bluuebunny/crossref_metadata_2025 huggingface dataset:
Closed-loop Control of Mean Arterial Blood Pressure during Surgery with Alfentanil
Authors: Luginbühl Martin , Bieniok Christian , Leibundgut Daniel , Wymann Rolf , Gentilini Andrea , Schnider Thomas W.
Published: August 2006

Background

In contrast to hypnosis, there is no surrogate parameter for analgesia in anesthetized patients. Opioids are titrated to suppress blood pressure response to noxious stimulation. The authors evaluated a novel model predictive controller for closed-loop administration of alfentanil using mean arterial blood pressure and predicted plasma alfentanil concentration (Cp Alf) as input parameters.

Methods

The authors studied 13 healthy patients scheduled to undergo minor lumbar and cervical spine surgery. After induction with propofol, alfentanil, and mivacurium and tracheal intubation, isoflurane was titrated to maintain the Bispectral Index at 55 (+/- 5), and the alfentanil administration was switched from manual to closed-loop control. The controller adjusted the alfentanil infusion rate to maintain the mean arterial blood pressure near the set-point (70 mmHg) while minimizing the Cp Alf toward the set-point plasma alfentanil concentration (Cp Alfref) (100 ng/ml).

Results

Two patients were excluded because of loss of arterial pressure signal and protocol violation. The alfentanil infusion was closed-loop controlled for a mean (SD) of 98.9 (1.5)% of presurgery time and 95.5 (4.3)% of surgery time. The mean (SD) end-tidal isoflurane concentrations were 0.78 (0.1) and 0.86 (0.1) vol%, the Cp Alf values were 122 (35) and 181 (58) ng/ml, and the Bispectral Index values were 51 (9) and 52 (4) before surgery and during surgery, respectively. The mean (SD) absolute deviations of mean arterial blood pressure were 7.6 (2.6) and 10.0 (4.2) mmHg (P = 0.262), and the median performance error, median absolute performance error, and wobble were 4.2 (6.2) and 8.8 (9.4)% (P = 0.002), 7.9 (3.8) and 11.8 (6.3)% (P = 0.129), and 14.5 (8.4) and 5.7 (1.2)% (P = 0.002) before surgery and during surgery, respectively. A post hoc simulation showed that the Cp Alfref decreased the predicted Cp Alf compared with mean arterial blood pressure alone.

Conclusion

The authors' controller has a similar set-point precision as previous hypnotic controllers and provides adequate alfentanil dosing during surgery. It may help to standardize opioid dosing in research and may be a further step toward a multiple input-multiple output controller.
Airway Injuries after One-lung Ventilation: A Comparison between Double-lumen Tube and Endobronchial Blocker
Authors: Knoll Heike , Ziegeler Stephan , Schreiber Jan-Uwe , Buchinger Heiko , Bialas Patric , Semyonov Kirill , Graeter Thomas , Mencke Thomas
Published: August 2006

Background

Vocal cord injuries, postoperative hoarseness, and sore throat are common complications after general anesthesia. One-lung ventilation can be achieved via two techniques: double-lumen endotracheal tube or endobronchial blocker such as the Arndt blocker. The current study was designed to assess the impact of these techniques for one-lung ventilation on the incidence and severity of postoperative hoarseness, vocal cord lesions, and sore throat.

Methods

In this prospective trial, 60 patients were randomly assigned to two groups. One-lung ventilation was achieved with either an endobronchial blocker (blocker group) or a double-lumen-tube (double-lumen group). Postoperative hoarseness and sore throat were assessed at 24, 48, and 72 h after surgery. Bronchial injuries and vocal cord lesions were examined by bronchoscopy immediately after surgery.

Results

In 56 included patients, postoperative hoarseness occurred significantly more frequently in the double-lumen group compared with the blocker group: 44% versus 17%, respectively (P = 0.046). Similar findings were observed for vocal cord lesions: 44% versus 17%, respectively (P = 0.046). The incidence of bronchial injuries was comparable between groups (P = 0.540). Cumulative number of days with hoarseness and sore throat were significantly increased in the double-lumen group compared with the blocker group (P < 0.01). No major complications such as bronchial ruptures were observed.

Conclusions

Clinicians should be aware of an increased incidence of minor airway injuries that may impair patient satisfaction when using a double-lumen tube instead of an endobronchial blocker for one-lung ventilation.
Human Skin Microcirculation after Brachial Plexus Block Evaluated by Wavelet Transform of the Laser Doppler Flowmetry Signal
Authors: Landsverk Svein A. , Kvandal Per , Kjelstrup Trygve , Benko Uros , Bernjak Alan , Stefanovska Aneta , Kvernmo Hebe , Kirkeboen Knut A.
Published: August 2006

Background

The skin microcirculation may be evaluated noninvasively by laser Doppler flowmetry and iontophoresis with acetylcholine and sodium nitroprusside. Wavelet transform of the perfusion signal shows periodic oscillations of five characteristic frequencies in the interval 0.0095-1.6 Hz. The aim of the current study was to investigate alterations in skin microcirculation induced by brachial plexus block, with emphasis on the periodic oscillations.

Methods

Healthy nonsmokers undergoing hand surgery (n = 13) were anesthetized with brachial plexus block, using bupivacaine, lidocaine, and epinephrine. Skin microcirculation was evaluated by laser Doppler flowmetry and iontophoresis with acetylcholine and sodium nitroprusside before and after brachial plexus block. Wavelet transform of the perfusion signal was performed. As a control group, 10 healthy nonsmokers were included.

Results

In the anesthetized arm, skin perfusion after brachial plexus block increased from 19 (12-30) to 24 (14-39) arbitrary units (P < 0.01). A significant increase was also seen in the contralateral arm from 17 (14-32) to 20 (14-42) arbitrary units (P < 0.01). After brachial plexus block, spectral analysis revealed a significant reduction in relative amplitude of the oscillatory components within the 0.0095- to 0.021- (P < 0.001) and 0.021- to 0.052-Hz (P < 0.001) intervals in the anesthetized arm.

Conclusion

Alterations in skin microcirculation induced by brachial plexus block can be evaluated by wavelet transform of the laser Doppler flowmetry signal. Brachial plexus block reduces the oscillatory components within the 0.0095- to 0.021- and 0.021- to 0.052-Hz intervals of the perfusion signal. These alterations are related to inhibition of sympathetic activity and a possible impairment of endothelial function.
Association between Increases in Urinary Neutrophil Gelatinase–associated Lipocalin and Acute Renal Dysfunction after Adult Cardiac Surgery
Authors: Wagener Gebhard , Jan Michael , Kim Mihwa , Mori Kiyoshi , Barasch Jonathan M. , Sladen Robert N. , Lee H Thomas
Published: August 2006

Background

Acute renal dysfunction (ARD) and subsequent acute renal failure after cardiac surgery are associated with high mortality and morbidity. Early therapeutic or preventive intervention is hampered by the lack of an early biomarker for acute renal injury. Recent studies showed that urinary neutrophil gelatinase-associated lipocalin (NGAL or lipocalin 2) is up-regulated early (within 1-3 h) after murine renal injury and in pediatric ARD after cardiac surgery. The authors hypothesized that postoperative urinary NGAL concentrations are increased in adult patients developing ARD after cardiac surgery compared with patients without ARD.

Methods

After institutional review board approval, 81 cardiac surgical patients were prospectively studied. Urine samples were collected immediately before incision and at various time intervals after surgery for NGAL analysis by quantitative immunoblotting. ARD was defined as peak postoperative serum creatinine increase by 50% or greater compared with preoperative serum creatinine.

Results

Sixteen of 81 patients (20%) developed postoperative ARD, and the mean urinary NGAL concentrations in patients who developed ARD were significantly higher early after surgery (after 1 h: 4,195 +/- 6,520 [mean +/- SD] vs. 1,068 +/- 2,129 ng/ml; P < 0.01) compared with patients who did not develop ARD. Mean urinary NGAL concentrations continued to increase and remained significantly higher at 3 and 18 h after cardiac surgery in patients with ARD. In contrast, urinary NGAL in patients without ARD decreased rapidly after cardiac surgery.

Conclusions

Patients developing postoperative ARD had significantly higher urinary NGAL concentrations early after cardiac surgery. Urinary NGAL may therefore be a useful early biomarker of ARD after cardiac surgery. These findings may facilitate the early detection of acute renal injury and potentially prevent progression to acute renal failure.
Tail Clamp Responses in Stomatin Knockout Mice Compared with Mobility Assays in Caenorhabditis elegans during Exposure to Diethyl Ether, Halothane, and Isoflurane
Authors: Sedensky Margaret M. , Pujazon Melissa A. , Morgan Phil G.
Published: August 2006

Background

The gene unc-1 plays a central role in determining volatile anesthetic sensitivity in Caenorhabditis elegans. Because different unc-1 alleles cause strikingly different phenotypes in different volatile anesthetics, the UNC-1 protein is a candidate to directly interact with volatile anesthetics. UNC-1 is a close homologue of the mammalian protein stomatin, for which a mouse knockout was recently constructed. Because the stomatin gene is expressed in dorsal root ganglion cells, the authors hypothesized that the knockout would have an effect on anesthetic sensitivity in mice similar to that seen in nematodes.

Methods

Mice were placed in semiclosed chambers and exposed to continuous flows of diethyl ether, halothane, or isoflurane in air. Using lack of response to tail clamp as an endpoint, the authors determined the EC50s for the knockout strain compared with the nonmutated parental strain. They compared the differences seen in the mouse strains with the differences seen in the nematode strains.

Results

Stomatin-deficient mice had a 12% increase in sensitivity to diethyl ether but no significant change in sensitivity to halothane or isoflurane compared with wild type. No defect in locomotion was noted in the mutant mouse.

Conclusions

Nematodes and mice with deletions of the stomatin gene both have increased sensitivity to diethyl ether. Neither nematodes nor mice with stomatin deficiencies have significantly altered sensitivity to isoflurane or halothane. The effects of stomatin deficiency cross phylogenetic boundaries and support the importance of this protein in anesthetic response and the use of C. elegans as a model for anesthetic action in mammals.
Role of the β1-Adrenergic Pathway in Anesthetic and Ischemic Preconditioning against Myocardial Infarction in the Rabbit Heart In Vivo
Authors: Lange Markus , Smul Thorsten M. , Blomeyer Christoph A. , Redel Andreas , Klotz Karl-Norbert , Roewer Norbert , Kehl Franz
Published: August 2006

Background

Anesthetic and ischemic preconditioning share similar signal transduction pathways. The authors tested the hypothesis that the beta1-adrenergic signal transduction pathway mediates anesthetic and ischemic preconditioning in vivo.

Methods

Pentobarbital-anesthetized (30 mg/kg) rabbits (n = 96) were instrumented for measurement of systemic hemodynamics and subjected to 30 min of coronary artery occlusion and 3 h of reperfusion. Sixty minutes before occlusion, vehicle (control), 1.0 minimum alveolar concentration desflurane, or sevoflurane, and esmolol (30.0 mg x kg(-1) x h(-1)) were administered for 30 min, respectively. Administration of a single 5-min cycle of ischemic preconditioning was instituted 35 min before coronary artery occlusion. In separate groups, the selective blocker esmolol or the protein kinase A inhibitor H-89 (250 microg/kg) was given alone and in combination with desflurane, sevoflurane, and ischemic preconditioning.

Results

Baseline hemodynamics and area at risk were not significantly different between groups. Myocardial infarct size (triphenyltetrazolium staining) as a percentage of area at risk was 61 +/- 4% in control. Desflurane, sevoflurane, and ischemic preconditioning reduced infarct size to 34 +/- 2, 36 +/- 5, and 23 +/- 3%, respectively. Esmolol did not alter myocardial infarct size (65 +/- 5%) but abolished the protective effects of desflurane and sevoflurane (57 +/- 4 and 52 +/- 4%, respectively) and attenuated ischemic preconditioning (40 +/- 4%). H-89 did not alter infarct size (60 +/- 4%) but abolished preconditioning by desflurane (57 +/- 5%) and sevoflurane (61 +/- 1%). Ischemic preconditioning (24 +/- 7%) was not affected by H-89.

Conclusions

The results demonstrate that anesthetic preconditioning is mediated by the beta1-adrenergic pathway, whereas this pathway is not essential for ischemic preconditioning. These results indicate important differences in the mechanisms of anesthetic and ischemic preconditioning.
Distinct Pharmacologic Properties of Neuromuscular Blocking Agents on Human Neuronal Nicotinic Acetylcholine Receptors
Authors: Jonsson Malin , Gurley David , Dabrowski Michael , Larsson Olof , Johnson Edwin C. , Eriksson Lars I.
Published: August 2006

Background

Nondepolarizing neuromuscular blocking agents (NMBAs) are extensively used in the practice of anesthesia and intensive care medicine. Their primary site of action is at the postsynaptic nicotinic acetylcholine receptor (nAChR) in the neuromuscular junction, but their action on neuronal nAChRs have not been fully evaluated. Furthermore, observed adverse effects of nondepolarizing NMBAs might originate from an interaction with neuronal nAChRs. The aim of this study was to examine the effect of clinically used nondepolarizing NMBAs on muscle and neuronal nAChR subtypes.

Methods

Xenopus laevis oocytes were injected with messenger RNA encoding for the subunits included in the human alpha1beta1epsilondelta, alpha3beta2, alpha3beta4, alpha4beta2, and alpha7 nAChR subtypes. The interactions between each of these nAChR subtypes and atracurium, cisatracurium, d-tubocurarine, mivacurium, pancuronium, rocuronium, and vecuronium were studied using an eight-channel two-electrode voltage clamp setup. Responses were measured as peak current and net charge.

Results

All nondepolarizing NMBAs inhibited both muscle and neuronal nAChRs. The neuronal nAChRs were reversibly and concentration-dependently inhibited in the low micromolar range. The mechanism (i.e., competitive vs. noncompetitive) of the block at the neuronal nAChRs was dependent both on subtype and the NMBA tested. The authors did not observe activation of the nAChR subtypes by any of the NMBAs tested.

Conclusions

The authors conclude that nondepolarizing NMBAs concentration-dependently inhibit human neuronal nAChRs. The inhibition of the presynaptic alpha3beta2 nAChR subtype expressed at the motor nerve ending provides a possible molecular explanation for the tetanic and train-of-four fade seen during a nondepolarizing neuromuscular block.
Mechanism of Cardiac Sarcolemmal Adenosine Triphosphate–sensitive Potassium Channel Activation by Isoflurane in a Heterologous Expression System
Authors: Bienengraeber Martin , Warltier David C. , Bosnjak Zeljko J. , Stadnicka Anna
Published: August 2006

Background

Activation of the cardiac sarcolemmal adenosine triphosphate-sensitive potassium (KATP) channel during metabolic stress initiates cellular events that preserve cardiac performance. Previous studies showed that halogenated anesthetics prime KATP channels under whole cell voltage clamp and act in intracellular pH (pHi)-dependent manner on KATP channels in excised membrane patches. However, it is not known how halogenated anesthetics interact with these channels.

Methods

The authors evaluated the effect of pHi and isoflurane on the KATP channel subunits, the pore-forming inward rectifier Kir6.2, and the regulatory sulfonylurea receptor SUR2A, using HEK293 cells as a heterologous expression system. Single channel activity was recorded in the inside-out patch configuration.

Results

At pHi 7.4, isoflurane had negligible effect on activity of wild-type Kir6.2/SUR2A, but at pHi 6.8, the channel open probability was increased by isoflurane (0.177 +/- 0.077 to 0.364 +/- 0.164). By contrast, the open probability of truncated Kir6.2DeltaC26, which forms a functional channel without SUR2A, was attenuated by isoflurane at both pHi 7.4 and pHi 6.8. Coexpression of Kir6.2DeltaC26 with SUR2A restored pHi sensitivity of channel activation by isoflurane. Site-directed mutagenesis within the Walker motifs of SUR2A abolished isoflurane activation of KATP channel at pHi 6.8. In addition, the pancreatic-type channels expressing sulfonylurea receptor SUR1 could not be activated by isoflurane.

Conclusions

The nucleotide binding domains of SUR2A play a crucial role in isoflurane facilitation of the KATP channel activity at moderately acidic pHi as would occur during early ischemia. These findings support direct and differential interaction of isoflurane with the subunits of the cardiac sarcolemmal KATP channel.
κ-Opioid Receptors Mediate Cardioprotection by Remote Preconditioning
Authors: Zhang Shi-zhong , Wang Ning-fu , Xu Jian , Gao Qin , Lin Guo-hua , Bruce Iain C. , Xia Qiang
Published: August 2006

Background

Remote preconditioning is known to be cardioprotective, but the exact mechanism has not been fully elucidated. The objective of the current study was to investigate the role of kappa-opioid receptors in cardioprotection by remote preconditioning and reveal possible underlying mechanisms.

Methods

Remote preconditioning was induced in anesthetized male Sprague-Dawley rats by three cycles of 5 min of right femoral artery occlusion followed by 5 min of reperfusion. Myocardial ischemia-reperfusion was achieved by ligation of the left anterior descending coronary artery for 30 min and then reperfusion for 120 min. Infarct size was determined by 2,3,5-triphenyltetrazolium chloride staining. Levels of lactate dehydrogenase, dynorphin, and met-enkephalin in plasma were measured. The opening of the mitochondrial permeability transition pore was monitored with fluorescent calcein in isolated ventricular myocytes.

Results

Both remote preconditioning and U-50,488H (10 mg/kg intravenous), a kappa-opioid receptor agonist, significantly decreased the infarct size and plasma lactate dehydrogenase level induced by ischemia-reperfusion, and these effects were attenuated by nor-binaltorphimine (10 mg/kg intravenous), a kappa-opioid receptor antagonist, and atractyloside (5 mg/kg intravenous), a mitochondrial permeability transition pore activator. However, administration of naltrindole (5 mg/kg), a delta-opioid receptor antagonist, had no effect on the cardioprotection by remote preconditioning. The dynorphin plasma level was increased after remote preconditioning treatment, but the met-enkephalin level did not change. In isolated ventricular myocytes loaded with calcein, U-50,488H (300 microM) decreased the mitochondrial permeability transition pore opening induced by calcium (200 microM), and this effect was attenuated by cotreatment with nor-binaltorphimine (5 microM) or atractyloside (20 microM).

Conclusion

Activation of cardiac kappa-opioid receptors is involved in the cardioprotection induced by remote preconditioning, and the mitochondrial permeability transition pore may participate in the postreceptor pathway.
Postoperative Left Prefrontal Repetitive Transcranial Magnetic Stimulation Reduces Patient-controlled Analgesia Use
Authors: Borckardt Jeffrey J. , Weinstein Mitchel , Reeves Scott T. , Kozel F Andrew , Nahas Ziad , Smith Arthur R. , Byrne T Karl , Morgan Katherine , George Mark S.
Published: August 2006

Background

Several recent studies suggest that repetitive transcranial magnetic stimulation can temporarily reduce pain perception in neuropathic pain patients and in healthy adults using laboratory pain models. No studies have investigated the effects of prefrontal cortex stimulation using transcranial magnetic stimulation on postoperative pain.

Methods

Twenty gastric bypass surgery patients were randomly assigned to receive 20 min of either active or sham left prefrontal repetitive transcranial magnetic stimulation immediately after surgery. Patient-controlled analgesia pump use was tracked, and patients also rated pain and mood twice per day using visual analog scales.

Results

Groups were similar at baseline in terms of body mass index, age, mood ratings, pain ratings, surgery duration, time under anesthesia, and surgical anesthesia methods. Significant effects were observed for surgery type (open vs. laparoscopic) and condition (active vs. sham transcranial magnetic stimulation) on the cumulative amount of patient-delivered morphine during the 44 h after surgery. Active prefrontal repetitive transcranial magnetic stimulation was associated with a 40% reduction in total morphine use compared with sham during the 44 h after surgery. The effect seemed to be most prominent during the first 24 h after cortical stimulation delivery. No effects were observed for repetitive transcranial magnetic stimulation on mood ratings.

Conclusions

A single session of postoperative prefrontal repetitive transcranial magnetic stimulation was associated with a reduction in patient-controlled analgesia pump use in gastric bypass surgery patients. This is important because the risks associated with postoperative morphine use are high, especially among obese patients who frequently have obstructive sleep apnea, right ventricular dysfunction, and pulmonary hypertension. These preliminary findings suggest a potential new noninvasive method for managing postoperative morphine use.
The Sheath of the Brachial Plexus
Authors: Cornish Philip B. , Leaper Christopher
Published: August 2006

Background

The concept of the axillary "sheath" has been a central tenet of brachial plexus regional anesthesia for many years. Recent investigations have cast doubt on its nature and existence. This study further examines the issue.

Methods

Computerized axial tomographic dye studies were performed using continuous catheter systems for the sciatic nerve and the brachial plexus. The resultant images were compared and contrasted.

Results

The images of the two catheter systems were the same, with the exception that one was of the upper extremity and the other was of the lower extremity.

Conclusions

The sciatic nerve is not surrounded or enveloped by a "sheath"--it lies in the tissue plane between rigid anatomical structures. Similarly, the brachial plexus lies in the tissue plane between the rigid anatomy of the chest wall, scapula, humerus, and pectoral fascia. This finding is inconsistent with the concept of the axillary sheath.
Effect of Patient-controlled Perineural Analgesia on Rehabilitation and Pain after Ambulatory Orthopedic Surgery
Authors: Capdevila Xavier , Dadure Christophe , Bringuier Sophie , Bernard Nathalie , Biboulet Philippe , Gaertner Elisabeth , Macaire Philippe
Published: August 2006

Background

Efficacy of continuous perineural and patient-controlled ropivacaine infusion at home after orthopedic surgery was compared with patient-controlled intravenous morphine for functional recovery and postoperative analgesia in a multicenter randomized trial.

Methods

Eighty-three patients scheduled to undergo acromioplasty or hallux valgus surgery received an interscalene (n = 40) or popliteal (n = 43) peripheral nerve block with 30 ml ropivacaine, 0.5%. After randomization, patients were discharged home 24 h after surgery with a disposable infusion pump delivering either patient-controlled intravenous morphine (n = 23) or perineural 0.2% ropivacaine infusion, either continuous infusion without bolus (n = 30) or basal infusion plus bolus (n = 30). The patients recorded pain scores on movement and/or walking and were directed to take paracetamol and rescue analgesics if necessary. The time necessary to be able to walk for 10 min; daily activities on days 1, 2, and 3; adverse events; and overall satisfaction scores were noted and graded by the patient.

Results

Basal-bolus ropivacaine decreased the time to 10 minutes' walk, optimized daily activities (P < 0.01), and decreased the amount of ropivacaine used. The morphine group had greater pain scores and consumption of morphine and ketoprofen compared with both ropivacaine groups (P < 0.05). The incidence of nausea/vomiting, sleep disturbance, and dizziness increased, and the patient satisfaction score decreased in the morphine group (P < 0.05).

Conclusions

After ambulatory orthopedic surgery, 0.2% ropivacaine delivered as a perineural infusion using a disposable elastomeric pump with patient-controlled anesthesia bolus doses optimizes functional recovery and pain relief while decreasing the consumption of rescue analgesics and ropivacaine, and the number of adverse events.
Enhancement of Morphine Analgesic Effect with Induction of μ-Opioid Receptor Endocytosis in Rats
Authors: Hashimoto Tatsuya , Saito Yoji , Yamada Kazuo , Hara Nobumasa , Kirihara Yumiko , Tsuchiya Mikako
Published: August 2006

Background

Morphine can desensitize mu-opioid receptor (MOR), but it does not cause internalization of the receptor after binding. Acute desensitization of MOR impairs the efficiency of signaling, whereas the receptor internalization restores the cell responsiveness to the agonists. Thereby, the property of morphine may limit the analgesic effects of this opiate drug. It has been shown that [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO), a potent MOR agonist inducing the internalization, facilitates morphine to internalize MOR, suggesting that MOR agonists with low relative activity versus endocytosis (RAVE) values such as DAMGO can potentiate analgesic effects of morphine through stimulating MOR internalization. The authors examined whether the acute analgesic effect of morphine can be potentiated by low relative activity versus endocytosis agonists DAMGO and fentanyl.

Methods

Rats injected intrathecally with opioids were subjected to a hot plate test for antinociceptive effect. Immunostained spinal dorsal horn was analyzed by confocal microscopy.

Results

Fentanyl induced MOR internalization to a lesser extent than DAMGO at equianalgesic doses. Coadministration of fentanyl promoted morphine-induced MOR internalization. The analgesic effect of morphine was greatly potentiated together with decrease in the relative activity versus endocytosis value when MOR internalization was induced by coadministration of a subanalgesic dose of DAMGO or fentanyl. In contrast, the combination of DAMGO and fentanyl increased neither the analgesic effect nor the internalization of MOR.

Conclusions

The results suggest that the coadministration of morphine with MOR-internalizing agonist is clinically applicable to develop successful pain-management regimens to achieve satisfactory analgesia using less morphine.
Time Course and Role of Morphine Dose and Concentration in Intrathecal Granuloma Formation in Dogs
Authors: Allen Jeffrey W. , Horais Kjersti A. , Tozier Nicolle A. , Wegner Kirsten , Corbeil Jacqueline A. , Mattrey Robert F. , Rossi Steven S. , Yaksh Tony L.
Published: August 2006

Background

Intrathecal morphine infusion leads to intrathecal granulomas. In dogs, the authors examined time course of granuloma formation and the role of concentration in granuloma development.

Methods

Dogs were prepared with lumbar intrathecal catheters and vest-mounted pumps. To define the time course of granuloma formation, serial magnetic resonance imaging was performed in animals receiving 10 or 31 days of morphine infusion (12.5 mg/ml at 40 microl/h). At these times, morphine was removed from the infusate, and further magnetic resonance images were acquired over 14-35 additional days. To assess dose versus concentration, dogs received 28-day infusions of vehicle, 12 mg morphine/day as 12.5 mg/ml at 40 microl/h, or 1.5 mg/ml at 334 microl/h (12 mg/day) for 28 days. Additional dogs received 3 mg/day as 12.5 mg/ml at 10 mul/h.

Results

Serial magnetic resonance images in dogs receiving morphine (12.5 mg/ml at 40 microl/h) revealed pericatheter-enhancing tissues as early as 3 days with a prominent signal by 10 days. Removal of morphine reduced the mass volume within 7 days. At a fixed infusion rate, the incidence of granuloma formation with the continuous intrathecal infusion of morphine ranged from 0 in vehicle-treated dogs to 100% in dogs treated with 12.5 mg/ml at 40 microl/h (12 mg/day). Infusion of 12 mg/day at 1.5 mg/ml (334 microl/h) resulted in granuloma in one of four animals. The authors found that infusion of morphine in different concentrations at a fixed rate resulted in a dose-dependent increase in concentration, with the granuloma-producing, dose-yielding lumbar cerebrospinal fluid morphine concentrations around 40 microg/ml.

Conclusions

Serial magnetic resonance imaging showed a rapid formation and regression of the masses initiated by intrathecal morphine infusion. These masses are dependent on local concentration.
Opiate Pharmacology of Intrathecal Granulomas
Authors: Allen Jeffrey W. , Horais Kjersti A. , Tozier Nicolle A. , Yaksh Tony L.
Published: August 2006

Background

Chronic intrathecal morphine infusion produces intradural granulomas. The authors examined a variety of opioids infused intrathecal for analgesic activity and toxicity.

Methods

Two sets of experiments were undertaken in dogs with chronic intrathecal catheters: (1) Six-hour intrathecal infusions were used to determine the full analgesic dose and the maximum tolerated dose. (2) To establish toxicity, the maximum tolerated dose was given for up to 28 days by continuous intrathecal infusion. Drugs examined were morphine sulfate, hydromorphone, D/L-methadone, L-methadone, D-methadone, fentanyl, [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO), naloxone, or saline. RESULTS ANALGESIA AND TOLERABILITY: Six-hour intrathecal infusion of agonists resulted in a time-dependent increase in thermal escape latency. At higher concentrations, dose-limiting motor dysfunction and sedation occurred, and hypersensitivity occurred. The concentrations, in mg/ml, for full analgesic dose/maximum tolerated dose were as follows: morphine, 0.9/12.0; hydromorphone, 1.0/3.0; D/L-methadone, 2.8/3; L-methadone, 1.0/> 1.0; fentanyl, 0.3/2.0; DAMGO, 0.1/> 2.0; D-methadone, > 1/> 1; naloxone, > 10/> 10. SPINAL PATHOLOGY: Chronic intrathecal infusion of the maximum tolerated dose revealed 100% intradural granuloma formation after morphine, hydromorphone, L-methadone, and naloxone. DAMGO induced a mass in only a single animal (one of three). D/L- and D-methadone produced intradural granulomas but were also associated with parenchymal necrosis. Saline and fentanyl animals displayed no granulomas.

Conclusions

Intrathecal opiate-induced granulomas are not strictly dependent on opioid receptor activation. Therefore, opiates at equianalgesic doses present different risks for granuloma formation. Importantly, D/L- and D-methadone also resulted in parenchymal necrosis, an affect associated with the N-methyl-D-aspartate antagonist action of the D-isomer.
The Vasopressin System
Authors: Treschan Tanja A. , Peters Jürgen , Warltier David C.
Published: August 2006

Vasopressin, synthesized in the hypothalamus, is released by increased plasma osmolality, decreased arterial pressure, and reductions in cardiac volume. Three subtypes of vasopressin receptors, V1, V2, and V3, have been identified, mediating vasoconstriction, water reabsorption, and central nervous system effects, respectively. Vasopressin and its analogs have been studied intensively for the treatment of states of "relative vasopressin deficiency," such as sepsis, vasodilatory shock, intraoperative hypotension, and cardiopulmonary resuscitation. Infusion of vasopressin (0.01-0.04 U/min) decreases catecholamine requirements in patients with sepsis and other types of vasodilatory shock. Bolus application of 1 mg terlipressin, the V1 agonist, reverses refractory hypotension in anesthetized patients and has been studied in patients with septic shock and chronic liver failure. During cardiopulmonary resuscitation, a 40-U bolus dose of vasopressin may be considered to replace the first or second bolus of epinephrine regardless of the initial rhythm. The side effects of vasopressin and its analogs must be further characterized.
Gender and Post–Dural Puncture Headache
Authors: Wu Christopher L. , Rowlingson Andrew J. , Cohen Seth R. , Michaels Robert K. , Courpas Genevieve E. , Joe Emily M. , Liu Spencer S.
Published: August 2006

Gender is believed to be an independent risk factor for the development of post-dural puncture headache, but there are some of the inconsistencies in the available data. This systematic review examined a total of 18 trials (2,163 males, 1,917 females). The odds of developing a post-dural puncture headache were significantly lower for male than nonpregnant female subjects (odds ratio = 0.55; 95% confidence interval, 0.44-0.67). Although the authors found that nonpregnant female subjects seem to have a higher incidence of post-dural puncture headache than males, the etiology behind these findings is not clear from the current meta-analysis.
Trajectory Shifts in the Arctic and Subarctic Freshwater Cycle
Authors: Peterson Bruce J. , McClelland James , Curry Ruth , Holmes Robert M. , Walsh John E. , Aagaard Knut
Published: August 2006

Manifold changes in the freshwater cycle of high-latitude lands and oceans have been reported in the past few years. A synthesis of these changes in freshwater sources and in ocean freshwater storage illustrates the complementary and synoptic temporal pattern and magnitude of these changes over the past 50 years. Increasing river discharge anomalies and excess net precipitation on the ocean contributed ∼20,000 cubic kilometers of fresh water to the Arctic and high-latitude North Atlantic oceans from lows in the 1960s to highs in the 1990s. Sea ice attrition provided another ∼15,000 cubic kilometers, and glacial melt added ∼2000 cubic kilometers. The sum of anomalous inputs from these freshwater sources matched the amount and rate at which fresh water accumulated in the North Atlantic during much of the period from 1965 through 1995. The changes in freshwater inputs and ocean storage occurred in conjunction with the amplifying North Atlantic Oscillation and rising air temperatures. Fresh water may now be accumulating in the Arctic Ocean and will likely be exported southward if and when the North Atlantic Oscillation enters into a new high phase.
Discrete Sandwich Compounds of Monolayer Palladium Sheets
Authors: Murahashi Tetsuro , Fujimoto Mayu , Oka Masa-aki , Hashimoto Yasuhiro , Uemura Tomohito , Tatsumi Yasuki , Nakao Yoshihide , Ikeda Atsushi , Sakaki Shigeyoshi , Kurosawa Hideo
Published: August 2006

Despite the abundance of “sandwich” complexes, in which two cyclic aromatic hydrocarbon ligands flank a metal center, this motif has not been extended to sheets of multiple metal atoms. We prepared and isolated two such compounds. In the first, three palladium centers form a planar triangular array, capped by chlorides, between two cycloheptatrienyl ligands. In the second, a pentapalladium sheet adopts an edge-sharing triangle-trapezoid skeleton between two naphthacene rings. The compounds were characterized by x-ray crystallography and nuclear magnetic resonance spectroscopy. The nature of bonding in the clusters was analyzed by quantum calculations.
Ice Record of δ
13
C for Atmospheric CH
4
Across the Younger Dryas-Preboreal Transition
Authors: Schaefer Hinrich , Whiticar Michael J. , Brook Edward J. , Petrenko Vasilii V. , Ferretti Dominic F. , Severinghaus Jeffrey P.
Published: August 2006

We report atmospheric methane carbon isotope ratios (δ
13
CH
4
) from the Western Greenland ice margin spanning the Younger Dryas–to–Preboreal (YD-PB) transition. Over the recorded ∼800 years, δ
13
CH
4
was around –46 per mil (‰); that is, ∼1‰ higher than in the modern atmosphere and ∼5.5‰ higher than would be expected from budgets without
13
C-rich anthropogenic emissions. This requires higher natural
13
C-rich emissions or stronger sink fractionation than conventionally assumed. Constant δ
13
CH
4
during the rise in methane concentration at the YD-PB transition is consistent with additional emissions from tropical wetlands, or aerobic plant CH
4
production, or with a multisource scenario. A marine clathrate source is unlikely.
Symbiotic Bacteria Direct Expression of an Intestinal Bactericidal Lectin
Authors: Cash Heather L. , Whitham Cecilia V. , Behrendt Cassie L. , Hooper Lora V.
Published: August 2006

The mammalian intestine harbors complex societies of beneficial bacteria that are maintained in the lumen with minimal penetration of mucosal surfaces. Microbial colonization of germ-free mice triggers epithelial expression of RegIIIγ, a secreted C-type lectin. RegIIIγ binds intestinal bacteria but lacks the complement recruitment domains present in other microbe-binding mammalian C-type lectins. We show that RegIIIγ and its human counterpart, HIP/PAP, are directly antimicrobial proteins that bind their bacterial targets via interactions with peptidoglycan carbohydrate. We propose that these proteins represent an evolutionarily primitive form of lectin-mediated innate immunity, and that they reveal intestinal strategies for maintaining symbiotic host-microbial relationships.
Individual Cell Migration Serves as the Driving Force for Optic Vesicle Evagination
Authors: Rembold Martina , Loosli Felix , Adams Richard J. , Wittbrodt Joachim
Published: August 2006

The cellular mechanisms underlying organ formation are largely unknown. We visualized early vertebrate eye morphogenesis at single-cell resolution by in vivo imaging in medaka (
Oryzias latipes
). Before optic vesicle evagination, retinal progenitor cells (RPCs) modulate their convergence in a fate-specific manner. Presumptive forebrain cells converge toward the midline, whereas medial RPCs remain stationary, predetermining the site of evagination. Subsequent optic vesicle evagination is driven by the active migration of individual RPCs. The analysis of mutants demonstrated that the retina-specific transcription factor
rx3
determines the convergence and migration behaviors of RPCs. Hence, the migration of individual cells mediates essential steps of organ morphogenesis.
Waterborne Infectious DiseasesCould They Be Consigned to History?
Authors: Fenwick Alan
Published: August 2006

The development of water resources, particularly in Africa, has changed the face of the continent, opening up land for agriculture, providing electric power, encouraging settlements adjacent to water bodies, and bringing prosperity to poor people. Unfortunately, the created or altered water bodies provide ideal conditions for the transmission of waterborne diseases and a favorable habitat for intermediate hosts of tropical parasitic infections that cause disease and suffering. The recent progress in control of these waterborne and vector-borne diseases, such as guinea worm, schistosomiasis, lymphatic filariasis, and onchocerciasis, suggests that many of them could be controlled effectively by 2015, which is the target for reaching the Millennium Development Goals. Donations of safe and effective drugs by several pharmaceutical companies, funds for delivering these donated drugs from foundations and bilateral donors, and effective global health partnerships should make these diseases history.
The Challenge of Micropollutants in Aquatic Systems
Authors: Schwarzenbach René P. , Escher Beate I. , Fenner Kathrin , Hofstetter Thomas B. , Johnson C. Annette , von Gunten Urs , Wehrli Bernhard
Published: August 2006

The increasing worldwide contamination of freshwater systems with thousands of industrial and natural chemical compounds is one of the key environmental problems facing humanity. Although most of these compounds are present at low concentrations, many of them raise considerable toxicological concerns, particularly when present as components of complex mixtures. Here we review three scientific challenges in addressing water-quality problems caused by such micropollutants. First, tools to assess the impact of these pollutants on aquatic life and human health must be further developed and refined. Second, cost-effective and appropriate remediation and water-treatment technologies must be explored and implemented. Third, usage and disposal strategies, coupled with the search for environmentally more benign products and processes, should aim to minimize introduction of critical pollutants into the aquatic environment.
ATM Engages Autodegradation of the E3 Ubiquitin Ligase COP1 After DNA Damage
Authors: Dornan David , Shimizu Harumi , Mah Angie , Dudhela Tanay , Eby Michael , O'Rourke Karen , Seshagiri Somasekar , Dixit Vishva M.
Published: August 2006

The ataxia telangiectasia mutated (ATM) protein kinase is a critical component of a DNA-damage response network configured to maintain genomic integrity. The abundance of an essential downstream effecter of this pathway, the tumor suppressor protein p53, is tightly regulated by controlled degradation through COP1 and other E3 ubiquitin ligases, such as MDM2 and Pirh2; however, the signal transduction pathway that regulates the COP1-p53 axis following DNA damage remains enigmatic. We observed that in response to DNA damage, ATM phosphorylated COP1 on Ser
387
and stimulated a rapid autodegradation mechanism. Ionizing radiation triggered an ATM-dependent movement of COP1 from the nucleus to the cytoplasm, and ATM-dependent phosphorylation of COP1 on Ser
387
was both necessary and sufficient to disrupt the COP1-p53 complex and subsequently to abrogate the ubiquitination and degradation of p53. Furthermore, phosphorylation of COP1 on Ser
387
was required to permit p53 to become stabilized and to exert its tumor suppressor properties in response to DNA damage.
Comment on "Cell Type Regulates Selective Segregation of Mouse Chromosome 7 DNA Strands in Mitosis"
Authors: Haber James E.
Published: August 2006

Armakolas and Klar (Reports, 24 February 2006, p. 1146) suggested that segregation of mouse chromosome 7, after induction of a site-specific crossover between homologous chromosomes, is driven by a preferential inheritance of the old Watson and the old Crick DNA strands. However, this interpretation only considered half of the possible outcomes. The conjecture fails when all possible outcomes are examined.
Learning Induces Long-Term Potentiation in the Hippocampus
Authors: Whitlock Jonathan R. , Heynen Arnold J. , Shuler Marshall G. , Bear Mark F.
Published: August 2006

Years of intensive investigation have yielded a sophisticated understanding of long-term potentiation (LTP) induced in hippocampal area CA1 by high-frequency stimulation (HFS). These efforts have been motivated by the belief that similar synaptic modifications occur during memory formation, but it has never been shown that learning actually induces LTP in CA1. We found that one-trial inhibitory avoidance learning in rats produced the same changes in hippocampal glutamate receptors as induction of LTP with HFS and caused a spatially restricted increase in the amplitude of evoked synaptic transmission in CA1 in vivo. Because the learning-induced synaptic potentiation occluded HFS-induced LTP, we conclude that inhibitory avoidance training induces LTP in CA1.
Chemical Chaperones Reduce ER Stress and Restore Glucose Homeostasis in a Mouse Model of Type 2 Diabetes
Authors: Özcan Umut , Yilmaz Erkan , Özcan Lale , Furuhashi Masato , Vaillancourt Eric , Smith Ross O. , Görgün Cem Z. , Hotamisligil Gökhan S.
Published: August 2006

Endoplasmic reticulum (ER) stress is a key link between obesity, insulin resistance, and type 2 diabetes. Here, we provide evidence that this mechanistic link can be exploited for therapeutic purposes with orally active chemical chaperones. 4-Phenyl butyric acid and taurine-conjugated ursodeoxycholic acid alleviated ER stress in cells and whole animals. Treatment of obese and diabetic mice with these compounds resulted in normalization of hyperglycemia, restoration of systemic insulin sensitivity, resolution of fatty liver disease, and enhancement of insulin action in liver, muscle, and adipose tissues. Our results demonstrate that chemical chaperones enhance the adaptive capacity of the ER and act as potent antidiabetic modalities with potential application in the treatment of type 2 diabetes.
An Aegialodontid Upper Molar and the Evolution of Mammal Dentition
Authors: Lopatin Alexey V. , Averianov Alexander O.
Published: August 2006

The most obvious key synapomorphy of the therian mammals is the tribosphenic pattern of their molars. Tribosphenic teeth are capable of both shearing and grinding, which substantially increase effectiveness of food processing and, in turn, permit evolution of a wide range of dietary specializations. Functional tribospheny developed repeatedly during mammalian evolution but was successful only in the Boreosphenida. The earliest stage in the development of boreosphenidan tribospheny has remained poorly understood, being documented only by lower molars of aegialodontids. Here, we report a known upper molar of an aegialodontid mammal, Kielantherium, from the Early Cretaceous of Mongolia.
Response to Comment on "Cell Type Regulates Selective Segregation of Mouse Chromosome 7 DNA Strands in Mitosis"
Authors: Klar Amar J. S. , Armakolas Athanasios
Published: August 2006

To explain how all chromosome recombinants can become homozygous for a marker located distal to the crossover point, we proposed that mitotic recombination must be restricted to two specific chromatids and that the selective chromatid segregation process follows recombination. We refute Haber's contention that our results can be explained by the conventional X-segregation process if recombination of all possible combinations of chromatids is considered.
Detection, Stimulation, and Inhibition of Neuronal Signals with High-Density Nanowire Transistor Arrays
Authors: Patolsky Fernando , Timko Brian P. , Yu Guihua , Fang Ying , Greytak Andrew B. , Zheng Gengfeng , Lieber Charles M.
Published: August 2006

We report electrical properties of hybrid structures consisting of arrays of nanowire field-effect transistors integrated with the individual axons and dendrites of live mammalian neurons, where each nanoscale junction can be used for spatially resolved, highly sensitive detection, stimulation, and/or inhibition of neuronal signal propagation. Arrays of nanowire-neuron junctions enable simultaneous measurement of the rate, amplitude, and shape of signals propagating along individual axons and dendrites. The configuration of nanowire-axon junctions in arrays, as both inputs and outputs, makes possible controlled studies of partial to complete inhibition of signal propagation by both local electrical and chemical stimuli. In addition, nanowire-axon junction arrays were integrated and tested at a level of at least 50 “artificial synapses” per neuron.
Global Hydrological Cycles and World Water Resources
Authors: Oki Taikan , Kanae Shinjiro
Published: August 2006

Water is a naturally circulating resource that is constantly recharged. Therefore, even though the stocks of water in natural and artificial reservoirs are helpful to increase the available water resources for human society, the flow of water should be the main focus in water resources assessments. The climate system puts an upper limit on the circulation rate of available renewable freshwater resources (RFWR). Although current global withdrawals are well below the upper limit, more than two billion people live in highly water-stressed areas because of the uneven distribution of RFWR in time and space. Climate change is expected to accelerate water cycles and thereby increase the available RFWR. This would slow down the increase of people living under water stress; however, changes in seasonal patterns and increasing probability of extreme events may offset this effect. Reducing current vulnerability will be the first step to prepare for such anticipated changes.