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ST-changes in ECG at rest or during exercise indicate a high risk of severe coronary lesions after an episode of unstable coronary artery disease.

After an episode of unstable coronary artery disease, 190 patients performed a predischarge exercise test. A postdischarge exercise test and coronary angiography was performed by 172 patients after 1 month. A subgroup of 104 men performed both exercise tests with a computer-aided system. More sophisticated methods of evaluating the ECG reaction during exercise were not diagnostically superior to the simple identification of ST-depression of > or = 0.1 mV. ST-depression in ECG at rest indicated a 70% risk of severe coronary lesions and in such patients, the ECG reaction at exercise carried no additional diagnostic information. Stepwise multiple regression analysis showed that ST-depression and low maximal work load were the most important exercise variables for identification of severe coronary lesions. Using a combination of these parameters, the sensitivity and specificity for identification of severe coronary lesions were, respectively, 77% and 61% predischarge and 77% and 70% after 1 month.

Adult↗

A new approach to closed-loop linear system identification via a vector autoregressive model.

A new vector autoregressive (VAR) model algorithm is developed for closed-loop identification. The new VAR approach is an extension of a recently developed algorithm, named the optimal parameter search (OPS), thus, we call the new technique VOPS, for vector OPS. Monte Carlo simulations of closed-loop systems were performed to compare the performance of VOPS to the widely utilized vector least squares (VLS) and vector fast orthogonal search (VFOS) approaches. In addition, we examined the effect on parameter estimates obtained via open-loop identification techniques, when using data from closed-loop systems. Comparative results show that both the VOPS and VFOS algorithms produce far more accurate parameter estimates than does the VLS. Furthermore, open-loop identification via univariate OPS and to a lesser extent univariate FOS for closed-loop systems, does not adversely affect the accuracy of the parameter estimates. An open-loop identification via the univariate least-squares method for closed-loop systems showed the most deleterious effect on the accuracy of the parameter estimates. In addition to developing the VOPS algorithm, we also developed approaches termed constrained OPS (COPS) and constrained FOS (CFOS). For closed-loop systems considered in this paper, both COPS and CFOS resulted in more accurate parameter estimates (less biased and more efficient) than did VLS, VFOS, and VOPS.

Algorithms↗

Cell behavior and cell-cell communication during fruiting body morphogenesis in Myxococcus xanthus.

Formation of spatial patterns of cells from a mass of initially identical cells is a recurring theme in developmental biology. The dynamics that direct pattern formation in biological systems often involve morphogenetic cell movements. An example is fruiting body formation in the gliding bacterium Myxococcus xanthus in which an unstructured population of identical cells rearranges into an asymmetric, stable pattern of multicellular fruiting bodies in response to starvation. Fruiting body formation depends on changes in organized cell movements from swarming to aggregation. The aggregation process is induced and orchestrated by the cell-surface associated 17 kDa C-signal protein. C-signal transmission depends on direct contact between cells. Evidence suggests that C-signal transmission is geometrically constrained to cell ends and that productive C-signal transmission only occurs when cells engage in end-to-end contacts. Here, we review recent progress in the understanding of the pattern formation process that leads to fruiting body formation. Gliding motility in M. xanthus involves two polarly localized gliding machines, the S-machine depends on type IV pili and the A-machine seems to involve a slime extrusion mechanism. Using time-lapse video microscopy the gliding motility parameters controlled by the C-signal have been identified. The C-signal induces cells to move with increased gliding speeds, in longer gliding intervals and with decreased stop and reversal frequencies. The combined effect of the C-signal dependent changes in gliding motility behaviour is an increase in the net-distance travelled by a cell per minute. The identification of the motility parameters controlled by the C-signal in combination with the contact-dependent C-signal transmission mechanism have allowed the generation of a qualitative model for C-signal induced aggregation. In this model, the directive properties of the C-signal are a direct consequence of the contact-dependent signal-transmission mechanism, which is a local event involving direct contact between cells that results in a global organization of cells. This pattern formation process does not depend on a diffusible substance. Rather it depends on a cell-surface associated signal to direct the cells appropriately.

Bacterial Proteins↗

What is needed for effective antitumor immunotherapy? Lessons learned using Listeria monocytogenes as a live vector for HPV-associated tumors.

As a vaccine vector, Listeria monocytogenes targets the innate immune system, resulting in a cytokine response that enhances antigen-presenting cell function as well as inducing a Th1 profile. It also enhances cell-mediated immunity by targeting antigen delivery in antigen-presenting cells to both the MHC class I pathway of exogenous presentation that activates CD8 T cells and the MHC class II pathway that processes antigen endogenously and presents it to CD4 T cells. In this review, we describe the development of vaccine constructs that target the human papillomavirus 16 (HPV-16) E7 antigen, and we characterize their effects on tumor regression as well as various immune parameters both innate and adaptive. In particular, we describe the effect on tumor angiogenesis, induction of antitumor suppressor factors like CD4+CD25+ T cells and regulatory cytokines TGF-beta and IL-10, homing and infiltration of antigen-specific CD8+ T cells to the tumor, and also effects of the vaccines on antigen-presenting cells, especially focusing on dendritic cell maturation and ability to influence tumor regression. We believe that the identification of several immune parameters that correlate with antitumor efficacy, and of some that have a negative correlation, may have wider application for other cancer immunotherapeutic approaches.

Animals↗

Linear model and algorithm to automatically estimate the pressure limit of pressure controlled ventilation for delivering a target tidal volume.

OBJECTIVE: To theoretically assess the viability of an automatic procedure to support the anesthesiologist in properly setting mechanical ventilators when the operating conditions are switched from volume controlled to pressure controlled ventilation whilst maintaining the preset tidal volume. The procedure is based on a simple linear model of the ventilator breathing system with constant parameters and utilizes the signals gathered by the ventilator without the need to add further equipment. After a short period of stable volume controlled ventilation with the desired tidal volume, the herewith described algorithm allows the calculation of the value of pressure limit to set in pressure controlled mode which assures the previously settled tidal volume with the same breathing frequency and inspiratory-expiratory time ratio. METHODS: The algorithm allows the online identification of the four parameters necessary for the mathematical model that are obtained by means of a direct comparison between the pressure, flow and volume waveforms generated by the model and the analog signals provided by the ventilator. The theoretical approach was validated by two different ventilators, various settings, two breathing circuits, endotracheal tubes of various sizes and two mechanical simulators of the respiratory system operating in various conditions. RESULTS: Errors usually less than 5% (p < 0.05) on the target tidal volume were obtained for various settings typically used for adult ventilation in less than 10 s. The theoretical approach shows its limitations (errors of 10+/- 5%, p < 0.05) at high breathing frequencies (30-40 bpm) and low tidal volumes (200-300 ml). CONCLUSIONS: The proposed theoretical approach shows the viability, for adult settings, of one of the simplest mathematical model for mechanical ventilation in order to quickly and safely switch from volume controlled to pressure controlled ventilation. The algorithm could easily be in perspective implemented in the software of the ventilator providing the anesthesiologist with an indication on the value of pressure limit to set in order to safely switch ventilation mode.

Algorithms↗

Parameter fitting of digital models of pulsatile hemodynamics based on intravascular measurements in the rabbit aorta.

The objective was to describe and evaluate methods of in vivo intravascular assessment of pressure and flow within the systemic arterial tree for further digital processing and individualized simulation. In rabbits intra-aortic pressure and flow were measured by insertion of microcatheters and/or a Doppler probe, which were moved to different angiographically documented sites. Various catheters and sheaths were evaluated prior to digitized processing of the obtained data, which was based on electrotechnical analoga for description of elastic vascular segments. Fourier transformation and filtering provided signal data for further identification of the investigated parameters. Catheters with an inner diameter > or = 0.9 mm produced reliable pressure signals. Simultaneous measurement of pressure and flow reduced the reliability of the absolute values by reduction of the cross-sectional diameter of the investigated vascular segments. Numerical optimization methods were used to identify parameters in the proposed models from the measured data sets. Characterization of hemodynamics by intravascular measurements of pressure and flow proved feasible. Pressure recordings should be judged critically if the cross-sectional area of the catheter covers a significant fraction of the vessel. Post-processing of such data sets may assist in future treatment planning and simulation of concomitant changes of intravascular pressure and flow.

Animals↗

Identification of patterns of neuronal connectivity--partial spectra, partial coherence, and neuronal interactions.

The cross-correlation histogram has provided the primary tool for inferring the structure of common inputs to pairs of neurones. While this technique has produced useful results it not clear how it may be extended to complex networks. In this report we introduce a linear model for point process systems. The finite Fourier transform of this model leads to a regression type analysis of the relations between spike trains. An advantage of this approach is that the full range of techniques for multivariate regression analyses becomes available for spike train analysis. The two main parameters used for the identification of neural networks are the coherence and partial coherences. The coherence defines a bounded measure of association between two spike trains and plays the role of a squared correlation coefficient defined at each frequency lambda. The partial coherences, analogous to the partial correlations of multiple regression analysis, allow an assessment of how any number of putative input processes may influence the relation between any two output processes. In many cases analytic solutions may be found for coherences and partial coherences for simple neural networks, and in combination with simulations may be used to test hypotheses concerning proposed networks inferred from spike train analyses.

Animals↗

Symbolic programs for structural identification of linear pharmacokinetic systems.

Most parameter estimation techniques implicitly assume that it is possible to determine the parameters of the system uniquely if there were no noise in the output. In practice, this is not always the case. Whether or not this assumption is true for a given input-output experiment is the problem of structural identification. Two programs utilizing symbolic matrix calculus are presented which aid in solving this problem for linear systems. Pharmacokinetic examples are given.

Computers↗

Estimating mechanical parameters of leg segments in individuals with and without physical disabilities.

Methods are described for estimating the inertia, viscosity, and stiffness of the lower leg around the knee and of the whole leg around the hip that are applicable even to persons with considerable spasticity. These involve: 1) a "pull" test in which the limb is slowly moved throughout its range of motion while measuring angles (with an electrogoniometer) and torques (with a hand-held dynamometer) to determine passive stiffness and 2) a "pendulum" test in which the limb is moved against gravity and then dropped, while again measuring angles and torques. By limiting the extent of the movement and choosing a direction (flexion or extension) that minimizes reflex responses, the mechanical parameters can be determined accurately and efficiently using computer programs. In the sample of subjects studied (nine with disability related to spinal cord injury, head injury, or stroke, and nine with no neurological disability), the inertia of the lower leg was significantly reduced in the subjects with disability (p < 0.05) as a result of atrophy, but the stiffness and viscosity were within normal limits. The values of inertia were also compared with anthropometric data in the literature. The identification of these passive parameters is particularly important in designing systems for functional electrical stimulation of paralyzed muscles, but the methods may be widely applicable in rehabilitation medicine.

Adult↗

Analyzing multi-response data using forcing functions.

INTRODUCTION: Two analytic strategies can be taken to the analysis of multi-response data: a multivariate output model can be fit to all the response components simultaneously (SIM), or each response component can be fit separately to a univariate output model, conditioning in some way on the non-modeled components, the so-called forcing function approach (FFA). Focusing on a special case of multi-response model corresponding to a (pharmacokinetic) physiological f low model (PFM), the aims of this study are to (i) provide an algorithm for applying FFA to multi-response data from a PFM; (ii) examine the performance of FFA vs. SIM under optimal conditions for both, and in the presence of model misspecification; (iii) make recommendations regarding the use of FFA for multi-response data analysis. METHODS: The basic PFM we use (variants of the basic model are used for simulation) has four homogenous compartments among which drug distributes. All are sampled arterial blood (A), non-eliminating tissue (N), eliminating tissue (E), and venous blood (V), which is also the drug dosing site. Parameters are blood f low rates to E and N, volumes of distribution of A, E, N, and V, elimination rate constant from E, and observation error variances. Observations from a generic individual under various study designs and parameter values are simulated. Using data-analytic models (DAM) both the same as, and different than the data simulation model (DSM), SIM fits the PFM to all data simultaneously; FFA first fits each type of response (one per tissue) separately, approximating the tissue's input by linearly interpolating the observed concentrations from the donor tissue(s), estimates the identifiable parameter combinations for the response type, and then solves the simultaneous equations linking these across tissues, to obtain the primary model parameters of interest. This simulation and analysis steps are repeated to generate reliable performance statistics. Performances are compared with respect to parameter estimation error (when DAM and DSM are identical), and interpolated prediction error (when DAM and DSM are/are-not identical). The ability of SIM and FFA to identify the correct analytic model is also examined by comparing their failure rates in rejecting the wrong DAM. RESULTS: The parameter estimation errors with FFA are generally about two times greater than those with SIM when the DAM is identical to the DSM. The prediction errors of FFA are about ten times greater than those of SIM when the DAM is identical to the DSM, and are about three times greater when the two are different. However, SIM fails to identify the correct model twice as often as FFA. CONCLUSIONS: Despite its greater convenience for model building, and its clear advantages for model identification, FFA's final parameter estimates cannot be trusted when the multi-response system being modeled involves feedback. The size of the ratio of the two FFA residuals (obtained from the response-specific fits and from predictions made with the final FFA parameters) can, however, be used to indicate when FFA's final estimates may be trustworthy.

Algorithms↗

Semantic factors in episodic recognition of common odors in early and late adulthood: a review.

Information on long-term memory for common odors is discussed. Olfactory parameters (i.e. familiarity, recognition, identification) and their relationship to current memory theory are highlighted. Emphasis is focused on the impact of semantic memory on episodic odor recognition. In contrast to previous research suggesting that verbal/semantic factors play a negligible role in olfactory memory, the present review indicates that episodic odor information is mediated by factors that can be subsumed under the rubric of semantic memory. Specific odor knowledge, such as perceived familiarity and identifiability, is strongly and positively related to episodic odor memory performance. Age-related impairments in various olfactory and cognitive parameters and the potential detrimental effects in episodic odor memory are discussed. Finally, the issue of whether olfactory memory should be conceptualized as an independent process, or whether it shares characteristics with memory for verbal and visual information, is addressed.

Adult↗

Effects of calcitriol on parathyroid function and on bone remodelling in secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism (2HPT) develops in chronic renal failure due to disturbances of calcium, phosphorus and vitamin D metabolism. It is characterized by high turnover bone disease and an altered calcium-parathyroid hormone (PTH) relationship. Calcitriol has been widely used for the treatment of 2HPT. However, it remains controversial whether calcitriol is capable of inducing changes of the calcium-PTH curve. The aim of the present study was to examine this issue and to determine the effect of calcitriol on bone remodelling in patients with severe 2HPT. METHODS: We evaluated 16 chronic haemodialysis patients with severe 2HPT (PTH 899+/-342 pg/ml). Each patient underwent a dynamic parathyroid function test (by infusion of calcium gluconate and sodium citrate) and a bone biopsy before and after a 6 month period of i.v. calcitriol therapy (CTx). RESULTS: After treatment, eight patients were identified as calcitriol responders and the other eight as non-responders, based on plasma PTH level (<300 pg/ml for responders and >300 pg/ml for non-responders). The first group had higher plasma 25OHD(3) levels (39+/-8 vs 24+/-7 ng/ml, P<0.005). As to the calcium-PTH curve, we found differences in slope (-12.7+/-5.2 vs -21.7+/-11.4, P=0.05), basal/maximum PTH ratio (48.8+/-14.9 vs 71.05+/-20.1%, P=0.01) and time to achieve hypocalcaemia (79.0+/-13.5 vs 94.3+/-13.7 min, P<0.001). Initial histomorphometric parameters did not allow identification of the different groups. After the 6-month CTx, alterations in the calcium-PTH curve were clearly seen in responders [a drop in maximum PTH (from 1651+/-616 to 938+/-744 pg/ml, P<0.05) and minimum PTH (from 163+/-75.4 to 102.2+/-56.7 pg/ml, P<0.005)], associated with an increase in minimum/basal PTH ratio (from 23.3+/-11.6 to 34.5+/-20.4%, P<0.05) and maximum calcium (from 0.99+/-0.07 to 1.1+/-0.09 mmol/l, P<0.05). Set point and slope were not altered after calcitriol treatment, in responders (set point=1.17+/-0.08 vs 1.15+/-0.1 mmol/l, ns; slope=-12.7+/-5.2 vs -12.9+/-9.3, ns) or non-responders (set point=1.21+/-0.05 vs 1.21+/-0.2 mmol/l, ns; slope=-21.7+/-11.4 vs -17.3+/-8.4, ns). Bone formation parameters were reduced in all patients [osteoid surface (OS/BS)=from 57.1+/-21.6 to 41.6+/-26%, P<0.05 for responders, and from 76.7+/-12 to 47.1+/-15%, P<0.001 in non-responders], but non-responders had increased bone resorption [eroded surface (ES/BS)=7.1+/-3.4 vs 16.6+/-4.9, P<0.05]. CONCLUSION: Calcitriol had non-uniform effects on parathyroid function and bone remodelling in uraemic patients. Non-responders exhibited a decoupled remodelling process that could further influence mineral balance or possibly also bone structure. To avoid such undesirable effects, early identification of non-responder patients is crucial when using calcitriol for the treatment of 2HPT.

Adult↗

Quantitative comparison of polyethylenimine formulations and adenoviral vectors in terms of intracellular gene delivery processes.

An objective of designing molecular vehicles exhibiting virus-like transgene delivery capabilities but with low toxicity and immunogenicity continues to drive synthetic vector development. As no single step within the gene delivery pathway represents the critical limiting barrier for all vector types under all circumstances, improvements in synthetic vehicle design may be aided by quantitative analysis of the contributions of each step to the overall delivery process. To our knowledge, however, synthetic and viral gene delivery methods have not yet been explicitly compared in terms of these delivery pathway steps in a quantitative manner. As a first address of this challenge, we compare here quantitative parameters characterizing intracellular gene delivery steps for an E1/E3-deleted adenoviral vector and three polyethylenimine (PEI)-based vector formulations, as well as the liposomal transfection reagent Lipofectamine and naked DNA; the cargo is a plasmid encoding the beta-galactosidase gene under a CMV promoter, and the cell host is the C3A human hepatocellular carcinoma line. The parameters were determined by applying a previously validated mathematical model to transient time-course measurements of plasmid uptake and trafficking (from whole-cell and isolated nuclei lysates, by real-time quantitative PCR), and gene expression levels, enabling discovery of those for which the adenoviral vector manifested superiority. Parameter-sensitivity analysis permitted identification of processes most critically rate-limiting for each vector. We find that the adenoviral vector advantage in delivery appears to reside partially in its import to the nuclear compartment, but that its vast superiority in transgene expression arises predominantly in our situation from postdelivery events: on the basis of per-nuclear plasmid, expression efficiency from adenovirus is superior by orders of magnitude over the PEI vectors. We find that a chemical modification of a PEI-based vector, which substantially improves its performance, appears to do so by enhancing certain trafficking rate parameters, such as binding and uptake, endosomal escape, and binding to nuclear import machinery, but leaves endosomal escape as a barrier over which transgene delivery could be most sensitively increased further for this polymer.

Adenoviridae↗

Binding of phenylbutazone to human serum albumin. Characterization and identification of binding sites.

The quantitative parameters characterizing the binding of phenylbutazone (CAS 50-33-9) to human serum albumin are determined using the circular dichroism titration method and a combined mathematical approach. The values of affinity constants obtained are in good agreement with those found in the literature. The characterization and identification of binding sites is also performed. A conclusion is derived that phenylbutazone can be used as a model compound for investigation of ligand-macromolecule interactions.

Anti-Inflammatory Agents, Non-Steroidal↗

Measurement of relative nerve fiber layer surface height in glaucoma.

A new parameter of structural optic nerve damage from glaucoma is reported, the relative nerve fiber layer surface height (RNFLH). Relative nerve fiber layer surface height is calculated from magnification-corrected surface contour measurements of the peripapillary retina made with computerized image analysis of stereoscopic videographic images. The technique measures the average height of the nerve fiber layer surface within a circumference 200 microns from the disc edge, as detected with narrow-band green light, with respect to a standardized reference plane. This parameter was examined in a group of 36 glaucoma patients with early to moderate visual field loss, and in 33 age-matched normal controls. The measured surface of the peripapillary nerve fiber layer was, on the average, 74 microns lower in glaucomatous eyes than in normal eyes, a statistically significant difference (P = 0.000). The ability of RNFLH to distinguish glaucomatous eyes from normal eyes was tested by its sensitivity (83%) and specificity (88%), which were greater than the sensitivities and specificities of computerized measurements of cup-disc ratio, disc rim area, and cup volume. This approach represents a step toward the identification of quantitative structural parameters to reflect the number of retinal ganglion cell axons that enter the optic nerve. Such measurements may facilitate the early diagnosis of glaucoma and provide important information on rates of ganglion cell death in aging and disease.

Female↗

Identification of individuals susceptible to high-altitude pulmonary oedema at low altitude.

Individuals susceptible to high-altitude pulmonary oedema (HAPE) are characterised by an abnormal increase of pulmonary artery systolic pressure (PASP) in hypoxia and during normoxic exercise, reduced hypoxic ventilatory response, and smaller lung volume. In 37 mountaineers with well-documented altitude tolerance, it was investigated whether any combination of these noninvasive measurements, including exercise in hypoxia, could improve the identification of HAPE-susceptible subjects at low altitude. HAPE-susceptible subjects showed a significant higher increase of PASP during hypoxia at rest (48+/-10 mmHg) compared with controls (38+/-3 mmHg), as well as during normoxic exercise (57+/-14 versus 38+/-7 mmHg) and hypoxic exercise (69+/-13 versus 49+/-8 mmHg). PASP could not be assessed in three and eight subjects during normoxic or hypoxic exercise, respectively, due to insufficient Doppler profiles or systemic arterial hypertension. Sensitivity (77-94%) and specificity (76-93%) were not significantly different between the various testing conditions. Additional assessment of hypoxic ventilatory response and lung function parameters did not improve identification of HAPE-susceptible subjects in a multivariate analysis. Due to the greater number of missing values in pulmonary artery systolic pressure measurements during hypoxic exercise, it was concluded that pulmonary artery systolic pressure measurements at rest during hypoxia or exercise in normoxia are most feasible for the identification of high-altitude pulmonary oedema-susceptible subjects.

Altitude↗

Determination of characteristic parameters of human postural dynamics.

Posture control performance was quantified in three variables (swiftness, stiffness, damping). Subjects were tested with a force platform recording body sway induced by vibrators attached to the calf muscles. Parameter estimation was made with identification of a transfer function representing the stabilized inverted pendulum. It is conjectured that the state feedback parameters identified are suitable for use in assessing ability to maintain posture.

Adult↗

[Analysis of various taxon specific parameters of the guard hair cuticles for development of the mammalian identification system by morphometric characteristics of their hair].

Mathematical indices of the structure of the external surface of guard hairs have been developed on the basis of a KS300 system of automatic image analysis (Kontrom Elektronik, Germany), which are capable of serving, in some cases, as diagnostic parameters of large taxa (order, family). The guard hair morphology is affected by various factors, such as body region where a given hair is located, season, diet, sex of individual, and state of its health, which is expressed in changes of some morphometric data. For a more complete analysis of the characteristics of the guard hair structure, it is necessary to use indices that describe the macro- and microstructure of the external surface of the stem and its internal structure.

Animals↗