Competition between acetylcholine and a nondepolarizing muscle relaxant for binding to the postsynaptic receptors at the motor end plate: simulation of twitch strength and neuromuscular block

The goal of the study was to simulate twitch strength and neuromuscular block produced by nondepolarizing muscle relaxants. Methods: In the proposed model, affinities of the two binding sites at a single postsynaptic receptor for acetylcholine (A) and the muscle relaxant (D) define the formation of three complexes with A only, three complexes with D only, and two complexes with both A and D. Twitch strength was postulated to be a function of the receptors with both binding sites occupied by A, and two constants. Neuromuscular block (NMB) was calculated from NMB=1-twitch. Results: Stimulus-induced release of A results in rapid, but transient, changes in the concentrations of free A, the eight complexes, and the unoccupied receptors. Muscle relaxants that display either a congruous or an inverse pattern of affinities for the binding sites relative to those of A produce NMB vs. [D] curves with slightly different slopes but markedly different estimates for IC50. Depending on the number of activated receptors at the end plates of muscle fibers, the simulations represent the distributions of contracting fibers in a whole muscle. Conclusion: Simulations of competition between A and D for binding to two sites at a receptor reveal that the potencies of muscle relaxants, defined by IC50, and the slopes of the NMB vs. [D] curves depend on (1) the affinities of D for the two binding sites, (2) the orientation of the affinities relative to those of A, and (3) the affinities of A for the same two sites.     

EEG abnormalities associated with antipsychotics: a comparison of quetiapine, olanzapine, haloperidol and healthy subjects

In this study the effects of the atypical antipsychotics quetiapine and olanzapine, and the typical antipsychotic haloperidol on EEG patterns were retrospectively investigated in 81 patients under stable monotherapy with either drug (quetiapine: n=22, olanzapine: n=37, haloperidol: n=22). These three subgroups were compared with a control group of healthy subjects (n=30) which were matched regarding sex and age. Diagnoses of patients were schizophrenia (DSM-IV 295.xx, n=61), brief psychotic disorder (DSM-IV 298.8, n=9), schizoaffective disorder (DSM-IV 295.70, n=8) and delusional disorder (DSM-IV 297.1, n=3). There were no statistically significant differences regarding demographic characteristics between the groups. Digital EEG recordings were retrieved from a database and visually assessed by two independent investigators, and one blinded regarding medication. One patient from the quetiapine group (5%), 13 olanzapine patients (35%), five of the haloperidol patients (23%) and two subjects of the control group (7%) had an abnormal EEG. Epileptiform activity was observed in four patients (11%) of the olanzapine group, and none in the others. EEG abnormalities were statistically significantly increased with dose in the olanzapine group, in contrast to patients treated with haloperidol, quetiapine or healthy subjects. In conclusion, EEG abnormalities seem to occur rarely in patients treated with quetiapine comparable to the control group, but significantly more often with haloperidol and olanzapine, possibly due to different receptor profiles of these substances. To our knowledge, this is the first electrophysiological investigation comparing the new atypical antipsychotics quetiapine, haloperidol, olanzapine with healthy subjects.     

Global air quality and health co-benefits of mitigating near-term climate change through methane and black carbon emission controls

Background: Tropospheric ozone and black carbon (BC), a component of fine particulate matter (PM ≤ 2.5 µm in aerodynamic diameter; PM_2.5), are associated with premature mortality and they disrupt global and regional climate.Objectives: We examined the air quality and health benefits of 14 specific emission control measures targeting BC and methane, an ozone precursor, that were selected because of their potential to reduce the rate of climate change over the next 20–40 years.Methods: We simulated the impacts of mitigation measures on outdoor concentrations of PM_2.5 and ozone using two composition-climate models, and calculated associated changes in premature PM_2.5- and ozone-related deaths using epidemiologically derived concentration–response functions.Results: We estimated that, for PM_2.5 and ozone, respectively, fully implementing these measures could reduce global population-weighted average surface concentrations by 23–34% and 7–17% and avoid 0.6–4.4 and 0.04–0.52 million annual premature deaths globally in 2030. More than 80% of the health benefits are estimated to occur in Asia. We estimated that BC mitigation measures would achieve approximately 98% of the deaths that would be avoided if all BC and methane mitigation measures were implemented, due to reduced BC and associated reductions of nonmethane ozone precursor and organic carbon emissions as well as stronger mortality relationships for PM_2.5 relative to ozone. Although subject to large uncertainty, these estimates and conclusions are not strongly dependent on assumptions for the concentration–response function.Conclusions: In addition to climate benefits, our findings indicate that the methane and BC emission control measures would have substantial co-benefits for air quality and public health worldwide, potentially reversing trends of increasing air pollution concentrations and mortality in Africa and South, West, and Central Asia. These projected benefits are independent of carbon dioxide mitigation measures. Benefits of BC measures are underestimated because we did not account for benefits from reduced indoor exposures and because outdoor exposure estimates were limited by model spatial resolution.     

Physiologic-pharmacologic interpretation of the constants in the Hill equation for neuromuscular block: a hypothesis

Neuromuscular block (NMB) is simulated in pharmacodynamic models using the concentration of a muscle relaxant (MR) in the effect compartment and two constants, and IC50. No physiologic or pharmacologic interpretation is offered for either constant. We desired to explore whether the constants are properties of the muscle or the MR and to simulate NMB when the MR binds to two sites at a single receptor. Based on steady state conditions, we defined receptor occupancy using the equilibrium dissociation constants. Two concepts are introduced: threshold occupancy and occupancy at half-maximal NMB, Occ_NMB50. Threshold occupancy is defined as receptor occupancy at the motor end plate of a muscle fiber when the fiber fails to contract and Occ_NMB50 as the median threshold occupancy. NMB may be simulated as a function of either the concentration of the muscle relaxant or receptor occupancy. We suggest: (1) The distribution of threshold occupancies is an intrinsic property of a muscle and is characterized by two constants (_O and Occ_NMB50); (2) _O is numerically equal to the slope of the NMB vs. concentration curves and is independent of the equilibrium dissociation constants. IC50 is codetermined by Occ_NMB50 and by the equilibrium dissociation constants. (3) Binding of a muscle relaxant to the second binding site influences only the estimate of IC50 but not .     

Effects of morphine on oedema and tissue concentration of nerve growth factor in experimental inflammation of the rat paw

Injection of carrageenan (1 mg) into the rat hind paw caused a time-dependent increase in paw volume that was maximal 3 h after injection. At this time, the concentration of nerve growth factor (NGF) in the skin of the inflamed paw was more than twofold higher than in the contralateral, non-inflamed paw. Treatment of rats with indomethacin reduced inflammatory oedema by 57%, morphine treatment attenuated oedema by 62%. While indomethacin had no statistically significant effect on the concentration of NGF in the skin of inflamed paws, morphine attenuated the NGF response by 24.2% in a naloxone reversible manner. These data suggest that drug-induced inhibition of inflammatory oedema is not predictive of its effect on an inflammation-induced rise in tissue NGF. Furthermore, our results confirm and extend previous observations suggesting an anti-inflammatory activity of morphine.     

Sperm-bound amidase activity as a marker for acrosomal integrity in bull spermatozoa

An assay for sperm-bound amidase activity was validated using bovine spermatozoa and N-benzoyl-DL-arginine p-nitroanilide as substrate. The assay had intra- and interassay coefficients of variations of 5 and 12%, respectively. It is an inexpensive, simple and rapid assay since 100 samples can be evaluated in 2 hours and it requires only 4 X 10(6) spermatozoa per sample. Sperm-bound amidase activity was proportional (r = 0.95) to the percentage of spermatozoa with an intact acrosome, as determined by differential interference-contrast microscopy. A change of five percentage units in the incidence of damaged spermatozoa was detectable. Using this procedure, assessment of sperm-bound amidase activity is therefore a sensitive and efficient means of evaluating acrosomal integrity.     

Effect of intersection spacing on MR image contrast and study time

The effects of section separation on image contrast and calculated T1 relaxation times were investigated in healthy volunteers and a phantom using an early commercial version magnetic resonance imaging system. The effects are explained qualitatively on the basis of side lobes of excitation occurring outside the selected section resulting in reduction of the time permitted for T1 relaxation. The options for dealing with imperfect section selection, including separation of the sections (i.e., leaving gaps) and nonsequential excitation, are illustrated and the trade-offs involved in each explained.     

Rapid and accurate stability-indicating assay for nitroglycerin.

A rapid high-pressure liquid chromatographic method for determining the nitroglycerin concentration in liquid dosage forms and intravenous admixture solutions is presented. A coefficient of variation of less than 1.8% was achieved over the concentration range most commonly encountered (50-500 microgram/ml). A variable wavelength detector (lambda = 218 nm) and a micro-alkyl phenyl column were employed. The mobile phase was acetonitrile-tetrahydrofuran-water (26:10:64). Total analysis time was 12 min.     

Fibropolycystic diseases of the liver and bile ducts--a case report and review of the literature

A case of congenital cystic dilatation of the intrahepatic bile ducts (Caroli's disease) is reported. This 20-year-old patient presented also with congenital hepatic fibrosis, fusiform dilatation of the common bile duct and cysts of the liver parenchyma, accompanied by medullary sponge kidneys. The dominant clinical feature was recurrent septic cholangitis. Clinical picture, as well as the diagnostic and therapeutic problems of the individual entities of hepatobiliary fibropolycystic disease are discussed. Although these belong to a family of closely related malformations, whereby involvement of different anatomic levels varies from case to case, such a complex combination as in this patient has not, to our knowledge, been reported before.