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PubMed2002

Oxygen balance for small organisms: an analytical model.

An analytical model is developed that describes oxygen transport and oxygen consumption for small biological structures without a circulatory system. Oxygen inside the organism is transported by diffusion alone. Oxygen transfer towards the organism is retarded by a thin static fluid film at the surface of the organism. The thickness of this film models the outward water conditions, which may range from completely stagnant water conditions to so-called well-stirred water conditions. Oxygen consumption is concentration-independent above a specified threshold concentration (regulator behaviour) and is proportional to the oxygen concentration below this threshold (conformer behaviour). The model takes into account shape and size of the organism and predicts the transition from (pure) regulator behaviour to (pure) conformer behaviour, as well as the mean oxygen consumption rate. Thereby the model facilitates a proper analysis of the physical constraints set on shape and size of organisms without an active internal oxygen transport mechanism. This analysis is carried out in some detail for six characteristic shapes (infinite sheet, cylinder and beam; finite cylinder, sphere and block). In a well-stirred external medium, a flattened shape appears to be the most favourable for oxygen supply, while a compact shape (cube) is more favourable if the external medium is nearly stagnant. The theoretical framework is applied to oxygen consumption data of eight teleost embryos. This reveals relative insensitivity to external flow conditions in some species (e.g., winter flounder, herring), while others appear to rely on external stirring for a proper oxygen supply (e.g., largemouth bass). Interestingly, largemouth bass is the only species in our analysis that exhibits 'fin-fanning'.

Animals↗

PubMed2003

Calcium requirements for exocytosis do not delimit the releasable neuropeptide pool.

Recently, it was proposed that secretory vesicles have widely varying Ca(2+) thresholds for exocytosis. This model can explain adaptation of secretory responses and predicts that incomplete release is a consequence of insufficient Ca(2+). However, membrane capacitance-based measurements have not supported varying Ca(2+) thresholds. Here, Green Fluorescent Protein (GFP) imaging is used to test whether a Ca(2+) limitation determines the size of the releasable neuropeptide pool in differentiated PC12 cells. We show that depolarization-evoked release correlates with failure to sustain fully elevated [Ca(2+)](i). However, this is coincidental because release remains incomplete when [Ca(2+)](i) is maintained at a relatively high level by application of an ionophore or by dialysis with a buffered Ca(2+) solution. Furthermore, in contradiction with the existence of high threshold vesicles, stimulating maximal release with moderate [Ca(2+)](i) prevents secretory responses to large increases in [Ca(2+)](i) induced by photolysis of the caged dimethoxynitrophenyl-EGTA-4 (DMNPE-4). Thus, optical measurements show that limited capacity for neuropeptide release in response to depolarization is not caused by an insufficient duration of [Ca(2+)](i) elevation or by variation among vesicles in Ca(2+) sensitivity for exocytosis.

Action Potentials↗

PubMed2006

Arterial wall cholesterol content is a predictor of development and severity of arterial thrombosis.

BACKGROUND: It is unclear if total cholesterol content contributes to the severity of cardiovascular events by affecting the amount of thrombosis. This study evaluated relationships between cholesterol levels and the amount of thrombosis in an atherosclerotic rabbit model of plaque disruption and thrombosis. METHODS: Three groups of NZW rabbits were used: normal rabbits (Group I, n = 4); atherosclerotic rabbits (Group II, n = 4); and atherosclerotic rabbits with pharmacologically triggered thrombosis (Group III, n = 16). Atherosclerosis was induced by feeding a cholesterol enriched diet and balloon deendothelialization. At post-mortem, platelet-rich thrombus and arterial wall cholesterol were quantified and histology performed by light and electron microscopy. RESULTS: Arterial wall cholesterol was strongly correlated to serum cholesterol in all groups (r = 0.94, p < 0.0001). There was a significant correlation between the thrombus surface area with arterial wall cholesterol in Group III (r = 0.71, p < 0.002). Serum cholesterol, arterial wall cholesterol, and thrombus surface area were all significantly correlated but only arterial wall cholesterol was an independent predictor of thrombosis. A threshold specific for this model was noted for serum and arterial cholesterol levels above which thrombosis consistently occurred. CONCLUSIONS: Arterial wall cholesterol was strongly correlated to serum cholesterol and thrombosis severity. Serum cholesterol, arterial wall cholesterol and thrombus surface area were all integrally related.A model of plaque disruption and thrombosis was used to demonstrate a correlation between serum and arterial wall cholesterol (r = 0.94; p < 0.0001); arterial wall cholesterol and the amount of thrombosis (surface area; r = 0.71, p < 0.002). A threshold of serum and arterial cholesterol was determined at which thrombosis occurred in this model.

Animals↗

PubMed1988

Unilateral inflammation of the hindpaw in rats as a model of prolonged noxious stimulation: alterations in behavior and nociceptive thresholds.

Unilateral intraplantar injection of Freund's complete adjuvant (FCA) into one hindpaw of rats led to a localized inflammation that became apparent within 12 hours and reached its peak between 2 and 3 weeks. FCA-treated rats displayed a diminished rate of body weight gain, a reduction of food and water intake and a disruption of circadian temperature regulation, as well as decreased locomotor activity and pronounced scratching behavior in the open field. Paw pressure thresholds were reduced only in inflamed paws. Contralateral, noninflamed paws showed comparable thresholds to those of control animals. Tail-flick and tail-pressure responses were not different from controls. These data suggest that FCA-treated animals experience increased noxious input from the inflamed limb and that changes in thresholds to acutely applied nociceptive stimuli are due to a peripheral hypersensitivity of inflamed tissue. The present condition resembles most closely a state of acute inflammatory pain. The term "chronic pain" in its strict sense is not appropriate in this model.

Animals↗

PubMed2002

Heterogeneity in older people: examining physiologic failure, age, and comorbidity.

OBJECTIVES: To derive a clinically relevant age-independent physiologic failure scoring system and to use this system to examine aspects of the association of physiologic failure, age, and comorbidity with inpatient mortality. DESIGN: Retrospective, secondary analysis of a derivation and validation cohort selected from the Cleveland Health Quality Choice Coalition data set. SETTING: Thirty hospitals in greater Cleveland. PARTICIPANTS: Thirty-one thousand nine hundred seventy-six inpatients aged 50 and older discharged in 1993 with a diagnosis of congestive heart failure, pneumonia, or stroke. MEASUREMENTS: The Inpatient Physiologic Failure Score (IPFS) was developed and used to calculate physiologic failure. Forty-four candidate variables were examined for their association with inpatient mortality, and 12 were selected. A point value (2, 3, 4, or 6) based on adjusted odds ratio was assigned for an abnormal result for each of the 12 common physiologic variables. Each patient's abnormal physiology points were summed to produce a physiologic failure score (range 0-39). Comorbidity was quantified using the Patient Management Category Severity Scale. The association between mortality and increasing physiologic failure, increasing age and comorbidity, and distribution of physiologic failure with increasing age and comorbidity were examined. A threshold age was sought. Models for predicting inpatient mortality were developed. RESULTS: Twelve physiologic variables constitute the IPFS. Increasing physiologic failure, age, and comorbidity were associated with increasing mortality. Increasing physiologic failure was not associated with increasing age or comorbidity. We did not find a threshold age. The area under the receiver operating characteristic (ROC) curve for predicting inpatient mortality for IPFS was 0.730, and for comorbidity was 0.741 (not significant). The area under the ROC curve for a mortality prediction model based on age was significantly less (0.603). Accounting for patient age did not significantly improve the predictive ability of the IPFS model (area = 0.752, P <.05). The complete model best predicted mortality (0.829). CONCLUSIONS: The IPFS represents a clinically relevant method for scoring physiologic failure. Physiologic failure, age, and comorbidity are independently and differently associated with inpatient mortality. Physiology fails independent of age and comorbidity.

Age Factors↗

PubMed1999

Characterization of phenytoin-resistant kindled rats, a new model of drug-resistant partial epilepsy: influence of experimental and environmental factors.

It has been recently shown that the variable anticonvulsant effect of phenytoin in the kindling model is not a characteristic of all kindled rats. In a population of amygdala-kindled Wistar rats, subgroups can be selected which consistently respond to phenytoin with an increase in afterdischarge threshold (responders) or which never show such an increase (non-responders). This study examined retrospectively the influence of technical and environmental factors on the results of several prospectively performed phenytoin selections during the last few years. Male and female Wistar rats were implanted with bipolar electrodes aimed at the basolateral amygdala and subsequently kindled. The fully kindled rats were tested for their ability to consistently respond to phenytoin (75 mg/kg i.p.) with an increase of afterdischarge threshold in three consecutive trials. Analysis of 158 Wistar rats of both genders revealed no significant influence of either plasma concentration of phenytoin, kindling parameters, precise electrode location, or differences in focal histology on the result of phenytoin selection. Furthermore, the ability to respond to phenytoin was not associated with the season or the ambient atmospheric pressure during the selection procedure. The data suggest that the difference between phenytoin responders and non-responders is not due to experimental factors, but may rather be genetically determined.

Animals↗

PubMed1988

A comparison of the risk of vertebral fracture in menopausal osteopenia and other metabolic disturbances.

The risk of atraumatic compression fracture in postmenopausal women increases as vertebral trabecular bone density decreases. To determine whether the risk is similar for patients who have other metabolic disorders, we compared eight-nine patients who had various disturbances affecting bone and sixty-three postmenopausal women who had no evidence of underlying disease. Trabecular bone density was measured by quantitative computed tomography of the lumbar spine. The relationship between frequency of fracture and bone density was modeled mathematically with spline threshold, quadratic polynomial, and decaying exponential functions. Analysis of covariance showed that the diagnostic category did not influence the relationship between frequency of fracture and bone density in any of the three models. We concluded that the risk of atraumatic compression fracture, as assessed by measurement of vertebral trabecular bone density using quantitative computerized tomography, is independent of the underlying metabolic disturbance.

Adult↗

PubMed2002

A biophysical model of nonlinear dynamics underlying plateau potentials and calcium spikes in purkinje cell dendrites.

Computational capabilities of Purkinje cells (PCs) are central to the cerebellum function. Information originating from the whole nervous system converges on their dendrites, and their axon is the sole output of the cerebellar cortex. PC dendrites respond to weak synaptic activation with long-lasting, low-amplitude plateau potentials, but stronger synaptic activation can generate fast, large amplitude calcium spikes. Pharmacological data have suggested the involvement of only the P-type of Ca channels in both of these electric responses. However, the mechanism allowing this Ca current to underlie responses with such different dynamics is still unclear. This mechanism was explored by constraining a biophysical model with electrophysiological, Ca-imaging, and single ion channel data. A model is presented here incorporating a simplified description of [Ca](i) regulation and three ionic currents: 1) the P-type Ca current, 2) a delayed-rectifier K current, and 3) a generic class of K channels activating sharply in the sub-threshold voltage range. This model sustains fast spikes and long-lasting plateaus terminating spontaneously with recovery of the resting potential. Small depolarizing, tonic inputs turn plateaus into a stable membrane state and endow the dendrite with bistability properties. With larger tonic inputs, the plateau remains the unique equilibrium state, showing long traces of transient inhibitory inputs that are called "valley potentials" because their dynamics mirrors that of inverted, finite-duration plateaus. Analyzing the slow subsystem obtained by assuming instantaneous activation of the delayed-rectifier reveals that the time course of plateaus and valleys is controlled by the slow [Ca](i) dynamics, which arises from the high Ca-buffering capacity of PCs. A bifurcation analysis shows that tonic currents modulate sub-threshold dynamics by displacing the resting state along a hysteresis region edged by two saddle-node bifurcations; these bifurcations mark transitions from finite-duration plateaus to bistability and from bistability to valley potentials, respectively. This low-dimensionality model may be introduced into large-scale models to explore the role of PC dendrite computations in the functional capabilities of the cerebellum.

Algorithms↗

PubMed2004

High levels of atmospheric carbon dioxide necessary for the termination of global glaciation.

The possibility that the Earth suffered episodes of global glaciation as recently as the Neoproterozoic period, between about 900 and 543 million years ago, has been widely discussed. Termination of such 'hard snowball Earth' climate states has been proposed to proceed from accumulation of carbon dioxide in the atmosphere. Many salient aspects of the snowball scenario depend critically on the threshold of atmospheric carbon dioxide concentrations needed to trigger deglaciation. Here I present simulations with a general circulation model, using elevated carbon dioxide levels to estimate this deglaciation threshold. The model simulates several phenomena that are expected to be significant in a 'snowball Earth' scenario, but which have not been considered in previous studies with less sophisticated models, such as a reduction of vertical temperature gradients in winter, a reduction in summer tropopause height, the effect of snow cover and a reduction in cloud greenhouse effects. In my simulations, the system remains far short of deglaciation even at atmospheric carbon dioxide concentrations of 550 times the present levels (0.2 bar of CO2). I find that at much higher carbon dioxide levels, deglaciation is unlikely unless unknown feedback cycles that are not captured in the model come into effect.

Journal Article↗

PubMed1987

Microinjection of a benzodiazepine into substantia nigra elevates kindled seizure threshold.

The purpose of these experiments was to initiate investigations of the brain site(s) at which the benzodiazepines exert their anticonvulsant effect. We examined the effects of microinjections of clonazepam into substantia nigra (SN) on seizure threshold in the kindling model. We also examined the distribution of microinjected [3H]methylclonazepam with autoradiographic methods. Microinjection of clonazepam bilaterally into substantia nigra pars reticulata (SNR), but not nearby, produced a 75% elevation of generalized seizure threshold. Quantitative analysis of autoradiographic studies indicated that the vast majority of [3H]methylclonazepam was distributed within 400 micron of the injection cannula tip; even optimally placed injections did not result in drug access throughout the entire SN. The data demonstrate that local application of an anticonvulsant benzodiazepine to the substantia nigra alone is sufficient to suppress seizures. We suggest that the substantia nigra is one site at which systemically administered benzodiazepines act to suppress seizures.

Animals↗

PubMed1995

Auditory and vestibular function in experimental hydrops.

Endolymphatic hydrops is the characteristic morphopathology observed at postmortem examination of temporal bones of Meniere's disease. Surgical induction of endolymphatic hydrops in the guinea pig provides a reproducible animal model for the investigation of some effects of endolymphatic hydrops on inner ear function. Episodic and incapacitating vertigo are classic features of Meniere's disease, although very limited vestibular dysfunction has ever been described for the animal model. On the other hand, the auditory deficits peculiar to Meniere's disease, including fluctuant sensitivity losses and a peak audiogram, are also observed at different stages in the development of experimental hydrops. In future studies the model is likely to provide a means of investigating osmoregulatory function of the inner ear.

Animals↗

PubMed2005

Sensitivity analysis of a two-dimensional probabilistic risk assessment model using analysis of variance.

This article demonstrates application of sensitivity analysis to risk assessment models with two-dimensional probabilistic frameworks that distinguish between variability and uncertainty. A microbial food safety process risk (MFSPR) model is used as a test bed. The process of identifying key controllable inputs and key sources of uncertainty using sensitivity analysis is challenged by typical characteristics of MFSPR models such as nonlinearity, thresholds, interactions, and categorical inputs. Among many available sensitivity analysis methods, analysis of variance (ANOVA) is evaluated in comparison to commonly used methods based on correlation coefficients. In a two-dimensional risk model, the identification of key controllable inputs that can be prioritized with respect to risk management is confounded by uncertainty. However, as shown here, ANOVA provided robust insights regarding controllable inputs most likely to lead to effective risk reduction despite uncertainty. ANOVA appropriately selected the top six important inputs, while correlation-based methods provided misleading insights. Bootstrap simulation is used to quantify uncertainty in ranks of inputs due to sampling error. For the selected sample size, differences in F values of 60% or more were associated with clear differences in rank order between inputs. Sensitivity analysis results identified inputs related to the storage of ground beef servings at home as the most important. Risk management recommendations are suggested in the form of a consumer advisory for better handling and storage practices.

Analysis of Variance↗

PubMed2006

Development of respiratory control instability in heart failure: a novel approach to dissect the pathophysiological mechanisms.

Observational data suggest that periodic breathing is more common in subjects with low F(ETCO(2)), high apnoeic thresholds or high chemoreflex sensitivity. It is, however, difficult to determine the individual effect of each variable because they are intrinsically related. To distinguish the effect of isolated changes in chemoreflex sensitivity, mean F(ETCO(2)) and apnoeic threshold, we employed a modelling approach to break their obligatory in vivo interrelationship. We found that a change in mean CO(2) fraction from 0.035 to 0.045 increased loop gain by 70 +/- 0.083% (P < 0.0001), irrespective of chemoreflex gain or apnoea threshold. A 100% increase in the chemoreflex gain (from 800 l min(-1) (fraction CO(2))(-1)) resulted in an increase in loop gain of 275 +/- 6% (P < 0.0001) across a wide range of values of steady state CO(2) and apnoea thresholds. Increasing the apnoea threshold F(ETCO(2)) from 0.02 to 0.03 had no effect on system stability. Therefore, of the three variables the only two destabilizing factors were high gain and high mean CO(2); the apnoea threshold did not independently influence system stability. Although our results support the idea that high chemoreflex gain destabilizes ventilatory control, there are two additional potentially controversial findings. First, it is high (rather than low) mean CO(2) that favours instability. Second, high apnoea threshold itself does not create instability. Clinically the apnoea threshold appears important only because of its associations with the true determinants of stability: chemoreflex gain and mean CO(2).

Animals↗

PubMed2001

Predicting tissue outcome in acute human cerebral ischemia using combined diffusion- and perfusion-weighted MR imaging.

BACKGROUND AND PURPOSE: Tissue signatures from acute MR imaging of the brain may be able to categorize physiological status and thereby assist clinical decision making. We designed and analyzed statistical algorithms to evaluate the risk of infarction for each voxel of tissue using acute human functional MRI. METHODS: Diffusion-weighted MR images (DWI) and perfusion-weighted MR images (PWI) from acute stroke patients scanned within 12 hours of symptom onset were retrospectively studied and used to develop thresholding and generalized linear model (GLM) algorithms predicting tissue outcome as determined by follow-up MRI. The performances of the algorithms were evaluated for each patient by using receiver operating characteristic curves. RESULTS: At their optimal operating points, thresholding algorithms combining DWI and PWI provided 66% sensitivity and 83% specificity, and GLM algorithms combining DWI and PWI predicted with 66% sensitivity and 84% specificity voxels that proceeded to infarct. Thresholding algorithms that combined DWI and PWI provided significant improvement to algorithms that utilized DWI alone (P=0.02) but no significant improvement over algorithms utilizing PWI alone (P=0.21). GLM algorithms that combined DWI and PWI showed significant improvement over algorithms that used only DWI (P=0.02) or PWI (P=0.04). The performances of thresholding and GLM algorithms were comparable (P>0.2). CONCLUSIONS: Algorithms that combine acute DWI and PWI can assess the risk of infarction with higher specificity and sensitivity than algorithms that use DWI or PWI individually. Methods for quantitatively assessing the risk of infarction on a voxel-by-voxel basis show promise as techniques for investigating the natural spatial evolution of ischemic damage in humans.

Acute Disease↗

PubMed1999

Evidence for different nonlinear summation schemes for lines and gratings at threshold.

Within a wide class of multichannel models of the visual system it is suggested that spatial distributions of luminance are processed by the independent activation of grating detectors, or spatial frequency channels. Probability summation is often described in terms of Quick's nonlinear pooling model [Quick RF (1974) Kybernetik 16:65-67]. Using this model, we find evidence for the existence of different kinds of nonlinear summation at threshold; for compound gratings with well-separated spatial frequency components, the threshold functions indicate nonlinear summation which is not compatible with probability summation, while for line patterns well separated in the spatial domain the probability summation rule proves compatible with the data.

Animals↗

PubMed2005

Disclosing disease mechanisms with a spatio-temporal summation paradigm.

BACKGROUND: We develop the logic for a stimulus that can evaluate cone-dependent spatial summation and detail the modelling and interpretation of thresholds obtained with this stimulus. METHODS: Fifteen observers participated, including two young normals tested extensively in control experiments, and a clinical trial based on four observers with age-related macular degeneration (AMD), four age-similar controls and five young observers. Monocular spatial summation functions were measured with contrast-modulated Gabor targets that approximated the optimal visual contrast detector. Thresholds were returned from a yes/no adaptive psychophysical algorithm. By fine titration along the size domain it was demonstrated that the spatial summation of normal observers can be adequately described by a two-component model. A reduced set of variables are proposed for clinical applications and the model was applied to data derived using these variables in persons with AMD and age-similar controls. RESULTS: We do not find a significant age-related loss of contrast sensitivity in our normal group. On the other hand, persons with early AMD exhibited a 0.41 log unit loss of sensitivity (P=0.04) from age-similar controls, without any change in their maximum summation area (A(max)). CONCLUSIONS: The nature of the spatial summation is consistent with the interpretation that early AMD produces a decrease in cone input to post-receptoral mechanisms in the absence of neural remodelling.

Adult↗

PubMed2005

Modelling encapsulation tissue around cochlear implant electrodes.

The objective of the study was to explore the effect of electrode encapsulation by fibrous scar tissue on electrical potential distributions and auditory nerve fibre excitation patterns. A finite element model in combination with an auditory nerve fibre model was used to predict changes in threshold currents and auditory nerve fibre excitation patterns. The model showed that electrical potentials at the target nerve fibres and the electrode contacts changed in the presence of encapsulation tissue. This led to changes in threshold currents and spread of excitation. The effect of electrode encapsulation on threshold currents and spread of excitation depended on the thickness of the perilymph layer separating the fibrous tissue encapsulation and the electrode array, nerve fibre survival status, electrode geometry and configuration, and array location. Model results suggested that arrays located close to the modiolus were most sensitive to threshold changes caused by electrode encapsulation (changes were between -0.26 and 2.41 dB), whereas encapsulation of an electrode array had less effect on threshold currents when the array was located in a lateral position in the scala tympani (changes were between -0.64 and 1.5 dB). For medially located arrays, changes in the spread of excitation varied between an increase of 0.21 mm and a decrease of 0.33 mm along the length of the basilar membrane, and an increase of 0.18 mm and a decrease of 0.66 mm along the length of the basilar membrane were calculated for laterally located arrays.

Cicatrix↗

PubMed1999

Weighted combination of size and disparity: a computational model for timing a ball catch.

How do we time hand closure to catch a ball? Binocular disparity and optical looming provide two sources of information about an object's motion in depth, but the relative effectiveness of the two cues depends on ball size. Based on results from a virtual reality ball-catching task, we derive a simple model that uses both cues. The model is sensitive to the relative effectiveness of size and disparity and implicitly switches its response to the cue that specifies the earliest arrival and away from a cue that is lost or below threshold. We demonstrate the model's robustness by predicting the response of participants to some very unusual ball trajectories in a virtual reality task.

Cues↗