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PubMed1987

Facilitation and masking of briefly presented gratings: time-course and contrast dependence.

We measured two-alternative forced-choice contrast thresholds for briefly presented sinusoidal gratings in the presence of superimposed masking gratings of various contrasts, and at a range of onset asynchronies. Facilitation (lower thresholds) occurred when the mask was simultaneous, in-phase, and near-threshold, but was abolished at asynchronies of 50 msec or more and by presenting the test grating as a brief contrast reversal instead of a pulse. We argue that facilitation requires temporal summation of responses within the same neural channels, but our results do not distinguish between transducer and uncertainty models. Masking (threshold elevation) occurred over a broader range of asynchronies, and was not abolished by test contrast reversal. Masking and facilitation probably depend on different processes with different time-courses. The occurrence of masking at asynchronies outside the range of temporal summation suggests that a static, compressive transducer does not, in general, account for masking. Brief masking and prolonged contrast adaptation are very similar in magnitude, and as a function of contrast and relative spatial frequency. Masking and adaptation may have a common origin, but differ in speed of recovery.

Adaptation, Ocular↗

PubMed1998

Nonmonotonicity of informational masking.

Neff and Green [Percept. Psychophys. 41, 409-415 (1987)] report that the masking of single tones by random-frequency multitone maskers varies nonmonotonically with number of masker components (peaking at 10-50 components). In this paper it is shown that such results are well predicted by a model (the component-relative-entropy model, CoRE) wherein thresholds increase linearly with the ensemble variance of masker spectra smoothed by peripheral auditory filters [R. A. Lutfi, J. Acoust. Soc. Am. 94, 748-758 (1993)]. Three experiments were conducted. In the first, the nonmonotonic relation was replicated for 9 of 11 listeners in conditions similar to those of Neff and Green. In the second, the frequencies of masker components were fixed and the levels of components were varied randomly across presentations to simulate Gaussian noise. In this case, the nonmonotonicity and the total amount of masking for these listeners were shown to be significantly reduced. In the third experiment, masked thresholds for the signal were found to vary monotonically with the frequency spacing of masker components for a fixed number of masker components. Large individual differences among listeners were obtained in some experimental conditions. Individual as well as mean thresholds were well predicted by the CoRE model with an appropriate selection of the values of the two free parameters of the model for each listener.

Adult↗

PubMed2006

Modularity and intrinsic evolvability of Hsp90-buffered change.

Hsp90 controls dramatic phenotypic transitions in a wide array of morphological features of many organisms. The genetic-background dependence of specific abnormalities and their response to laboratory selection suggested Hsp90 could be an 'evolutionary capacitor', allowing developmental variation to accumulate as neutral alleles under normal conditions and manifest selectable morphological differences during environmental stress. The relevance of Hsp90-buffered variation for evolution has been most often challenged by the idea that large morphological changes controlled by Hsp90 are unconditionally deleterious. To address this issue, we tested an Hsp90-buffered abnormality in Drosophila for unselected pleiotropic effects and correlated fitness costs. Up to 120-fold differences in penetrance among six highly related selection lines, started from an initially small number of flies and rapidly selected for and against a deformed eye trait (dfe), did not translate into measurable differences in any of several tests of viability, lifespan or competitive fitness. Nor were 17 dfe Quantitative Trait Loci (QTL) associated with fitness effects in over 1,400 recombinant lines. Our ability to detect measurable effects of inbreeding, media environment and the white mutation in the selection line backgrounds independent of dfe penetrance suggests that, within the limitations of laboratory tests of fitness, this large morphological change controlled by Hsp90 was selectable independent of strong, correlated and unconditionally deleterious effects--abundant, polygenic variation hidden by Hsp90 allows potentially deleterious alleles to be readily replaced during selection by less deleterious alleles with similar phenotypic effects. Hsp90 links environmental stress with the expression of developmental variation controlling unprecedented morphological plasticity. As outlined here and in the companion paper of this issue, the complex genetic architecture of Hsp90-buffered variation supports a remarkable modularity of Hsp90 effects on quantitative and qualitative phenotypes, consistent with the 'Hsp90 capacitor hypothesis' and standard quantitative genetic models of threshold traits.

Alleles↗

PubMed2004

Variation of biological responses to different respirable quartz flours determined by a vector model.

BACKGROUND: The hypothesis of widely differing lung damage due to commonly used types of quartz was studied in 16 samples of respirable quartzes (> 99% silica) from sites of the European quartz industry, using an in vitro test, the vector model. Two samples with high and 2 with low biological activities were identified and subsequently examined for their in vivo lung toxicity (inflammation, fibrosis, genotoxicity) and surface characteristics. Alveolar macrophages (AM) are considered the target cells of primary dust effects. The vector model mimics some of the elemental dust cell effects such as cell toxicity, effects on the metabolism and stimulatory effects, e.g., TNF alpha and dust-induced ROS secretion. METHODS: Doses of 15, 30, 60 and 120 microg dust per 10(6) AM were used together with the control dusts (quartz DQ12 and corundum). Testing parameters were LDH, glucuronidase, PMA forced ROS release, TNF alpha and dust induced ROS secretion. The main criterion for the selection of low or high activity samples was the secretion of TNF alpha. RESULTS: (i) Apart from quartz samples with an activity close to that of DQ12, one also finds examples with a very low activity. (ii) In comparison particular parameters are linked with a specific dose response relationship and different dose points for the leveling off of the effects. The levels of TNF alpha represent a conspicuously broad response pattern; some samples induce secretion at the lowest dose and others are not active even at the highest dose investigated at already apparent toxicity. (iii) Regarding various parameters the dust samples led to distinct dose response profiles considered as vectors. The current study indicates that within the particle type "quartz fine dust" varying harmful doses and different elements of damage must be present. (iv) The lung damage of the subchronic animal assay coincides with in vitro tests thus confirming the concept of the vector model. CONCLUSION: Threshold effects in the range of 15 - > or = 120 microg can be demonstrated for the discriminant vector TNF alpha, i.e. over 4 steps of dose doubling. These studies show very toxic quartzes but also quartzes of low biological activity comparable to corundum.

Animals↗

PubMedDate not supplied

The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. IV. Protective indices.

Calculation of protective or therapeutic indices is widely used in primary and secondary screening for drugs with selective anticonvulsant activity. The protective index is the median minimal 'neurotoxic' dose, TD50, divided by median effective dose, ED50. TD50s are usually determined by tests, such as the rotarod test or the chimney test, for quantification of 'minimal neurological deficit', such as motor impairment, while median effective doses are commonly determined in the maximal electroshock seizure (MES) test or the s.c. pentylenetetrazol (PTZ) seizure test in mice or rats. For antiepileptic drug development, it has been proposed previously that only compounds with an estimated protective index of at least 5 should proceed to further evaluation. However, various technical, biological and pharmacological factors can influence anticonvulsant or 'neurotoxic' potencies and thereby protective indices. In order to reevaluate the value of protective indexes in the prediction of drugs with selective anticonvulsant action, protective indices were determined for various clinically used antiepileptic drugs in standardized seizure tests, i.e. MES and s.c. PTZ tests in mice and rats, as well as in seizure threshold tests. For most drugs, similar TD50s were determined in the rotarod and chimney test. When protective indices were calculated for the different seizure models, only few drugs reached an index of 5 (some not even reaching an index of 2) in the traditional MES or s.c. PTZ tests in mice and rats. In contrast, using anticonvulsant doses determined by seizure threshold tests, the 5 primary drugs against generalized tonic-clonic seizures, i.e., carbamazepine, phenytoin, phenobarbital, primidone and valproate, had indices of more than 5 in the MES threshold model, while drugs with efficacy against absence and myoclonic seizures, i.e., valproate, ethosuximide and the benzodiazepines, had protective indices of at least 5 in the i.v. PTZ seizure threshold model. The data substantiate that valuable information can be obtained by estimation of protective indices. However, in order to minimize the possibility that an interesting new anticonvulsant compound is overlooked during primary or secondary screening, a protective index of 2 should be considered sufficient in case of traditional MES or s.c. PTZ models with fixed seizure stimulus. Alternatively, seizure threshold models could be used for calculation of protective indices in order to avoid underestimation of anticonvulsant selectivity of test compounds.

Animals↗

PubMed2004

[A study on early detection for seven infectious diseases].

OBJECTIVE: To provide methods and alert thresholds which are scientific, sensitive, specific and practical for Early Warning System in Public Health Surveillance. METHODS: Alert data was based on historical infectious diseases reports. Control chart was used to detect outbreaks or epidemics. An epidemic was defined by consulting Specialists. After calculating sensitivity, specificity, positive predictive value and describing receiver-operating characteristic curve (ROC), the optimal model and thresholds were chosen. RESULTS: At 80 percentile, the sensitivities and the specificities of epidemic haemorragia fever, hepatitis A, dysentery, epidemic cerebrospinal meningitis and malaria were over 90%, and there was a high efficacy of early warning. At 90 percentile, the sensitivities and the specificities of tuberculosis and measles were over 85%, and there was a high efficacy of early warning also. CONCLUSION: Control chart based on five years was chose as a essential method in early warning system. The alert threshold for epidemic haemorragia fever, hepatitis A, dysentery, epidemic cerebrospinal meningitis and malaria was 80 percentile. The alert threshold for tuberculosis and measles was 90 percentile.

China↗

PubMed2002

Effects of active compression-decompression cardiopulmonary resuscitation with the inspiratory threshold valve in a young porcine model of cardiac arrest.

Active compression-decompression (ACD) cardiopulmonary resuscitation (CPR) with the inspiratory threshold valve (ITV) has been recently recommended by the American Heart Association for treatment of adults in cardiac arrest (class IIb: alternative, useful intervention), but this new technique has never been used in a pediatric population. Thus, this study was designed to evaluate ACD + ITV CPR in a young porcine model of cardiac arrest. After 10 min of ventricular fibrillation, and 8 min of standard CPR, ACD + ITV CPR was performed in seven 4- to 6-wk-old pigs (8-12 kg); defibrillation was attempted 8 min later. Within 2 min after initiation of ACD + ITV CPR, mean (+/- SEM) coronary perfusion pressure increased from 18 +/- 2 to 24 +/- 3 mm Hg (p = 0.018). During standard versus ACD + ITV CPR, mean left ventricular myocardial and total cerebral blood flow was 59 +/- 21 versus 126 +/- 32 mL.min(-1).100 g(-1), and 36 +/- 7 versus 60 +/- 15 mL.min(-1).100 g(-1), respectively (p = 0.028). Six of seven animals were successfully defibrillated, and survived >15 min. In conclusion, the combination of ACD + ITV CPR significantly increased both coronary perfusion pressure and vital organ blood flow after prolonged standard CPR in this young porcine model of ventricular fibrillation.

Adult↗

PubMed2002

Quantifying the implications of nonlinear cochlear tuning for auditory-filter estimates.

The relation between auditory filters estimated from psychophysical methods and peripheral tuning was evaluated using a computational auditory-nerve (AN) model that included many of the response properties associated with nonlinear cochlear tuning. The phenomenological AN model included the effects of dynamic level-dependent tuning, compression, and suppression on the responses of high-, medium-, and low-spontaneous-rate AN fibers. Signal detection theory was used to evaluate psychophysical performance limits imposed by the random nature of AN discharges and by random-noise stimuli. The power-spectrum model of masking was used to estimate psychophysical auditory filters from predicted AN-model detection thresholds for a tone signal in fixed-level notched-noise maskers. Results demonstrate that the role of suppression in broadening peripheral tuning in response to the noise masker has implications for the interpretation of psychophysical auditory-filter estimates. Specifically, the estimated psychophysical auditory-filter equivalent-rectangular bandwidths (ERBs) that were derived from the nonlinear AN model with suppression always overestimated the ERBs of the low-level peripheral model filters. Further, this effect was larger for an 8-kHz signal than for a 2-kHz signal, suggesting a potential characteristic-frequency (CF) dependent bias in psychophysical estimates of auditory filters due to the increase in strength of cochlear nonlinearity with increases in CF.

Auditory Perception↗

PubMed2000

The contribution of noise to contrast invariance of orientation tuning in cat visual cortex.

Feedforward models of visual cortex appear to be inconsistent with a well-known property of cortical cells: contrast invariance of orientation tuning. The models' fixed threshold broadens orientation tuning as contrast increases, whereas in real cells tuning width is invariant with contrast. We have compared the orientation tuning of spike and membrane potential responses in single cells. Both are contrast invariant, yet a threshold-linear relation applied to the membrane potential accurately predicts the orientation tuning of spike responses. The key to this apparent paradox lies in the noisiness of the membrane potential. Responses that are subthreshold on average are still capable of generating spikes on individual trials. Unlike the iceberg effect, contrast invariance remains intact even as threshold narrows orientation selectivity. Noise may, by extension, smooth the average relation between membrane potential and spike rate throughout the brain.

Action Potentials↗

PubMed1997

Curvilinearity in the dose-response curve for cancer in Japanese atomic bomb survivors.

Recently released data on cancer incidence in Japanese atomic bomb survivors are analyzed using a variety of relative risk models that take account of errors in estimates of dose to assess the dose response at low doses. If a relative risk model with a threshold (the dose response is assumed linear above the threshold) is fitted to solid cancer data, a threshold of more than about 0.2 Sv is inconsistent with the data, whereas these data are consistent with there being no threshold. Among solid cancer subtypes there is strong evidence for a possible dose threshold only for nonmelanoma skin cancer. If a relative risk model with a threshold (the dose response is assumed linear above the threshold) is fitted to the leukemia data, a threshold of more than about 0.3 Sv is inconsistent with the data. In contrast to the estimates for the threshold level for solid cancer data, the best estimate for the threshold level in the leukemia data is significantly different from zero even when allowance is made for a possible quadratic term in the dose response, albeit at borderline levels of statistical significance (p = 0.04). There is little evidence for curvature in the leukemia dose response from 0.2 Sv upwards. However, possible underestimation of the errors in the estimates of the dose threshold as a result of confounding and uncertainties not taken into account in the analysis, together with the lack of biological plausibility of a threshold, makes interpretation of this finding questionable.

Dose-Response Relationship, Radiation↗

PubMed1993

Effect of age, gender and anaesthetic technique on the pharmacodynamics of atracurium.

We have measured in 38 patients the plasma concentration profile of atracurium and its effect on the electromyographic first response of the train-of-four. One of three techniques was used to supplement anaesthesia with 66% nitrous oxide in oxygen, 0.9% isoflurane (end-tidal), 0.5% halothane (end-tidal) or midazolam 3-10 mg. A four-parameter threshold pharmacodynamic model was fitted to the data in each patient. Compared with a group of patients anaesthetized with an i.v. technique, the steady-state plasma concentration producing 50% block (Cpss50) was reduced by halothane, and to a greater extent by isoflurane. The rate constant for exit from the effect compartment (k(eo)) correlated negatively with age and was greater in female patients, but unaffected by anaesthetic technique. The values of gamma, the slope of the concentration-response curve, and of the threshold (Cpss theta) were not affected significantly by age, sex or anaesthetic technique.

Adolescent↗

PubMed2002

Error threshold transition in the random-energy model.

We perform a statistical analysis of the error threshold transition in quasispecies evolution on a random-energy fitness landscape. We obtain a precise description of the genealogical properties of the population through extensive numerical simulations. We find a clear phase transition and can distinguish two regimes of evolution: The first, for low mutation rates, is characterized by strong selection, and the second, for high mutation rates, is characterized by quasineutral evolution.

Journal Article↗

PubMed1996

Intrinsic uncertainty and integration efficiency in bisection acuity.

A spatial perturbation paradigm was used to determine equivalent intrinsic uncertainty and spatial integration efficiency in bisection. Specifically, three-line bisection thresholds were measured in the fovea of four normal observers with stimulus lines comprised of discrete dark dots distributed randomly around the mean line position according to a Gaussian function. The standard deviation of the Gaussian distribution (sigma e), the number (N), and the strength (C) of the dots as well as line separation were varied. Bisection thresholds were modeled by an ideal integrator, from which the magnitude of equivalent internal uncertainty (sigma i), the equivalent effective number of dots (k), and equivalent integration efficiency (k/N) were quantified. At the 2 min arc separation, sigma i decreases (down to a few sec arc) as N and/or C increases. The effects of both N and C can be accounted for by the stimulus visibility (V, in multiples of detection threshold). At the 16 min arc separation, sigma i is independent of N, C, or V, and is about 1 min arc. The two different forms of sigma i indicate that bisection judgments are limited by at least two separate sources of limiting noise, consistent with the hypothesis of two separate mechanisms (i.e. spatial filters and local signs). A visibility dependent sigma i at the 2 min arc separation can be explained on the basis of contrast sensitive spatial filter mechanisms. A fixed sigma i at the 16 min arc separation indicates a genuine positional uncertainty, consistent with local-sign mechanisms. Interestingly, equivalent integration efficiency (k/N) is very similar at the two line separations. k/N is critically dependent on, and proportional to C, indicating a common limitation in a detection mechanism.

Depth Perception↗

PubMed2003

Spatial relationships in electrostimulation: application to electromagnetic field standards.

Spatial relationships in electrostimulation are examined with a myelinated nerve model. Excitation thresholds are determined for: 1) terminated axon within a locally constant electric field; 2) bent axon within a locally constant field; and 3) a field of finite extent over the affected axon. For application to electromagnetic field standards, the minimum excitation threshold of the in situ electric field applies to a straight, terminated axon; a field measurement averaging distance of 5 mm is recommended.

Action Potentials↗

PubMed1987

Photoreceptor processes in visual adaptation.

In this paper we have stressed two experimental results in need of explanation: (i) the reduced efficacy with which (remaining, abundant) rhodopsin in the light-adapted receptor mediates the flash response; and (ii) the disparity in conditions of irradiation (weak background vs. extensive bleaching) leading to equivalent conditions of threshold. The model discussed above suggests, in molecular terms, a possible basis for both properties of receptor adaptation. On the view developed here, property (i) derives from the ability of photoactivated or bleached pigment (R or B) to restrict dramatically the availability of a substance required for phototransduction. Property (ii) derives in large part from the pronounced disparity in the effectiveness of R (during illumination) and B (remaining after illumination) in reducing the availability of this substance. On this view, the "equivalence" of threshold elevation in states of light- vs. dark-adaptation derives from an overall equality of a product of factors (Q, Etot/Es, and J of equation 2). Under all but extreme conditions, this aggregate of factors is dominated by the term Etot/Es, reflecting the functional state of E.

Animals↗

PubMed2004

Early neuro-otologic effects of three-dimensional irradiation in children with primary brain tumors.

PURPOSE: Central nervous system (CNS) irradiation can cause sensorineural hearing loss. The relationship between the dose to the cochlea and the development of hearing loss is unknown. Conformal radiation therapy (CRT) techniques facilitate accurate cochlear dosimetry. We modeled hearing threshold levels (HTL) after CRT in children with localized primary brain tumors (ependymoma, low- or high-grade astrocytoma, craniopharyngioma, or CNS germinoma) by using cochlear dose and clinical variables. PATIENTS AND METHODS: We evaluated 72 children (median age, 9.5 years) with audiograms before and every 6 months after CRT (median follow-up, 16.6 months; range, 4.3-42.6 months). We used a mixed-effects model to predict change in hearing for each ear as a function of time, cochlear dose, and clinical variables. RESULTS: Hearing was affected the greatest in patients with CSF shunts and pre-CRT ototoxic chemotherapy, enhanced by cochlear dose, and was more prominent on the right side. Hearing impairment after CRT alone occurred at low and intermediate frequencies in patients with shunts and supratentorial tumors when the cochlear dose exceeded 32 Gy. Patients with shunts and central supratentorial tumors developed intermediate-frequency hearing loss after CRT alone regardless of dose. CONCLUSIONS: Hearing loss during the first 4 years after CRT alone is uncommon, although patients with shunts and supratentorial tumors appear to be at increased risk for low- and intermediate-frequency effects. CSF shunting and increased cochlear dose enhance the effect of ototoxic chemotherapy. If possible, the average cochlear dose should be <32 Gy over a 6-week course of treatment until more specific dose data become available.

Adolescent↗

PubMed2003

Thresholds for disease persistence in models for tick-borne infections including non-viraemic transmission, extended feeding and tick aggregation.

Lyme disease and Tick-Borne Encephalitis (TBE) are two emergent tick-borne diseases transmitted by the widely distributed European tick Ixodes ricinus. The life cycle of the vector and the number of hosts involved requires the development of complex models which consider different routes of pathogen transmission including those occurring between ticks that co-feed on the same host. Hence, we consider here a general model for tick-borne infections. We assumed ticks feed on two types of host species, one competent for viraemic transmission of infection, the second incompetent but included a third transmission route through non-viraemic transmission between ticks co-feeding on the same host. Since a blood meal lasts for several days these routes could lead to interesting nonlinearities in transmission rates, which may have important effects.We derive an explicit formula for the threshold for disease persistence in the case of viraemic transmission, also for the case of viraemic and non-viraemic transmission. From this formula, the effect of parameters on the persistence of infection can be determined. When only viraemic transmission occurs, we confirm that, while the density of the competent host has always a positive effect on infection persistence, the density of the incompetent host may have either a positive effect, by amplifying tick population, or a negative ("dilution") effect, by wasting tick bites on an incompetent host. With non-viraemic transmission, the "dilution" effect becomes less relevant. On the other hand, if the nonlinearity due to extended feeding is included, the dilution effect always occurs, but often at unrealistically high host densities. Finally, we incorporated the effects of tick aggregation on the hosts and correlation of tick stages and found that both had an important effect on infection persistence, if non-viraemic transmission occurred.

Animals↗

PubMed2003

Computerized heart allograft-recipient monitoring: a multicenter study.

Computerized heart allograft recipient monitoring (CHARM) is a unique concept of patient surveillance after heart transplantation (HTx), based on the evaluation of intramyocardial electrograms (IEGMs) recorded non-invasively with telemetric pacemakers. Previous open, single-center studies had indicated a high correlation between CHARM results and clinical findings. The present study was initiated to assess the suitability of CHARM for monitoring the absence of rejection in a blind, multicenter context. During the HTx procedure, telemetric pacemakers and two epimyocardial leads were implanted in 44 patients at four European HTx centers. IEGMs during pacing were recorded and transferred via the Internet to the CHARM computer center, for automatic data processing and extraction of diagnostically relevant information, i.e., the maximum slew rate of the descending part of the repolarization phase of the ventricular evoked response (VER T-slew). The study period comprised the first 6 months after HTx, during which the transplant centers were blind to the CHARM results. A single threshold diagnosis model was prospectively defined to assess the ability of the VER T-slew to indicate clinically significant rejection, which was defined as an endomyocardial biopsy (EMB) grade greater than or equal to 2, according to the grading system of the International Society for Heart and Lung Transplantation. All EMB slides from three centers were reviewed blind by the pathologist of the fourth center in order that agreement among the histological diagnoses at the various centers could be assessed. Totals of 839 follow-ups and 366 EMBs were obtained in 44 patients. Thirty-seven patients were alive at the end of the study period. Age at HTx, EMB grade distribution, and rejection prevalence varied significantly between the centers. Review of the EMB results showed considerable differences with respect to classification of significant rejection. Comparison of average VER T-slew values with and without rejection in the 15 patients who exhibited both states revealed significantly lower values under the influence of rejection (97+/-13% vs 79+/-15%, P<0.0001). Twenty out of the 25 cases with significant rejection were correctly identified by VER T-slew values below a threshold of 98% (sensitivity =80%, specificity =50%, negative predictive value =97%, positive predictive value =11%; P<0.0005). Of the EMBs, 48% could have been saved if the diagnosis model had been used to indicate the need for EMB. A high negative predictive value for the detection of cases with significant rejection has been obtained in a prospective, blind, multicenter study. The presented method can, therefore, be used to supplement patient monitoring after HTx non-invasively, in particular to indicate the need for EMBs. In centers with patient management similar to the ones who participated in the study, this may allow a reduction in the number of surveillance EMBs.

Decision Making, Computer-Assisted↗