The influence of stimulation parameters on the potency and reversibility of neuromuscular blocking agents

Summary Voluntary muscle movements in mammalian muscles are initiated by short trains of 16 to 60 Hz impulses (Zierler, 1974). Despite this in most neurophysiological and neuropharmacological studies either single stimuli of 0.1 to 2 Hz or 5 to 10 sec 50 to 500 Hz tetani have been employed. Neither of these two types of stimuli are ideal for the testing of the functional integrity of the motor unit. Stimulation with single impulses, at slow rates, does not reveal incipient pathological or drug induced defects. Recovery of neuromuscular (NM) activity after 5 to 10 sec tetanic stimulation is prolonged and after repeated stimulation of this type the preparations decay rapidly. Stimulation with 0.1 sec trains of 50 Hz impulses applied every 10 to 20 sec eliminate the above disadvantages. This type of stimulation represents adequate challenge for revealing more moderate degrees of functional defects of the myoneural apparatus without causing rapid decay of thein vitro orin vivo preparations. In agreement with this the ED₅₀ of NM blocking agents were found to be significantly lower in both thein vitro phrenic nerve-hemidiaphragm preparation and thein vivo sciatic nervetibialis anterior muscle preparation of rats during stimulation with 0.1 sec trains of 50 Hz impulses, than when single stimuli of 0.1 Hz were used. Recovery of thein vitro preparations after washout orin vivo after discontinuation of the infusion was also slower during stimulation with short trains of tetani. The antagonist potency of anticholinesterases or 4-aminopyridine and maximal recovery after the use of the optimal concentrations of these antagonists was less in the preparations stimulated with short trains of tetani than in those stimulated with single impulses.     

Comparison of myocardial preservation techniques for aortocoronary bypass surgery.

The myocardial properties of three different techniques for cardiac arrest during aortocoronary bypass surgery were analyzed. Ventricular fibrillation and moderate total body hypothermia (30–33°C) (Group I) was found to be an insecure method of preservation. It produced a high incidence of focal irreversible ultrastructural changes (7 of 10 patients), high post-bypass CK-MB levels (mean 85.54 U/liter) indicative of myocardial damage, and impaired clinical and physiologic recovery courses. Six out of ten patients needed inotropic support, three had prolonged stay in ICU, and three patients showed Type III (unacceptable) recovery trajectories, one of whom died of myocardial decompensation four weeks after surgery. This method, which was the most common one used in our institution, was completely abandoned as a result of these studies. Potassium induced cardioplegia combined with methylprednisolone sodium succinate, hypertonic glucose and intermittent moderate topical cooling (25–27°C) of the heart (Group III) offered a generally acceptable form of myocardial protection, as only one patient showed irreversible ultrastructural changes. The mean post-bypass CK-MB level was only moderately elevated (mean 22.32 U/liter), but seven of ten patients needed inotropic support. There were no Type III recovery trajectories and two patients showed an optimal Type I recovery. Only one patient had a prolonged stay in ICU, and another patient exhibited electrocardiographic evidence of a perioperative myocardial injury pattern. Selective intracavitary profound hypothermic arrest (15–18°C) (SIPHA) offered the best myocardial protection as evidenced by remarkably well preserved ultrastructure and significantly (P< 0.005) lower post-bypass CK-MB levels (mean 7.85 U/L). All SIPHA patients had acceptable physiologic recovery trajectories of the Type I or Type II with minimal need for inotropic support (one patient), and none had a Type III recovery.These data also suggest that the major determinant of a successful myocardial preservation is the level of myocardial layer temperature, being best at the lowest temperature (15–18°C), worst at the highest temperature (30–33°C) and intermediate at 25–27°C. Additional injury may also be induced by ventricular fibrillation which by itself increases myocardial metabolic demands.     

Chondroblastic osteosarcoma of the larynx.

Osteosarcoma of the larynx is a rare lesion. Acceptable cases in the literature are difficult to find. We report a case in which total laryngectomy was carried out for a large, obstructing mass that arose from the cricoid cartilage. We present the histologic criteria for the diagnosis of chondroblastic osteosarcoma.     

The influence of white noise on sleep in subjects exposed to ICU noise

BACKGROUND AND PURPOSE: There is disagreement in the literature about the importance of sleep disruption from intensive care unit (ICU) environmental noise. Previous reports have assumed that sleep disruption is produced by high-peak noise. This study aimed to determine whether peak noise or the change in noise level from baseline is more important in inducing sleep disruption. We hypothesized that white noise added to the environment would reduce arousals by reducing the magnitude of changing noise levels. PATIENTS AND METHODS: Four subjects underwent polysomnography under three conditions: (1) baseline, (2) exposure to recorded ICU noise and (3) exposure to ICU noise and mixed-frequency white noise, while one additional subject completed the first two conditions. Baseline and peak noise levels were recorded for each arousal from sleep. RESULTS: A total of 1178 arousals were recorded during these studies. Compared to the baseline night (13.3+/-1.8 arousals/h) the arousal index increased during the noise (48.4+/-7.6) but not the white noise/ICU noise night (15.7+/-4.5) (P<0.004). The change in sound from baseline to peak, rather than the peak sound level, determined whether an arousal occurred and was the same for the ICU noise and white noise/ICU noise condition (17.7+/-0.4 versus 17.5+/-0.3 DB, P=0.65). CONCLUSIONS: Peak noise was not the main determinant of sleep disruption from ICU noise. Mixed frequency white noise increases arousal thresholds in normal individuals exposed to recorded ICU noise by reducing the difference between background noise and peak noise.     

Expression of the vesicular glutamate transporters during development indicates the widespread corelease of multiple neurotransmitters

Three closely related proteins transport glutamate into synaptic vesicles for release by exocytosis. Complementary patterns of expression in glutamatergic terminals have been reported for VGLUT1 and VGLUT2. VGLUT3 shows expression by many cells not considered to be glutamatergic. Here we describe the changes in VGLUT expression that occur during development. VGLUT1 expression increases gradually after birth and eventually predominates over the other isoforms in telencephalic regions. Expressed at high levels shortly after birth, VGLUT2 declines with age in multiple regions, in the cerebellum by 14-fold. In contrast, Coexpression of the two isoforms occurs transiently during development as well as permanently in a restricted subset of glutamatergic terminals in the adult. VGLUT3 is transiently expressed at high levels by select neuronal populations, including terminals in the cerebellar nuclei, scattered neurons in the cortex, and progenitor-like cells, implicating exocytotic glutamate release in morphogenesis and development. VGLUT3 also colocalizes extensively during development with the neuronal vesicular monoamine transporter VMAT2, with the vesicular acetylcholine transporter VAChT, and with the vesicular gamma-aminobutyric acid transporter VGAT. Such coexpression occurs particularly at some specific developmental stages and is restricted to certain sets of cells. In skeletal muscle, VGLUT3 localizes to granular organelles in the axon terminal as well as in the muscle sarcoplasm. The results suggest novel mechanisms and roles for regulated transmitter release.     

Paroxysmal kinesigenic dyskinesia manifestation of hyperthyroidism

Sporadic paroxysmal kinesigenic dyskinesia (PKD) secondary to thyrotoxicosis is an extremely rare entity. A 36-year-old female presented with the features of PKD. Her investigations revealed thyrotoxicosis. Her dyskinesia did not respond to carbamazepine but remitted with the anti-thyroid drug, neomercazole. Perhaps hyperthyroidism-related PKD is a result of a metabolic disturbance of the basal ganglia circuits rather than a permanent and irreversible change.     

Effect of methotrexate and folinic acid on skeletal growth in mice

AIM: To investigate whether chronic administration of medium doses of methotrexate (MTX) causes suppression of skeletal growth in young mice and to determine whether folinic acid supplementation could reverse this effect. METHODS: Four equal groups of Balb/c young male mice (6 animals in each group; mean body weight 11.9 +/- 0.25 g, in their rapid growth phase) were subjected to the following drug treatment for a period of 3 wk. Group 1 was given intraperitoneal MTX (3.5 mg kg(-1) body weight) every second day. Group 2 received folinic acid (7.0 mg kg(-1) body weight) intraperitoneally every second day. Group 3 was given both drugs (MTX every second day and folinic acid 8 h post-MTX injection). Group 4 was injected with physiological saline every other day to serve as a control group. Total body weight of the animals in each group was monitored every second day for the entire study period. The animals were sacrificed, the bilateral femurs and tibias of each animal were harvested and X-rays of the bones were taken. The length of each femur and tibia was measured using a micrometer. Measurements from the radiographs were also recorded using image analysis software. The MTX concentrations in the plasma and the folate levels in erythrocytes were determined. The heights of the distal femoral and the proximal tibial growth plate for each animal were measured on histological tissue sections. RESULTS: Mean lengths of both the tibia and femur of animals were compared in the four treatment groups. A significant decrease in the mean lengths (one-way ANOVA, p < 0.005) was observed in the group receiving MTX alone. Similarly, there was a significant decrease (p < 0.001) in the height of the femoral and tibial growth plate in this group when compared with the other groups. The main effect of MTX seemed to be on the hypertrophic proliferative zone of chondrocytes in the growth plate. Furthermore, animals in this MTX-treated group also showed increased levels of MTX in plasma and low levels of erythrocyte folate. CONCLUSION: These data show that chronic administration of MTX induces suppression of skeletal growth in mice, possibly through the inhibition of the pathway of de novo DNA synthesis. Folinic acid treatment following MTX administration appears to reverse this growth inhibition. Based on these observations, children suffering from juvenile rheumatoid arthritis, osteosarcoma or acute lymphoblastic leukaemia and receiving MTX over long periods of time could be at risk of short-term suppression of skeletal growth. If this is the case, it is possible that they could benefit from dietary supplementation with folinic acid.     

17 beta-estradiol induces L-type Ca2+ channel activation and regulates redox function in macrophages

17 beta-estradiol induces rapid effects on cells of the immune system via plasma membrane surface receptor but the ways in which delayed signals involving intracellular receptors affect the same functions are not well understood. To study the delayed but sustained events in estradiol signaling, we have investigated macrophage Ca(2+) signaling, detected specific Ca(2+) ion channel activated and found a relationship between intracellular calcium [Ca(2+)](i) and macrophage release of reactive oxygen species (ROS) and nitric oxide (NO) during delayed 17 beta-estradiol activity. We found evidence of additional effect of estradiol on capacitative entry of Ca(2+), Ca(2+) entry through L-type channel and a direct relationship between [Ca(2+)](i) and generation of ROS and NO. This study demonstrates that 17 beta-estradiol exhibits a delayed phase of Ca(2+) influx involving L-type channel and regulates macrophage immune redox function.