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PubMed1995

1995 Volvo Award in basic sciences. The use of an osteoinductive growth factor for lumbar spinal fusion. Part II: Study of dose, carrier, and species.

STUDY DESIGN: Efficacy of a bovine-derived osteoinductive growth factor was studied in a rabbit model and in a nonhuman primate model of posterolateral lumbar spinal fusion. OBJECTIVES: To determine the minimum effective dose of growth factor and the influence of different carrier material on the outcome of intertransverse process lumbar fusion. SUMMARY OF BACKGROUND DATA: Bone morphogenetic proteins and related growth factors are becoming increasingly available in purified extract or genetically engineered forms and are capable of inducing new bone formation in vivo. Osteoinductive growth factors to enhance lumbar spinal infusion have not been well studied in models of posterolateral intertransverse process fusion. Because of the diminished potential of bone regeneration in primates (including humans) compared with phylogenetically lower animals, extrapolations regarding dose and efficacy cannot be made directly from results obtained in experiments performed on phylogenetically lower animals. Experiments on non-human primates are a critical step before attempting to use these growth factors on humans. METHODS. One hundred fifteen adult New Zealand white rabbits and 10 adult rhesus macaques underwent single level posterolateral intertransverse process lumbar spinal arthrodesis to evaluate different doses and carrier materials for a bovine-derived osteoinductive bone protein extract. Rabbit fusion masses were evaluated 5 weeks after arthrodesis by manual palpation, radiography, biomechanical testing, and light microscopy. Monkey fusion masses were evaluated 12 weeks after arthrodesis by radiography and light microscopy. RESULTS: Successful posterolateral intertransverse process spinal fusions were achieved in the rabbit models using an osteoinductive growth factor with three different carriers (autogenous iliac bone, demineralized allogeneic bone matrix, and natural coral). There was a dose-dependent response to the osteoinductive growth factor in the rabbit model, indicating that a threshold must be overcome before bone formation is induced. The methodology for biologic enhancement of spinal fusion developed in the rabbit model transferred successfully to the rhesus monkey, where the use of the osteoinductive growth factor with a demineralized bone matrix carrier resulted in spinal fusion in 12 weeks. CONCLUSION: These experiments provide an essential building block in the understanding of the biology of spinal fusion and the use of osteoinductive growth factors to enhance a posterolateral intertransverse process spinal fusion. The achievement of posterolateral spinal fusion in the rhesus monkey using an osteoinductive growth factor is a significant step toward the biologic enhancement of spinal fusion in humans.

Animals↗
PubMed2006

Virtual pitch in a computational physiological model.

A computational model of nervous activity in the auditory nerve, cochlear nucleus, and inferior colliculus is presented and evaluated in terms of its ability to simulate psychophysically-measured pitch perception. The model has a similar architecture to previous autocorrelation models except that the mathematical operations of autocorrelation are replaced by the combined action of thousands of physiologically plausible neuronal components. The evaluation employs pitch stimuli including complex tones with a missing fundamental frequency, tones with alternating phase, inharmonic tones with equally spaced frequencies and iterated rippled noise. Particular attention is paid to differences in response to resolved and unresolved component harmonics. The results indicate that the model is able to simulate qualitatively the related pitch-perceptions. This physiological model is similar in many respects to autocorrelation models of pitch and the success of the evaluations suggests that autocorrelation models may, after all, be physiologically plausible.

Auditory Threshold↗
PubMed1981

Kindling in developing rats: variability of afterdischarge thresholds with age.

In the kindling model, the occurrence of afterdischarges is necessary for the development of seizures. In this study, the afterdischarge thresholds of the amygdala were determined in rats of 4 different age groups, beginning with 15-day-old suckling rats. Afterdischarges were triggered in 75% of the suckling rats and in all of the rats in the older age groups. The afterdischarge thresholds varied with age, being highest in the suckling group, lowest in the 35-day-old group and intermediate in the older groups. This variability of the thresholds did not correlate with the alterations in the catecholamine levels in the amygdala that occur during maturation. The failure of 25% of suckling rats to develop afterdischarges may explain why some suckling rats do not kindle.

Aging↗
PubMed2002

Near-threshold reflectivity fluctuations in the independent-convective-hot-spot-model limit of a spatially smoothed laser beam.

In the framework of the independent-hot-spot model, it is shown that the reflectivity resulting from scattering instabilities when a spatially smoothed laser beam interacts with a plasma exhibits large statistical fluctuations near threshold. The importance of the fluctuations is discussed in terms of a confidence interval for the reflectivity, which is more relevant to experimental measurements than the average reflectivity. An analytical model for the fluctuating reflectivity is developed and shown to be in good agreement with numerical simulations. The influence of the transverse size of the interaction region is studied.

Journal Article↗
PubMed1989

Models of the additivity of masking.

Three models of masking additivity are reviewed, which are referred to as the high-compression model [M. J. Penner, J. Acoust. Soc. Am. 67, 608-616 (1980); M. J. Penner and R. M. Shiffrin, J. Acoust. Soc. Am. 67, 617-627 (1980)], the power-law model [R. A. Lutfi, J. Acoust. Soc. Am. 73, 262-267 (1983); 80, 422-428 (1986)], and the modified power-law model with compressed internal noise [Humes et al., J. Acoust. Soc. Am. 83, 188-202 (1988)]. While the high-compression model was derived from data for two or more nonsimultaneous maskers and the power-law model was derived from data for two or more simultaneous maskers, the modified power-law model can be applied to both cases. The modified power-law model assumes that the threshold in quiet is equivalent to a masked threshold resulting from an internal noise that is continually present. Additional assumptions concern the interaction of two maskers prior to the addition of the masking effects. Most of the data on the additivity of masking are well described by the modified power-law model, regardless of the nature of the maskers. Thus the model provides a good description of data for combined simultaneous maskers and combined nonsimultaneous maskers, a task heretofore requiring the use of at least two separate and independently developed models.

Auditory Threshold↗
PubMed2004

A base triple in the Tetrahymena group I core affects the reaction equilibrium via a threshold effect.

Previous work on group I introns has suggested that a central base triple might be more important for the first rather than the second step of self-splicing, leading to a model in which the base triple undergoes a conformational change during self-splicing. Here, we use the well-characterized L-21 ScaI ribozyme derived from the Tetrahymena group I intron to probe the effects of base-triple disruption on individual reaction steps. Consistent with previous results, reaction of a ternary complex mimicking the first chemical step in self-splicing is slowed by mutations in this base triple, whereas reaction of a ternary complex mimicking the second step of self-splicing is not. Paradoxically, mechanistic dissection of the base-triple disruption mutants indicates that active site binding is weakened uniformly for the 5'-splice site and the 5'-exon analog, mimics for the species bound in the first and second step of self-splicing. Nevertheless, the 5'-exon analog remains bound at the active site, whereas the 5'-splice site analog does not. This differential effect arises despite the uniform destabilization, because the wild-type ribozyme binds the 5'-exon analog more strongly in the active site than in the 5'-splice site analog. Thus, binding into the active site constitutes an additional barrier to reaction of the 5'-splice site analog, but not the 5'-exon analog, resulting in a reduced reaction rate constant for the first step analog, but not the second step analog. This threshold model explains the self-splicing observations without the need to invoke a conformational change involving the base triple, and underscores the importance of quantitative dissection for the interpretation of effects from mutations.

Animals↗
PubMed2006

A study of crop-to-crop gene flow using farm scale sites of fodder maize (Zea mays L.) in the UK.

From 2000 to 2003 a range of Farm Scale Evaluation (FSE) trials were established in the UK to assess the effect of the release and management of herbicide tolerant (HT) crops on arable weeds and invertebrates. The FSE trials for maize were also used to investigate crop-to-crop gene flow and to develop a statistical model for the prediction of gene flow frequency that can be used to evaluate current separation distance guidelines for GM crops. Seed samples were collected from the non-GM half of 55 trial sites and 1,055 were tested for evidence of gene flow from the GM HT halves using a quantitative PCR assay specific to the HT (pat) gene. Rates of gene flow were found to decrease rapidly with increasing distance from the GM source. Gene flow was detected in 30% of the samples (40 out of 135) at 150 m from the GM source and events of GM to non-GM gene flow were detected at distances up to and including 200 m from the GM source. The quantitative data were subjected to statistical analysis and a two-step model was found to provide the best fit for the data. A dynamic whole field model predicted that a square field (150 m x 150 m in size) of grain maize would require a separation distance of 3 m for the adjacent crop to be below a 0.9% threshold (with <2% probability of exceeding the threshold). The data and models presented here are discussed in the context of necessary separation distances to achieve various possible thresholds for adventitious presence of GM in maize.

Agriculture↗
PubMedDate not supplied

Decision curve analysis: a novel method for evaluating prediction models.

BACKGROUND: Diagnostic and prognostic models are typically evaluated with measures of accuracy that do not address clinical consequences. Decision-analytic techniques allow assessment of clinical outcomes but often require collection of additional information and may be cumbersome to apply to models that yield a continuous result. The authors sought a method for evaluating and comparing prediction models that incorporates clinical consequences,requires only the data set on which the models are tested,and can be applied to models that have either continuous or dichotomous results. METHOD: The authors describe decision curve analysis, a simple, novel method of evaluating predictive models. They start by assuming that the threshold probability of a disease or event at which a patient would opt for treatment is informative of how the patient weighs the relative harms of a false-positive and a false-negative prediction. This theoretical relationship is then used to derive the net benefit of the model across different threshold probabilities. Plotting net benefit against threshold probability yields the "decision curve." The authors apply the method to models for the prediction of seminal vesicle invasion in prostate cancer patients. Decision curve analysis identified the range of threshold probabilities in which a model was of value, the magnitude of benefit, and which of several models was optimal. CONCLUSION: Decision curve analysis is a suitable method for evaluating alternative diagnostic and prognostic strategies that has advantages over other commonly used measures and techniques.

Decision Support Techniques↗
PubMed1978

Amplitude-modulated noise: the detection of modulation versus the detection of modulation rate.

Modulation threshold, that is, the modulation depth required to discriminate a sample of amplitude-modulated (AM) noise from a sample of unmodulated noise, was measured as a function of modulation rate (16--320 Hz), modulator waveform (sine or square), and the bandwidth of the AM noise (0.5--8.0 kHz). Modulation threshold increases monotonically with modulation rate, sine-wave thresholds are greater than square-wave thresholds, and threshold rises as the bandwith of the AM stimulus decreases. These effects all support the use of some form of energy detection model to explain modulation threshold. The modulation thresholds were compared with pitch thresholds gathered under precisely the same conditions. Pitch threshold or, alternatively, rate threshold was taken to be the modulation depth required to decide which of two samples had the higher modulation; the rate difference was 20%--just over three semitones. In the region above about 70 Hz, rate threshold is essentially a constant multiple of modulation threshold, indicating that the primary constraint on rate threshold is the audibility of the modulation. Below 70 Hz, rate and modulation threshold diverge; it is argued that the limit on rate threshold in this region is probably the length of the correlation required to extract the periodicity.

Adult↗
PubMed1987

Blood lactate concentration increases as a continuous function in progressive exercise.

The relationship between arterialized blood lactate concentration [( La-]) and O2 uptake (VO2) was examined during a total of 23 tests by eight subjects. Exercise was on a cycle ergometer with work rate incremented from loadless pedaling to exhaustion as a 50-W/min ramp function. Two different mathematical models were studied. One model employed a log-log transformation of [La-] and VO2 to yield [La-] threshold as proposed by Beaver et al. (J. Appl. Physiol. 59: 1936-1940, 1985). The other model was a continuous exponential plus constant of the form La- = a + b[exp(cVO2)]. In 21 of 23 data sets, the mean square error (MSE) of the continuous model was less than that of the log-log model (P less than 0.001). The MSE was on average 3.5 times greater in the log-log model than in the continuous model. The residuals were randomly distributed about the line of best fit for the continuous model. In contrast, the log-log model showed a nonrandom pattern indicating an inappropriate model. As an index of the position of the [La-]-VO2 continuous model, the VO2 at which the rate of increase of [La-] equaled the rate of increase of VO2 (d[La-]/dVO2 = 1) was determined. This VO2 was 2.241 +/- 0.081 l/min, which averaged 64.6% of maximal VO2. It is proposed that this lactate slope index could be used as a relative indicator of fitness instead of the previously applied threshold concept. The change in [La-] could be better described mathematically by a continuous model rather than the threshold model of Beaver et al.

Adolescent↗
PubMed2001

Receptor subtype-specific pronociceptive and analgesic actions of galanin in the spinal cord: selective actions via GalR1 and GalR2 receptors.

Galanin is a 29-aa neuropeptide with a complex role in pain processing. Several galanin receptor subtypes are present in dorsal root ganglia and spinal cord with a differential distribution. Here, we describe a generation of a specific galanin R2 (GalR2) agonist, AR-M1896, and its application in studies of a rat neuropathic pain model (Bennett). The results show that in normal rats mechanical and cold allodynia of the hindpaw are induced after intrathecal infusion of low-dose galanin (25 ng per 0.5 microl/h). The same effect is seen with equimolar doses of AR-M1896 or AR-M961, an agonist both at GalR1 and GalR2 receptors. In allodynic Bennett model rats, the mechanical threshold increased dose-dependently after intrathecal injection of a high dose of AR-M961, whereas no effect was observed in the control or AR-M1896 group. No effect of either of the two compounds was observed in nonallodynic Bennett model rats. These data indicate that a low dose of galanin has a nociceptive role at the spinal cord level mediated by GalR2 receptors, whereas the antiallodynic effect of high-dose galanin on neuropathic pain is mediated by the GalR1 receptors. Thus, a selective GalR1 agonist may be used to treat neuropathic pain.

Analgesics, Non-Narcotic↗
PubMed1991

Somatosensory evoked potentials in intracranial hypertension: analysis of the effects of hypoxia.

The loss of somatosensory evoked potentials (SSEP's) was investigated in a feline model of intracranial hypertension. Threshold values of cerebral perfusion pressure (CPP) and cerebral blood flow (CBF) required for maintenance of SSEP's are defined using a mathematical model. The model describes loss of amplitude of SSEP's using the form of a dose-response curve. Amplitude of the SSEP's declined to 50% of control values at a CBF of 15 ml/100 gm/min and a CPP of 20 mm Hg in the normoxic animal; in the presence of mild hypoxia (8 to 9 kPa), a significant increase in these values to 18 ml/100 gm/min and 32 mm Hg, respectively, occurred. No reliable changes in latency or central conduction time were demonstrated. It is concluded that given adequate oxygenation, evoked electrical activity is lost at too low a level of CPP for this parameter to be useful in clinical monitoring. However, even mild hypoxia, when combined with intracranial hypertension, produces a major risk to neuronal integrity.

Animals↗
PubMed2005

In vitro activation of retinal cells: estimating location of stimulated cell by using a mathematical model.

Activation of neurons at different depths within the retina and at various eccentricities from the stimulating electrode will presumably influence the visual percepts created by a retinal prosthesis. With an electrical prosthesis, neurons will be activated in relation to the stimulating charge that impacts their cell membranes. The common model used to predict charge density is Coulomb's law, also known as the square law. We propose a modified model that can be used to predict neuronal depth that takes into account: (1) finite dimensions related to the position and size of the stimulating and return electrodes and (2) two-dimensional displacements of neurons with respect to the electrodes, two factors that are not considered in the square law model. We tested our model by using in vitro physiological threshold data that we had obtained previously for eight OFF-center brisk-transient rabbit retinal ganglion cells. For our most spatially dense threshold data (25 microm increments up to 100 microm from the cell body), our model estimated the depth of one RGC to be 76 +/- 76 microm versus 87 +/- 62 microm (median: SD) for the square law model, respectively. This difference was not statistically significant. For the seven other RGCs for which we had obtained threshold data up to 800 microm from the cell body, the estimate of the RGC depth (using data obtained along the X axis) was 96 +/- 74 versus 20 +/- 20 microm for the square law and our modified model, respectively. Although this difference was not statistically significant (Student t-test: p = 0.12), our model provided median values much closer to the estimated depth of these RGCs (>>25 microm). This more realistic estimate of cell depth predicted by our model is not unexpected in this latter data set because of the more spatially distributed threshold data points that were evaluated. Our model has theoretical advantages over the traditional square law model under certain conditions, especially when considering neurons that are horizontally displaced from the stimulating electrode. Our model would have to be tested with a larger threshold data pool to permit more conclusive statements about the relative value of our model versus the traditional square law model under special circumstances.

Action Potentials↗
PubMed2005

Adverse neurodevelopmental effects of dexamethasone modeled in PC12 cells: identifying the critical stages and concentration thresholds for the targeting of cell acquisition, differentiation and viability.

The use of dexamethasone (DEX) to prevent respiratory distress in preterm infants is suspected to produce neurobehavioral deficits. We used PC12 cells to model the effects of DEX on different stages of neuronal development, utilizing exposures from 24 h up to 11 days and concentrations from 0.01 to 10 microM, simulating subtherapeutic, therapeutic, and high-dose regimens. In undifferentiated cells, even at the lowest concentration, DEX inhibited DNA synthesis and produced a progressive deficit in the number of cells as evaluated by DNA content, whereas cell growth (evaluated by the total protein to DNA ratio) and cell viability (Trypan blue exclusion) were promoted. When cell differentiation was initiated with nerve growth factor, the simultaneous inclusion of DEX still produced a progressive deficit in cell numbers and promoted cell growth and viability while retarding the development of neuritic projections as monitored by the membrane/total protein ratio. Again, even 0.01 microM DEX was effective. We next assessed effects at mid-differentiation by introducing nerve growth factor for 4 days followed by coexposure to DEX. Although effects on cell number, growth, and neurite extension were still detectable, the outcomes were generally less notable. DEX also shifted the fate of PC12 cells away from the cholinergic phenotype and toward the adrenergic phenotype, with the maximum effect achieved at the outset of differentiation. Our results indicate that DEX directly disrupts neuronal cell replication, differentiation, and phenotype at concentrations below those required for the therapy of preterm infants, providing a mechanistic link between glucocorticoid use and neurodevelopmental sequelae.

Animals↗
PubMed1994

Modeling the additivity of nonsimultaneous masking.

Thresholds were measured for detecting a brief 6-kHz sinusoidal signal preceded by a broadband noise masker (forward masking), followed by the masker (backward masking), or both preceded by and followed by the masker (combined masking). The masker-signal interval was systematically varied. Consistent with the literature, thresholds in the combined-masking condition were higher than would be predicted by an energy-sum of the effects of the individual forward and backward maskers. This is often referred to as 'excess' masking. The data were modeled by subjecting the amplitude of the stimuli to a power-law nonlinearity followed by a sliding temporal integrator ('window'). It was assumed that threshold corresponds to a fixed signal-to-noise ratio at the output of the window. The best fits to the data were obtained using a power less than unity (0.5 to 0.7), i.e. by a compressive nonlinearity. Generally good fits to the data were achieved, indicating that the model is able to account for the decay of forward and backward masking as well as the effects of combining pairs of maskers (excess masking). The temporal windows derived from the data are also able to predict thresholds in decrement and increment detection tasks, and to account for the longer-term effects of masker duration in forward masking.

Acoustic Stimulation↗
PubMed1978

Analysis of the detection of a moving line.

A model is proposed to explain the effects of line motion on visual sensitivity. The model incorporates recent evidence for parallel "pattern" and "flicker" systems. An element of either system consists of a spatial filter followed by a temporal filter; the characteristics of these filters were derived from previous psychophysical measurements. The model may be used to demonstrate why visual sensitivity to optimum triangular-wave motion is greater than for optimum square-wave motion, which, in turn, is greater than for on-off presentation. The predictions of the model are in reasonable agreement with threshold-amplitude data for triangular-wave and square-wave motion; the model is also consistent with threshold-frequency data for small-amplitude sinusoidal motion.

Differential Threshold↗