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PubMed1996

Large change in voltage at phase reversal improves biphasic defibrillation thresholds. Parallel-series mode switching.

BACKGROUND: Multiple factors contribute to an improved defibrillation threshold of biphasic shocks. The leading-edge voltage of the second phase may be an important factor in reducing the defibrillation threshold. METHODS AND RESULTS: We tested two experimental biphasic waveforms with large voltage changes at phase reversal. The phase 2 leading-edge voltage was twice the phase 1 trailing-edge voltage. This large voltage change was achieved by switching two capacitors from parallel to series mode at phase reversal. Two capacitors were tested (60/15 microfarads [microF] and 90/22.5 microF) and compared with two control biphasic waveforms for which the phase 1 trailing-edge voltage equaled the phase 2 leading-edge voltage. The control waveforms were incorporated into clinical (135/135 microF) or investigational devices (90/90 microF). Defibrillation threshold parameters were evaluated in eight anesthetized pigs by use of a nonthoracotomy transvenous lead to a can electrode system. The stored energy at the defibrillation threshold (ion joules) was 8.2 +/- 1.5 for 60/15 microF (P < .01 versus 135/135 microF and 90/90 microF), 8.8 +/- 2.4 for 90/22.5 microF (P < .01 versus 135/135 microF and 90/90 microF), 12.5 +/- 3.4 for 135/135 microF, and 12.6 +/- 2.6 for 90/90 microF. CONCLUSIONS: The biphasic waveform with large voltage changes at phase reversal caused by parallel-series mode switching appeared to improve the ventricular defibrillation threshold in a pig model compared with a currently available biphasic waveform. The 60/15-microF capacitor performed as well as the 90/ 22.5-microF capacitor in the experimental waveform. Thus, smaller capacitors may allow reduction in device size without sacrificing defibrillation threshold energy requirements.

Animals↗

PubMed1996

Measuring the difference limen for identification of order of onset for complex auditory stimuli.

The approximately 20-msec perceptual threshold for identifying order of onset for components of auditory stimuli has been considered both as a possible factor contributing to the perception of voicing contrasts in speech and as no more than a methodological artifact. In the present research, we investigate the identification of the temporal order of onset of spectral components in terms of the first of a sequence of thresholds for complex stimuli (modeled after consonant-vowel [CV] syllables) that vary in degree of onset. The results provide clear evidence that the difference limen (DL) for discriminating differences in onset time follows predictions based on a fixed perceptual threshold or limit at relatively short onset differences. Furthermore, the DL seems to be a function of context coding of stimulus information, with both the DL and absolute threshold probably reflecting limits on the effective perception and coding of the short-term stimulus spectrum.

Adolescent↗

PubMed2003

Effects of exposure measurement error when an exposure variable is constrained by a lower limit.

Epidemiologic studies routinely suffer from bias due to exposure measurement error. In this paper, the authors examine the effect of measurement error when the exposure variable of interest is constrained by a lower limit. This is an important consideration, since often in epidemiologic studies an exposure variable is constrained by a lower limit such as zero or a nonzero detection limit. In this paper, attenuation of exposure-disease associations is defined within the framework of a classical model of uncorrelated additive error. Then, the special case of nonlinearity due to the effect of a lower threshold is examined. A general model is developed to characterize the effect of random measurement error when there is a lower threshold for recorded values. Findings are illustrated under the assumption that the true exposure follows the lognormal and gamma distributions. The authors show that the direction and magnitude of bias in estimated exposure-response associations depends on the population distribution of the exposure, the magnitude of the recording threshold, the value assigned to below-threshold measurement results, and the variance in the measured exposure due to random measurement error.

Bias↗

PubMed2025

Noninvasive detection and differentiation of gastric malignancy using cell-free DNA biomarkers.

INTRODUCTION: Gastric cancer remains a major global health burden, with high mortality driven by late-stage diagnoses that limit treatment options and reduce survival. Current diagnostic methods such as endoscopy and biopsy are invasive, resource-intensive, and impractical for large-scale early detection. OBJECTIVES: This study aimed to develop and validate an ensemble machine learning model integrating four cell-free DNA (cfDNA) fragmentomic feature classes derived from 5 × whole genome sequencing (WGS) data to non-invasively differentiate malignant gastric cancer from benign gastric lesions in high-risk or symptomatic patients. METHODS: A total of 681 plasma samples were prospectively collected, comprising 329 from patients with gastric cancer or high-grade intraepithelial neoplasia (HGIN) and 352 from individuals with benign gastric conditions. The dataset was divided into a training cohort (n = 333) and a temporally independent validation cohort (n = 348). An external validation cohort of 305 participants was also included. RESULTS: The ensemble model achieved an AUROC of 0.920 in cross-validation testing on the training cohort, 0.912 in the independent validation cohort, and 0.896 (95% CI 0.860-0.932) in the external cohort. At a pre-specified prediction threshold of 0.402, the model demonstrated 93.3% sensitivity and 71.9% specificity in the validation cohort, yielding a PPV of 71.3% and an NPV of 93.5%. In the external cohort, sensitivity and specificity were 91.7% and 69.1%, respectively (PPV 75.7%, NPV 88.8%). Model scores correlated with clinical stage, tumor grade, and histopathological subtype. Approximately 71% of non-cancer patients could have been spared unnecessary endoscopy. CONCLUSIONS: The cfDNA fragmentomics-based ensemble model enables accurate, non-invasive differentiation between gastric cancer and benign gastric lesions in high-risk or symptomatic patients. This approach demonstrates strong potential as a pre-endoscopy triage tool, supporting earlier detection and more efficient use of diagnostic resources.

Humans↗

PubMed2002

Simple model for 1/f(alpha) noise.

We present a simple stochastic mechanism which generates pulse trains exhibiting a power-law distribution of the pulse intervals and a 1/f(alpha) power spectrum over several decades at low frequencies with alpha close to 1. The essential ingredient of our model is a fluctuating threshold which performs a Brownian motion. Whenever an increasing potential V(t) hits the threshold, V(t) is reset to the origin and a pulse is emitted. We show that if V(t) increases linearly in time, the pulse intervals can be approximated by a random walk with multiplicative noise. Our model agrees with recent experiments in neurobiology and explains the high interpulse interval variability and the occurrence of 1/f(alpha) noise observed in cortical neurons and earthquake data.

Journal Article↗

PubMed2001

A biophysical analysis of stem and root diameter variations in woody plants.

A comprehensive model of stem and root diameter variation was developed. The stem (or root) was represented using two coaxial cylinders corresponding with the mature xylem and the extensible tissues. The extensible tissues were assumed to behave as a single cell separated from the mature xylem by a virtual membrane. The mature xylem and the extensible tissues are able to dilate with temperature and grow. Moreover, the extensible tissues are able to shrink and swell according to water flow intensity. The model is mainly based on the calculation of water volume flows in the "single cell" that are described using the principles of irreversible thermodynamics. The elastic response to storage volume and plastic extension accompanying growth are described. The model simulates diameter variation due to temperature, solute accumulation, and xylem, water potential. The model was applied to the peach (Prunus persica) stem and to the plum (Prunus domestica x Prunus spinosa) root. The simulation outputs corresponded well with the diameter variation observed. The model predicts that variations of turgor pressure and osmotic potential are smaller than the variations of xylem water potential. It also demonstrates correlations between the xylem water potential, the turgor pressure, the elastic modulus, and the osmotic potential. The relationship between the diameter and the xylem water potential exhibits a substantial hysteresis, as observed in field data. A sensitivity analysis using the model parameters showed that growth and shrinkage were highly sensitive to the initial values of the turgor pressure and to the reflection coefficient of solutes. Shrinkage and growth were sensitive to elastic modulus and wall-yielding threshold pressure, respectively. The model was not sensitive to changes in temperature.

Biophysical Phenomena↗

PubMed2003

Locomotor recovery after spinal cord contusion injury in rats is improved by spontaneous exercise.

We have recently shown that enriched environment (EE) housing significantly enhances locomotor recovery following spinal cord contusion injury (SCI) in rats. As the type and intensity of locomotor training with EE housing are rather poorly characterized, we decided to compare the effectiveness of EE housing with that of voluntary wheel running, the latter of which is both well characterized and easily quantified. Female Wistar rats were made familiar with three types of housing conditions, social housing (nine together) in an EE (EHC), individual housing in a running wheel cage (RUN, n = 8), and standard housing two together (CON, n = 10). Subsequently, a 12.5 gcm SCI at Th8 was produced and animals were randomly divided over the three housing conditions. Locomotor function was measured regularly, once a week by means of the BBB score, BBB sub score, TLH test, Gridwalk test, and CatWalk test. In the RUN group, daily distance covered was also measured. Locomotor recovery in the EHC and the RUN groups was equal and significantly better than in the CON group. The extent of recovery at 8 weeks post injury in the RUN group did not correlate with distance covered. We conclude that locomotor training needs to exceed a given threshold in order to be effective in enhancing locomotor recovery in this experimental model, but that once this threshold is exceeded no further improvement occurs, and that the specificity of locomotor training plays little role.

Animals↗

PubMed2006

Scanning for the scanner: FMRI of audition by read-out omissions from echo-planar imaging.

Echo-planar imaging (EPI) generates considerable acoustic noise by rapidly oscillating gradients. In functional magnetic resonance imaging (FMRI), unshielded EPI sounds activate the auditory system inasmuch as it is responsive. Instead of attenuating EPI noise, our goal was to utilize it for auditory FMRI by omitting read-outs from the pulse sequence's gradient train. Read-out gradient pulses are the primary noise determinant of EPI introducing its peak sound level and fundamental frequency peak which inversely relates to twice the echo spacing. Using model-driven analyses, we demonstrate that withholding read-outs from EPI is suited to reliably evoke hemodynamic blood oxygenation level-dependent (BOLD) signal modulations bilaterally in the auditory cortex of normal hearing subjects (n=60). To investigate the utility of EPI read-out omissions for auditory FMRI at an individual subject's level, we compare traditional Family-Wise-Error-Rate (FWER)-corrected maximum height thresholding to spatial mixture modeling (SMM). With the latter, appropriate bilateral auditory activations were confirmed in 95% of the individuals, whereas FWER-based voxel thresholding detected such activations in up to 72%. We illustrate the applicability of this novel EPI modification for clinical diagnostic purposes and report on a patient with bilateral large vestibular aqueducts (LVAs) and severe binaural sensorineural hearing loss (SNHL). In this particular case, read-out omissions from EPI were used to assert residual audition prior to cochlear implantation (CI). Requiring no specific task compliance or sophisticated stimulation equipment other than the scanner on its own, FMRI by read-out omissions lends itself to auditory investigations and to quickly probe audition.

Acoustic Stimulation↗

PubMed1995

Frequency selectivity and consonant recognition for hearing-impaired and normal-hearing listeners with equivalent masked thresholds.

Thresholds in notched-noise maskers (NN) and narrow-band maskers (NB) were measured for normal-hearing and hearing-impaired subject pairs who were listening in a background of spectrally shaped broadband noise (SSBB). Consonant recognition was also measured in SSBB. SSBB was adjusted so that thresholds in that noise for each normal-hearing/hearing-impaired subject pair were equal. Threshold and signal-level differences between subject pairs were minimized with the addition of threshold-elevating SSBB, and the presence of a noise background for both groups provided a comparable listening environment for all subjects. At signal frequencies outside masker passbands, thresholds in NN and NB for hearing-impaired subjects were higher than for normal-hearing subjects, although threshold differences were much smaller than observed between normal-hearing and hearing-impaired subjects without SSBB. No consistent differences in consonant recognition measured in SSBB were observed between groups. The pattern of results is comparable to that observed in a previous experiment [Dubno and Schaefer, J. Acoust. Soc. Am. 91, 2110-2121 (1992)] in which thresholds in NN and NB, and consonant recognition, for hearing-impaired listeners were compared to results obtained for normal-hearing subjects, but only normal-hearing subjects listened in SSBB. Using a modified power-law model of masking additivity, thresholds in combined-masker conditions were estimated. Masking effects for spectrally overlapping maskers were similar for normal-hearing and hearing-impaired listeners and suggest that residual differences between subject groups are not due to the presence of an additional background noise.

Audiometry, Pure-Tone↗

PubMed1978

Theory of flicker and transient responses. III. An essential nonlinearity.

From our stead-state flicker data, Kelly's (1971) model correctly predicts the transient thresholds for rectangular pulses of variable duration when the (flickering or flashed) stimulus is a 4 cycle/deg grating, but the same prediction fails for a uniform (8 degrees) field. However, if we augment the model with a "hard" nonlinearity, we can fit both types of transient thresholds as well as the steady-state thresholds. The most plausible embodiment of this essential nonlinearity is an asymmetric recifier, which seems to represent the behavior of retinal ganglion cells. Unlike the symmetric models of Roufs and Rashbass, this asymmetry also correctly predicts that the decrement thresholds for some stimuli are smaller than the corresponding increment thresholds.

Animals↗

PubMedDate not supplied

A continuous attractor network model without recurrent excitation: maintenance and integration in the head direction cell system.

Motivated by experimental observations of the head direction system, we study a three population network model that operates as a continuous attractor network. This network is able to store in a short-term memory an angular variable (the head direction) as a spatial profile of activity across neurons in the absence of selective external inputs, and to accurately update this variable on the basis of angular velocity inputs. The network is composed of one excitatory population and two inhibitory populations, with inter-connections between populations but no connections within the neurons of a same population. In particular, there are no excitatory-to-excitatory connections. Angular velocity signals are represented as inputs in one inhibitory population (clockwise turns) or the other (counterclockwise turns). The system is studied using a combination of analytical and numerical methods. Analysis of a simplified model composed of threshold-linear neurons gives the conditions on the connectivity for (i) the emergence of the spatially selective profile, (ii) reliable integration of angular velocity inputs, and (iii) the range of angular velocities that can be accurately integrated by the model. Numerical simulations allow us to study the proposed scenario in a large network of spiking neurons and compare their dynamics with that of head direction cells recorded in the rat limbic system. In particular, we show that the directional representation encoded by the attractor network can be rapidly updated by external cues, consistent with the very short update latencies observed experimentally by Zugaro et al. (2003) in thalamic head direction cells.

Action Potentials↗

PubMed2006

mGlu1 and mGlu5 receptor antagonists lack anticonvulsant efficacy in rodent models of difficult-to-treat partial epilepsy.

Modulation of metabotropic glutamate (mGlu) receptors represents an interesting new approach for the treatment of a range of neurological and psychiatric disorders. Several lines of evidence suggest that functional blockade of group I (mGlu1 and mGlu5) receptors may be beneficial for treatment of epileptic seizures. This study was conducted to investigate whether mGlu1 or mGlu5 receptor antagonists have the potential to block partial or secondarily generalized seizures as occurring in partial epilepsy, the most common and difficult-to-treat type of epilepsy in patients. For this purpose, we systemically administered novel highly selective and brain penetrable group I mGlu receptor antagonists, i.e., the mGlu1 receptor antagonist EMQMCM [3-ethyl-2-methyl-quinolin-6-yl-(4-methoxy-cyclohexyl)-methanone methanesulfonate] and the mGlu5 receptor antagonist MTEP ([(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine), at doses appropriate for mGlu1 or mGlu5 receptor-mediated effects in rodent models of partial seizures. Two models were used: the 6-Hz electroshock model of partial seizures in mice and the amygdala-kindling model in rats. Clinically established antiepileptic drugs were included in the experiments for comparison. Antiepileptic drugs exerted significant anticonvulsant effects in both models, while EMQMCM and MTEP were ineffective in this regard, although both compounds were administered up to doses associated with essentially full receptor occupancy and with typical mGlu receptor-mediated effects in rodent models of anxiety or pain. Brain microdialysis for determining extracellular levels of MTEP following i.p. administration in rats substantiated that effective brain concentrations were reached at times of our experiments in seizure models. The present results do not support a significant anticonvulsant potential of group I mGlu receptor antagonists in rodent models of difficult-to-treat partial epilepsy.

Animals↗

PubMed2005

Detection of pulses in a colored noise setting.

Cortical neurons are exposed to a considerable amount of synaptic background activity, which increases the neurons' conductance and which leads to a fluctuating membrane potential. Here we investigate how the presence and the properties of this background noise influence the ability of a neuron to detect transient inputs, a task that is important for coincidence detection as well as for the detection of synchronous spiking events in a neural system. Using a leaky integrate-and-fire neuron as well as a biologically more realistic Hodgkin-Huxley type point neuron we find that noise enhances the detection of subthreshold input pulses and that the phenomenon of stochastic resonance occurs. When the noise is colored, pulse detection becomes more robust, because the number of false positive events decreases with increasing temporal correlation while the number of correctly detected events is almost unaffected. Therefore, the optimal variance of the noise also changes with the degree of temporal correlations of the background activity. For the integrate-and-fire model these effects can be described using an ansatz by Brunel and Sergi [J. Theor. Biol. 195, 87 (1998)]. Numerical simulations show that the leaky integrate-and-fire model and the Hodgkin-Huxley type point neuron behave qualitatively similarly.

Action Potentials↗

PubMed1998

Interactions between implantable cardioverter-defibrillators and class III agents.

Although implantable cardioverter-defibrillators (ICDs) can successfully terminate ventricular arrhythmias, antiarrhythmic drugs are often required to prevent recurrent events. Class III antiarrhythmic agents have emerged as the safest, most effective, and widely used agents in the 40-70% of ICD patients who require concomitant antiarrhythmic medication. Antiarrhythmic agents can influence the effectiveness of ICDs to terminate arrhythmias through their effect on defibrillation threshold. All class III agents share the ability to prolong ventricular refractoriness and those with "pure" class III activity consistently decrease defibrillation threshold in the normal canine heart model. Sotalol, amiodarone, and bretylium all have other Vaughan Williams class actions that influence their respective effects on defibrillation threshold. Sotalol has been associated with a decrease in defibrillation threshold in both animal and in clinical studies, whereas amiodarone has been associated with variable effects in animal models and an increase in defibrillation threshold in clinical studies. Additionally, antiarrhythmic agents may prolong ventricular tachycardia (VT) cycle length, which may affect the ability to pace terminate or cardiovert VT. Amiodarone has a moderate slowing effect on the VT cycle length. Finally, class III drugs also have proarrhythmic potential that may affect the defibrillator's function. Sotalol can be associated with dose-related torsade de pointes, whereas amiodarone may slow the VT cycle length below the tachycardia detection rate cutoff. In conclusion, class III pharmacotherapy can be safely administered in conjunction with ICD therapy as long as the interaction between these therapeutic modalities is appreciated.

Amiodarone↗

PubMed2006

Genetic and environmental contributions to depressive personality disorder in a population-based sample of Norwegian twins.

BACKGROUND: Depressive personality disorder (DPD) was introduced in DSM-IV as a new category requiring further study. The aim of this study was to estimate genetic and environmental contributions to DPD in a population-based twin sample, and include data on criteria performance, prevalence and diagnostic overlap. METHODS: Axis I and Axis II diagnoses were obtained by structured interviews in a population-based sample of 2794 young adult twins. Statistical analyses included correlation and factor analysis based on polychoric correlation coefficients, and diagnostic overlap applying adjusted odds ratios. Contributions from additive genetic and common and unique environmental influences to the liability to DPD were computed using structural equation modelling, applying a multiple threshold variable. RESULTS: Liability to DPD could best be explained by additive genetic and unique environmental factors, with heritability estimates of 49% (95% CI 0.41-0.57) in females and 25% (95% CI 0.12-0.40) in males. The best-fitting model indicated that some of the genes contributing to DPD differ between men and women. Chronbach's alpha was 0.87. 2.0% of participants fulfilled the criteria for DPD, and overlap was most pronounced for dysthymic disorder and avoidant personality disorder. LIMITATIONS: Low prevalence rates and subsequent inclusion of subthreshold criteria could have influenced parameter estimates, especially in males. CONCLUSIONS: DPD was almost twice as heritable in females as in males, comparable to previous studies on major depression. The proposed criteria showed good measurement properties, and DPD was not completely subsumed within any other disorder.

Adult↗

PubMed2001

Cooperation in the dark: signalling and collective action in quorum-sensing bacteria.

The study of quorum-sensing bacteria has revealed a widespread mechanism of coordinating bacterial gene expression with cell density. By monitoring a constitutively produced signal molecule, individual bacteria can limit their expression of group-beneficial phenotypes to cell densities that guarantee an effective group outcome. In this paper, we attempt to move away from a commonly expressed view that these impressive feats of coordination are examples of multicellularity in prokaryotic populations. Here, we look more closely at the individual conflict underlying this cooperation, illustrating that, even under significant levels of genetic conflict, signalling and resultant cooperative behaviour can stably exist. A predictive two-trait model of signal strength and of the extent of cooperation is developed as a function of relatedness (reflecting multiplicity of infection) and basic population demographic parameters. The model predicts that the strength of quorum signalling will increase as conflict (multiplicity of infecting strains) increases, as individuals attempt to coax more cooperative contributions from their competitors, leading to a devaluation of the signal as an indicator of density. Conversely, as genetic conflict increases, the model predicts that the threshold density for cooperation will increase and the subsequent strength of group cooperation will be depressed.

Bacterial Physiological Phenomena↗

PubMed1993

An application of mechanostat theory to research design: a theoretical model.

In this paper a theoretical model for research into the area of bone health is proposed. The model is based on the mechanostat theory of bone biology, originally proposed by Harold M. Frost, and is directed toward research in the area of osteoporosis. The mechanostat theory is briefly reviewed, including the concept of changes in minimum effective strain thresholds. Each of the model's five levels is then detailed, followed by discussion of their application to research design and interpretation. The proposed research model may provide a systematic approach to research design, and thereby a method to increase the current understanding of bone biology.

Biomechanical Phenomena↗

PubMed1996

Test of a model of foveal vision by using simulations.

The appearance of four different images from three different distances was simulated by using the individual contrast sensitivity functions (CSF's) of normally sighted observers. The simulations were generated by using the observers' CSF's as a threshold in a pyramidal vision model of band-limited local contrast [J. Opt. Soc. Am A 7, 2030 (1990)]. Simulations based on CSF's obtained in an orientation discrimination task underestimated the observer's sensitivity in discriminating the images. Simulations based on CSF's obtained in a detection task provided a good estimate of observer's performance. The testing method was shown to be sensitive enough to be affected by the high-frequency residual, which is frequently ignored in visual models and simulations. An image-dependence effect found when the high-frequency residual was present was eliminated when the residual artifact was removed. The simulations based on the pyramidal vision model accurately predicted the distance at which they were discriminated from the original image, and thus this model may also serve as the basis for image-quality metrics. The testing method developed can also be used to determine the type of CSF that best represents observer performance in a task.

Computer Simulation↗