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PubMed2026

Development and validation of a plasma miRNA-CEA biomarker panel for early detection of lung cancer.

Lung cancer remains a leading cause of cancer-related mortality worldwide, underscoring the critical need for early detection to improve patient outcomes. This study aimed to develop and validate a plasma microRNA biomarker panel for the early detection of non-small cell lung cancer in a Japanese cohort. We enrolled 525 participants, comprising 261 LC cases and 264 non-LC controls, divided into optimization and validation cohorts. A 12-miRNA panel was optimized and further combined with CEA to enhance diagnostic performance. The miRNA-alone model demonstrated robust performance in both the optimization (AUC = 77.0%) and validation cohorts (AUC = 77.9%). Integration with CEA significantly improved accuracy, achieving AUCs of 86.2% in optimization and 84.9% in validation, with particularly high performance in late-stage cancers (AUC = 94.4%) and squamous cell carcinoma (AUC = 90.7%). Sensitivity and specificity thresholds were evaluated, enabling model customization for diverse clinical scenarios. These findings highlight the potential of the miRNA-CEA panel as a minimally invasive tool for early LC detection, especially in non-smoking populations.

Humans↗
PubMed2005

Signal-to-noise ratio gain of a noisy neuron that transmits subthreshold periodic spike trains.

The transmission properties of an integrate-and-fire neuron model that transmits coherent subthreshold spike trains in a shot noise environment are investigated by numerical simulation. For very weak coherent couplings, it is shown that the input-output signal-to-noise ratio (SNR) gain is easier to exceed unity; while for stronger coherent couplings it is difficult to observe the SNR gain larger than unity at the optimal noise intensity. These observations are different from those acquired in the case of continuous noise. Our analysis further suggests that the larger SNR gain in the very weak coherent coupling case should be due to the noise-induced resonance. It is also shown that there is more possibility of the SNR gain above unity for slower periodic spike trains transmitted by the model. The results may be useful in understanding the performance of real noisy neurons acting as signal-processing elements.

Action Potentials↗
PubMed1999

Implications of relaxation dynamics in the synaptic control of olfactory cortex activity.

In a previous work (Ballain et al., 1998. Biol. Cyber. 79, 323-336) we reported the analysis of a model for the piriform cortex activity in rats based on experimental data. In this paper, we study an extension of this model by supplementing it with equations for the post-synaptic conductance and/or the pre-synaptic activation threshold. We use the present model's outputs to account for experimental data based on paired stimulation in the opossum or the rat, obtained either through electrical recording or optical mapping of the cortex activity. The model exhibits great robustness when it comes to large variation in synaptic characteristics. Model outputs mimic satisfactorily the three kind of responses to paired stimuli (Litaudon and Cattarelli, 1996. Eur. J. Neurosci. 8, 21-29) and the recovery of the excitable capacities as demonstrated by Haberly (1973. J. Neurophysiol. 36 (4), 789-802) and Ferreyra-Moyano et al. (1985. Brain Res. Bull. 15, 237 248).

Animals↗
PubMed1985

Importance of the pacing mode in the initiation of ventricular tachyarrhythmia in a canine model of chronic myocardial infarction.

The use of unipolar anodal or bipolar pacing, as compared with unipolar cathodal pacing, purportedly increases the likelihood of inducing inadvertent ventricular fibrillation in susceptible patients. In this study, the ability to initiate sustained ventricular tachycardia or fibrillation with unipolar cathodal, unipolar anodal and bipolar pacing modes was compared using programmed ventricular stimulation at 82 subendocardial periinfarction sites in 11 dogs with chronic myocardial infarction. The late diastolic excitability threshold was significantly higher and the ventricular refractory period was significantly shorter (p less than 0.001) with anodal pacing (mean 0.62 mA, 156 ms, respectively) than with pacing in either the cathodal (0.12 mA, 174 ms) or the bipolar (0.13 mA, 173 ms) mode. At a current intensity twice that of the excitability threshold, the introduction of one or two extrastimuli induced ventricular tachycardia and ventricular fibrillation comparably among the three pacing modes. However, when three extrastimuli were used, ventricular fibrillation was induced with anodal pacing twice as frequently (50 [61%] of 82 sites) as with either of the other two pacing modes (each 23 [28%] of 82 sites, p less than 0.001), whereas the induction of ventricular tachycardia remained comparable with anodal pacing (15 [18%] of 82 sites) and cathodal and bipolar pacing (each 14 [17%] of 82 sites). Furthermore, a similarly high incidence of inducibility of ventricular fibrillation was observed with both cathodal pacing (56 [68%] of 82 sites) and bipolar pacing (40 [49%] of 82 sites) when an increased current equal to twice the anodal excitability threshold (1.23 mA) was used.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

ECT: Clinical Variables, Seizure Duration, and Outcome.

The ability to predict treatment response in patients administered electroconvulsive therapy remains limited. Variables such as the duration of the individual seizure or the cumulative seizure duration have been reported to relate to outcome in a "threshold" or "therapeutic window" model. In this study, total seizure time, as measured by bifrontal electroencephalogram (EEG) electrodes, did correlate with outcome (r(s) = 0.43, p < 0.01). In addition, 88% of patients with a cumulative seizure time exceeding 300 s responded favorably (chi(2) = 6.80, p < 0.01). This provides support for the concept of a minimum threshold of accumulated seizure time necessary for clinical response. However, no evidence of an upper limit of benefit suggesting a "therapeutic window" was found.

Journal Article↗
PubMed2004

Ultra-low dose naltrexone potentiates the anticonvulsant effect of low dose morphine on clonic seizures.

Significant potentiation of analgesic effects of opioids can be achieved through selective blockade of their stimulatory effects on intracellular signaling pathways by ultra-low doses of opioid receptor antagonists. However, the generality and specificity of this interaction is not well understood. The bimodal modulation of pentylenetetrazole-induced seizure threshold by opioids provide a model to assess the potential usefulness of this approach in seizure disorders and to examine the differential mechanisms involved in opioid anti- (morphine at 0.5-3 mg/kg) versus pro-convulsant (20-100 mg/kg) effects. Systemic administration of ultra-low doses of naltrexone (100 fg/kg-10 ng/kg) significantly potentiated the anticonvulsant effect of morphine at 0.5 mg/kg while higher degrees of opioid receptor antagonism blocked this effect. Moreover, inhibition of opioid-induced excitatory signaling by naltrexone (1 ng/kg) unmasked a strong anticonvulsant effect for very low doses of morphine (1 ng/kg-100 microg/kg), suggesting that a presumed inhibitory component of opioid receptor signaling can exert strong seizure-protective effects even at very low levels of opioid receptor activation. However, ultra-low dose naltrexone could not increase the maximal anticonvulsant effect of morphine (1-3 mg/kg), possibly due to a ceiling effect. The proconvulsant effects of morphine on seizure threshold were minimally altered by ultra-low doses of naltrexone while being completely blocked by a higher dose (1 mg/kg) of the antagonist. The present data suggest that ultra-low doses of opioid receptor antagonists may provide a potent strategy to modulate seizure susceptibility, especially in conjunction with very low doses of opioids.

Animals↗
PubMed1992

A note on neuronal firing and input variability.

The Ornstein-Uhlenbeck process with a constant forcing function has often been used as a model for the subthreshold membrane potential of a neuron. The mean, variance and coefficient of variation of the first passage time to a constant threshold are examined for this model in the limit of small synaptic noise and low thresholds. A comparison is made between the asymptotic results of Wan & Tuckwell, who used perturbation analysis, and several computationally simpler approximation methods. A generalization of Stein's method gives an overestimate of the mean interval while an approximation by a Wiener process with linear drift gives an underestimate of the mean interval. These bounds are simple to calculate and can be used as a prelude to a more detailed perturbation analysis.

Animals↗
PubMed1998

Finite element analysis of defibrillation fields in a human torso model for ventricular defibrillation.

In order to optimize defibrillation electrode systems for ventricular defibrillation thresholds (DFTs), a Finite Element Torso model was built from fast CT scans of a patient who had large cardiac dimensions (upper bound of normal) but no heart disease. Clinically used defibrillation electrode configurations, i.e. Superior Vena Cava (SVC) to Right Ventricle (RV) (SVC-RV), left pectoral Can to RV (Can-RV) and Can + SVC-RV, were analyzed. The DFTs were calculated based on 95% ventricular mass having voltage gradient > 5 V/cm and these results were also compared with clinical data. The low voltage gradient regions with voltage gradient < 5 V/cm were identified and the effect of electrode dimension and location on DFTs were also investigated for each system. A good correlation between the model results and the clinical data supports the use of Finite Element Analysis of a human torso model for optimization of defibrillation electrode systems. This correlation also indicates that the critical mass hypothesis is the primary mechanism of defibrillation. Both the FEA results and the clinical data show that Can + SVC-RV system offers the lowest voltage DFTs when compared with SVC-RV and Can-RV systems. Analysis of the effect of RV, SVC and Can electrode dimensions and locations can have an important impact on defibrillation lead designs.

Computational Biology↗
PubMed1994

A comparison of normal and nonnormal mixed models for number of lambs born in Norwegian sheep.

A comparison of linear (LM), threshold (TM), and Poisson (PM) mixed models for genetic analysis of number of lambs born (NLB) from 1-yr-old ewes was conducted using 37,718 and 18,633 records of two Norwegian breeds, Dala and Spaelsau, respectively. Models fitted included flock-year as a fixed effect and the random effect of sire. In the Poisson model, the residual variation was assumed to be Poisson, whereas it was normal in LM and multinomial in TM. The models were compared with respect to goodness of fit, predictive ability, and ranking of sires. Goodness of fit and predictive ability were assessed via the mean squared error and the correlation between observed NLB and fitted (predicted) values. Predictive ability was evaluated by estimating effects of sire and flock-year using a random half of the data and then using these estimates to predict records on the other half of the data. The heritability of NLB for Dala was estimated to be .20, .39, and .08 with LM, TM, and PM, respectively. For Spaelsau, corresponding estimates were .12, .26, and .00, respectively. In the PM, problems of low or zero estimates of sire variances were encountered. Hence, an alternative sire variance (PM-L) was approximated from the heritability estimated on the outward scale by REML. All models performed similarly with respect to goodness of fit, predictive ability, and ranking of sires. The TM was very slightly better for both breeds, but the PM and PM-L seemed clearly poorer than TM and LM. An approximate test rejected the hypothesis that the conditional distribution of NLB was Poisson.

Animals↗
PubMed2004

From innervation density to tactile acuity: 1. Spatial representation.

We tested the hypothesis that the population receptive field representation (a superposition of the excitatory receptive field areas of cells responding to a tactile stimulus) provides spatial information sufficient to mediate one measure of static tactile acuity. In psychophysical tests, two-point discrimination thresholds on the hindlimbs of adult cats varied as a function of stimulus location and orientation, as they do in humans. A statistical model of the excitatory low threshold mechanoreceptive fields of spinocervical, postsynaptic dorsal column and spinothalamic tract neurons was used to simulate the population receptive field representations in this neural population of the one- and two-point stimuli used in the psychophysical experiments. The simulated and observed thresholds were highly correlated. Simulated and observed thresholds' relations to physiological and anatomical variables such as stimulus location and orientation, receptive field size and shape, map scale, and innervation density were strikingly similar. Simulated and observed threshold variations with receptive field size and map scale obeyed simple relationships predicted by the signal detection model, and were statistically indistinguishable from each other. The population receptive field representation therefore contains information sufficient for this discrimination.

Animals↗
PubMed1985

Receptive-field symmetry probed using converging gratings.

Contrast-sensitivity functions (CSF's) for converging and diverging gratings were obtained under voluntary fixation at several field widths and under retinal stabilization at one field width. In general, these types of gratings had similar CSF's at all temporal frequencies tested, a result that can be explained by plausible spatiotemporal receptive-field models possessing spatial antisymmetry but not by models possessing pure (even) spatial symmetry. Phase condition at the central line in converging and diverging gratings affected grating detectability at high spatial frequencies, as expected.

Differential Threshold↗
PubMed2004

Using decision modeling to determine pricing of new pharmaceuticals: the case of neurokinin-1 receptor antagonist antiemetics for cancer chemotherapy.

OBJECTIVES: Decision analysis is commonly used to perform economic evaluations of new pharmaceuticals. The outcomes of such studies are often reported as an incremental cost per quality-adjusted life year (QALY) gained with the new agent. Decision analysis can also be used in the context of estimating drug cost before market entry. The current study used neurokinin-1 (NK-1) receptor antagonists, a new class of antiemetics for cancer patients, as an example to illustrate the process using an incremental cost of dollars Can20,000 per QALY gained as the target threshold. METHODS: A decision model was developed to simulate the control of acute and delayed emesis after cisplatin-based chemotherapy. The model compared standard therapy with granisetron and dexamethasone to the same protocol with the addition of an NK-1 before chemotherapy and continued twice daily for five days. The rates of complete emesis control were abstracted from a double-blind randomized trial. Costs of standard antiemetics and therapy for breakthrough vomiting were obtained from hospital sources. Utility estimates characterized as quality-adjusted emesis-free days were determined by interviewing twenty-five oncology nurses and pharmacists by using the Time Trade-Off technique. These data were then used to estimate the unit cost of the new antiemetic using a target threshold of dollars Can20,000 per QALY gained. RESULTS: A cost of dollars Can6.60 per NK-1 dose would generate an incremental cost of dollars Can20,000 per QALY. The sensitivity analysis on the unit cost identified a range from dollars Can4.80 to dollars Can10.00 per dose. For the recommended five days of therapy, the total cost should be dollars Can66.00 (dollars Can48.00-dollars Can100.00) for optimal economic efficiency relative to Canada's publicly funded health-care system. CONCLUSIONS: The use of decision modeling for estimating drug cost before product launch is a powerful technique to ensure value for money. Such information can be of value to both drug manufacturers and formulary committees, because it would facilitate negotiations for optimal pricing in a given jurisdiction.

Antiemetics↗
PubMed2005

Interleukin-1beta contributes to the generation of experimental febrile seizures.

Fever can provoke "febrile" seizures (FS). Because complex FS may promote development of temporal lobe epilepsy, understanding their mechanisms is clinically important. Using an immature rodent model and transgenic technology, we examined the role of interleukin-1beta, (IL-1beta), a pyrogenic, proinflammatory cytokine, in FS. IL-1beta receptor-deficient mice were resistant to experimental FS. This resistance appeared independent of genetic background and was attributed to lack of IL-1beta signaling, because exogenous cytokine reduced seizure threshold in wild-type but not receptor-deficient mice independent of strain. In addition, high IL-1beta doses induced seizures only in IL-1beta receptor-expressing mice. These data indicate that IL-1beta signaling contributes critically to fever-induced hyperexcitability underlying FS, constituting a potential target for their prevention.

Animals↗
PubMed1994

Modelling of parasitic populations: cestodes.

The philosophy of mathematical modelling as it applies to the epidemiology of cestode populations is reviewed. A model provides, via the "threshold theorem", a criterion for deciding in advance if a control programme can succeed in eradicating the parasite. In order to use this criterion it is necessary to have an estimate of the basic reproduction ratio, R0, which can only be obtained if reliable epidemiological data are available before the control programme is started. A model has been used to describe the population dynamics of Echinococcus granulosus, Taenia hydatigena and Taenia ovis in sheep and dogs in New Zealand. For these parasites, data from a 40-year longitudinal study, as well as short-term field and laboratory studies, were available. A model has also been used to evaluate a proposed control programme directed against Echinococcus multilocularis in foxes and voles in France. Here the type and extent of control intervention is predetermined by the existing rabies control programme. These two examples, which demonstrate the different techniques required to model cestodes in domestic and wild-animal populations, are reviewed, and the use of a model as the basis for a benefit/cost analysis of control options is discussed. These techniques could, in principal, be used to design control programmes for Taenia saginata or Taenia solium in humans.

Animals↗
PubMed1999

Cost-effectiveness of treatment for threshold retinopathy of prematurity.

OBJECTIVE: Retinopathy of prematurity (ROP) is a leading cause of adverse visual outcomes in premature infants. Both laser photocoagulation and cryotherapy have been demonstrated in clinical trials to be efficacious in reducing the incidence of visual loss occurring secondary to threshold ROP. Visual data recently have become available concerning the long-term clinical efficacy of both treatments, as have data concerning the utility value of visual states in general. Accordingly, we undertook an analysis to ascertain the cost-effectiveness of laser photocoagulation and cryotherapy in the treatment of threshold ROP. DESIGN: A computer simulation economic model is presented to evaluate the cost-effectiveness of cryotherapy and laser photocoagulation therapy, compared with the natural course of the disease, for treating premature infants with threshold ROP. The model applies long-term visual data from previous clinical trials, utility analysis, decision analysis, and economic principles, such as present value analysis, to account for the time value of money to arrive at a cost per quality-adjusted life-year (QALY) gained. OUTCOME MEASURES: Cost per QALY gained from laser therapy and cryotherapy. RESULTS: Laser photocoagulation therapy for threshold ROP costs $678 1998 US dollars (at a 3% discount rate to account for the time value of money) for each QALY gained from treatment. Cryotherapy for the same disease costs $1801 per QALY at a similar discount rate. CONCLUSIONS: From the point of view of cost-effectiveness, laser therapy seems to have an advantage over cryotherapy for the treatment of threshold ROP.

Computer Simulation↗
PubMedDate not supplied

Early experience as a determinant of adult behavioural responses to reward: the effects of repeated maternal separation in the rat.

Depression is a major public health concern, representing one of the most significant causes of disability and morbidity. Despite significant advances in the definition of specific cognitive, emotional and neural dysfunctions that are associated with depression, there has been frustratingly little progress in the elucidation of plausible aetiological and pathophysiological mechanisms. The complex, multi-system dysfunctions of depressive illness do not lend themselves to hypothesis-driven, systematic manipulation in patients. For this reason, there is a need to develop valid and reliable models of affective psychopathology in laboratory animals. In this paper, we review briefly some of our previous work demonstrating that a specific periodic neonatal maternal separation procedure leads to a robust constellation of behavioural changes in the adult rat that resemble core aspects of human depressive psychopathology. We also present data from a study of the adult effects of the same manipulation on electrical intracranial self-stimulation behaviour. These data further support the hypothesis that it is possible to model vulnerability to anhedonia in the adult rat by manipulation of early experience.

Adult↗
PubMedDate not supplied

Direction selectivity in a model of the starburst amacrine cell.

The starburst amacrine cell (SBAC), found in all mammalian retinas, is thought to provide the directional inhibitory input recorded in On-Off direction-selective ganglion cells (DSGCs). While voltage recordings from the somas of SBACs have not shown robust direction selectivity (DS), the dendritic tips of these cells display direction-selective calcium signals, even when gamma-aminobutyric acid (GABAa,c) channels are blocked, implying that inhibition is not necessary to generate DS. This suggested that the distinctive morphology of the SBAC could generate a DS signal at the dendritic tips, where most of its synaptic output is located. To explore this possibility, we constructed a compartmental model incorporating realistic morphological structure, passive membrane properties, and excitatory inputs. We found robust DS at the dendritic tips but not at the soma. Two-spot apparent motion and annulus radial motion produced weak DS, but thin bars produced robust DS. For these stimuli, DS was caused by the interaction of a local synaptic input signal with a temporally delayed "global" signal, that is, an excitatory postsynaptic potential (EPSP) that spread from the activated inputs into the soma and throughout the dendritic tree. In the preferred direction the signals in the dendritic tips coincided, allowing summation, whereas in the null direction the local signal preceded the global signal, preventing summation. Sine-wave grating stimuli produced the greatest amount of DS, especially at high velocities and low spatial frequencies. The sine-wave DS responses could be accounted for by a simple mathematical model, which summed phase-shifted signals from soma and dendritic tip. By testing different artificial morphologies, we discovered DS was relatively independent of the morphological details, but depended on having a sufficient number of inputs at the distal tips and a limited electrotonic isolation. Adding voltage-gated calcium channels to the model showed that their threshold effect can amplify DS in the intracellular calcium signal.

Amacrine Cells↗