgammaS completely eliminated the block of 0.3 mm isoflurane and reduced the apparent isoflurane potency by approximately 2.4 times (IC50 approximately 0.68 mm). Pretreatment with pertussis toxin or cholera toxin did not eliminate the GTPgammaS-induced protection against the isoflurane block. Furthermore, isoflurane reduced the magnitude of voltage-dependent G-protein-mediated inhibition of N-type Ba2+ currents, and this effect was eliminated by pretreatment with pertussis toxin or cholera toxin.

Conclusions

It was found that activation of G-proteins in a neuronal environment dramatically reduced the isoflurane potency for inhibiting N-type Ba2+ currents and, in turn, isoflurane affected the G-protein regulation of N-type Ba2+ currents.
Reactive Oxygen Species Precede the ε Isoform of Protein Kinase C in the Anesthetic Preconditioning Signaling Cascade
Authors: Novalija Enis , Kevin Leo G. , Camara Amadou K.S. , Bosnjak Zeljko J. , Kampine John P. , Stowe David F.
Published: November 2003

Background

Protein kinase C (PKC) and reactive oxygen species (ROS) are known to have a role in anesthetic preconditioning (APC). Cardiac preconditioning by triggers other than volatile anesthetics, such as opioids or brief ischemia, is known to be isoform selective, but the isoform required for APC is not known. The authors aimed to identify the PKC isoform that is involved in APC and to elucidate the relative positions of PKC activation and ROS formation in the APC signaling cascade.

Methods

Isolated guinea pig hearts were subjected to 30 min of ischemia and 120 min of reperfusion. Before ischemia, hearts were either untreated or treated with sevoflurane (APC) in the absence or presence of the nonspecific PKC inhibitor chelerythrine, the PKC-delta inhibitor PP101, or the PKC-epsilon inhibitor PP149. Spectrofluorometry and the fluorescent probes dihydroethidium were used to measure intracellular ROS, and effluent dityrosine as used to measure extracellular ROS release.

Results

Previous sevoflurane exposure protected the heart against ischemia-reperfusion injury, as previously described. Chelerythrine or PP149 abolished protection, but PP101 did not. ROS formation was observed during sevoflurane exposure and was not altered by any of the PKC inhibitors.

Conclusions

APC is mediated by PKC-epsilon but not by PKC-delta. Furthermore, PKC activation probably occurs downstream of ROS generation in the APC signaling cascade.
Brachial Plexus Examination and Localization Using Ultrasound and Electrical Stimulation
Authors: Perlas Anahi , Chan Vincent W. S. , Simons Martin
Published: November 2003

Background

Current techniques of brachial plexus block are "blind," and nerve localization can be frustrating and time consuming. Previous studies on ultrasound-assisted brachial plexus blocks are mostly performed with scanning probes of 10 MHz or less. The authors tested the usefulness of a state-of-the-art, high-resolution ultrasound probe (up to 12 MHz) in identifying the brachial plexus in five locations of the upper extremity and in guiding needle advancement to target before nerve stimulation.

Methods

In this prospective observational study, 15 volunteers underwent brachial plexus examination using an L12-L5 MHz probe and a Philips-ATL 5000 ultrasound unit in the interscalene, supraclavicular, infraclavicular, axillary, and midhumeral regions. Thereafter, an insulated block needle was advanced under direct ultrasound guidance to target nerves before confirmation by electrical nerve stimulation in five volunteers in each of the interscalene, supraclavicular, and axillary regions. The quality of brachial plexus images, anatomic variations, and the technique of needle advancement for nerve localization were recorded.

Results

The brachial plexus components were successfully identified in the transverse view as round to oval hypoechoic structures with small internal punctuate echos in all regions examined except the infraclavicular area (visualized in 27% of the cases). The authors' technique of advancing the needle in-line with the ultrasound beam allowed moment-by-moment observation of the needle shaft and tip movement at the time of nerve localization. Hypoechoic structures were stimulated electrically and confirmed to be nerves.

Conclusions

These preliminary data show that the high-resolution L12-L5 probe provides good quality brachial plexus ultrasound images in the superficial locations i.e., the interscalene, supraclavicular, axillary, and midhumeral regions. The needle technique described here for ultrasound-assisted nerve localization provides real-time guidance and is potentially valuable for brachial plexus blocks.
Evaluation of the Lateral Modified Approach for Continuous Interscalene Block after Shoulder Surgery
Authors: Borgeat Alain , Dullenkopf Alexander , Ekatodramis Georgios , Nagy Ladislav
Published: November 2003

Background

Continuous interscalene block is the technique of choice for postoperative pain relief treatment after shoulder surgery. The authors prospectively evaluated the modified lateral approach for the performance of the interscalene catheter block and monitored 700 patients for clinical efficacy and complications during the first 6 months after placement of the catheter.

Methods

A total of 700 adults scheduled to undergo elective shoulder surgery performed with an interscalene brachial plexus block through an interscalene catheter were included in this study. The interscalene brachial plexus block procedure was standardized for all patients. Difficulties in placement of the catheter, clinical efficacy of anesthesia and analgesia, patient satisfaction, and acute and chronic complications were recorded. Patients were observed daily for 5 days for any complications and were evaluated at 1, 3, and 6 months after surgery. Persistence of neurologic complication was investigated by electroneuromyography.

Results

A total of 700 adults completed the study. Easy placement of the catheter (one attempt) was achieved in 86% of the patients. Resistance to thread the catheter was encountered in 6%; no major complications were observed during injection of the initial bolus. The success rate for anesthesia was 97%. Postoperative analgesia was efficient in 99%. The concentration and the rate of infusion of ropivacaine had to be increased in 31 patients (6%). In five patients (0.7%), signs of local infection around the puncture point were noted; in one patient (0.1%), a collection of pus was surgically drained. Patient satisfaction was 9.6 on a scale of 0-10. Minor neurologic complications (paresthesias, dysesthesias, pain not related to surgery) were observed in 2.4%, 0.3%, and 0% at 1, 3, and 6 months, respectively. At 1 month, three sulcus ulnaris syndromes, one carpal tunnel syndrome, and one complex regional pain syndrome were diagnosed. Two patients (0.2%) had sensory-motor deficit, which necessitated 19 and 28 weeks to recover. Electromyography was suggestive of partial axonotmesis.

Conclusion

The lateral modified approach provides good conditions for placement of the interscalene catheter. Anesthesia and analgesia performed through the catheter are efficient. The rates of infection and neurologic complications are low, and patient satisfaction is high.
Epidural, Cerebrospinal Fluid, and Plasma Pharmacokinetics of Epidural Opioids (Part 1)
Authors: Bernards Christopher M. , Shen Danny D. , Sterling Emily S. , Adkins Jason E. , Risler Linda , Phillips Brian , Ummenhofer Wolfgang
Published: November 2003

Background

The pharmacokinetics of epidurally administered drugs has been the subject of many studies, yet drug concentration in the epidural space has never been measured. This study was undertaken to characterize the epidural, cerebrospinal fluid, and plasma pharmacokinetics of epidurally administered opioids on the basis of measurement of drug concentration in each of these compartments after epidural administration.

Methods

Morphine plus alfentanil, fentanyl, or sufentanil were administered epidurally in anesthetized pigs. Microdialysis was used to sample the epidural space and the cerebrospinal fluid for measurement of opioid concentration over time. Plasma samples were obtained from the central venous plasma and the epidural venous plasma. These data were used to calculate relevant pharmacokinetic parameters, including mean residence time, elimination half-lives, areas under the concentration versus time curves, clearance, and volume of distribution for each opioid in each compartment.

Results

Some of the more important findings were that the cerebrospinal fluid and plasma pharmacokinetics of the opioids did not parallel their epidural pharmacokinetics and that their hydrophobic character governed multiple aspects of their lumbar epidural pharmacokinetics.

Conclusions

The findings indicate that the spinal pharmacokinetics of these drugs are complex and, in some ways, counterintuitive. Also, the bioavailability of opioids in the cerebrospinal fluid and epidural space is determined primarily by their hydrophobicity, with less hydrophobic drugs having greater bioavailability.
Effect of Increasing Depth of Propofol Anesthesia on Upper Airway Configuration in Children
Authors: Evans Russell G. , Crawford Mark W. , Noseworthy Michael D. , Yoo Shi-Joon
Published: November 2003

Background

The upper airway tends to be obstructed during anesthesia in spontaneously breathing patients. The purpose of the current study was to determine the effect of increasing depth of propofol anesthesia on airway size and configuration in children.

Methods

Magnetic resonance images of the upper airway were obtained in 15 children, aged 2-6 yr. Cross-sectional area, anteroposterior dimension, and transverse dimension were measured at the level of the soft palate, dorsum of the tongue, and tip of the epiglottis. Images were obtained during infusion of propofol at a rate of 50-80 microg.kg-1.min-1 and after increasing the depth of anesthesia by administering a bolus dose of propofol and increasing the infusion rate to 240 microg.kg-1.min-1.

Results

Overall, the cross-sectional area of the entire pharyngeal airway decreased with increasing depth of anesthesia. The reduction in cross-sectional area was greatest at the level of the epiglottis (24.5 mm2, 95% confidence interval = 16.9-32.2 mm2; P < 0.0001), intermediate at the level of the tongue (19.3 mm2, 95% confidence interval = 9.2-29.3 mm2; P < 0.0001), and least at the level of the soft palate (12.6 mm2, 95% confidence interval = 2.7-22.6 mm2; P < 0.005) in expiration and resulted predominantly from a reduction in anteroposterior dimension. The airway cross-sectional area decreased further in inspiration at the level of the epiglottis. The narrowest portion of the airway resided at the level of the soft palate or epiglottis in the majority of children.

Conclusion

Increasing depth of propofol anesthesia in children is associated with upper airway narrowing that occurs throughout the entire upper airway and is most pronounced in the hypopharynx at the level of the epiglottis.
Mechanisms of Direct Inhibitory Action of Isoflurane on Vascular Smooth Muscle of Mesenteric Resistance Arteries
Authors: Akata Takashi , Kanna Tomoo , Yoshino Jun , Takahashi Shosuke
Published: November 2003

Background

Isoflurane has been shown to directly inhibit vascular reactivity. However, less information is available regarding its underlying mechanisms in systemic resistance arteries.

Methods

Endothelium-denuded smooth muscle strips were prepared from rat mesenteric resistance arteries. Isometric force and intracellular Ca2+ concentration ([Ca2+]i) were measured simultaneously in the fura-2-loaded strips, whereas only the force was measured in the beta-escin membrane-permeabilized strips.

Results

Isoflurane (3-5%) inhibited the increases in both [Ca2+]i and force induced by either norepinephrine (0.5 microM) or KCl (40 mM). These inhibitions were similarly observed after depletion of intracellular Ca2+ stores by ryanodine. Regardless of the presence of ryanodine, after washout of isoflurane, its inhibition of the norepinephrine response (both [Ca2+]i and force) was significantly prolonged, whereas that of the KCl response was quickly restored. In the ryanodine-treated strips, the norepinephrine- and KCl-induced increases in [Ca2+]i were both eliminated by nifedipine, a voltage-gated Ca2+ channel blocker, whereas only the former was inhibited by niflumic acid, a Ca2+-activated Cl- channel blocker. Isoflurane caused a rightward shift of the Ca2+-force relation only in the fura-2-loaded strips but not in the beta-escin-permeabilized strips.

Conclusions

In mesenteric resistance arteries, isoflurane depresses vascular smooth muscle reactivity by directly inhibiting both Ca2+ mobilization and myofilament Ca2+ sensitivity. Isoflurane inhibits both norepinephrine- and KCl-induced voltage-gated Ca2+ influx. During stimulation with norepinephrine, isoflurane may prevent activation of Ca2+-activated Cl- channels and thereby inhibit voltage-gated Ca2+ influx in a prolonged manner. The presence of the plasma membrane appears essential for its inhibition of the myofilament Ca2+ sensitivity.
Corticotropin-releasing Factor Mediates the Antinociceptive Action of Nitrous Oxide in Rats
Authors: Sawamura Shigehito , Obara Mizuki , Takeda Kenji , Maze Mervyn , Hanaoka Kazuo
Published: November 2003

Background

Exposure to nitrous oxide activates brainstem noradrenergic nuclei and descending inhibitory pathways, which produce the acute antinociceptive action of nitrous oxide. Because corticotropin-releasing factor (CRF) can produce activation of noradrenergic neurons in the locus ceruleus, the authors sought to determine whether it might be responsible for the antinociceptive action of nitrous oxide.

Methods

Male Sprague-Dawley rats (250-300 g) were exposed for 60 min to room air or 25, 50 or 70% nitrous oxide in oxygen. Brain sections including the hypothalamus were immunostained for both c-Fos (a marker of neuronal activation) and CRF and the percentage of CRF-positive neurons expressing c-Fos was determined. The functional consequences of changes in CRF were investigated by assessing the effect of intracerebroventricular administration of a CRF antagonist (alpha-helical CRF9-41, 20 microg/10 microl) on both activation of locus ceruleus noradrenergic neurons and the antinociception (with the tail-flick latency test) produced by nitrous oxide.

Results

Inhalation of nitrous oxide induced a dose-dependent increase in c-Fos expression in CRF-positive neurons in the paraventricular nucleus of the hypothalamus. Intracerebroventricular administration of CRF antagonist inhibited nitrous oxide-induced c-Fos expression in the locus ceruleus and the antinociceptive effect of nitrous oxide.

Conclusions

Nitrous oxide activates the CRF system in the brain, which results in stimulation of noradrenergic neurons in the locus ceruleus and its consequent antinociceptive effect.