Isoflurane Increases the Apparent Agonist Affinity of the Nicotinic Acetylcholine Receptor

Background: Volatile general anesthetics increase agonist-mediated ion flux through the gamma-aminobutyric acidA, glycine, and 5-hydroxytryptamine3 (5-HT3) receptors. This action reflects an anesthetic-induced increase in the apparent agonist affinity of these receptors. In contrast, volatile anesthetics block ion flux through the nicotinic acetylcholine receptor (nAcChoR). The authors tested the hypothesis that in addition to blocking ion flux through the nAcChoR, isoflurane also increases the apparent affinity of the nAcChoR for agonist.

Methods: Nicotinic acetylcholine receptors were obtained from the electroplax organ of Torpedo nobiliana. The apparent agonist affinity of the nAcChoR was determined using a new stopped-flow fluorescence assay. This assay derives the apparent agonist affinity of the nAcChoR from the apparent rates with which agonists convert nAcChoRs from the resting state to the desensitized state.

Results: Isoflurane significantly increased the apparent affinity (decreased the apparent dissociation constant) of acetylcholine for the nAcChoR at clinically relevant concentrations. The apparent dissociation constant decreased exponentially with the isoflurane concentration from a control value of 44 +/- 4 [micro sign]M to 1.0 +/- 0.1 [micro sign]M in the presence of 1.5 mM isoflurane, the highest concentration studied.     

A unifying principle relating stress to trabecular bone morphology

The relationships between cancellous bone apparent density, trabecular orientation, and stress are developed and a mathematical theory describing these relationships is proposed. The bone is assumed to be a self-optimizing material. Using a continuum model, sufficient conditions are developed which ensure that, for a given stress encountered during normal activity, the theory will predict both trabecular orientation and apparent density. Using two special approaches, one based on optimizing strain energy density (stiffness) and the other on optimizing strength, the relationship between apparent density and stress is derived. This is the first time that a single theory has been advanced to predict both the orientation and apparent density of cancellous bone.     

Standardized biomechanical measurement for varus-valgus stiffness and rotation in normal knees

Seventeen female and 24 male subjects had varus and valgus and apparent rotations measured using a standardized mechanical testing device that cyclically applied a 20-Nm moment in each direction. Five parameters--apparent varus rotation, apparent valgus rotation, apparent overall rotation, varus stiffness, and valgus stiffness showed intersubject variations approaching 40%. Right-left variations in the same subject averaged 12%, with no significant right-left differences overall. Female knees rotated 66% more than male knees and were 35% less stiff. The ratio of apparent valgus rotation to apparent varus rotation averaged 0.775, and the ratio of valgus stiffness to varus stiffness averaged 1.23 for all knees. Stiffness and rotation parameters were highly correlated for both genders in the valgus phase of testing. Results suggest that although magnitudes of measured parameters vary considerably from subject to subject, common relationships between parameters from the same normal knee exist.     

Nonhalogenated Alkane Anesthetics Fail to Potentiate Agonist Actions on Two Ligand-gated Ion Channels

Background: Although ether, alcohol, and halogenated alkane anesthetics potentiate agonist actions or increase the apparent agonist affinity of ligand-gated ion channels at clinically relevant concentrations, the effects of nonhalogenated alkane anesthetics on ligand-gated ion channels have not been studied. The current study assessed the abilities of two representative nonhalogenated alkane anesthetics (cyclopropane and butane) to potentiate agonist actions or increase the apparent agonist affinity of two representative ligand-gated ion channels: the nicotinic acetylcholine receptor and [gamma]-aminobutyric acid type A (GABAA) receptor.

Methods: Nicotinic acetylcholine receptors were obtained from the electroplax organ of Torpedo nobiliana, and human GABAA receptors ([alpha]1[beta]2[gamma]2L) were expressed in human embryonic kidney 293 cells. The Torpedo nicotinic acetylcholine receptors apparent agonist affinity in the presence and absence of anesthetic was assessed by measuring the apparent rates of desensitization induced by a range of acetylcholine concentrations. The GABAA receptor's apparent agonist affinity in the presence and absence of anesthetic was assessed by measuring the peak currents induced by a range of GABA concentrations.

Results: Neither cyclopropane nor butane potentiated agonist actions or increased the apparent agonist affinity (reduced the apparent agonist dissociation constant) of the Torpedo nicotinic acetylcholine receptor or GABAA receptor. At clinically relevant concentrations, cyclopropane and butane reduced the apparent rate of Torpedo nicotinic acetylcholine receptor desensitization induced by low concentrations of agonist.     

Nonhalogenated alkane anesthetics fail to potentiate agonist actions on two ligand-gated ion channels

BACKGROUND: Although ether, alcohol, and halogenated alkane anesthetics potentiate agonist actions or increase the apparent agonist affinity of ligand-gated ion channels at clinically relevant concentrations, the effects of nonhalogenated alkane anesthetics on ligand-gated ion channels have not been studied. The current study assessed the abilities of two representative nonhalogenated alkane anesthetics (cyclopropane and butane) to potentiate agonist actions or increase the apparent agonist affinity of two representative ligand-gated ion channels: the nicotinic acetylcholine receptor and y-aminobutyric acid type A (GABA(A)) receptor. METHODS: Nicotinic acetylcholine receptors were obtained from the electroplax organ of Torpedo nobiliana, and human GABA(A) receptors (alpha1beta2gamma2L) were expressed in human embryonic kidney 293 cells. The Torpedo nicotinic acetylcholine receptors apparent agonist affinity in the presence and absence of anesthetic was assessed by measuring the apparent rates of desensitization induced by a range of acetylcholine concentrations. The GABA(A) receptor's apparent agonist affinity in the presence and absence of anesthetic was assessed by measuring the peak currents induced by a range of GABA concentrations. RESULTS: Neither cyclopropane nor butane potentiated agonist actions or increased the apparent agonist affinity (reduced the apparent agonist dissociation constant) of the Torpedo nicotinic acetylcholine receptor or GABA(A) receptor. At clinically relevant concentrations, cyclopropane and butane reduced the apparent rate of Torpedo nicotinic acetylcholine receptor desensitization induced by low concentrations of agonist. CONCLUSIONS: Our results suggest that the in vivo central nervous system depressant effects of nonhalogenated alkane anesthetics do not result from their abilities to potentiate agonist actions on ligand-gated ion channels. Other targets or mechanisms more likely account for the anesthetic activities of nonhalogenated alkane anesthetics.     

The alkyl chain dependence of the effect of normal alcohols on agonist-induced nicotinic acetylcholine receptor desensitization kinetics.

BACKGROUND: The nAcChoR is the prototypical member of a superfamily of ligand-gated ion channels that are all relevant targets of anesthetics and undergo desensitization upon prolonged exposure to agonist. This study was designed to investigate the effects of representative normal alcohols on the apparent rate of acetylcholine-induced nAcChoR desensitization. METHODS: Nicotinic acetylcholine receptors were obtained from the electroplax organ of Torpedo nobiliana. The apparent rate of acetylcholine-induced desensitization in the presence and absence of normal alcohols was measured using stopped-flow fluorescence. RESULTS: Normal alcohols as long as octanol (the longest studied) increased the apparent rate of desensitization induced by low concentrations of acetylcholine, shifting the agonist concentration-response curve for desensitization to the left Ethanol butanol, and, to a lesser extent, hexanol increased the maximal rate of desensitization induced by high, saturating concentrations of agonist. Beyond hexanol, heptanol and octanol had no effect on this maximal apparent rate of desensitization, even at concentrations that approach those that directly induce desensitization in the absence of agonist. CONCLUSION: Normal alcohols ranging from ethanol to octanol increase the apparent affinity of nAcChoR for agonist with potencies that are proportional to their hydrophobicities. However, normal alcohol effects on the rate constant for desensitization show a cutoff beyond hexanoL This suggests that the effects of normal alcohols on the apparent agonist affinity and rate constant for desensitization of nAcChoR may be modulated by distinct sites that have different steric constraints; the site(s) responsible for increasing the maximal rate of desensitization are predicted to be smaller than those that increase the apparent agonist affinity.     

Load distribution and the predictive power of morphological indices in the distal radius and tibia by high resolution peripheral quantitative computed tomography

A 3D high resolution peripheral quantitative computed tomography scanner (HR-pQCT) (XtremeCT, Scanco Medical, voxel size 82 microm) has been recently developed that can perform in vivo human measurements on peripheral sites, including the wrist and tibia. The goals of this study were to use HR-pQCT measurements to determine the ability of morphological and density measurements to predict bone apparent stiffness and apparent Young's modulus in the distal radius and tibia, to determine the relative importance of cortical and trabecular bone in carrying load in the human distal radius and tibia. Furthermore, the ability of a sub-volume of trabecular bone apparent Young's modulus to predict the Young's modulus of a whole radius and tibia section was determined. A total of 25 measurements of the radius and 12 measurements of the tibia were used for morphological and finite element analyses of sections, and sub-volume cubes of trabecular bone from the distal radius and tibia. The subjects were chosen to obtain a large variation in age ranges and bone architecture and density. By combining multiple measurements, a strong ability to predict bone apparent stiffness and apparent Young's modulus was found for morphological and density measurements in the radius and tibia (R(2)>0.80). The relative importance of the trabecular and cortical bone in carrying load was also found to vary consistently with location in the sample for both the radius and the tibia. This indicates that measurements of the cortical and trabecular bone are required for assessing fracture risk. A cubic section of trabecular bone was found to be insufficient to accurately represent the apparent bone Young's modulus of a radius or tibia section. Morphological and density measurements of the distal radius and tibia have been shown in this study to predict bone apparent Young's modulus and apparent stiffness, and may indicate when a more time consuming finite element analysis is warranted. It should be noted that these results may be an overestimation of the predictive ability of structural parameters, as the influence of bone density is removed from the finite element analyses, and the results were only influenced by bone structure. A measurement of bone apparent Young's modulus is independent of subject size (as opposed to reaction force), and may provide the ability to distinguish between two patients that have similar mean morphological and density measurements; but different overall structures, and therefore, different fracture risk.     

Roentgenographic measurement of pedicle screw penetration

Potential complications due to pedicle screw penetration of the anterior cortex include injury to vascular, visceral, ureteral, sympathetic, and neural structures. This study examined the accuracy of lateral roentgenographic techniques in determining actual screw penetration in vertebral levels T12 through S1 of ten unilateral sets of pedicles in five anatomic specimens. A true lateral roentgenogram alone was inaccurate for determining the penetration of the anterior cortex by a pedicle screw. The greatest discrepancy between roentgenographically apparent and actual screw penetration was found at the L4 and L5 levels. Deviation from a true lateral roentgenographic axis resulted in the most pronounced change in roentgenographically apparent screw penetration at L4 and L5. The roentgenographic axes resulting in the closest approximation of actual screw penetrations were 5 degrees and 10 degrees above the true lateral axis for the T12-L3 and the L4-S1 levels, respectively. At 50% apparent penetration, the screw may be safely assumed to not be penetrating the anterior cortex using a true lateral roentgenogram. At 80% apparent penetration, 30% and 10% probabilities of actual screw penetration of the anterior cortex exist at L4 and L5, respectively. At 100% apparent penetration, there is an almost 100% probability that the screw is actually protruding through the anterior cortex.     

Metastatic renal cell carcinoma to prostate

Clinically apparent renal cell carcinoma that has metastasized to the prostate is a rare finding. When identified, it has been associated with widespread metastatic disease and short-term survival. We present a case of metachronous renal cell carcinoma found only in the prostate with the longest reported interval of 9 years between radical nephrectomy and clinically apparent disease.     

The Alkyl Chain Dependence of the Effect of Normal Alcohols on Agonist-induced Nicotinic Acetylcholine Receptor Desensitization Kinetics

Background: The nAcChoR is the prototypical member of a superfamily of ligand-gated ion channels that are all relevant targets of anesthetics and undergo desensitization upon prolonged exposure to agonist. This study was designed to investigate the effects of representative normal alcohols on the apparent rate of acetylcholine-induced nAcChoR desensitization.

Methods: Nicotinic acetylcholine receptors were obtained from the electroplax organ of Torpedo nobiliana. The apparent rate of acetylcholine-induced desensitization in the presence and absence of normal alcohols was measured using stopped-flow fluorescence.

Results: Normal alcohols as long as octanol (the longest studied) increased the apparent rate of desensitization induced by low concentrations of acetylcholine, shifting the agonist concentration-response curve for desensitization to the left. Ethanol, butanol, and, to a lesser extent, hexanol increased the maximal rate of desensitization induced by high, saturating concentrations of agonist. Beyond hexanol, heptanol and octanol had no effect on this maximal apparent rate of desensitization, even at concentrations that approach those that directly induce desensitization in the absence of agonist.     

Damage-based finite-element vertebroplasty simulations

The objectives of this study were to quantify the efficacy of vertebroplasty according to: (1) damage and (2) cement quantity (fill) and modulus. Vertebral body damage was numerically simulated using a previously validated two-dimensional finite-element model coupled with an elasto-plastic modulus reduction (EPMR) scheme. The effects of cement fill (% marrow replaced by cement, % MRC) and cement modulus on vertebral apparent modulus and trabecular bone tissue stress concentrations were parametrically assessed for four EPMR damage models (19%, 33%, 60%, and 91% modulus reduction). For this analysis, the elastic modulus of the trabecular bone tissue and marrow elements were assumed to be 10 GPa and 10 kPa, respectively. The effect of cement modulus (varied in the range 1 GPa to 9 GPa) on vertebral apparent modulus was also examined for partial fill (39% MRC) and complete fill (100% MRC) using the 33% modulus reduction damage model. In the case of polymethylmethacrylate (PMMA cement modulus = 2.16 GPa), restoration of the thoracic vertebral body (T10) apparent modulus to undamaged levels required 71% and 100% cement fill for the 19–33% and 60–91% modulus reduction damage models, respectively. Variations in cement modulus had no appreciable effect on the recovery of vertebral apparent modulus to undamaged levels for simulations of partial cement fill (39% MRC). For complete cement fill, however, a PMMA cement modulus produced approximately a 2-fold increase (82%) in vertebral apparent modulus relative to the undamaged vertebral body. Increasing the cement modulus to 9 GPa increased the vertebral apparent modulus over 2.5-fold (158%) relative to the undamaged state. The EPMR damage scheme and repair simulations performed in this study will help clinicians and cement manufacturers to improve vertebroplasty procedures.     

Antenatal hydroureteronephrosis presenting as an apparent solid renal mass

We present a patient with an apparent renal mass that was identified antenatally with pyelocaliectasis and ureterectasis. A right ectopic ureter with an apparent cystic upper pole was eventually confirmed at 5 months of age. The definitive diagnosis in this case eluded an initial exhaustive neonatal radiologic and surgical evaluation.     

Heterogeneity of Trabecular Bone Structure in the Calcaneus Using Magnetic Resonance Imaging

The purpose of this study was to quantify the heterogeneity in the trabecular bone structure in the calcaneus. Magnetic resonance (MR) images of the calcaneus were obtained in the sagittal plane at an inplane resolution of 195 μm and a slice thickness of 1000 μm in 12 young normal subjects. Regions of interest (ROI) were selected to cover the calcaneus using a grid of square boxes (10 mm per side). A thresholding technique based on the regional intensity histogram was used to segment the images into trabecular bone and marrow phases and to calculate measures such as apparent trabecular bone area fraction, apparent trabecular spacing, apparent trabecular thickness and apparent trabecular number. Bone mineral density (BMD) of the calcaneus was assessed using dual-energy X-ray absorptiometry (DXA). Histological sections of three calcanei were also analyzed using transmission light illumination, and the results used to calibrate our computational software. For a relatively narrow inter-subject variation in posterior BMD, a significant inter-subject variation was seen in MRI-derived structural parameters. Furthermore, the spatial heterogeneity of the structural parameters in the posterior region was as high as 40%. Thus, the posterior tuberosity of the calcaneus, a typical site for BMD and single-point ultrasound assessments, can demonstrate significant regional variation in trabecular bone structure.     

Bilobar atelectasis after difficult tracheal intubation

Acute intra-operative collapse of a lobe without apparent cause is rare. We report a case of transient bilobar atelectasis that developed without any apparent cause after a difficult tracheal intubation in a healthy young patient. Intrabronchial obstruction was ruled out by bronchoscopy. The bilobar atelectasis developed acutely and resolved quickly with mechanical ventilation. The characteristics of the lung collapse were atypical, suggesting either its reflex nature or acute reduction of lung volume owing to intubation-induced coughing. We present a review of the mechanisms of atelectasis.     

Apnoea and unconsciousness after apparent recovery from alfentanil-supplemented anaesthesia

Several cases of recurrent respiratory depression progressing to apnoea and unconsciousness after apparent recovery from sufentanil have been reported recently. Alfentanil has the shortest elimination half-time of the narcotics used in anaesthesia, suggesting that it should be the least likely to cause postoperative respiratory depression. A case of recurrent unconsciousness and respiratory arrest after apparent recovery from alfentanil-isoflurane-nitrous oxide anaesthesia is reported. A total dose of 137 micrograms.kg-1 alfentanil was given over a 3.25-hr period to a 45-year-old female undergoing partial gastrectomy. Naloxone, 0.16 mg IV, rapidly restored spontaneous ventilation and consciousness. This case demonstrates that apnoea and unconsciousness can also recur after apparent recovery from alfentanil. Recovery room personnel should be aware of this phenomenon. Earlier detection may permit treatment before apnoea occurs. Patients given narcotic-supplemented anaesthesia should be monitored by capnography and/or pulse oximetry in the early postoperative period.     

A validated technique for the analysis of biliary bile acid secretion in donor livers prior to transplantation

Many parameters currently used for the pre-transplant assessment of liver allografts, are not reliable enough in predicting the likelihood of early graft dysfunction or non-function. It is generally accepted that bile secretion is a sign of hepatic function post-transplant and that bile flow shows a close linear relationship to the secretion of bile acids (“apparent choleretic activity”). We have studied bile flow, biliary bile acid concentrations and composition and measured apparent choleretic activity from hepatic bile collected with a new technique under controlled conditions at the time of retrieval from 18 donor livers. More than three samples were collected from each of 13 donors and a total of 65 samples of hepatic bile were analysed. Of these, ten showed typical apparent choleretic activity with a positive slope in the regression line analysis (correlation coefficient of 0.9), validating our collection technique. Received: 1 September 1997 Received after revision: 15 December 1997 Accepted: 9 January 1998     

Properties of growing trabecular ovine bone. Part I: mechanical and physical properties

Our aim was to determine the relationship between age and the mechanical and physical properties of trabecular bone, to describe the patterns in which the variations in these properties take place, and to investigate the influence of the physical properties on the mechanical characteristics of trabecular bone during growth. We used 30 lambs in three age groups and 20 sheep in two age groups. Cubes of subchondral bone were cut from the proximal tibia according to a standardised protocol. We performed non-destructive compression tests of the specimens in three orthogonal directions and compression tests to failure in the axial direction. The physical properties of the specimens were also determined. The data were correlated with age and compared in skeletally immature and mature animals. Multiple regression analyses were performed between the mechanical and the physical properties. Age correlated positively with elastic modulus, bone strength, energy absorption to failure, elastic energy, mechanical anisotropy ratio, tissue density, apparent density, apparent ash density, and bone mineral content, and inversely with ultimate strain, viscoelastic energy absorption, relative energy loss, the collagen content of bone and the percentage porosity. The values of all variables were significantly different in the skeletally mature and immature groups. The apparent density of trabecular bone tissue was found to be the major predictor of its compressive mechanical properties. Together with the content of bone muscle and bone collagen, the apparent density could explain 84% of the variation in the elastic modulus, whereas only a small portion of the variation in ultimate strain could be explained by the variation in apparent density.     

Results of endoscopic management of carpal-tunnel syndrome in longterm haemodialysis versus idiopathic patients

The purpose of this paper is to compare the results of our endoscopicmanagement of carpal-tunnel syndrome caused by long-term haemodialysisto that with no apparent cause (idiopathic). We have operatedon 551 hands in 370 patients using the Universal SubcutaneousEndoscope system under local anaesthesia without a pneumatictourniquet on an out-patient basis since 1986. Ninety-six handsin 64 patients who suffered from carpal-tunnel syndrome fromlong-term haemodialysis and 85 hands in 52 patients who sufferedfrom carpal-tunnel syndrome for no apparent cause were statisticallyanalysed using complete pre- and postoperative electrophysiologicaland clinical studies for periods of time ranging from over 6months to 4.8 years (mean 16.9 months). Electrophysiologicaland clinical results showed that our endoscopic management inlong-term haemodialysis patients is effective, safe and yieldsthe same results as in patients who suffered from carpal-tunnelsyndrome for no apparent cause.     

Interpretation of calcaneus dual-energy X-ray absorptiometry measurements in the assessment of osteopenia and fracture risk.

Dual-energy X-ray absorptiometry (DXA) of the calcaneus is useful in assessing bone mass and fracture risk at other skeletal sites. However, DXA yields an areal bone mineral density (BMD) that depends on both bone apparent density and bone size, potentially complicating interpretation of the DXA results. Information that is more complete may be obtained from DXA exams by using a volumetric density in addition to BMD in clinical applications. In this paper, we develop a simple methodology for determining a volumetric bone mineral apparent density (BMAD) of the calcaneus. For the whole calcaneus, BMAD = (BMC)/ADXA3/2, where BMC and ADXA are, respectively, the bone mineral content and projected area measured by DXA. We found that ADXA3/2 was proportional to the calcaneus volume with a proportionality constant of 1.82 +/- 0.02 (mean +/- SE). Consequently, consistent with theoretical predictions, BMAD was proportional to the true volumetric apparent density (rho) of the bone according to the relationship rho = 1.82 BMAD. Also consistent with theoretical predictions, we found that BMD varied in proportion to rho V1/3, where V is the bone volume. We propose that the volumetric apparent density, estimated at the calcaneus, provides additional information that may aid in the diagnosis of osteopenia. Areal BMD or BMD2 may allow estimation of the load required to fracture a bone. Fracture risk depends on the loading applied to a bone in relation to the bone's failure load. When DXA is used to assess osteopenia and fracture risk in patients, it may be useful to recognize the separate and combined effects of applied loading, bone apparent density, and bone size.     

SOME EFFECTS OF THE STEROIDAL MUSCLE RELAXANT, DACURONIUM BROMIDE, IN ANAESTHETIZED PATIENTS

The neuromuscular blocking properties of a new steroidal drug,dacuronium bromide, were investigated in twenty-three anaesthetizedpatients. Dacuronium produced a competitive type of neuromuscularblock with a potency of approximately one-tenth that of tubocurarineand one-fiftieth that of pancuronium. When compared with thesedrugs its maximal action was apparent earlier and the recoveryfrom its effects was somewhat quicker. One patient showed thesyndrome of the return of block after apparent adequate antagonismby neostigmine. Its actions in anaesthetized patients are discussedand compared with its actions in animals.