Magnitude Of Peak Response Research Articles

Inhaled milrinone in cardiac surgical patients: pharmacokinetic and pharmacodynamic exploration

Mean arterial pressure to mean pulmonary arterial pressure ratio (mAP/mPAP) has been identified as a strong predictor of perioperative complications in cardiac surgery. We therefore investigated the pharmacokinetic/pharmacodynamic (PK/PD) relationship of inhaled milrinone in these patients using this ratio (R) as a PD marker. Following approval by the ethics and research committee and informed consent, we performed the following experiment. Before initiation of cardiopulmonary bypass in 28 pulmonary hypertensive patients scheduled for cardiac surgery, milrinone (5 mg) was nebulized, plasma concentrations measured (up to 10 h) and compartmental PK analysis carried out. Baseline (R0) and peak (Rmax) ratios as well as magnitude of peak response (∆Rmax-R0) were measured. During inhalation, individual area under effect-time (AUEC) and plasma concentration–time (AUC) curves were correlated. Potential relationships between PD markers and difficult separation from bypass (DSB) were explored. In this study, we observed that milrinone peak concentrations (41–189 ng ml−1) and ΔRmax-R0 (− 0.12–1.5) were obtained at the end of inhalation (10–30 min). Mean PK parameters agreed with intravenous milrinone published data after correction for the estimated inhaled dose. Paired comparisons yielded a statistically significant increase between R0 and Rmax (mean difference, 0.58: 95% CI 0.43–0.73; P < 0.001). Individual AUEC correlated with AUC (r = 0.3890, r2 = 0.1513; P = 0.045); significance increased after exclusion of non-responders (r = 4787, r2 = 0.2292; P = 0.024). Individual AUEC correlated with ∆Rmax-R0 (r = 5973, r2 = 0.3568; P = 0.001). Both ∆Rmax-R0 (P = 0.009) and CPB duration (P < 0.001) were identified as predictors of DSB. In conclusion, both magnitude of peak response of the mAP/mPAP ratio and CPB duration were associated with DSB.

The galvanic whole-body sway response in health and disease

ObjectiveTo explore the galvanic-evoked vestibulospinal reflex in health and disease. MethodsVestibular-evoked whole-body movement was measured in 60 controls and eight patients with bilateral vestibular impairment, using 1mA×2s Galvanic Vestibular Stimulation (GVS). The displacement (s) and velocity (v) of 7 markers placed on the head, neck, shoulders, mid-thorax and hips and ground reaction forces (F) were recorded. ResultsMonaural GVS evoked anterolateral whole-body movement away from the cathode. For controls, peak response magnitudes were 22.3±12.4mm, 25.9±14.3mms−1 and 3.2±1.3N for s, v and F. Left right asymmetry measured using the Jongkee’s formula was 12.59±8.64%, 11.94±11.09% and 11.68±8.99% for s, v and F. All three measures were symmetrical for left and right mastoid stimulation and showed good to excellent test retest reliability. Patients with bilateral vestibular failure had absent or attenuated responses. For this patient group, the (“R/B”) ratios between the “response period” and baseline body-sway for s, v and F were 2.1±0.8, 1.7±1.1 and 1.3±0.6, which were significantly lower than 5.4±4.2, 4.1±2.5 and 2.3±0.8 for controls, with s and v providing better separation between controls and patients. There were no significant correlations between the amplitudes of galvanic body sway responses and vestibular-evoked myogenic potentials (VEMPs). ConclusionGVS enables non-invasive assessment of the vestibulospinal reflex. SignificanceThis method offers a clinically applicable, test of vestibular contributions to standing balance.

Sex-dependent hemispheric asymmetries for processing frequency-modulated sounds in the primary auditory cortex of the mustached bat.

Species-specific vocalizations of mammals, including humans, contain slow and fast frequency modulations (FMs) as well as tone and noise bursts. In this study, we established sex-specific hemispheric differences in the tonal and FM response characteristics of neurons in the Doppler-shifted constant-frequency processing area in the mustached bat's primary auditory cortex (A1). We recorded single-unit cortical activity from the right and left A1 in awake bats in response to the presentation of tone bursts and linear FM sweeps that are contained within their echolocation and/or communication sounds. Peak response latencies to neurons' preferred or best FMs were significantly longer on the right compared with the left in both sexes, and in males this right-left difference was also present for the most excitatory tone burst. Based on peak response magnitudes, right hemispheric A1 neurons in males preferred low-rate, narrowband FMs, whereas those on the left were less selective, responding to FMs with a variety of rates and bandwidths. The distributions of parameters for best FMs in females were similar on the two sides. Together, our data provide the first strong physiological support of a sex-specific, spectrotemporal hemispheric asymmetry for the representation of tones and FMs in a nonhuman mammal. Specifically, our results demonstrate a left hemispheric bias in males for the representation of a diverse array of FMs differing in rate and bandwidth. We propose that these asymmetries underlie lateralized processing of communication sounds and are common to species as divergent as bats and humans.

Right–left asymmetry in the cortical processing of sounds for social communication vs. navigation in mustached bats

In the Doppler-shifted constant frequency processing area in the primary auditory cortex of mustached bats, Pteronotus parnellii, neurons respond to both social calls and to echolocation signals. This multifunctional nature of cortical neurons creates a paradox for simultaneous processing of two behaviorally distinct categories of sound. To test the possibility of a stimulus-specific hemispheric bias, single-unit responses were obtained to both types of sounds, calls and pulse-echo tone pairs, from the right and left auditory cortex. Neurons on the left exhibited only slightly higher peak response magnitudes for their respective best calls, but they showed a significantly higher sensitivity (lower response thresholds) to calls than neurons on the right. On average, call-to-tone response ratios were significantly higher for neurons on the left than for those on the right. Neurons on the right responded significantly more strongly to pulse-echo tone pairs than those on the left. Overall, neurons in males responded to pulse-echo tone pairs with a much higher spike count compared to females, but this difference was less pronounced for calls. Multidimensional scaling of call responses yielded a segregated representation of call types only on the left. These data establish for the first time, a behaviorally directed right-left asymmetry at the level of single cortical neurons. It is proposed that a lateralized cortex emerges from multiparametric integration (e.g. combination-sensitivity) within a neuron and inhibitory interactions between neurons that come into play during the processing of complex sounds.

The Relation Between Peak Response Magnitudes and Agreement in Diagnoses Obtained From Two Different Phallometric Tests for Pedophilia

Phallometric testing is widely considered the best psychophysiological procedure for assessing erotic preferences in men. Researchers have differed, however, on the necessity of setting some minimum criterion of penile response for ascertaining the interpretability of a phallometric test result. Proponents of a minimum criterion have generally based their view on the intuitive notion that "more is better" rather than any formal demonstration of this. The present study was conducted to investigate whether there is any empirical evidence for this intuitive notion, by examining the relation between magnitude of penile response and the agreement in diagnoses obtained in two test sessions using different laboratory stimuli. The results showed that examinees with inconsistent diagnoses responded less on both tests and that examinees with inconsistent diagnoses responded less on the second test after controlling for their response on the first test. Results also indicated that at response levels less than 1 cm(3), diagnostic consistency was no better than chance, supporting the establishment of a minimum response level criterion.

Magnetoencephalographic study of speed-dependent responses in apparent motion.

There have been only few studies of visually-evoked cortical responses to apparent motion as a function of stimulus speed. Most earlier findings on evoked peak magnitudes and latencies, utilizing various types of smooth and apparent motion stimuli, have demonstrated that greater spatial separation/speed resulted in enhanced peak magnitudes, decreasing onset latencies in individual extrastriate neurons and in shorter motor reaction times in subjects. However, some reports using partial-coverage magnetoencephalography stated that increasing the stimulus displacement actually triggered a substantial reduction of the evoked main peak latency while the magnitude showed no clear change. To resolve the issue of the dependency of evoked responses on stimulus speed in apparent motion, we presented moving bar stimuli to 6 subjects at velocities within a 100 fold range and investigated the ensuing evoked visual cortical activity using a whole-cortex magnetoencephalograph. The magnitude and the latency of the first major evoked peak M1 was measured and compared for 6 discrete bar-stimuli displacements in all subjects. Our results showed clearly that the M1 peak response magnitudes increased in a nonlinear way with higher apparent speeds (larger displacements), in compliance with the logarithmic Fechner law. We observed also that the fluctuations of the mean evoked M1 peak latency (140+/-10.6 ms) did not reach significance over the tested range of stimulus velocities. These findings probably reflect global motion processing mechanisms which rely on nonlinear speed-dependent feedback connectivity between striate and extrastriate visual cortex areas.

A cell-based immunobiosensor with engineered molecular recognition— Part II: enzyme amplification systems

Immune cells in vivo routinely perform highly selective immunosensing in blood and tissues as part of their normal immune surveillance functions. We have been investigating the potential of exploiting the immunosensing detection abilities of excitable immune cells (i.e. the mast cell) for the development of whole cell immunobiosensors. A key feature is that these immune cells can be selectively engineered to recognize specific antigens in vitro. In the presence of antigen, these cells undergo excitable activation responses which result in increased metabolism and the exocytosis of stored intracellular mediators. We have previously determined that mast cell metabolic responses can be thermally transduced in real time, thus indicating the possibility of whole cell thermoelectric immunobiosensing. In this work we investigated the use of enzyme amplification systems to enhance the direct transduction of immune cell responses to analyte. It was found that with appropriate enzymes, peak outputs occurred within ∼ 5 min (4–20 times faster than without enzymes) and peak response magnitudes were up to nine-fold greater than without enzymes.

Cutaneous responses to topical methyl nicotinate in human forearm and vulvar skin

In order to identify and define differences in percutaneous absorption and microcirculatory sensitivity between forearm and vulvar skin we studied the response of human forearm and vulvar (labium majus) skin to topical methyl nicotinate (MN) in 11 healthy premenopausal volunteers. MN-induced erythema was assessed by laser Doppler velocimetry (LDV). The following parameters were compared: 1) basal cutaneous blood flow, 2) the time to peak response, 3) the magnitude of LDV peak response, 4) the area under the LDV resonse-time curve and 5) the decay time to 75% of peak response. Basal cutaneous blood flow at the vulva was higher than at the forearm ( P < 0.05); the magnitude of peak response was lower at the vulva than at the forearm ( P < 0.01); the area under the curve was lower at the vulva than at the forearm ( P < 0.001); the decay time to 75% of peak response was shorter at the vulva than at the forearm ( P < 0.001). The time to peak response showed no significant differences between sites. The results indicate that the MN-induced vasodilatation is less intense and lasts shorter in vulvar compared to forearm skin.

Effects of Spatially-Distributed Rainfall on Runoff for a Conceptual Catchment

A physically-based rainfall-runoff model is used to investigate effects of moving storms on the runoff hydrograph of throughflow dominated idealised catchments. Simulations are undertaken varying the storm speed, direction, intensity, the part of the catchment affected by rainfall, and the spatial definition of rainfall zones. For a 100 km2 catchment, under the circumstances investigated, an efficient spatial resolution of rainfall data is around 2.5 km along the path of the storm. Storms moving downstream produce earlier, higher peaks than do storms moving upstream. Error is most likely to be introduced into lumped-rainfall predictions for slower storm speeds, and the likely direction of this error can be specified. Differences in magnitude of peak response between downstream and upstream storm directions reach a maximum at a storm speed and direction similar to the average peak channel velocity. These results are qualitatively similar to those reported for overland flow dominated catchments, but differences in peak runoff between downstream and upstream storm directions are much smaller where rainfall inputs are modified by a period of hillslope throughflow.

Comparative effects of forskolin and isoproterenol on the cyclic AMP content of human adipocytes

Alterations in adipocyte cyclic AMP concentrations in response to 100 μM forskolin and 10 μM isoproterenol over a 4 hour period were found to be similar; with each agent, a peak response was noted within 30 minutes. In general, the greater the magnitude of peak response, the more rapid the decline of cyclic AMP concentration during the ensuing 3 1 2 hours. Alpha-2 adrenergic activation, achieved with 10 μM clonidine or 10 μM epinephrine, substantially reduced the cyclic AMP concentrations in cells stimulated by 100 μM forskolin or 10 μM isoproterenol. Isoproterenol-stimulated cells appeared to be more sensitive to alpha adrenergic inhibition than did forskolin-stimulated cells. Cells preincubated for 3 hours with 100 μM forskolin were markedly less responsive to a second exposure to the diterpine. Cells exposed to forskolin for 3 hourd also had a reduced response when incubated with isoproterenol; thus, desensitization to forskolin appears to be heterologous. Forskolin desensitization did not appear to be dependent on cellular ATP depletion since cells mildly stimulated during preincubation were as severely desensitized as those adipocytes strongly stimulated. Maximum desensitization required a preincubation time of 1–2 hours with either isoproterenol or forskolin.

Prolonged pulse-entry of pilocarpine with a soluble drug insert.

Apparent biophase availability of pilocarpine was studied in the eyes of albino rabbits. Pilocarpine doses of 0.85 and 2.30 mg in aqueous solutions, 1.00 mg in oil and 0.85 mg in a solid insert, were applied ocularly. The insert was a water soluble polyvinylpyrrolidone (PVP) matrix, which released 80% of its pilocarpine content in 35 min in vitro. In the inferior fornix of the eye this insert gelled in about 5 min and dissolved in 1 h. Pupillary diameters were measured and converted to values for the response parameter (RP). Time delay and magnitude of peak response, apparent biophasic availability (area under the curve of RP vs time), and a constant for the apparent rate of elimination were calculated from RP values. The time delay for the peak response was 16.l3-24.0 min, and the constant for apparent rate of elimination was 0.69-0.81 h-1. Neither time delay nor this constant was affected by the dose or the dosage form. Magnitude of the peak response and apparent biophasic availability were influenced by the vehicle and the dose: insert (0.85 mg) greater than oily solution (1.00 mg) greater than aqueous solution (2.30 mg) greater than aqueous solution (0.85 mg). The insert and oily solution did not show vehicle-controlled drug absorption and can be regarded as prolonged pulse-entry medication.

The gastric secretory response to insulin: an 'all-or-none' phenomenon?

Dogs were prepared with Pavlov pouches which could be perfused with saline so as to detect rapidly changes occurring in acid secretion.Dose-response studies were performed by the intravenous injection of insulin (0.06, 0.12, 0.25, 0.5, or 1.0 unit/kg). Both the magnitude of peak response and the duration of response were dose-related and both were related to the magnitude of fall in plasma glucose. These results are not consistent with an ;all-or-none' hypothesis for insulin-stimulated gastric acid secretion, but favour the alternative hypothesis that insulin provides a graded glycopenic stimulus producing a graded secretory response.