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PubMed1998

Pheromone deactivation catalyzed by receptor molecules: a quantitative kinetic model.

A quantitative model of pheromone-receptor interaction and pheromone deactivation, the supposed rate-limiting processes underlying the receptor potential kinetics, is worked out for the moth Antheraea polyphemus. In this model, the pheromone interacts with the receptor molecule while bound to the reduced form of the pheromone binding protein. The receptor molecules--besides their receptor function--catalyze the observed shift of the pheromone-binding protein from the reduced to the oxidized form (Ziegelberger, G., Eur. J. Biochem., 232, 706-711, 1995), which deactivates the pheromone bound to pheromone binding protein. With the following parameters, the model fits morphological, radiometric, electrophysiological and biochemical data: a maximum estimate of 1.7 x 10(7) receptor molecules/cell (with 40,000 units/micron 2 of receptor cell membrane), rate constants k1 = 0.2/(s.microM) for the association, k2 = 10/s for the dissociation of the ternary complex of binding protein, pheromone and receptor, and k3 = 10/s for the deactivation via the redox shift. With these parameters, the duration of elementary receptor potentials elicited by single pheromone molecules (approximately 50 ms) reflects the lifetime of the ternary complex, tau = 1/(k2 + k3). The receptor occupancy produced by the model for threshold stimuli fits the sensitivity of the receptor cell to single pheromone molecules.

Animals↗

PubMedDate not supplied

Mathematical modelling of American cutaneous leishmaniasis: incidental hosts and threshold conditions for infection persistence.

We present a model for the dynamics of transmission of American Cutaneous Leishmaniasis (ACL) that includes a population of incidental hosts for parasites (that is, they act only as sinks of infection), along with species that are reservoir hosts (that is, both source and sink of infection). Although, there is evidence that suggests the existence of incidental hosts for Leishmania parasites, there are no mathematical models developed to account for this. Based on this model we obtained expressions that allow computing the threshold conditions for the persistence of the infection using three different approaches. The three expressions agree in the parameters involved in the computation of the threshold, and also in the parameters that are excluded from it, which are those related to the transmission in incidental hosts. We also suggest alternatives for future development in the modelling of the dynamics of transmission of ACL, according to the needs of a more realistic, precise, or general character of the model.

Animals↗

PubMed1988

Familial links between schizophrenia and other disorders: application of the multifactorial polygenic model.

A substantial number of patients do not meet diagnostic criteria for schizophrenia yet exhibit psychotic phenomena characteristic of that disorder (e.g., schizophreniform disorder, schizoaffective disorder, paranoid disorder, atypical psychosis). The relationship between schizophrenia and these disorders is poorly understood. This paper describes how the two-threshold multifactorial model of familial transmission can be applied to test the hypothesis that these disorders share a multifactorial etiology with schizophrenia. The procedure is illustrated using data from a blind family study of the major psychoses. Results support the hypothesis that the disorders under examination share a common multifactorial familial etiology. Methodological issues are discussed along with suggestions for future research in this area.

Adult↗

PubMed2005

Anticonvulsant effects of LY456236, a selective mGlu1 receptor antagonist.

Several lines of evidence suggest that mGlu1 metabotropic glutamate receptors may be involved in seizure disorders such as epilepsy. For example, the mGlu1 agonist DHPG produces limbic seizures and group I antagonists such as 4C3HPG and 4CPG are anticonvulsant when administered intracerebrally. The purpose of the present experiments was to characterize the anticonvulsant effects of the selective mGlu1 receptor antagonist LY456236 in mice and rats. In male and female DBA/2 mice, LY456236 produced a dose-related inhibition of sound-induced clonic-tonic seizures. In male CF1 mice, LY456236 produced a dose-related inhibition of tonic extensor seizures in the threshold electroshock model, and limbic seizures in the 6-Hz focal seizure model. However, this antagonist did not inhibit clonic seizures produced by pentylenetetrazol. In amygdala-kindled male Sprague-Dawley rats, LY456236 produced dose-related decreases in behavioral and electrographic seizures at threshold stimulus intensity. In addition, LY456236 produced a dose-related increase in the stimulus intensity required to produce generalized seizures. Taken together, the present results support the conclusion that mGlu1 receptor antagonists such as LY456236 may have clinical utility in the treatment of epilepsy and other seizure disorders.

Acoustic Stimulation↗

PubMed2001

The effect of remifentanil on the heat pain threshold in volunteers.

Remifentanil offers a wide range of clinical uses and has been successfully combined with general anesthetics. However, there are few human experimental studies demonstrating the analgesic property of remifentanil. It was our aim to determine the analgesic effect of remifentanil with regard to dose-dependent increments in a human model of heat pain threshold assessment. Twenty healthy volunteers were randomized in a double-blinded cross-over design to receive an infusion of remifentanil or saline. The stepped infusion was increased every 5 min by 0.01 microg. kg(-1). min(-1) up to 0.17 microg. kg(-1). min(-1)and terminated in case of defined safety limits. Thermal sensory testing of the heat pain threshold was performed every 5 min at the left forearm. The dose-response relationship and the effective dose for at least 50% of the subjects (ED(50)) were determined. Remifentanil led to a clear dose-dependent increase of the heat pain threshold differing significantly from placebo (P < 0.0007). The ED(50) of remifentanil equals 0.05 microg. kg(-1). min(-1) (first quartile 0.025 microg. kg(-1). min(-1) and third quartile 0.06 microg. kg(-1). min(-1)) in this experimental setting. In conclusion, an opioid-mediated analgesic effect of remifentanil was determined in a human heat pain threshold model. The dose of 0.05 microg. kg(-1). min(-1) is an effective and safe increment in healthy volunteers.

Adult↗

PubMed1995

Modelling series of visual fields to detect progression in normal-tension glaucoma.

BACKGROUND: Use of statistical modelling techniques to identify models that both describe glaucomatous sensitivity decay and allow predictions of future field status. METHOD: Twelve initially normal fellow eyes of untreated patients with confirmed normal tension glaucoma were studied. All had in excess of 15 Humphrey fields (mean follow-up 5.7 years). From this cohort individual field locations were selected for analysis if they demonstrated unequivocal deterioration at the final two fields. Forty-seven locations from five eyes satisfied this criterion and were analysed using curve-fitting software which automatically applies 221 different models to sensitivity (y) against time of follow up (x). Curve-fitting was then repeated on the first five fields, followed by projection to the date of the final field to generate a predicted threshold which was compared to the actual threshold. Competing models were therefore assessed on their performance at adequately fitting the data (R2) and their potential to predict future field status. RESULTS: Models that provide the best fit to the data were all complex polynomial expressions (median R2 0.93). Other simple expressions fitted fewer locations and exhibited lower R2 values. However, accuracy in predicting future deterioration was superior with these less complex models. In this group a linear expression demonstrated an adequate fit to the majority of the data and generated the most accurate predictions of future field status. CONCLUSIONS: A linear model of the pointwise sensitivity values against time of follow-up can provide a framework for detecting and forecasting glaucomatous field progression. Linear modelling allows the clinically important rate of sensitivity loss to be estimated.

Cohort Studies↗

PubMed2003

The LNT model is the best we can do--today.

The form of the dose-response curve for radiation-induced cancers, particularly at low doses, is the subject of an ongoing and spirited debate. The present review describes the current database and basis for establishing a low dose, linear no threshold (LNT) model. The requirement for a dose-response model to be used for risk assessment purposes is that it fits the great majority of data derived from epidemiological and experimental tumour studies. Such is the case for the LNT model as opposed to other nonlinear models. This view is supported by data developed for radiation-induced mutations and chromosome aberrations. Potential modifiers of low dose cellular responses to radiation (such as adaptive response, bystander effects and genomic instability) have not been shown to be associated with tumour development. Such modifiers tend to influence the slope of the dose-response curve for cellular responses at low doses and not the shape--thereby resulting in a quantitative modification rather than a qualitative one. Additional data pertinent to addressing the shape of the tumour dose-response relationship at low doses are needed.

Chromosome Aberrations↗

PubMed1998

Determination of the ischemic threshold for brain oxygen tension.

Measuring brain tissue oxygenation is now possible due to major advances in the technical development of Clark-electrodes and fiberoptic systems. However, to make this technique clinically useful for both nurses and medical staff, the ischemic threshold for brain tissue oxygen tension (brain pO2) must be determined. Three end points were used for determination of the critical brain pO2 value. 1) Infarct determination after permanent middle cerebral artery occlusion in a feline model. 2) Threshold analysis using the schemic threshold for cerebral blood flow (CBF) as a "gold standard" in severely head injury patients. 3) Outcome analysis in severely head injured patients. Brain pO2 dropped to 19 +/- 6 mm Hg and 23 +/- 6, 4 to 5 hours after MCA occlusion in the cat (n = 12). In severely head injured patients, a brain pO2 < or = 19 mm Hg was correlated with poor outcome (n = 24). The ischemic threshold for (r)CBF of 18 ml/100 g/min corresponded to a brain pO2 of 22 mm Hg, in the same patients. By using the above mentioned end points as a reference, we found the critical value for brain pO2 to be in between 19 and 23 mm Hg. Clearly, the difference between our threshold value and the lower critical brain pO2 level found by other groups using the Licox system, needs to be clarified in a comparison study before a uniform threshold for brain pO2 can be determined.

Animals↗

PubMed1979

Using color substitution pupil response to expose chromatic mechanisms.

It is well known that pupillary threshold shows a scotopic spectral behavior, even for foveal stimuli. However, when two scotopically balanced fields at different wavelengths are alternated, the pupil shows a constriction response at each transition, exposing innervation from chromatic mechanisms. Using a suitable model for pupillary innervation, this substitution response is systematically studied for different wavelengths and radiant power levels to yield (within the accuracy of the assumptions of the model) spectral threshold curves for the chromatic mechanism as indicated by the pupil. Four mechanisms have thus been identified, having peak sensitivities near 450, 525, 580, and 495 nm. We propose that these represent the blue, green, red and scotopic mechanisms as maintained before the level of the lateral geniculate body.

Color Perception↗

PubMed2001

Improving standard cardiopulmonary resuscitation with an inspiratory impedance threshold valve in a porcine model of cardiac arrest.

To improve the efficiency of standard cardiopulmonary resuscitation (CPR), we evaluated the potential value of impeding respiratory gas exchange selectively during the decompression phase of standard CPR in a porcine model of ventricular fibrillation. After 6 min of untreated cardiac arrest, anesthetized farm pigs weighing 30 kg were randomized to be treated with either standard CPR with a sham valve (n = 11) or standard CPR plus a functional inspiratory impedance threshold valve (ITV(TM)) (n = 11). Coronary perfusion pressure (CPP) (diastolic aortic minus right atrial pressure) was the primary endpoint. Vital organ blood flow was assessed with radiolabeled microspheres after 6 min of CPR, and defibrillation was attempted 11 min after starting CPR. After 2 min of CPR, mean +/- SEM CPP was 14 +/- 2 mm Hg with the sham valve versus 20 +/- 2 mm Hg in the ITV group (P < 0.006). Significantly higher CPPs were maintained throughout the study when the ITV was used. After 6 min of CPR, mean +/- SEM left ventricular and global cerebral blood flows were 0.10 +/- 0.03 and 0.19 +/- 0.03 mL. min(-1). g(-1) in the Control group versus 0.19 +/- 0.03 and 0.26 +/- 0.03 mL. min(-1). g(-1) in the ITV group, respectively (P < 0.05). Fifteen minutes after successful defibrillation, 2 of 11 animals were alive in the Control group versus 6 of 11 in the ITV group (not significant). In conclusion, use of an inspiratory impedance valve during standard CPR resulted in a marked increase in CPP and vital organ blood flow after 6 min of cardiac arrest.

Animals↗

PubMed2003

A role for neural integrators in perceptual decision making.

Decisions based on uncertain information may benefit from an accumulation of information over time. We asked whether such an accumulation process may underlie decisions about the direction of motion in a random dot kinetogram. To address this question we developed a computational model of the decision process using ensembles of neurons whose spiking activity mimics neurons recorded in the extrastriate visual cortex (area MT or V5) and a sensorimotor association area of the parietal lobe (area LIP). The model instantiates the hypothesis that neurons in sensorimotor association areas compute the time integral of sensory signals from the visual cortex, construed as evidence for or against a proposition, and that the decision is made when the integrated evidence reaches a threshold. The model explains a variety of behavioral and physiological measurements obtained from monkeys.

Action Potentials↗

PubMed2006

Genetic variation of Mycobacterium avium ssp. paratuberculosis infection in US Holsteins.

The objective of this study was to estimate genetic variability of Mycobacterium avium ssp. paratuberculosis infection in US Holsteins. Blood and fecal samples were collected primarily from daughters of 12 bulls in their second or third lactation. Routine disease testing of the sires documented that they were not infected. Herds without a "suspect" or positive ELISA (sample/positive ratio > or = 0.10) or positive fecal culture test were deleted from the data set. The remaining 4,603 cows from 238 herds and 46 sires were used to estimate heritability of M. paratuberculosis infection. Heritability was estimated with 3 Johne's disease diagnostic tests: 1) fecal culture alone, 2) serum antibody ELISA alone, and 3) both tests (combined) with a positive animal defined as all animals with either a positive fecal culture or ELISA test. Four statistical models were used to estimate heritability: 1) linear (ELISA), 2) threshold (fecal culture and combined), 3) ordered threshold (ELISA), and 4) bivariate linear-threshold (ELISA-fecal culture). A sire model and Bayesian approach using Markov chain Monte Carlo methods were used in each case. Heritability of infection based on the fecal culture test was 0.153 [posterior standard deviation (PSD) = 0.115]. Heritability with the ELISA was 0.159 (PSD = 0.090) with a linear model and 0.091 (PSD = 0.053) with an ordered threshold model. Heritability of the combined tests was 0.102 (PSD = 0.066). Heritability estimates of fecal culture and ELISA with the bivariate model varied slightly from estimates obtained with the univariate models (0.125 and 0.183, respectively), with a corresponding increase in precision (PSD = 0.096 and 0.082, respectively). This study demonstrates that exploitable genetic variation exists in dairy cattle for M. paratuberculosis infection susceptibility.

Animals↗

PubMed1990

Cat and monkey cortical columnar patterns modeled by bandpass-filtered 2D white noise.

A simple algorithm based on bandpass-filtering of white noise images provides good quality computer reconstruction of the cat and monkey ocular dominance and orientation column patterns. A small number of parameters control the frequency, orientation, "branchedness", and "regularity" of the column patterns. An oriented (anisotropic) bandpass filter followed by a threshold operation models the macaque ocular dominance column pattern and cat orientation column system. An unoriented (isotropic) bandpass filter models the cat ocular dominance column pattern and the macaque orientation column system. The resemblance of computer graphic simulations produced by this algorithm and histological pattern data, is strong. Since this algorithm is very fast, we have been able to extensively explore its parameters space in order to determine filter parameters which closely match the structure of the various cortical systems. In particular, we have applied spectral analysis to our recent computer reconstruction of the macaque ocular dominance column system, and the model produced by the present algorithm is in close agreement with this detailed data analysis.

Algorithms↗

PubMed1995

Relationship between psychophysical tuning curves and critical bandwidths.

In Experiment I, band noises were used as signals and pure tones were used as maskers. The conventional psychophysical tuning curves (PTCs) present the following characteristics depending on the signal level; slopes of the PTC are steeper than those of the auditory nerve fibers frequency threshold curve (FTC). This result from the large effect of the combination tones and, especially, of the off-frequency listening. Bandwidths of PTC do not depend on both signal levels and duration, but they are narrower than the equivalent rectangular bandwidth (ERB) of auditory filters. Masked thresholds at tips of PTC are affected by the temporal integration of signal sound at signal levels of 10- and 20-dB SL, but are not affected at 30-dB SL. This implies a close relation between PTCs and critical bandwidths (CB-widths). In Experiment II, pure tones were used as signals and band noise were used as maskers. The low- and high-frequency slopes were steeper in Experiment I. The flat parts of the masked threshold at the tips of curves become broader as the signal duration increased. No such flattening was found at a 30-dB signal level, irrespective of signal duration. The results of Experiment II coincide with the prediction derived from the excitation-pattern model. Masked thresholds at the tip of PTC were the same as in Experiment I. The conventional PTC represents the psychological frequency selectivity, and its 3-dB bandwidth corresponds to the CB-width. However, the quantitative properties depend greatly upon the bandwidths of the band noises used as signals or maskers.

Attention↗

PubMed1988

Threshold and stability results for an epidemic model with an age-structured meeting rate.

This paper examines threshold and stability results for simple mathematical models for the transmission of infectious diseases with permanent natural immunity. Examples of such diseases are measles, chicken-pox, hepatitis, and mumps. An important feature of this work is the introduction of an age structure into the population amongst whom the disease is spreading and, in particular, the realization of the fact that the contact rate itself may depend on age. Equilibrium and stability analyses are performed on these models. These results are in part directed towards establishing conditions sufficient for the existence of a nonzero equilibrium disease level to be possible. Conjectures about the existence of a nonzero solution to a set of partial integrodifferential equations are examined. These conditions determine the circumstances under which the disease will persist. Particular emphasis is devoted to the case where the meeting rate depends on age.

Age Factors↗

PubMedDate not supplied

Comparative pharmacodynamics and brain distribution of E-delta 2-valproate and valproate in rats.

The E-isomer of 2-unsaturated valproate (E-delta 2-VPA) is a pharmacologically active metabolite of VPA that is less teratogenic and hepatotoxic than its saturated precursor. To assess potential use of E-delta 2-VPA as an alternate to VPA, a dose-response study comparing the anticonvulsant activity and neurotoxicity of E-delta 2-VPA and VPA was conducted in rats using the intravenous (i.v.) pentylenetetrazol (PTZ)-infusion threshold seizure model. Assay of drug in whole brain and plasma allowed comparison of the drug concentration-effect relationships and the brain distribution characteristics of the two compounds. E-delta 2-VPA was two to three times more potent than VPA in elevating the clonic seizure threshold of PTZ, in reference to either plasma or whole-brain drug concentrations. Furthermore, much steeper response curves were observed with E-delta 2-VPA as compared with VPA. Within the pharmacologic concentration range (defined as EC25 to EC75), E-delta 2-VPA was less neurotoxic than VPA as assessed by behavioral tests. Therefore, E-delta 2-VPA has a much more favorable protective index than VPA. At low doses, the concentration ratios of brain to plasma for both E-delta 2-VPA and VPA increased markedly with increasing plasma drug concentration. E-delta 2-VPA and VPA were previously shown to exhibit saturable binding to rat plasma proteins. If we assume that uptake of drug into the CNS is limited to the equilibrium plasma free fraction in the brain microvasculature, much of the nonlinear brain distribution features of VPA could be accounted for by saturable drug plasma protein binding. On the other hand, more complex kinetics involving simultaneous saturation of plasma protein binding and blood-to-brain transport are proposed to explain the brain distribution of the unsaturated compound. In addition, the brain-to-free drug concentration ratios for both E-delta 2-VPA and VPA were below unity at high drug-concentration range, consistent with the presence of an efficient efflux mechanism of these compounds from brain.

Animals↗

PubMed1980

Off-frequency listening and auditory-filter asymmetry.

The phenomenon of off-frequency listening, and the asymmetry of the auditory filter, were investigated by performing a masking experiment in which a 2.0-kHz tonal signal (0.4 sec in duration) was masked by a pair of noise bands, one below and the other above the tone. The noise bands were 0.8-hKz wide. The edges of the bands were very sharp, the spectrum level in the band was 40 dB SPL, and the masker was on continuously throughout the experiment. Tone threshold was measured as a function of the distances from the tone to the nearer edge of each noise band. It was assumed that conditions in which one noise band was near the tone and the other remote from the tone would encourage the observer to listen off frequency, that is, to center his auditory filter, not at the tone frequency, but at the frequency that optimizes the signal-to-noise ratio at the output of the filter. The threshold data were analysed with a power spectrum model of masking in which it was assumed that the general form of the filter shape was a rounded exponential (a pair of back-to-back, negative exponentials with the peak smoothed and the tails raised). The specific filter shape obtained by applying this model to the threshold data has a broad passband (a 200-Hz, 3-dB bandwidth), steep skirts (slopes of 100 dB/octave) and shallower tails (slopes of 30-50 dB/octave) that take over 30-35 dB down from the peak of sensitivity. The filter is asymmetric, with the lower branch slightly broader than the upper. The filter is shifted off frequency by more than half its bandwidth in some cases, and the shift can improve the signal-to-noise ratio by up to 5.0 dB.

Auditory Threshold↗

PubMed1995

Phonation threshold pressure in a physical model of the vocal fold mucosa.

The vocal fold mucosa, which consists of the epithelium and the superficial layer of the lamina propria, has been modeled by a fluid encapsulated in a silicone membrane. The artificial mucosa was attached to a rigid (metal) vocal fold body and introduced into an airflow channel, creating a rectangular glottis. Flow-induced oscillation of the mucosa was achieved at various subglottal pressures and glottal diameters. Phonation threshold pressure, the parameter of interest, was lowest (on the order of 0.4 kPa) for glottal diameters between 0.0 and 0.1 mm and for fluids with the lowest viscosity. There was a consistent hysteresis effect; that is, phonation threshold pressure was always lower for oscillation offset than onset.

Auditory Threshold↗