Distinct Pharmacologic Properties of Neuromuscular Blocking Agents on Human Neuronal Nicotinic Acetylcholine Receptors: A Possible Explanation for the Train-of-four Fade

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

Methods: Xenopus laevis oocytes were injected with messenger RNA encoding for the subunits included in the human [alpha]1[beta]1[varepsilon][delta], [alpha]3[beta]2, [alpha]3[beta]4, [alpha]4[beta]2, and [alpha]7 nAChR subtypes. The interactions between each of these nAChR subtypes and atracurium, cisatracurium, d-tubocurarine, mivacurium, pancuronium, rocuronium, and vecuronium were studied using an eight-channel two-electrode voltage clamp setup. Responses were measured as peak current and net charge.

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

Mother's education and perinatal problems in Finland.

This study using nationwide data expands a previous study from one area in Finland. The purpose was to study how perinatal problems (mortality, short gestation, low birthweight and low Apgar scores) vary by mother's social class, which is measured by level of education. Outcomes of all births in the 1987 Medical Birth Register were linked to the 1988 National Education Register with gives the estimated number of years of completed education. In unadjusted analyses, the lowest educational groups (less than 9 years) had the worst results for outcomes other than neonatal mortality. Results in the two highest educational groups (greater than or equal to 13 and 12 years of education) were similar and if anything, better in the second highest group. Excluding twins and adjusting for confounding variables (age, parity, county, urbanization of residence) by logistic regression analysis did not alter the results much. Adjustment for possible mechanisms correlated with social class (marital status, smoking, time of first antenatal visit) decreased the higher occurrence of low birthweight infants in the low educational groups. Reported previous miscarriages were more common in the higher educational groups. Based on the available background characteristics one would expect to have found the usual social gradient in perinatal problems to have persisted between the two highest educational groups. Further studies on factors causing the plateau in the gradient between these groups might be useful.     

Ropivacaine for dental anesthesia: a dose-finding study.

PURPOSE: The purpose of this study was to determine the optimal concentration and volumes of ropivacaine for dental anesthesia as regards onset and duration of action. SUBJECTS AND METHODS: Thirty healthy individuals with a mean age of 32 years participated in the study on a voluntary basis. All subjects received a ropivacaine injection in 1 of 3 randomized concentrations (2.0, 5.0, or 7.5 mg/mL) for infiltration anesthesia and mandibular nerve block in a double-blind manner. The onset time and duration of anesthesia were assessed by electric pulp test, pinprick test of the gingiva, and presence of feeling of numbness of the lip. RESULTS: Regardless of dose, only 5 patients received pulpal anesthesia after infiltration, but all 3 concentrations anesthetized the gingiva and upper lip. The onset of pulpal anesthesia occurred less than 5 minutes after injection and lasted for 4 to 58 minutes. Pinprick anesthesia lasted for 8 to 48 minutes, and numbness of the upper lip lasted 1 to 4 hours. The effectiveness of the mandibular nerve block with regard to pulpal anesthesia was dose dependent. Only ropivacaine at 7.5 mg/mL produced sufficient anesthesia. The onset of pulpal anesthesia occurred less than 10 minutes after injection and lasted for 2 to 6 hours. Pinprick anesthesia lasted for 3 to 6 hours and numbness of the lower lip lasted for 5 to 9 hours. CONCLUSION: This study shows that ropivacaine could be useful as a local anesthetic for mandibular nerve block in dentistry and that the very long duration of both pulpal and soft tissue anesthesia may be favorable in reducing postoperative pain.     

Cerebrospinal fluid cytology in granulocytic sarcoma with meningeal extension but without bone marrow involvement

Granulocytic sarcoma (GS) is a localized tumour of immature granulocytes that is usually associated with myelogenous leukaemia. We report an unusual case of mastoid GS with meningeal extension but no bone marrow involvement on presentation. Histological examination of the surgical specimen and the characteristic cerebrospinal fluid (CSF) cytology showing cytoplasmic granulations and Auer bodies led to the diagnosis of GS. Positive cytochemical staining of the immature CSF cells for naphtol-ASD chloroacetate esterase and myeloperoxidase confirmed their myeloid origin. Immunophenotyping did not reveal common acute lymphoblastic leukaemia antigen, cytokeratin, T or B-cell antigens. The patient underwent surgical resection of the localized tumour, followed by radiation therapy, intrathecal and systemic chemotherapy, as if he had acute myelogenous leukaemia (AML). He did not develop AML in the 21 months after the tumour resection. This case emphasizes the value of CSF cytological examination of tumour cells and the use of an immumocytochemical marker for differentiating GS from malignant lymphoma.     

Probing the coupling of Ca2+ and rigor activation of rabbit psoas myofibrillar ATPase with ethylene glycol

We have exploited solvent perturbation to probe the coupling of Ca²⁺ and rigor activation of the ATPase of myofibrils from rabbit psoas. Three techniques were used: overall myofibrillar ATPases by the rapid-flow quench method; kinetics of the interaction of ATP with myofibrils by fluorescence stopped-flow; and myofibrillar shortening by optical microscopy. Because of its extensive use with muscle systems, ranging from myosin subfragment-1 to muscle fibres, we chose 40% ethylene glycol as the relaxing agent. At 4°C, the glycol had little effect on the myofibrillar ATPase at low [Ca²⁺], but at high [Ca²⁺] the activity was reduced 50-fold, close to the level found under relaxing conditions, and there was no shortening. However, the ATPase of chemically cross-linked myofibrils (permanently activated even without Ca²⁺) was reduced only 3–4-fold. The lesser reduction of the ATPase of permanently activated myofibrils was also observed in single turnover experiments in which activation occurs by a few heads in the rigor state activating the remaining heads. The addition of ADP, which also promotes strong head-thin filament interactions, also activated the ATPase but only in the presence of Ca²⁺. Further experiments revealed that in 40% ethylene glycol, Ca²⁺ does initiate shortening but only with the aid of strong interactions and at temperatures above 15°C. This confirms that in the organized and intact myofibril, Ca²⁺ and rigor activation are coupled, as proposed previously for regulated actomyosin subfragment-1. This revised version was published online in September 2006 with corrections to the Cover Date.     

Riluzole suppresses motor cortex facilitation in correlation to its plasma level

The aim of our study was to measure the effects of the glutamate antagonist riluzole on different parameters of motor excitability, using transcranial magnetic stimulation (TMS) during 7 days of riluzole administration, and to correlate these effects with riluzole plasma levels. Nine healthy volunteers received a dose of 100 mg riluzole from day 1 to 7 of the study period. Electrophysiological examinations were performed on day 1 before and 2 h, 5 h and 8 h after riluzole administration, on day 2, day 3 and day 5 before riluzole administration, and on day 8. Plasma samples were taken simultaneously. The excitability of the motor cortex, supraspinal and spinal motor pathways was tested by studying intracortical facilitation and inhibition, the cortical silent period and motor threshold after TMS, as well as the peripheral silent period and F-wave amplitudes after electrical peripheral nerve stimulation. We found a significant reduction of intracortical facilitation, which correlated significantly with riluzole plasma levels. To a lesser extent, intracortical inhibition was enhanced on day 1, motor threshold was increased on day 8 and F-wave amplitudes were reduced. These changes did not correlate with riluzole plasma levels. We conclude that the main effect of riluzole in vivo is a reduction of intracortical facilitation, which is closely related to the drug's level in the plasma. The most probable mechanism involves an effect on glutamatergic synaptic transmission.