Are normal hearing thresholds a sufficient condition for click-evoked otoacoustic emissions?

Transiently evolked otoacoustic emissions (TEOAE) have been reported in several studies as absent in a small minority of normal ears. Other studies have reported TEOAEs in all normal ears. Differences between studies may arise directly from criteria for TEOAE identification, criteria for selection of normals, or statistically due to limited sample sizes. In order to understand and model cochlear processes involved in TEOAE generation, it needs to be known whether the presence of normal hearing leads automatically to generation of TEOAEs. The present study set out to establish in a large sample if any ears could be found that lacked TEOAEs despite normal hearing threshold levels (HTL). A total of 397 ears from highly cooperative adult subjects were examined under laboratory conditions. Using cross correlation between replicate nonlinear waveforms as the criterion, TEOAEs were present in 99.2% of the sample (lower CI 98.1%). However, careful visual assessment of the recorded waveforms for the remaining ears did not unequivocally show absence of TEOAE characteristics in any ear with normal HTLs. While TEOAE strength varies widely among ears, no clear evidence was found to show that TEOAEs can be absent when HTLs are normal.     

Basal cochlear lesions result in increased amplitude of otoacoustic emissions

We have measured the changes in transient otoacoustic emissions (TEOAEs) and distortion product otoacoustic emissions (DPOAEs) during and after ototoxic amikacin treatment in an animal (chinchilla) model. TEOAE and DPOAE were recorded from 6 adult chinchillas over a 6-week time course starting just before a 5-day or 7-day treatment period with amikacin sulphate (400 mg/kg/day, i.m.). After final recordings, cochlear morphology was assessed by scanning electron microscopy. Generally, both DPOAE and TEOAE amplitudes change during and after treatment in a systematic fashion. High-frequency components change first, followed by lower-frequency components. We note that there is often a long latency to the onset of changes in otoacoustic emissions (OAE), and that these changes can continue for weeks after treatment. Most importantly we report that when the basal region of the cochlea is damaged in the frequency region above the OAE recording bandwidth (0.6-6 kHz for TEOAE; 1-6.7 kHz for DPOAE), we often find an increase in OAE amplitudes. More specifically, we note that as a cochlear lesion progresses apically, there is often a transient increase in a frequency-specific OAE before it reduces or is lost. Our results suggest that the increase in OAE amplitudes precedes the expression of detectable cochlear pathology.     

The effect of suxamethonium alone and its interaction with gallamine on the indirectly elicited tetanic and single twitch contractions of skeletal muscle in man during anaesthesia

Simultaneous measurements of tetanic and single twitch contractions of the adductor politics muscle in man were made during neuromuscular blockade induced by suxamethonium (0.2 mg/kg) under nitrous oxide, oxygen and pentazocine anaesthesia. 2. After a suitable control period, suxamethonium (0.2 mg/kg) was given intravenously and the same dose was repeated 15 min later. After a further 15 min gallamine (0.2 mg/kg) was administered intravenously. When recovery from gallamine reached a plateau on the tetanic contraction recording a third injection of suxamethonium was given. 3. In most patients, suxamethonium (0.2 mg/kg) caused a partial blockade of the single twitch and complete blockade of the tetanic contraction. In every instance, the tetanic contraction was more depressed and recovered more slowly than the single twitch which not only recovered promptly but also showed overshoot. 4. After gallamine marked antagonism to suxamethonium block developed and this was greater with the single twitch than with the tetanic contractions. 5. Tetanic-tension fade was observed after every injection of suxamethonium and the degree of fade was dependent on the frequency of the tetanic stimulation.     

Transient evoked otoacoustic emissions in patients with normal hearing and in patients with hearing loss

OBJECTIVES: 1) To evaluate transient evoked otoacoustic emission (TEOAE) test performance when measurements are made under routine clinical conditions. 2) To evaluate TEOAE test performance as a function of frequency and as a function of the magnitude of hearing loss. 3) To compare test performance using univariate and multivariate approaches to data analyses. 4) To provide a means of interpreting clinical TEOAE measurements. DESIGN: TEOAEs were measured in 452 ears of 246 patients. All measurements were made after acoustic immittance assessments, which were used to demonstrate that middle-ear function was normal at the time of the TEOAE test. TEOAE amplitudes and signal to noise ratios (SNRs), analyzed into octave bands centered at 1, 2, and 4 kHz, were compared with the pure-tone threshold at the same frequencies. Data were analyzed with clinical decision theory, cumulative distributions, discriminant analyses, and logistic regressions. RESULTS: Using univariate analysis techniques, TEOAEs accurately identified auditory status at 2 and 4 kHz but were less accurate at 1 kHz. Test performance was best when audiometric thresholds between 20 and 30 dB HL were used as the criteria for normal hearing. TEOAE SNR resulted in better test performance than did TEOAE amplitude alone; this effect decreased as frequency increased. Multivariate analysis methods resulted in better separation between normal and impaired ears than did univariate approaches, which relied on only TEOAE amplitude or SNR when test frequency band and audiometric frequency were the same. This improvement in test performance was greatest at 1 kHz, decreased as frequency increased, and was negligible at 4 kHz. CONCLUSIONS: TEOAEs can be used to identify hearing loss in children under routine clinical conditions. Univariate tests accurately identified auditory status at mid and high frequencies but performed more poorly at lower frequencies. The decrease in performance as frequency decreases may be a result of increased noise at lower frequencies but also may be due to properties of the measurement paradigm ("QuickScreen," high-pass filter at 0.8 kHz), which would not be ideal for recording energy around 1 kHz. The improvement in test performance when SNR was used and the interaction of this effect with frequency, however, would be consistent with the view that test performance in lower frequencies is at least partially influenced by the level of background noise. Multivariate analysis techniques improved test performance compared with the more traditional univariate approaches to data analysis. An approach is provided that allows one to assign measured TEOAE amplitudes, SNRs, or outputs from multivariate analyses to one of three categories: response properties consistent with normal hearing; results consistent with hearing loss; hearing status undetermined.     

Changes in otoacoustic emissions in patients with idiopathic sudden deafness

Transiently click-evoked (TEOAE), distortion product (DPOAE) and spontaneous otoacoustic emissions (SOAE) were recorded and changes in these tests were studied during the recovery process in 15 cases of idiopathic sudden deafness (ISD). In all these cases the amplitudes of TEOAEs and DPOAEs increased concurrently with the recovery of the hearing threshold. Ears with ISD were not different in their OAE characteristics from ears with other forms of sensorineural hearing loss (SNHL). In 4 of the 15 cases, SOAEs could be detected when hearing had recovered. These results suggest that the function of outer hair cells (OHCs) had deteriorated when the hearing threshold was elevated and that OHC activity recovered as hearing improved to nearly normal levels in ISD cases with good outcome.     

Osmotic serum pressure in patients treated with furosemide and hypertonic mannitol solution

In patients with expanding intracranial lesion syndrome osmotic pressure of the serum was measured during administration of furosemide or 20% mannitol solution. Mannitol was administered by two methods: a) a dose of 1.5 g/kg during 3--4 hours, b) a dose of 1 g/kg for about 20 min. When mannitol was administered slowly the osmotic pressure of the serum at the end of infusion was 11--15% above the initial one and returned to the initial level 30--60 min. after the end of infusion. With rapid infusion the peak rise of pressure was observed after 30 min. usually after the end of infusion, and after one hour the pressure returned to values approaching the initial ones. Furosemide in a dose of 40 mg intramuscularly or intravenously caused slight changes of osmotic pressure reaching 13 mOsm/l.     

IL-15 induces the release of soluble IL-2Ralpha from human peripheral blood mononuclear cells

The present study was designed to investigate the applicability of transient evoked otoacoustic emissions (TEOAEs) as a method of screening for hearing losses among recruits attending obligatory military service. TEOAEs, tympanometry and puretone audiometry were recorded in 95 male recruits. Sixty-one recruits were tested after a 2-month period of gunfire exposure in order to document any permanent change in cochlear function. Screening by pure-tone audiometry showed an unexpectedly high prevalence of hearing losses > 20 dBHL, probably due to technical reasons. Thresholds were corrected using lower thresholds obtained at the end of service or by ENT specialists. The accuracy with which normal and impaired ears could be identified with TEOAEs analysed in frequency bands was determined by decision theory. Impairment was defined as mean hearing thresholds > or = 30 dBHL averaged from three neighbouring frequencies. Adequate accuracy was obtained in the middle frequencies. Further improvement of the technique is needed before it can be deemed suitable for detecting hearing losses at low and high frequencies. TEOAEs are quicker to measure and offer greater objectivity than pure-tone audiometry. A small decrease in TEOAE level was found after the training period. The TEOAEs were highly repeatable and had a higher sensitivity than pure-tone audiometry to detection of small changes in cochlear function under conditions normally found when testing recruits.     

MS-551 and KCB-328, two class III drugs aggravated adrenaline-induced arrhythmias

We investigated the proarrhythmic effects of MS-551 and KCB-328, class III antiarrhythmic drugs using adrenaline-induced arrhythmia models in halothane anaesthetized, closed-chest dogs. In the control period, adrenaline, starting from a low dose of 0.25 to up to 1.0 microg/kg/50 s i.v., was injected to determine the arrhythmia inducing dose and the non-inducing dose. After MS-551 or KCB-328 administration, the adrenaline injection was repeated and the interval between the injection and the occurrence of arrhythmia (latent interval), the changes in arrhythmic ratio (as calculated by dividing the number of ventricular premature contraction by the number of the total heart rate) and the severity of arrhythmia were observed. MS-551 infusion, 1 mg/kg/30 min, decreased the heart rate (HR) by 16% (P<0.01) and prolonged the QTc interval by 20% (P<0.01). During the 30 min of MS-551 infusion, arrhythmias occurred in three out of seven dogs (torsades de pointes (TdP) type VT in one dog). After these arrhythmias disappeared, MS-551 decreased the latent interval of the adrenaline arrhythmias produced by the inducing dose (30+/-2 s compared with 43+/-3 s of the control interval, P < 0.05), increased the arrhythmic ratio (P<0.05) and induced arrhythmias by non-inducing adrenaline doses (P<0.05). Effect of a new class III drug KCB-328 infusion, 0.3 mg/kg/30 min, was compared witih MS-551 using the same model. KCB-328 decreased the HR by 21% (P<0.01) and prolonged the QTc interval by 25% (P<0.01). During the 30 min of infusion, arrhythmias occurred in five out of seven dogs (TdP in two dogs). KCB-328 also decreased the latent interval of the adrenaline arrhythmias produced by the inducing doses (31+/-3 s compared with 49+/-7 s of the control period, P<0.05), but did not significantly alter the arrhythmic ratio. Adrenaline induced TdP only after MS-551 or KCB-328 was administered, i.e. after MS-551, 1 mg/kg/30 min, 3/7 versus 0/7 in the control; KCB, 0.3 mg/kg/30 min, 3/7 versus 0/7 in the control. To examine the direct arrhythmogenic effect of MS-551 and whether an adrenergic mechanism plays some role on this arrhythmogenesis, a bolus injection of MS-551, 3 mg/kg, was injected either without pre-treatment or after pre-treatment with propranolol 0.3 mg/kg. MS-551 induced arrhythmias in five out of seven dogs (TdP in one dog). Also in the propranolol pre-treated dogs, MS-551 induced arrhythmias in five out of seven dogs (TdP in 1 dog). In conclusion, these observations indicate that MS-551 and KCB-328 induced arrhythmias and intensified proarrhythmic effects of adrenaline, MS-551 being stronger than KCB-328 at the same QTc prolonging doses. The direct arrhythmogenic effect of MS-551 was not influenced by beta-blocker treatment.     

Sublethal damage repair capacity in carcinoma cell lines with p53 mutations

The pharmacokinetics of furosemide were investigated in anaesthetized horses with bilateral ureteral ligation (BUL) with (n = 5) or without (n = 5) premedication with phenylbutazone. Horses were administered an intravenous (i.v.) bolus dose of furosemide (1 mg/kg) approximately 60-90 min after BUL. Plasma samples collected up to 3 h after drug administration were analysed by a validated high performance liquid chromatography method. Median plasma clearance (CLp) of furosemide in anaesthetized horses with BUL was 1.4 mL/min/kg. Apparent steady state volume of distribution (Vd(ss)) ranged from 169 to 880 mL/kg and the elimination half life (t1/2) ranged from 83 min to 209 h. No differences in plasma concentration or kinetic parameter estimates were observed when phenylbutazone was administered before furosemide administration. BUL markedly reduces the elimination of furosemide in horses and models the potential effects that severe changes in kidney function may have on drug kinetics in horses.     

Ectopic pregnancy: criteria to choose therapy

The ectopic pregnancy (EP) could be treated by spontaneous resolution, or medical treatment or laparoscopic treatment. Spontaneous resolution of EP with beta hCG < 1,000 mUl/ml, plasmatic progesterone < 5 ng/ml had 74% success rate. Methotrexate (MTX) injection is the common Medical treatment of EP with beta hCG < or = 5,000 mUl/ml and mean diameter of EP < or = 3 cm: a single dose of 50 mg/m2 or 1 mg/kg intramuscular injection had 93.4% success rate; local injection under sonographic control (1 mg/kg) had 80.2% success rate. The surgical conservative treatment by laparoscopy had 94% success rate.     

Effect of intrathecal nimodipine on spinal cord blood flow and evoked potentials in the normal or injured cord

A method was developed for administering intrathecal pharmacotherapy in a rat model of spinal cord injury. The effects of intrathecal administration of nimodipine on spinal cord blood flow (SCBF) and evoked potentials (EPs) were measured in the normal and injured spinal cord. It had previously been shown that systemic nimodipine caused severe hypotension after spinal cord injury. After baseline SCBF and EPs, 15 uninjured rats were blindly allocated to one of three groups: one placebo group (n = 5); and two groups with intrathecal nimodipine, 0.05 mg/kg (n = 5), or 0.2 mg/kg (n = 5). Ten other rats received a 35 g acute clip compression injury of the spinal cord for 1 minute and, were allocated to one of two groups: placebo (n = 5); and intrathecal nimodipine 0.05 mg/kg (n = 5) given 60 min after injury. In the uninjured groups, neither 0.05 nor 0.2 mg/kg of nimodipine increased SCBF during, or 30 min after, intrathecal infusion. However, the mean arterial blood pressure (MABP) decreased significantly to 69.73.1% after the infusion of 0.2 mg/kg nimodipine and did not recover by 98 min. In all three groups of uninjured rats, the amplitude of the cerebellar EP was decreased 30 min after infusion. After spinal cord injury, there were significant decreases in MABP, SCBF and EP amplitude in both placebo and treatment groups, but there was no therapeutic benefit from nimodipine. Thus, intrathecal infusion of nimodipine did not prevent the hypotension encountered with systemic administration and exerted no beneficial effect on SCBF or EPs after acute spinal cord injury.     

Effects of caerulein and CCK antagonists on tolerance induced to morphine antinociception in mice

Different groups of mice received one daily dose (50 mg/kg) of morphine subcutaneously (SC) for 3, 4 or 5 days to develop tolerance to the opioid. The antinociceptive response of morphine (9 mg/kg) was tested in the hot-plate test 24 h after the last dose of the drug. Tolerance to morphine was obtained in all groups. The group of mice that received morphine for 4 days was employed for the rest of the experiments. Pretreatment of animals with a single dose of caerulein (0.025, 0.05, and 0.1 mg/kg, SC) 30 min prior to receiving morphine (50 mg/kg; during the development of tolerance to the opioid) on day 1, 2, 3, 4 or 5 of morphine administration potentiate antinociception induced by morphine (test dose of 9 mg/kg). The dose of 0.05 mg/kg of caerulein, used 30 min before morphine administration on day 3, was also used to evaluate the effects of antagonists on caerulein-induced decrease in tolerance. The selective cholecystokinin (CCK) receptor antagonists, MK-329 [1-methyl-3-(2 indoloyl)amino-5-phenyl-3H-1,4-benzodiazepin-2-one; 0.25 and 0.5 mg/kg] or L-365,260 [3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H- 1,4-benzodiazepin-3-yl)-N-(3-methyl-phenyl)urea: 0.25 and 0.5 mg/kg] decreased potentiation of morphine response induced by caerulein. MK-329 or L-365,260, when were injected 35 min before morphine injection during the development of tolerance and on day 3, decreased the tolerance to morphine. A single administration of MK-329 or L-365,260 (in the absence of caerulein) 35 min and 48 h before the test dose of morphine (9 mg/kg) potentiated the antinociception of morphine in nontolerant animals. In conclusion, CCK mechanism(s) may interact with morphine tolerance.     

Pharmacokinetics of a new reversible proton pump inhibitor, YH1885, after intravenous and oral administrations to rats and dogs: hepatic first-pass effect in rats

The pharmacokinetics of YH1885 were evaluated after intravenous (iv) and oral administrations of the drug to rats and dogs. The reason for the low extent of bioavailability (F) of YH1885 after oral administration of the drug to rats and the absorption of the drug from various rat gastrointestinal (GI) segments were also investigated. After iv administration of YH1885, 5-20 mg kg(-1), to rats, the pharmacokinetic parameters of YH1885 seem to be independent of the drug at the dose ranges studied. After oral administration of YH1885, 50-200 mg kg(-1), to rats, the area under the plasma concentration-time curve from time zero to 12 or 24 h (AUC(0-12 h) or AUC(0-24 h)) was proportional to the oral dose of the drug, 50-100 mg kg(-1), however, the AUC(0-24 h) value at 200 mg kg(-1) increased with less proportion to the dose increase (324, 689, and 815 microg x min mL(-1) for 50, 100, and 200 mg kg(-1), respectively) due to the poor water solubility of the drug. This was proved by the considerable increase in the percentages of the oral dose remaining in the entire GI tract as unchanged YH1885 at 24 h (11.8, 15.3, and 42.8% for 50, 100, and 200 mg kg(-1), respectively). The F value after oral administration of YH1885 to rats was relatively low; the value was approximately 40% at the oral dose of 50 and 100 mg kg(-1). The reason for the low F in rats was investigated. The liver showed the highest metabolic activity for YH1885 based on an in vitro rat tissue homogenate study; hence, the liver first-pass effect was estimated. The value of AUC after intraportal administration of the drug, 5 mg kg(-1), was approximately 70% (116 versus 163 microg x min mL(-1)) of that after iv administration of the drug, 5 mg kg(-1), to rats; the liver first-pass effect of YH1885 in rats was estimated to be approximately 30%. The total body clearance of YH1885 after iv administration of the drug, 5-20 mg kg(-1), to rats were considerably lower than the cardiac output of rats, indicating that the lung and/or heart first-pass effect of YH1885 could be negligible in rats. After oral administration of YH1885, 50 and 100 mg kg(-1), to rats, the F value was approximately 40%, and approximately 15% of the oral dose was recovered from the entire GI tract as unchanged YH1885 at 24 h, and 30% of the oral dose disappeared with the liver first-pass effect. Therefore, the remainder, approximately 15% of the oral dose, could have disappeared with the small intestine first-pass effect and/or degradation of the drug in the GI tract. YH1885 was absorbed from ileum, duodenum, and jejunum of rat, however, YH1885 was under the detection limit in plasma when the drug was instilled into the rat stomach and large intestine. After iv administration of YH1885, 5-20 mg kg(-1), to dogs, the pharmacokinetic parameters of YH1885 also seemed to be independent of the drug at the dose ranges studied. However, after oral administration of YH1885, 0.5 and 2 g per whole body weight, to dogs, the AUC(0-10 h) values were not significantly different (96.8 versus 98.2 microg x min mL(-1)) and this could be due to the poor water-solubility of the drug. YH1885 was not detected in the urine after both iv and oral administration of the drug to both rats and dogs.     

Eptastigmine-phosphotriesterase combination in DFP intoxication

A novel therapy against organophosphate exposure, the combination of a carbamate eptastigmine and an organophosphate hydrolase (phosphotriesterase) was studied in mice against diisopropylfluorophosphate (DFP) (1.75 mg/kg) exposure. Mice received eptastigmine (0.9 mg/kg; iv) 10 min prior to the ip injection of DFP. Phosphotriesterase (83 U/g body weight) was injected iv 10 min after DFP. Eptastigmine (1.5 mg/kg; iv) inhibited the acetylcholinesterase activities in brain and erythrocytes for a longer time than physostigmine. Eptastigmine caused only minor changes in the behavior and activity of the animals, whereas physostigmine clearly reduced their activity for about 30 min. The eptastigmine pretreatment clearly supplemented the protective effect of phosphotriesterase against DFP: the plasma butyrylcholinesterase activity was doubled and the activity recovered faster than in animals treated with phosphotriesterase alone. In lung, butyrylcholinesterase activity was initially lower after eptastigmine-phosphotriesterase than phosphotriesterase treatment alone. However, the activity returned 24 hr later to normal in eptastigmine-phosphotriesterase-treated groups. With phosphotriesterase only, it recovered only to 75% of the control level. Presumably eptastigmine, by preventing the binding of DFP to cholinesterases, caused an elevation of free DFP levels in body fluids and promoted phosphotriesterase hydrolysis of DFP.     

Subamnesic cycloheximide treatment delays consolidation in mice.

In Exp I, groups of C57 BL/6J mice were given passive avoidance training and then administered different doses of cycloheximide (CYC) immediately, 30 min, or 1 hr after training. Only the highest dose (150 mg/kg) administered immediately or 30 min after training impaired memory when the mice were tested 72 hrs after training. In Exp II, Ss were given a nonamnesic administration of CYC (30 mg/kg) or saline immediately after training and another injection of CYC (15, 30, or 75 mg/kg) or saline 1 hr after training. The combinations of 30 mg/kg?+?30 mg/kg and 30 mg/kg?+?75 mg/kg impaired memory. Exp III demonstrated that brief carbon dioxide anesthetization initiated immediately after training impaired memory. In Exp IV, mice were given either saline or 30 mg/kg CYC immediately after training and then subjected to either air or CO? anesthetization 30 min after training. Only the group given 30 mg/kg CYC?+?CO? was amnesic when tested 72 hrs after training. Results indicate that the administration of a nonamnesic dose of CYC immediately after training renders the memory susceptible to disruption by additional doses of CYC or other amnesic treatments for a longer period of time than normal. It is suggested that CYC delays consolidation and prolongs the labile period of memory formation. (11 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Vulnerability and adaptation of distortion product otoacoustic emissions to endocochlear potential variation

The endocochlear potential (EP) was reversibly decreased in adult gerbils by the intraperitoneal injection of furosemide, while cochlear functioning was monitored by measurement of distortion production otoacoustic emissions (DPE) at a range of stimulus intensities. Stimulus frequencies for DPEs were f1 = 6.8 and f2 = 8 kHz (f2/f1 = 1.18). Emissions monitored in the ear canal and scala media were 2f1-f2, 3f1-2f2, 2f2-f1, and f2-f1. Typically, the EP decreased smoothly, reached a minimum one-half hour after injection, then recovered slowly over several hours. Emissions at 2f1-f2 and 3f1-2f2 at low stimulus levels were particularly vulnerable to the change in EP. These vulnerable emissions showed characteristic trajectories in which the amplitudes changed little with the initial EP decrease, then dropped sharply as the EP continued to decrease. However, the amplitudes then began to recover even before the EP reached minimum, and recovered completely while the EP remained subnormal. The trajectories of the other odd order emissions were similar, but lacked the abrupt decrease. The variation of the even order (f2-f1) component was completely different, but appeared related to the odd order trajectories in a complex fashion. During the initial decrease for the vulnerable components, the decrease in emission amplitude (in dB) was found to be proportional to the square of the change in EP (in mV). The recovery with a subnormal EP was interpreted as an adaptive effect with a time constant of about 15 min.     

Contralateral suppression of transiently evoked otoacoustic emissions by harmonic complex tones in humans

Variations in the amplitude of transiently evoked otoacoustic emissions (TEOAEs) produced by a contralateral complex tone were measured in 26 normal-hearing human subjects. TEOAEs were evoked using a 1-kHz tone pip at 60 dB SPL. The contralateral complex consisted of harmonic components with frequencies between 400 and 2000 Hz; it was presented at levels ranging from 40 to 50 dB SL and its fundamental frequency (F0) was varied. In experiment 1, the dependence of TEOAE amplitude variations on the F0 of the contralateral complex was measured by varying the F0 from 50 to 400 Hz in octave steps. The results revealed a nonmonotonic dependence of TEOAE amplitude variations on contralateral F0, with significantly larger TEOAE suppression for F0's of 100 and 200 Hz than for F0's of 50 and 400 Hz. Experiment 2, in which the harmonics were summed in alternating sine-cosine phase instead of constant sine phase, showed a shift of the function relating TEOAE attenuation to F0 towards lower F0's, indicating that the waveform repetition rate, rather than harmonic spacing, was the actual factor of the dependence of contralateral TEOAE attenuation on F0. Furthermore, significantly smaller suppression was observed with the alternating-phase complexes than with the sine-phase complexes, suggesting an influence of the waveform crest factor. Experiment 3 showed no difference between the contralateral TEOAE attenuation effects produced by positive and negative Schroeder-phase complexes. Overall, these results bring further arguments for the notion that contralaterally induced medial olivocochlear bundle (MOCB) activity, as measured through the contralateral suppression of TEOAEs in humans, is sensitive to the rate of temporal envelope fluctuations of the contralateral stimulus, with preferential rates around 100-200 Hz.     

Airway occlusion pressures in awake and anesthetized goats

The ability of intramuscular injections of gonadal steroids to exert a positive feedback action on LH secretion was investigated in the ovariectomized hen. Plasma LH was measured by radioimmunoassay. Single injections of progesterone (dose range: 0.05-10 mg/kg) or oestradiol benzoate (dose range: 0.01-1 mg/kg) did not result in an increase in plasma LH concentration. After priming with 0.1 mg oestradiol benzoate/kg on alternate days for 7 days and with 0.5 mg progesterone/kg on days 5, 6 and 7, a single injection of progesterone on day 8 (dose range: 0.1-2 mg/kg) caused the plasma LH concentration to start increasing after 15 to 30 min. Peak LH concentration was reached around 1.5-2 h after injection. The magnitude of LH response to progesterone was dose related. In contrast, a single injection of oestradiol benzoate (dose range: 0.01-1 mg/kg) failed to stimulate LH release in the oestrogen-progesterone primed ovariectomized (O-P-OVX) hen. A single injection of testosterone (dose range: 0.1-2.0 mg/kg) failed to stimulate LH release in ten out of 12 O-P-OVX hens. A small increase in LH secretion was observed in the two remaining birds. When oestrogen or progesterone was omitted from the priming schedule, a LH positive feedback response to a single injection of progesterone was not observed. Increasing or decreasing the mount of oestrogen or progesterone in the priming schedule modified the LH response to a single injection of progesterone on the day following the last priming injection. This suggested that a critical oestrogen to progesterone ratio was required to prime the LH positive feedback mechanism. It is suggested that, in the hen, the release of LH is facilitated by the positive feedback effect of a combination of oestrogen and progesterone in a two-phase process. The first is the priming phase, which depends on the presence in the blood of oestrogen and progesterone; the second is the ind .uctive phase, which depends only on an incremental change in plasma progesterone concentration. Oestrogen is not involved in the induceive phase.     

cAMP analogues downregulate the expression of granulocyte macrophage colony-stimulating factor (GM-CSF) in human bone marrow stromal cells in vitro

STUDY OBJECTIVE: To determine the neuromuscular blocking effect and recovery profile of cisatracurium besylate in children after administration of a bolus dose that was twice the estimated dose required to produce 95% of the maximum effect (2 x ED95; 0.08 mg/kg) followed by an infusion during halothane-nitrous oxide anesthesia. STUDY DESIGN: Open-label study. SETTING: Teaching hospital. PATIENTS: 30 male and female (ASA physical status I and II) patients, 2 to 10 years of age, scheduled for elective surgery of low to moderate risk. INTERVENTIONS: After induction of general anesthesia, patients received cisatracurium 0.08 mg/kg administered over 5 to 10 seconds. For surgical procedures requiring neuromuscular block for at least 60 minutes, a second bolus dose of cisatracurium 0.02 mg/kg was administered after the first response to a train-of-four stimuli (T1) recovered to 25% of baseline. When T1 was 5% of baseline after the second dose, a 3 microg/kg/min infusion of cisatracurium was initiated and titrated to maintain 89% to 99% block for the duration of the surgery. For procedures requiring neuromuscular block of less than 60 minutes, one or more maintenance doses of 0.02 mg/kg cisatracurium were administered when T1 was 25% of baseline after the preceding dose. In 10 patients, recovery was facilitated with edrophonium 1.0 mg/kg administered when T1 was 26% to 48% of the final baseline. MEASUREMENTS AND MAIN RESULTS: Evoked muscular response at the adductor pollicis was measured by electromyography. With 0.08 mg/kg, onset time (mean +/- SEM) was 4.1 +/- 0.4 minutes, and clinically effective duration was 27.3 +/- 0.9 minutes. Mean 5% to 95% and 25% to 75% recovery indices were 28.4 +/- 2. 7 minutes and 11.2 +/- 0.8 minutes, respectively. The mean infusion rate necessary to maintain 89% to 99% T1 suppression for 17 to 145 minutes was 1.7 microg/kg/min. After termination of infusion, the mean 5% to 95% and 25% to 75% recovery indices were similar to those after a single bolus dose, and time to 95% recovery was 30.4 +/- 3.0 minutes. After administration of edrophonium, full recovery (T4:T1 > or = 70%) occurred in 1.5 +/- 0.4 minutes. No clinically significant changes in heart rate or blood pressure were noted during the first 5 minutes after administration of cisatracurium 0.08 mg/kg. CONCLUSIONS: Cisatracurium provided maximal neuromuscular block, cardiovascular stability, and predictable recovery at the doses tested. In view of this finding, cisatracurium should be a useful intermediate-duration neuromuscular blocking drug for children during general anesthesia.     

Absorption, disposition kinetics, and metabolic pathways of cyclohexene oxide in the male Fischer 344 rat and female B6C3F1 mouse

Cyclohexene oxide (CHO) is a monomer intermediate used in the synthesis of pesticides, pharmaceuticals, and perfumes. Although CHO has a variety of industrial uses where direct human exposure is possible, very little is known about its fate in the body. Therefore, the objectives of this study were to determine the absorption, distribution, metabolism, and excretion of cyclohexene oxide after oral, intravenous, and dermal exposure in male Fischer 344 rats and female B6C3F, mice. After intravenous administration of [14C]CHO (50 mg/kg), CHO was rapidly distributed, metabolized, and excreted into the urine. Plasma concentrations of CHO rapidly declined and were below the limit of detection within 60 min. Average (+/- SD) values for terminal disposition half-life, apparent volume of distribution at steady-state, and systemic body clearance were: 19.3 +/- 1.6 min; 0.44 +/- 0.08 liter/kg; and 31.3 +/- 0.5 ml/kg * min, respectively. After oral administration of [14C]CHO (10 and 100 mg/kg), it was found that 14C-equivalents were rapidly excreted in the urine of both species. At 48 hr, the majority of the dose (73-93%) was recovered in urine, whereas fecal elimination accounted for only 2-5% of the dose. At no time after oral administration was parent CHO detected in the blood. However, its primary metabolite cyclohexane-1,2-diol was present for different lengths of time depending on the dose. Four metabolites were detected and identified in mouse urine by MS: cyclohexane-1,2-diol; cyclohexane-1,2-diol-O-glucuronide; N-acetyl-S-(2-hydroxycyclohexyl)-L-cysteine; and cyclohexane-1,2-diol-O-sulfate. The sulfate conjugate was not present in rat urine. Topical application of [14C]CHO (60 mg/kg) provided poor absorption in both species. The majority of 14C-equivalents applied dermally were recovered from the charcoal skin trap (approximately 90% of the dose). Only 4% of the dose was absorbed, and the major route of elimination was via the urine. To evaluate the toxicity of CHO, animals were given daily doses of CHO orally and topically for 28 days. No statistically significant changes in final body weights or relative organ weights were noted in rats or mice treated orally with CHO up to 100 mg/kg or up to 60 mg/kg when given topically. Very few lesions were found at necropsy, and none were considered compound related. In conclusion, regardless of route, CHO is rapidly eliminated and excreted into the urine. Furthermore, after either oral or dermal administration, it is unlikely that CHO reaches the systemic circulation intact due to its rapid metabolism, and is therefore unable to cause toxicity in the whole animal under the test conditions used in this study.