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Halothane
Selected AbstractsBinding of the volatile general anesthetics halothane and isoflurane to a mammalian ,-barrel proteinFEBS JOURNAL, Issue 2 2005Jonas S. Johansson A molecular understanding of volatile anesthetic mechanisms of action will require structural descriptions of anesthetic,protein complexes. Porcine odorant binding protein is a 157 residue member of the lipocalin family that features a large ,-barrel internal cavity (515 ± 30 Å3) lined predominantly by aromatic and aliphatic residues. Halothane binding to the ,-barrel cavity was determined using fluorescence quenching of Trp16, and a competitive binding assay with 1-aminoanthracene. In addition, the binding of halothane and isoflurane were characterized thermodynamically using isothermal titration calorimetry. Hydrogen exchange was used to evaluate the effects of bound halothane and isoflurane on global protein dynamics. Halothane bound to the cavity in the ,-barrel of porcine odorant binding protein with dissociation constants of 0.46 ± 0.10 mm and 0.43 ± 0.12 mm determined using fluorescence quenching and competitive binding with 1-aminoanthracene, respectively. Isothermal titration calorimetry revealed that halothane and isoflurane bound with Kd values of 80 ± 10 µm and 100 ± 10 µm, respectively. Halothane and isoflurane binding resulted in an overall stabilization of the folded conformation of the protein by ,0.9 ± 0.1 kcal·mol,1. In addition to indicating specific binding to the native protein conformation, such stabilization may represent a fundamental mechanism whereby anesthetics reversibly alter protein function. Because porcine odorant binding protein has been successfully analyzed by X-ray diffraction to 2.25 Å resolution [1], this represents an attractive system for atomic-level structural studies in the presence of bound anesthetic. Such studies will provide much needed insight into how volatile anesthetics interact with biological macromolecules. [source] Does halothane or isoflurane affect hypoxic and post-hypoxic vascular response in rabbit aorta?ACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 4 2000E. Haddad Background: Halothane and isoflurane affect differently endothelium-dependent and -independent vasorelaxation at 95% O2. In addition, hypoxic vascular response might involve endothelium-dependent and -independent mechanisms. Therefore, we investigated, in rabbit aortic rings, 1) the influence of halothane and isoflurane on vasodilation at 95% O2 and on hypoxic-induced vasorelaxation at 0% O2 and 2) the influence of halothane and isoflurane on endothelium-dependent and -independent post-hypoxic vascular response. Methods: Endothelium-intact and endothelium-denuded rabbit aortic rings were used. Phenylephrine precontracted rings were exposed, at 95% O2, to acetylcholine (ACh, 10,9 to 10,4 M) or sodium nitroprusside (SNP, 10,9 to 10,4 M) in the presence or absence of anaesthetic at 1 or 2 MAC. Precontracted rings were also exposed to an acute reduction in O2 from 95% to 0% followed by an acute reoxygenation with 95% O2 in the absence or presence of anaesthetic at 1 or 2 MAC. Results: At 95% O2, halothane decreased endothelium-dependent relaxation to ACh, while endothelium-independent relaxation to SNP was decreased only at 2 MAC. Isoflurane did not modify ACh- or SNP-induced relaxation. At 0% O2, neither halothane nor isoflurane altered the hypoxic vascular relaxation. Post-hypoxic response was not changed either. Conclusion: Our results indicate that halothane and isoflurane do not alter vascular hypoxic response in conductance arteries. [source] Reaction of Halothane with sec-Butyllithium in the Presence of Zinc Halides , One-Pot Preparation of Chlorodifluorovinylzinc Reagent and Its Derivatization to ,-Chloro-,,,-difluorostyrene.CHEMINFORM, Issue 48 2003Masakazu Nishihara Abstract For Abstract see ChemInform Abstract in Full Text. [source] Gap junctional coupling between progenitor cells at the retinal margin of adult goldfishDEVELOPMENTAL NEUROBIOLOGY, Issue 3 2001Fuminobu Tamalu Abstract We prepared living slice preparations of the peripheral retina of adult goldfish to examine electrical membrane properties of progenitor cells at the retinal margin. Cells were voltage-clamped near resting potential and then stepped to either hyperpolarizing or depolarizing test potentials using whole-cell voltage-clamp recordings. Electrophysiologically examined cells were morphologically identified by injecting both Lucifer Yellow (LY) and biocytin. All progenitor cells examined (n = 37) showed a large amount of passively flowing currents of either sign under suppression of the nonjunctional currents flowing through K+ and Ca2+ channels in the cell membrane. They did not exhibit any voltage-gated Na+ currents. Cells identified by LY fills were typically slender. As the difference between the test potential and the resting potential increased, 13 out of 37 cells exhibited symmetrically voltage- and time-dependent current decline on either sign at the resting potential. The symmetric current profile suggests that the current may be driven and modulated by the junctional potential difference between the clamping cell and its neighbors. The remaining 24 cells did not exhibit voltage dependency. A gap junction channel blocker, halothane, suppressed the currents. A decrease in extracellular pH reduced coupling currents and its increase enhanced them. Dopamine, cAMP, and retinoic acid did not influence coupling currents. Injection of biocytin into single progenitor cells revealed strong tracer coupling, which was restricted in the marginal region. Immature ganglion cells closely located to the retinal margin exhibited voltage-gated Na+ currents. They did not reveal apparent tracer coupling. These results demonstrate that the marginal progenitor cells couple with each other via gap junctions, and communicate biochemical molecules, which may subserve or interfere with cellular differentiation. © 2001 John Wiley & Sons, Inc. J Neurobiol 48: 204,214, 2001 [source] Glutamatergic input governs periodicity and synchronization of bursting activity in oxytocin neurons in hypothalamic organotypic culturesEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2003Jean-Marc Israel Abstract During suckling, oxytocin (OT) neurons display a bursting electrical activity, consisting of a brief burst of action potentials which is synchronized throughout the OT neuron population and which periodically occurs just before each milk ejection in the lactating rat. To investigate the basis of such synchronization, we performed simultaneous intracellular recordings from pairs of OT neurons identified retrospectively by intracellular fluorescent labelling and immunocytochemistry in organotypic slice cultures derived from postnatal rat hypothalamus. A spontaneous bursting activity was recorded in 65% of OT neurons; the remaining showed only a slow, irregular activity. Application of OT triggered bursts in nonbursting neurons and accelerated bursting activity in spontaneously bursting cells. These cultures included rare vasopressinergic neurons showing no bursting activity and no reaction to OT. Bursts occurred simultaneously in all pairs of bursting OT neurons but, as in vivo, there were differences in burst onset, amplitude and duration. Coordination of firing was not due to electrotonic coupling because depolarizing one neuron in a pair had no effect on the membrane potential of its partner and halothane and proprionate did not desynchronize activity. On the other hand, bursting activity was superimposed on volleys of excitatory postsynaptic potentials (EPSPs) which occurred simultaneously in pairs of neurons. EPSPs, and consequently action potentials, were reversibly blocked by the non-NMDA glutamatergic receptor antagonist CNQX. Taken together, these data, obtained from organotypic cultures, strongly suggest that a local hypothalamic network governs synchronization of bursting firing in OT neurons through synchronous afferent volleys of EPSPs originating from intrahypothalamic glutamatergic inputs. [source] Binding of the volatile general anesthetics halothane and isoflurane to a mammalian ,-barrel proteinFEBS JOURNAL, Issue 2 2005Jonas S. Johansson A molecular understanding of volatile anesthetic mechanisms of action will require structural descriptions of anesthetic,protein complexes. Porcine odorant binding protein is a 157 residue member of the lipocalin family that features a large ,-barrel internal cavity (515 ± 30 Å3) lined predominantly by aromatic and aliphatic residues. Halothane binding to the ,-barrel cavity was determined using fluorescence quenching of Trp16, and a competitive binding assay with 1-aminoanthracene. In addition, the binding of halothane and isoflurane were characterized thermodynamically using isothermal titration calorimetry. Hydrogen exchange was used to evaluate the effects of bound halothane and isoflurane on global protein dynamics. Halothane bound to the cavity in the ,-barrel of porcine odorant binding protein with dissociation constants of 0.46 ± 0.10 mm and 0.43 ± 0.12 mm determined using fluorescence quenching and competitive binding with 1-aminoanthracene, respectively. Isothermal titration calorimetry revealed that halothane and isoflurane bound with Kd values of 80 ± 10 µm and 100 ± 10 µm, respectively. Halothane and isoflurane binding resulted in an overall stabilization of the folded conformation of the protein by ,0.9 ± 0.1 kcal·mol,1. In addition to indicating specific binding to the native protein conformation, such stabilization may represent a fundamental mechanism whereby anesthetics reversibly alter protein function. Because porcine odorant binding protein has been successfully analyzed by X-ray diffraction to 2.25 Å resolution [1], this represents an attractive system for atomic-level structural studies in the presence of bound anesthetic. Such studies will provide much needed insight into how volatile anesthetics interact with biological macromolecules. [source] Effect of halothane on type 2 immobility-related hippocampal theta field activity and theta-on/theta-off cell dischargesHIPPOCAMPUS, Issue 1 2003Brian H. Bland Abstract Rats were studied in acute and chronic (freely moving) recording conditions during exposure to different levels of the volatile anesthetic halothane, in order to assess effects on hippocampal theta field activity in the chronic condition and on theta-related cellular discharges in the acute condition. Previous work has shown that the generation of hippocampal type 2 theta depends on the coactivation of cholinergic and GABAergic inputs from the medial septum. Based on these data and recent findings that halothane acts on interneuron GABAA receptors, we predicted that exposure of rats to subanesthetic levels would result in the induction of type 2 theta field activity. In the chronic condition, exposure to subanesthetic levels of halothane (0.5,1.0 vol %) was found to induce theta field activity during periods of immobility (type 2 theta) with a mean increase of 39% in amplitude (mV) compared to control levels during movement. The total percentage of signal power (V2) associated with peak theta frequencies (80% compared to control levels of 47%) was also increased by halothane. Over the whole range of administered halothane concentrations, theta field frequency progressively declined from a mean peak frequency of 6.5 ± 0.8 Hz at 0.5 vol % halothane to a mean peak frequency of 4.0 ± 1.8 Hz at 2.0 vol % halothane. Subsequent administration of a muscarinic cholinergic antagonist, atropine sulfate, selectively abolished all type 2 immobility-related theta field activity, while type 1 movement-related theta was still intact. At anesthetic levels (1.5,2.0 vol %) in acute experiments, hippocampal field activity spontaneously cycled between theta and large-amplitude irregular activity. Analysis of depth profiles in four experiments revealed they were identical to those previously described for rats under urethane anesthesia conditions. In addition, the discharge properties of 31 theta-related cells, classified as tonic and phasic theta-on and tonic and phasic theta-off cells, did not differ significantly from those described previously in rats anesthetized with urethane. These data provide further support for an involvement of GABAA receptors in the generation of hippocampal theta. Hippocampus 2003;13:38,47. © 2003 Wiley-Liss, Inc. [source] Dissolution of root canal sealer cements in volatile solventsINTERNATIONAL ENDODONTIC JOURNAL, Issue 1 2000J. M. Whitworth Whitworth JM, Boursin EM. Dissolution of root canal sealer cements in volatile solvents. International Endodontic Journal, 33, 19,24, 2000. Aim There are few published data on the solubility profiles of endodontic sealers in solvents commonly employed in root canal retreatment. This study tested the hypothesis that root canal sealer cements are insoluble in the volatile solvents chloroform and halothane. Methodology Standardized samples (n=5) of glass ionomer (Ketac Endo), zinc oxide-eugenol (Tubli-Seal EWT), calcium hydroxide (Apexit) and epoxy resin (AH Plus) based sealers were immersed in chloroform or halothane for 30 s, 1 min, 5 min and 10 min. Mean loss of weight was plotted against time of exposure, and differences in behaviour assessed by multiple paired t-tests (P <0.01). Results Clear differences were shown in the solubility profiles of major classes of root canal sealer cements in two common volatile solvents. In comparison with other classes of material, Ketac Endo was the least soluble in chloroform and halothane (P <0.01), with less than 1% weight loss after 10 min exposure to either solvent. Apexit had low solubility with 11.6% and 14.19% weight loss after 10 min exposure to chloroform and halothane, respectively. The difference between solvents was not significant (P >0.01). Tubli-Seal EWT was significantly less soluble in halothane than chloroform (5.19% and 62.5% weight loss after 10 min exposure, respectively (P <0.01)). Its solubility in halothane was not significantly different from that of Apexit. AH Plus was significantly more soluble than all other materials in both chloroform and halothane (96% and 68% weight loss after 10 min exposure, respectively (P <0.01)). Conclusions There are significant differences in the solubility profiles of major classes of root canal sealer in common organic solvents. Efforts should continue to find a more universally effective solvent for use in root canal retreatment. [source] Effects of breed, sex and halothane genotype on fatty acid composition of triacylglycerols and phospholipids in pork longissimus muscleJOURNAL OF ANIMAL BREEDING AND GENETICS, Issue 4 2009S. Zhang Summary The objective of this study was to estimate the effects of breed, sex, and halothane (HAL-1843TM) genotype on fatty acid composition of triacylglycerols (TAG) and phospholipids (PL) extracted from porcine longissimus muscle (LM). Purebred Yorkshire (n = 131), Duroc (n = 136), Hampshire (n = 49), Spotted (n = 35), Chester White (n = 74), Poland China (n = 51), Berkshire (n = 169) and Landrace (n = 82) pigs (n = 727; 427 barrows and 300 gilts) from the 1994 and 2001 National Barrow Show Sire Progeny Tests were used. For statistical analyses, a mixed model was used that included fixed effects of breed, sex, HAL-1843TM genotype, year, slaughter date within each year, interaction of breed × sex and random effects of sire and dam within breed. Breeds and sex were significantly associated with the percentages of the majority fatty acids in TAG. Duroc pigs had greater total saturated fatty acids (SFA) and lower total monounsaturated fatty acids (MUFA) (p < 0.05) contents than did pigs of all other breeds except Berkshire (p > 0.05). The concentration of total polyunsaturated fatty acids (PUFA) was the greatest in Hampshire pigs (p < 0.05). The content of total SFA was greater (p < 0.01), whereas the concentrations of total MUFA and PUFA were lower (p < 0.01) in barrows than those in gilts. The contents of major SFA in PL did not differ significantly among pigs from different breeds and sex groups. However, breed and sex significantly affected the concentrations of major MUFA and PUFA in PL and strong negative correlation between the total contents of MUFA and PUFA in PL was observed in the current study. Chester White pigs had greater total MUFA and lower total PUFA contents (p < 0.05) in PL than did pigs of all other breeds except Spotted (p > 0.05). In contrast to breed and sex effects, the concentrations of fatty acids in PL were more affected by HAL-1843TM genotype than those in TAG. The content of C16:0, a major SFA in PL, differed significantly in pigs with different HAL-1843TM genotypes. In conclusion, these results suggest that breed and sex are important sources of the variations for fatty acid composition of TAG and PL in LM. [source] The combined neuroprotective effects of lidocaine and dexmedetomidine after transient forebrain ischemia in ratsACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 9 2009T. GOYAGI Background: We investigated whether coadministration of lidocaine and dexmedetomidine would reduce brain injury following transient forebrain ischemia in rats to a greater extent than either drug alone. Methods: Adult male Sprague,Dawleyrats were anesthetized with halothane to maintain normocapnia and normoxia. Rats received subcutaneous injection of saline 1 ml/kg, lidocaine 10 mg/kg, dexmedetomidine 3 ,g/kg, or lidocaine 10 mg/kg plus dexmedetomidine 3 ,g/kg. Thirty minutes after the drug injection, forebrain ischemia was induced by hemorrhagic hypotension and occlusion of the bilateral carotid arteries, and was confirmed by isoelectric EEG. At the end of 10-min ischemia, rats were reperfused. The same dose of drugs was administered 3, 24, and 48 h after ischemia. Neurological examination was done at 1, 2, and 7 days after ischemia. Seven days after ischemia, the brain was stained with hematoxylin and eosin. We counted ischemic cells in the CA1 hippocampal region, striatum, and cerebral cortex. We also measured extracellular glutamate and norepinephrine concentration in hippocampal CA1 in the four groups. Results: As compared with saline-treated rats, rats receiving dexmedetomidine plus lidocaine showed less than neurological deficit scores at 2 and 7 days after ischemia, and had less ischemic cells in the CA1 region. However, administration of dexmedetomidine plus lidocaine did not alter the area under the glutamate concentration curve and norepinephrine concentration during ischemia in the CA1 region, compared with saline-treated rats. Conclusions: Our results suggest coadministration of lidocaine and dexmedetomidine improves the neurological outcome without alteration of glutamate and norepinephrine concentrations during forebrain ischemia in rats. [source] Effect of gutta-percha solvents at different temperatures on the calcium, phosphorus and magnesium levels of human root dentinJOURNAL OF ORAL REHABILITATION, Issue 8 2001H. Do The aim of this study in vitro investigation was to evaluate the alterations caused by warmed gutta-percha solvents on the calcium, phosphorus and magnesium levels of root dentin. Extracted human anterior teeth, whose crowns and apical root thirds had been removed were used as root dentin specimens. The roots were sectioned longitudinally into two segments, cleaned and dried. Segments were divided into 12 groups (n=12). In 6 groups, the specimens received treatment with the following solvents at room temperature (22 °C): Chloroform, xylene, eucalyptol, orange oil, halothane and saline (control). Within each group, the specimens were further subgrouped into two to be incubated (100% humidity at 37 °C) for 5 and 10 min, respectively, following treatment with the solvents. The remaining six groups were treated with the same solvents which had been previously warmed to body temperature (37 °C) and received the same experimental procedures. The levels of calcium, phosphorus and magnesium in each specimen were analysed using energy dispersive spectrometric microanalysis. Statistical analysis of the readings showed that neither warming of the solvents nor prolonged incubation (treatment) time was capable of altering the histochemical composition of cut root dentin surfaces. [source] Effect of mivazerol, a ,2 -agonist, on striatal norepinephrine concentration during transient forebrain ischemia in rats,ACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 7 2008T. KIMURA Background: We have previously reported that mivazerol, a ,2 -agonist, possibly provides neuroprotection against transient forebrain ischemia in rats. This study was designed to investigate the ability of mivazerol to attenuate ischemia-induced increase in striatal norepinephrine concentration after transient forebrain ischemia in rats. Methods: Male Sprague,Dawley rats, anesthetized with halothane, were assigned to one of three groups (n=10 each); control (C, normal saline 1 ml/kg), mivazerol 20 ,g/kg (M20), and 40 ,g/kg (M40) groups. Monitored variables included temporal muscle temperature (maintained at 37.5±0.1 °C), electroencephalogram, systolic/diastolic blood pressure, heart rate, arterial blood gases, and blood glucose concentrations. Thirty minutes after subcutaneous drug administration, forebrain ischemia was induced with hemorrhagic hypotension (systolic arterial pressure: 40,50 mmHg) and bilateral carotid artery occlusion for 10 min, and then the brain was reperfused. Norepinephrine concentration in the interstitial fluids in the striatum was analyzed using in vivo microdialysis in combination with high-performance liquid chromatography. Results: Ischemia resulted in a prompt increase in norepinephrine concentrations in the striatum in all groups. However, there were no significant differences in norepinephrine concentrations in the striatum between the three groups at any period. Conclusions: Our results indicate that mivazerol did not attenuate ischemia-induced increase in striatal norepinephrine concentration. This suggests that the possible neuroprotective property of mivazerol is not related to inhibition of norepinephrine release in the brain. [source] Cardiovascular and Pulmonary Effects of Hetastarch Plus Hypertonic Saline Solutions during Experimental Endotoxemia in Anesthetized HorsesJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 6 2006DACVIM, Lucas G. Pantaleon MV Background:Small volume resuscitation has been advocated as a beneficial therapy for endotoxemia in horses but this therapy has not been investigated in a prospective manner. The objective of this study was to determine the cardiopulmonary effects of small-volume resuscitation using hypertonic saline solution (HSS) plus Hetastarch (HES) during experimental endotoxemia in anesthetized horses. Hypothesis:Treatment of horses with induced endotoxemia using HES-HSS does not alter the response of various cardiopulmonary indices when compared to treatment with either small-or large-volume isotonic crystalloid solutions. Animals:Eighteen healthy horses were randomly assigned to 1 of 3 groups. Anesthesia was maintained with halothane. Endotoxemia was induced by administering 50 ,g/kg of Escherichia coli endotoxin IV. The horses were treated over 30 minutes with 15 mL/kg of balanced polyionic crystalloid solution (control), 60 mL/kg of balanced polyionic crystalloid solution (ISO), or 5 mL/kg of HSS followed by 10 mL/kg of HES (HSS-HES). Methods:Prospective randomized trial. Results:Cardiac output (CO) after endotoxin infusion increased significantly (P < .05) from baseline in all groups, whereas mean central venous pressure increased significantly (P < .05) in the ISO group only. Mean pulmonary artery pressure increased from baseline (P < .05) in horses treated with isotonic fluids and HSS-HES. There was no effect of treatment with HSS-HES on CO, systemic vascular resistance (SVR), mean arterial pressure, blood lactate concentrations, or arterial oxygenation. Conclusions and Clinical Importance: The use of HSS-HES failed to ameliorate the deleterious hemodynamic responses associated with endotoxemia in horses. The clinical value of this treatment in horses with endotoxemia remains unconfirmed. [source] Bispectral IndexÔ values are higher during halothane vs. sevoflurane anesthesia in children, but not in infantsACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 8 2005J. J. Edwards Background:, Previously, we have shown in adult patients that bispectral index score (BIS) values are significantly higher during halothane anesthesia (53,61 units) as compared with those observed during equipotent concentrations of sevoflurane (39,43 units). Because halothane is frequently used in the pediatric setting, we tested the hypothesis that BIS values observed in children might also be higher during general anesthesia with halothane than with sevoflurane. Methods:, Forty-one healthy, unpremedicated pediatric patients scheduled for elective operations received either halothane or sevoflurane titrated as appropriate for surgical stimulation. Results:, During maintenance sevoflurane anesthesia (n = 20), the mean BIS values and percent end-tidal concentrations were 44 ± 14 and 2.1 ± 0.6, respectively, whereas for the halothane group (n = 21) the corresponding values were 61 ± 7 and 1.1 ± 0.4, respectively. Conclusion:, These findings suggest that BIS values are higher during halothane vs. sevoflurane anesthesia in children, but not in infants [source] Nociceptin system does not affect MAC of volatile anaestheticsACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 6 2005S. Himukashi Background:, Nociceptin is the endogenous agonist of the opioid receptor-like (ORL) 1 receptor (NOP), and both nociceptin and NOP are widely expressed in the brain and spinal cord, which are target organs of general anaesthetics. As nociceptin has been reported to be involved in modulating pain mechanisms and stress responses, it is possible that the activity of the nociceptin system affects the anaesthetic potency of general anaesthetics. To address this possibility, we investigated the minimum alveolar concentrations (MACs) of various volatile anaesthetics in nociceptin receptor knockout mice (NOP,/,) and wild-type mice (NOP+/+). Methods:, We used male NOP,/, mice and NOP+/+ mice. MACs for halothane, isoflurane and sevoflurane were determined by the tail-clamp method. Results:, MACs for halothane, isoflurane and sevoflurane in NOP,/, mice were 1.60 (SD 0.06), 1.68 (0.08) and 3.36 (0.07)%, respectively. In NOP+/+ mice, MACs for halothane, isoflurane and sevoflurane were 1.59 (SD 0.07), 1.72 (0.07) and 3.38 (0.09)%, respectively. Conclusion:, MACs in NOP,/, mice did not significantly differ from those in NOP+/+ mice for halothane, isoflurane and sevoflurane. This result suggests that the nociceptin system does not affect the anaesthetic potency of volatile anaesthetics. [source] Effects of intra-abdominal CO2 -insufflation on normal and impaired myocardial function: an experimental studyACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 6 2003C. A. Greim Background:, Intra-abdominal pressure (IAP) elevation during CO2 -pneumoperitoneum increases cardiac afterload and may enhance dysfunction of the already compromized heart. This study focused on the effects of acute IAP increases on left and right ventricular loadings and contractility in the heart with impaired global function. Methods:, Impairment of myocardial function (IMF) was pharmacologically induced in 16 pigs by administration of halothane and propranolol, while baseline arterial pressure was maintained by intravenous phenylephrine. Intra-abdominal pressure was gradually increased by 10 mmHg up to 30 mmHg in the supine position (IMF group 1, n = 8) or in a head-down tilted position (IMF group 2, n = 8). In two control groups with normal myocardial function, IAP was also increased in the supine position or the head-down tilted position. Cardiac function in all groups was assessed by epicardial echocardiography, intraventricular pressure measurements and pulmonary artery catheterization. Results:, The increase in IAP was accompanied by a transient rise in LV end-systolic wall stress and reduced cardiac output significantly by 16,24% in all groups. In the IMF groups, LV end-diastolic transmural pressure increased by 34,60% to peak values of 24 mmHg, while cross-sectional LV end-diastolic areas remained unchanged. Increases in right ventricular end-diastolic volume and decreases in right ventricular ejection fraction as well as in cardiac output were most pronounced at IAP 20 mmHg and significantly stronger in both IMF groups than in the control groups (P < 0.001). Conclusion:, Following the acute elevation of IAP, the right ventricular volume load shifted more extensively in the IMF groups than in the animals with normal myocardial function. Myocardial function in the impaired heart may worsen during IAP elevation due to right ventricular load alterations rather than a LV afterload increase. [source] Diabetes attenuates the minimum anaesthetic concentration (MAC) and MAC-blocking adrenergic response reducing actions of clonidine in ratsACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 10 2001T. Kita Background: It is well known that clonidine, an ,2 agonist, reduces anaesthetic requirement and attenuates haemodynamic responses against noxious stimuli. However, the diabetic state is known to affect several functions of ,2 adrenoceptors. We investigated the effects of streptozotocin (STZ)-induced diabetes mellitus (DM) on these beneficial actions of clonidine in halothane-anaesthetized rats. Methods: The rats were randomly assigned to one of three groups: diabetes (n=24, induced by 50 mg · kg,1 IV STZ), diabetes treated with insulin (n=24), or control (n=24). We evaluated the effects of clonidine on minimum anaesthetic concentration (MAC) and minimum concentration of halothane needed to suppress cardiovascular responses evoked by a noxious stimulus (MAC-blocking adrenergic responses: MAC-BAR) in each group. MAC and MAC-BAR of halothane were determined by the tail clamp method. MAC-BAR was defined as the MAC which attenuated haemodynamic responses within 10% following the tail clamp. Results: The diabetic state decreased MAC of halothane by approximately 10%, while MAC-BAR of halothane had been little affected. In the diabetes group, MAC reducing action of clonidine (30 and 100 ,g · kg,1, IV) was completely abolished and MAC-BAR reducing action of clonidine was partially reduced (30 but not 100 ,g · kg,1, IV). Insulin treatment preserved these actions of clonidine. Conclusion: It is suggested that the diabetic state attenuates the beneficial actions of clonidine and that insulin treatment of diabetes preserves these actions of clonidine. [source] Does halothane or isoflurane affect hypoxic and post-hypoxic vascular response in rabbit aorta?ACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 4 2000E. Haddad Background: Halothane and isoflurane affect differently endothelium-dependent and -independent vasorelaxation at 95% O2. In addition, hypoxic vascular response might involve endothelium-dependent and -independent mechanisms. Therefore, we investigated, in rabbit aortic rings, 1) the influence of halothane and isoflurane on vasodilation at 95% O2 and on hypoxic-induced vasorelaxation at 0% O2 and 2) the influence of halothane and isoflurane on endothelium-dependent and -independent post-hypoxic vascular response. Methods: Endothelium-intact and endothelium-denuded rabbit aortic rings were used. Phenylephrine precontracted rings were exposed, at 95% O2, to acetylcholine (ACh, 10,9 to 10,4 M) or sodium nitroprusside (SNP, 10,9 to 10,4 M) in the presence or absence of anaesthetic at 1 or 2 MAC. Precontracted rings were also exposed to an acute reduction in O2 from 95% to 0% followed by an acute reoxygenation with 95% O2 in the absence or presence of anaesthetic at 1 or 2 MAC. Results: At 95% O2, halothane decreased endothelium-dependent relaxation to ACh, while endothelium-independent relaxation to SNP was decreased only at 2 MAC. Isoflurane did not modify ACh- or SNP-induced relaxation. At 0% O2, neither halothane nor isoflurane altered the hypoxic vascular relaxation. Post-hypoxic response was not changed either. Conclusion: Our results indicate that halothane and isoflurane do not alter vascular hypoxic response in conductance arteries. [source] The behavioral importance of dynamically activated descending inhibition from the nucleus reticularis gigantocellularis pars alpha. (University Hospital of Wales, Cardiff, United Kingdom) Pain 2001;92:53,62.PAIN PRACTICE, Issue 4 2001J. Azami This study demonstrates the effects of nucleus reticularis gigantocellularis pars alpha (GiA) on the behavioral response during application of standardized noxious stimuli. As this system is activated in response to noxious stimulation, it is possible that chronic pain states may also activate GiA. Therefore, this study investigated this possibility in animals following partial sciatic nerve ligation (an animal model of chronic pain). Male Wistar rats (280,310 g) were anesthetized with halothane (0.5% to 2% in O2). Guide cannulae for microinjections were stereotaxically placed above GiA. In one group of animals the sciatic nerve was partially litigated. Animals were allowed to recover for 4,6 days. The responses of each animal during the formalin test and the tail flick test were recorded on different days. Microinjections (0.5 ,l) of either ,-aminobutyric acid (GABA, 200 mM), D-L homocysteic acid (DLH, 25 mM), or 0.9% saline (as control) into GiA were preformed during these tests in a randomized, blind manner. In animals without sciatic nerve ligation, microinjection of GABA to GiA did not significantly affect the animal's response during the tail flick test. However, microinjection of DLH significantly increased the latency of tail flick from 6.2 ± 0.8 to 8.4 ± 0.5 seconds for up to 15 minutes. Microinjection of GABA to GiA increased the behavioral response to formalin between 10 and 20 minutes postinjection, while microinjection of DLH reduced this response at all time points except 10 minutes postinjection (n = 8, p < 0.05, Mann-Whitney U -test). In animals with sciatic nerve ligation, microinjections (0.5 ,l) of either GABA (200 mM), or saline (as control) into GiA contralateral to the partial sciatic ligation were performed during these tests in a randomized, blind manner. Partial sciatic ligation significantly reduced the behavioral response to contralaterally applied formalin from 15 minutes postinjection onwards, compared to controls without sciatic nerve ligation. Microinjection of GABA GiA significantly increased the behavioral response to formalin from 20 to 50 minutes postinjection. The inactivation of GiA only causes behavioral effects in nociceptive tests of a long enough duration to activate the system (ie, the formalin test but not the tail flick test). Chemical activation of the system affects both tests. Conclude that these data strongly support the concept of an important analgesic system that is activated in response to noxious stimulation, and subsequently acts to reduce behavioral responses to noxious stimuli. Comment by Leland Lou, M.D. This is a rat study that looked at the presence of inhibitory spinal multireceptive cells modifying and decreasing the behavioural response to noxious stimuli. While no direction was given as to the source of noxious stimuli inhibition in chronic pain, great effort was made to report a possible differential response of the C-fiber pain system versus the large sensory fibers. After review it seems that the authors believed that the nucleus reticularis gigantocellularis pars alpha maybe a central processor of the inhibitory response. It is still too early to assess the clinical impact of this study. [source] Recovery characteristics of sevoflurane or halothane for day-case anaesthesia in children aged 1,3 yearsACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 1 2000H. Viitanen Background: Our objective was to compare the recovery characteristics of sevoflurane and halothane for short day-case anaesthesia in a specifically limited age group of children 1,3 yr. Methods: Eighty unpremedicated children undergoing day-case adenoidectomy were randomly assigned to receive inhalational induction with either sevoflurane 8% or halothane 5% and nitrous oxide in oxygen (70/30) via a face mask. Tracheal intubation was performed without a muscle relaxant. Anaesthesia was continued with the volatile anaesthetic, adjusted to maintain heart rate and blood pressure within ±20% of initial values. Recovery was evaluated using a modified Aldrete score, a Pain/Discomfort scale and by measuring recovery end-points. A postoperative questionnaire was used to determine the well-being of the child at home until 24 h after discharge. Results: Emergence and interaction occurred significantly earlier after sevoflurane than halothane but discharge times were similar. More children in the sevoflurane group achieved full Aldrete scores within the first 30 min after anaesthesia, although this group suffered more discomfort during the first 10 min. The amount of postoperative analgesic administered was higher and the first dose given earlier in the sevoflurane group. Postoperative vomiting was more common with halothane, but side-effects in the two groups were otherwise similar in the recovery room and at home. Conclusions: In children 1,3 yr, sevoflurane provided more rapid early recovery but not discharge after anaesthesia of <30-min duration. Apart from more vomiting with halothane and more discomfort during the first 10 min after awakening with sevoflurane, the quality of recovery was similar with the two anaesthestics. [source] A left paraglossal approach for oral intubation in children scheduled for bilateral orofacial cleft reconstruction surgery , a prospective observational studyPEDIATRIC ANESTHESIA, Issue 2 2009INDU SEN MD Summary Background:, Children with orofacial cleft defects are expected to have difficult airways. Conventional midline laryngoscopic approach of oral intubation can lead to iatrogenic tissue trauma. In this study, we evaluated the feasibility of left paraglossal laryngoscopy as a primary technique for airway management in these children. Methods:, After institutional ethical committee approval and informed consent, we enrolled 21 children with uncorrected bilateral lip and palate deformities (BL CL/P). Anesthesia was induced with halothane (0.5,4%) in 100% oxygen. After obtaining intravenous access, fentanyl 1.5 ,g·kg,1 and atracurium 0.5 mg·kg,1 were administered. Endotracheal intubation was performed with Miller's straight blade laryngoscope, introduced using left paraglossal approach. Difficulty of intubation was scored according to modified Intubation Difficulty Scale. Results:, Data consists of 21 children (15 males and six females), mean age 1.31 ± 1.18 years and weight 9.27 ± 2.57 kg. Laryngoscopic view obtained was CL II (7[33.3%]) and CL I (14[66.6%]) respectively (Figure 1). All the children could be easily intubated using left paraglossal approach, only 2/3 of them needed optimal external laryngeal manipulation to help achieving it. Though intubation could be done in the first attempt in 19 children, two infants (9½ and 11 months) required one size smaller endotracheal tube and were intubated in the second attempt using left paraglossal approach. Perioperative course was uneventful in all the children. Figure 1. ,Distribution of Intubation Difficulty scale (IDS) Score in BL CL/P patients. n (%) IDS: 0 (intubation without difficulty), IDS: 1 (slight difficulty; OELM applied/additional intubation attempt), IDS: >5 (Moderate to Major difficulty), IDS: = , (Impossible intubation). Conclusion:, Keeping in mind midline tissue support loss in cleft deformities, we propose routine use of left paraglossal laryngoscopic approach for intubating children with uncorrected BL CL/P anomalies. [source] Anesthesia for removal of inhaled foreign bodies in childrenPEDIATRIC ANESTHESIA, Issue 11 2004Amit Soodan MD Summary Background:, Foreign body aspiration may be a life-threatening emergency in children requiring immediate bronchoscopy under general anesthesia. Both controlled and spontaneous ventilation techniques have been used during anesthesia for bronchoscopic foreign body removal. There is no prospective study in the literature comparing these two techniques. This prospective randomized clinical trial was undertaken to compare spontaneous and controlled ventilation during anesthesia for removal of inhaled foreign bodies in children. Methods:, Thirty-six children posted for rigid bronchoscopy for removal of airway foreign bodies over a period of 2 years and 2 months in our institution were studied. After induction with sleep dose of thiopentone or halothane, they were randomly allocated to one of the two groups. In group I, 17 children were ventilated after obtaining paralysis with suxamethonium. In group II, 19 children were breathing halothane spontaneously in 100% oxygen. Results:, All the patients in the spontaneous ventilation group had to be converted to assisted ventilation because of either desaturation or inadequate depth of anesthesia. There was a significantly higher incidence of coughing and bucking in the spontaneous ventilation group compared with the controlled ventilation group (P = 0.0012). Conclusion:, Use of controlled ventilation with muscle relaxants and inhalation anesthesia provides an even and adequate depth of anesthesia for rigid bronchoscopy. [source] Postoperative behavioral changes following anesthesia with sevofluranePEDIATRIC ANESTHESIA, Issue 10 2004Aideen Keaney MB FRCA Summary Background :,Behavioral disturbance following hospitalization is a relatively frequent event, some children still having negative behavioral changes (NBC) 1 month following their operation. Sevoflurane has a propensity to induce ,excitement' during induction of anaesthesia, and delirium in the immediate postoperative phase. The aim of this study was to evaluate whether this translates into prolonged behavioral change. Methods :,A total of 120 children presenting for daycase surgical procedures under anesthesia were included in the study. Children were randomized to induction and maintenance of anesthesia with sevoflurane or halothane. No additional sedative drugs were administered. Postoperative behavioral change was assessed using the Post-Hospital Behavior Questionnaire (PHBQ) on postoperative days 1, 7 and 30. Results :,The Sevoflurane group (n = 63) were more distressed on emergence of anesthesia than the Halothane group (n = 57) (P < 0.05). About 58.3, 46.8 and 38.3% of all children exhibited NBC on postoperative days 1, 7 and 30, respectively. There was no association between anesthetic agent and behavior. There was a significant relationship between decreasing age and NBC (P < 0.005). Conclusions :,Children anesthetized with sevoflurane exhibit more immediate postoperative distress than those anesthetized with halothane. This difference is not carried over into the longer posthospital period. Negative behavioral changes occur more frequently with decreasing age. [source] Prevention of vomiting after strabismus surgery in children: dexamethasone alone versus dexamethasone plus low-dose ondansetronPEDIATRIC ANESTHESIA, Issue 5 2001FRCP(C), William M. Splinter MD Background: Postoperative vomiting is a common complication after strabismus surgery. The combination of dexamethasone and ondansetron decreases vomiting after strabismus surgery, while dexamethasone alone decreases vomiting after tonsillectomy in children. We compared the effect of dexamethasone alone to ondansetron plus dexamethasone on postoperative vomiting among children undergoing strabismus surgery. Methods: Healthy children, aged 2,14 years, who were undergoing strabismus surgery were entered into this randomized, blocked and stratified study. Patients were administered 0.5 mg·kg,1 midazolam p.o., 20,30 min preoperatively when indicated. The patients had an intravenous induction with 2.5,3.5 mg·kg,1 propofol or an inhalation induction of anaesthesia with halothane and N2O. All patients were given 20 ,g·kg,1 atropine i.v. Study drugs were administered in a double-blind fashion. Both groups received 150 ,g·kg,1 dexamethasone i.v. Group D patients received placebo and group OD received 50 ,g·kg,1 of ondansetron i.v. Anaesthesia was maintained with halothane and N2O. Postoperative fluid, vomiting and pain management were standardized. Patients were followed for 24 h. We studied 193 patients with 111 patients in the OD group. Demographic data were similar. Results: The overall incidence of vomiting was 23%; in group D and 5%; in group OD (P < 0.001). Each episode of vomiting increased the in-hospital length of stay by 29 min (P < 0.001). Conclusions: There was a remarkably low incidence of postoperative vomiting of 5%; with the combination of dexamethasone plus a low-dose of ondansetron which more effectively decreased vomiting after strabismus surgery in children when compared with dexamethasone alone. [source] Tropisetron reduces postoperative vomiting in children undergoing tonsillectomyPEDIATRIC ANESTHESIA, Issue 1 2000Anette B. Jensen MS Summary In this patient, parent and investigator blinded, randomized, placebo-controlled study, children undergoing tonsillectomy (mean age 6.4 years) received either intravenous placebo (n=36) or tropisetron 0.2 mg·kg,1 up to 5 mg (n=35) at induction of anaesthesia with halothane, nitrous oxide and oxygen. Morphine and paracetamol were given in theatre for postoperative pain. Episodes of vomiting were recorded during the first 24 h after surgery. Intravenous tropisetron was significantly (P<0.001, chi-squared) more effective than placebo in controlling the incidence and frequency of emesis during the first 24 h: vomiting was reduced from 89% to 46% and the mean number of vomits from 4.6 to 2.4. Minor side-effects occurred equally in both the placebo and active groups. Intravenous tropisetron is an effective and safe antiemetic for reducing postoperative vomiting in children undergoing tonsillectomy or adenotonsillectomy. [source] The acute hypoxic ventilatory response under halothane, isoflurane, and sevoflurane anaesthesia in rats,ANAESTHESIA, Issue 3 2010N. Karanovic Summary The relative order of potency of anaesthetic agents on the hypoxic ventilatory response has been tested in humans, but animal data are sparse. We examined the effects of 1.4, 1.6, 1.8, and 2.0 MAC halothane, isoflurane, and sevoflurane on phrenic nerve activity in euoxia (baseline) and during acute normocapnic hypoxia (inspired oxygen fraction 0.09) in adult male Sprague-Dawley rats. With halothane, all animals became apnoeic even in euoxia, and the hypoxic response was completely abolished at all anaesthetic levels. With isoflurane, 5 of 14 animals exhibited phrenic nerve activity in euoxia at 1.4 MAC and demonstrated a hypoxic response (302% of baseline activity), but all became apnoeic and lost the hypoxic response at higher doses. With sevoflurane, phrenic nerve activity and a hypoxic response was preserved in at least some animals at all doses (i.e. even the highest dose of 2.0 MAC). Similar to the rank order of potency previously observed in humans, the relative order of potency of depression of the hypoxic ventilatory response in rats was halothane (most depressive) > isoflurane > sevoflurane (p = 0.01 for differences between agents). [source] Speed of induction of anaesthesia in dogs administered halothane, isoflurane, sevoflurane or propofol in a clinical settingAUSTRALIAN VETERINARY JOURNAL, Issue 1-2 2008RG Pottie Objective To compare the speed and quality of induction of general anaesthesia using three different inhalant agents and one intravenous agent, in healthy dogs undergoing desexing surgery. Materials and methods Less excitable dogs were not premedicated; others were premedicated with intramuscular acepromazine and morphine. Anaesthesia induction protocol was randomly assigned, with halothane, isoflurane or sevoflurane delivered by mask, or propofol delivered intravenously. Maximum vaporiser settings were used for inhalant inductions. Induction of anaesthesia was considered complete at the time of endotracheal intubation. Quality of induction was scored by the administering veterinarian. Results Seventy-one dogs were enrolled. Twenty-four received no premedication and 47 received premedication. Isoflurane inductions were significantly faster than halothane inductions (2.86 ± 0.25 vs 3.71 ± 0.22 min; mean ± SE, P = 0.013). Sevoflurane inductions (3.29 ± 0.24 min) were not significantly different from either halothane (3.71 ± 0.22 min, P = 0.202) or isoflurane inductions (2.86 ± 0.25 min, P = 0.217). Induction with propofol (1.43 ± 0.13 min) was significantly faster than inhalant induction (P < 0.001 in each case). Premedication decreased the dose requirement and time to induction for dogs induced with propofol, but did not significantly change the time to intubation for inhalant inductions. Dogs administered propofol and/or premedication were significantly more likely to have an excellent quality of induction, but there was no difference between inhalant agents in terms of induction quality. Conclusion Sevoflurane possesses chemical properties that should produce a more rapid induction of anaesthesia in comparison to halothane or isoflurane. However, in clinical practice patient related factors outweigh this improvement. [source] Survey on small animal anaesthesiaAUSTRALIAN VETERINARY JOURNAL, Issue 9 2001A NICHOLSON Objective To ascertain anaesthetic practices used currently for dogs and cats in Australia. Methods A questionnaire was distributed to 4800 veterinarians throughout Australia, seeking data on numbers of dogs and cats anaesthetised per week; drug preferences for anaesthetic premedication, induction and maintenance; use of tracheal intubation, supplemental O2, nitrous oxide and anaesthetic antagonists; and types of vaporisers, breathing systems and anaesthetic monitoring devices used or available. Additional questions concerned proportions of different animal types seen in the practice, and the respondent's university and year of graduation. Results The response rate was 19%; 95% of respondents graduated from Australian universities, about half since 1985. Most responses (79%) came from mainly small animal practices. On average 16 dogs and 12 cats were anaesthetised each week. Premedication was used more often in dogs than cats, with acepromazine and atropine most favoured in both species. For anaesthetic induction, thiopentone was most preferred in dogs and alphaxalone/alphadolone in cats. Inhaled agents, especially halothane, were preferred for maintenance in both species. Most respondents usually employed tracheal intubation when using inhalational anaesthetic maintenance, but intubation rates were lower during injectable anaesthetic maintenance and a minority of respondents provided supplemental O2. Nitrous oxide was administered regularly by 13% of respondents. The agents most frequently used to speed recovery from anaesthesia were doxapram and yohimbine. The most widely used vaporisers were the Fluotec Mark III and the Stephens machine. Most (95%) respondents used a rebreathing circuit for large dogs and a non-rebreathing system was used for small dogs by 68% of respondents. Most respondents (93%) indicated some form of aid was available to monitor general anaesthesia: the three most mentioned were an apnoea alarm, oesophageal stethoscope and electrocardiogram. Conclusion Diverse approaches were evident, but there appeared to be less variation in anaesthetising dogs: premedication was more frequent and less varied in type, while thiobarbituates dominated for induction and inhalants for maintenance. Injectable maintenance techniques had substantial use in cats, but little in dogs. Evident disparity between vaporisers available and circuits used suggested either confusion in terminology or incorrect use of some vaporisers in-circuit. While most respondents used monitoring equipment or a dedicated observer to invigilate anaesthesia, the common reliance on apnoea alarms is of concern, because of unproven reliability and accuracy. [source] A rapid and simple method for determination of halothane, iso,urane and sevo,urane in blood using gas chromatographyBIOMEDICAL CHROMATOGRAPHY, Issue 9 2004Richard J. Atherley Abstract We have developed a technique to determine the concentration of volatile anesthetics (halothane, iso,urane and sevo,urane) in blood that is a modi,cation of a method used for volatile anesthetics in Krebs solution. Methylene chloride was the internal standard and chloroform was used to extract the volatile anesthetic from blood. The congealed blood proteins were separated from the chloroform solvent (containing anesthetic) using a two-compartment vial that ,ltered out the proteinaceous material during centrifuging. Recovery averaged 102%. Linearity was excellent (r = 0.992,0.999) in the 50,600, 50,300 and 50,300 µg/mL range for halothane, iso,urane and sevo,urane, respectively. Intra-day and inter-day precisions were likewise excellent, with relative standard deviations <5.3 and <7.1%, respectively. Accuracy ranged from 0.8 to 9.5% of the estimated theoretical value. Extracted anesthetic in chloroform solvent was stable over 4,5 days, with <3% variability. The time from obtaining the blood sample to determination of the concentration from the chromatographic peak was 15 min or less. Copyright © 2004 John Wiley & Sons, Ltd. [source] Inhalational anaesthetics and n -alcohols share a site of action in the neuronal Shaw2 Kv channelBRITISH JOURNAL OF PHARMACOLOGY, Issue 7 2010Aditya Bhattacharji Background and purpose:, Neuronal ion channels are key targets of general anaesthetics and alcohol, and binding of these drugs to pre-existing and relatively specific sites is thought to alter channel gating. However, the underlying molecular mechanisms of this action are still poorly understood. Here, we investigated the neuronal Shaw2 voltage-gated K+ (Kv) channel to ask whether the inhalational anaesthetic halothane and n -alcohols share a binding site near the activation gate of the channel. Experimental approach:, Focusing on activation gate mutations that affect channel modulation by n -alcohols, we investigated n -alcohol-sensitive and n -alcohol-resistant Kv channels heterologously expressed in Xenopus oocytes to probe the functional modulation by externally applied halothane using two-electrode voltage clamping and a gas-tight perfusion system. Key results:, Shaw2 Kv channels are reversibly inhibited by halothane in a dose-dependent and saturable manner (K0.5= 400 µM; nH= 1.2). Also, discrete mutations in the channel's S4S5 linker are sufficient to reduce or confer inhibition by halothane (Shaw2-T330L and Kv3.4-G371I/T378A respectively). Furthermore, a point mutation in the S6 segment of Shaw2 (P410A) converted the halothane-induced inhibition into halothane-induced potentiation. Lastly, the inhibition resulting from the co-application of n -butanol and halothane is consistent with the presence of overlapping binding sites for these drugs and weak binding cooperativity. Conclusions and implications:, These observations strongly support a molecular model of a general anaesthetic binding site in the Shaw2 Kv channel. This site may involve the amphiphilic interface between the S4S5 linker and the S6 segment, which plays a pivotal role in Kv channel activation. [source] | |||||||||||||||||||||||||||||||