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PubMedDate not supplied

Finite element based predictions of preferred material symmetries in saccular aneurysms.

Over the years, various hypotheses have implicated the role of structural instabilities in the expansion of intracranial saccular aneurysms. Recent nonlinear analyses suggest, however, that particular subclasses of aneurysms are structurally stable (in the mechanics sense) and that we must consider different hypotheses. Indeed, based on an ever-increasing database, it appears that aneurysms may well expand via the remodeling of their constituents. Although more data and a kinetics-based formulation of remodeling are needed to examine this hypothesis, we present results from quasistatic finite element analyses of 12 subclasses of lesions that support the remodeling hypothesis. Briefly, we identify regional variations in material symmetry, for a class of noncomplicated axisymmetric lesions subjected to a uniform distension pressure, that minimize local maxima in multiaxial stress and tend to homogenize the stress field. Such symmetries are termed preferred. It is shown that the numerical predictions are consistent with the teleological concept that some intracranial saccular aneurysms will seek to become spherical, since the sphere is an optimal geometry for resisting a distension pressure. To achieve this, however, different subclasses must develop differently. Lesions having an initially large neck:height ratio must increase in height and therefore may seek to become increasingly stiffer circumferentially from the fundus to the neck. Conversely, lesions having an initially small neck:height ratio must increase in breadth and therefore may seek to become increasingly stiffer meridionally from the fundus to the neck. We submit that these results demonstrate the need for a detailed histological examination of regional variations in collagen organization in human lesions, for it is upon data that an analysis of remodeling must be founded.

Anisotropy↗
PubMed2002

Development of biologic markers of response and assessment of antiangiogenic activity in a clinical trial of human recombinant endostatin.

PURPOSE: Angiogenesis is a target for the treatment of cancer and other diseases, and its complex biology suggests that establishing the appropriate dose and schedule for antiangiogenic treatment will require extensive study. We present the initial results of a dose-finding clinical trial of recombinant human endostatin (rh-Endo) that examined potential surrogates for response to antiangiogenic therapy. PATIENTS AND METHODS: Twenty-five patients were treated with escalating doses of rh-Endo. Positron emission tomography (PET) was used to assess tumor blood flow (with [15O]H2O) and metabolism (with [18F]fluorodeoxyglucose) before the start of therapy and then every 4 weeks. To directly assess the effects of rh-Endo on endothelial cells within the tumors, biopsy specimens of tumor tissue were obtained before therapy and again at 8 weeks and evaluated for endothelial cell and tumor cell apoptosis. RESULTS: Tumor blood flow and metabolism as measured by PET scans generally decreased with increasing doses of rh-Endo; however, the effects were complex and in some analyses nonlinear. Tumor biopsy analysis revealed a significant increase in tumor cell apoptosis (P =.027) and endothelial cell apoptosis (P =.027) after 8 weeks of therapy. However, there was no statistically significant relationship between rh-Endo dose and induction of tumor cell or endothelial cell apoptosis. CONCLUSION: These initial data suggest that rh-Endo has measurable effects on tumor blood flow and metabolism and induces endothelial and tumor cell apoptosis even in the absence of demonstrable anticancer effects. Further study and validation of these biomarkers in the context of antiangiogenic therapy will be required.

Adenocarcinoma↗
PubMed2006

Linear data mining the Wichita clinical matrix suggests sleep and allostatic load involvement in chronic fatigue syndrome.

OBJECTIVES: To provide a mathematical introduction to the Wichita (KS, USA) clinical dataset, which is all of the nongenetic data (no microarray or single nucleotide polymorphism data) from the 2-day clinical evaluation, and show the preliminary findings and limitations, of popular, matrix algebra-based data mining techniques. METHODS: An initial matrix of 440 variables by 227 human subjects was reduced to 183 variables by 164 subjects. Variables were excluded that strongly correlated with chronic fatigue syndrome (CFS) case classification by design (for example, the multidimensional fatigue inventory [MFI] data), that were otherwise self reporting in nature and also tended to correlate strongly with CFS classification, or were sparse or nonvarying between case and control. Subjects were excluded if they did not clearly fall into well-defined CFS classifications, had comorbid depression with melancholic features, or other medical or psychiatric exclusions. The popular data mining techniques, principle components analysis (PCA) and linear discriminant analysis (LDA), were used to determine how well the data separated into groups. Two different feature selection methods helped identify the most discriminating parameters. RESULTS: Although purely biological features (variables) were found to separate CFS cases from controls, including many allostatic load and sleep-related variables, most parameters were not statistically significant individually. However, biological correlates of CFS, such as heart rate and heart rate variability, require further investigation. CONCLUSIONS: Feature selection of a limited number of variables from the purely biological dataset produced better separation between groups than a PCA of the entire dataset. Feature selection highlighted the importance of many of the allostatic load variables studied in more detail by Maloney and colleagues in this issue [1] , as well as some sleep-related variables. Nonetheless, matrix linear algebra-based data mining approaches appeared to be of limited utility when compared with more sophisticated nonlinear analyses on richer data types, such as those found in Maloney and colleagues [1] and Goertzel and colleagues [2] in this issue.

Adult↗
PubMed2000

Effect of dietary concentration of metabolizable lysine on finishing cattle performance.

A finishing trial and a metabolism trial were conducted to determine the effect of supplemental metabolizable Lys level on finishing calf performance and to estimate the metabolizable Lys requirement of finishing calves. The finishing trial included 60 individually fed crossbred beef steer calves (237 kg; SD = 20 kg) supplemented with either incremental amounts of rumen-protected Lys and Met, or Met alone. Addition of Lys and Met improved gains and efficiencies (quadratic; P < .02) during the first 56 d. There was no response to supplemental Met alone, suggesting that supplemental Lys rather than Met was responsible for the improvement in performance. Using nonlinear analyses to compare gain relative to supplemental Lys intake, maximum gain was determined to be 2.10 kg/d, or .27 kg/d above the zero Lys control, at a supplemental Lys intake of 2.56 g/d. Steers supplemented with 3 and 4 g of Lys had a weight advantage over the control steers of 16 kg at 56 d and 32 kg at the end of the 161-d trial. However, there were no statistical responses to Lys or Met during any periods after 56 d. During a separate metabolism trial, four steers fed the control finishing diet were slaughtered, and abomasal contents were collected for amino acid analyses. The predicted (Level 1 NRC, 1996) metabolizable protein flow to the abomasum for the control diet was 715 g/d, and the predicted Lys flow was 37.9 g/d. A supplemental Lys intake of 2.56 g/d would increase the Lys flow to 40.5 g/d. Feedlot diets low in ruminal escape protein may be deficient in metabolizable Lys, especially early in the feeding period. The metabolizable Lys requirement of steer calves gaining 2.10 kg/d is estimated to be 40.5 g/d.

Amino Acids↗
PubMed1989

Analysis of the binding sites for the cardiotonic phosphodiesterase inhibitor [3H]LY186126 in ventricular myocardium.

The positive inotropic action of the newer cardiotonic phosphodiesterase inhibitors such as indolidan, milrinone, and imazodan has been previously attributed to selective inhibition of cGMP-inhibitable Type IV (high affinity) cAMP phosphodiesterase activity. However, the subcellular binding site(s) for this class of compounds has not been defined. We have characterized the binding of [3H]LY186126, an analogue of indolidan, in subcellular fractions prepared from rabbit and sheep ventricular myocardium. Binding required magnesium ion and exhibited rapid association and dissociation kinetics. Specific binding (defined by ligand displacement with 5 microM indolidan) to enriched rabbit sarcoplasmic reticulum (SR) membrane vesicles was saturable (Bmax = 714 +/- 77 fmol/mg of protein) and of high affinity (Kd = 6.2 +/- 1.4 nM). Linear and nonlinear analyses of the binding isotherms fit a single-site model. Mixed SR preparations from sheep myocardium exhibited binding characteristics (Bmax = 944 +/- 115 fmol/mg; Kd = 8.5 +/- 2.3 nM) comparable to those of rabbit cardiac SR. Further subfractionation of sheep SR indicated that the binding sites were equally distributed between free (Bmax = 630 fmol/mg; Kd = 4.4 nM) and junctional SR (Bmax = 569 fmol/mg; Kd = 10.9 nM). Specific binding of [3H]LY186126 was also demonstrated in the cytosolic subfraction of rabbit myocardium that contained Type IV phosphodiesterase activity (Peak III from anion exchange chromatography). Competition for [3H] LY186126 binding studied in rabbit SR showed that, of the compounds tested, lixazinone (RS 82856) competed most effectively (IC50 = 0.030 +/- 0.008 nM), followed by indolidan (0.14 +/- 0.05 nM), cGMP (17.8 +/- 2.6 nM), milrinone (39.3 +/- 13.2 nM), and imazodan (192 +/- 73 nM). In contrast, rolipram, which does not inhibit SR-associated Type IV phosphodiesterase activity, was not effective at competing for [3H]LY186126 binding (IC50 greater than 30 microM). These results indicate that [3H]LY186126 has specific binding sites in myocardial subcellular fractions that contain cGMP-inhibitable Type IV (high affinity) cAMP phosphodiesterase activity.

Animals↗
PubMed1998

[From Chronos to Chaos: from the determinism of circadian rhythm of arterial pressure to the undeterminism of hypertensive crises].

This paper delineates the scientific though about the disorder (chaos) in dynamic phenomena. The discussion shows how the periodic functions, which are intrinsically deterministic, can break down into chaotic patterns, either global or catastrophic, because of their "dependence on the limits in the oscillatory modulation" (cycle stress limits). The argumentations demonstrate that order and disorder, chronos and chaos, are intrinsic aspects of dynamic phenomena. The text presents the fractal mathematics for analysing nonlinear events. The fractal interpolation is proposed for predicting the potential risk of hypertensive crisis using the noninvasive ambulatory blood pressure monitoring.

Blood Pressure↗
PubMed2005

A comparison of nonlinear mixed-model analyses for a pediatric pharmacokinetic study.

Nonlinear mixed models are important tools for analyzing repeated measures data. In particular, these models are used for population pharmacokinetic analyses for estimating population pharmacokinetic parameters. As more clinical studies are performed for the advancement of treatment of pediatric patients, methodology is needed for comparing results from pharmacokinetic studies in pediatric patients and adult control groups. These pediatric studies introduce complexities to the design and analysis, including how analysis of sparse data affects the limitations of model selection. A case study is presented demonstrating that good communication with regulatory agencies and appropriate selection of analysis models are integral parts of completing population analyses for timely approval and labeling of drugs for treating pediatric patients.

Adult↗
PubMed1993

Nonlinear mixed model analyses of five production disorders of dairy cattle.

A standardized threshold model was used to estimate herd variability and the impact of some risk factors on the incidence of retained placenta, metritis, ketosis, ovulatory dysfunction, and mastitis. Data consisted of records for 18,110 Swedish Red and White cows in 924 herds and 14,940 Swedish Friesian cows in 772 herds. Only first, second, and third party cows were included, and the breeds were analyzed separately. Herds were considered to be random effects, and variance components were estimated by the counterpart of REML for a threshold model. Estimated intraherd correlations varied from .04 to .18 and were lowest for the incidence of retained placenta (for both breeds) and highest for ketosis and ovulatory dysfunction for Swedish Red and White and Swedish Friesian breeds, respectively. Parity increased predicted lactational incidence risks for all disorders except metritis, but season of calving had no profound effect. Dystocia and stillbirth increased the risk of retained placenta; dystocia and retained placenta increased the risk of metritis. The risk of ketosis was not influence by any of the considered risk factor diseases, and the risk of mastitis was influenced only by retained placenta for Swedish Red and White cows. For both breeds, the risk of ovulatory dysfunction was increased by metritis and ketosis.

Animals↗
PubMed2004

A numerical formulation for nonlinear ultrasonic waves propagation in fluids.

A finite-difference algorithm is developed for analysing the nonlinear propagation of pulsed and harmonic ultrasonic waves in fluid media. The time domain model allows simulations from linear to strongly nonlinear plane waves including weak shock. Effects of absorption are included. All the harmonic components are obtained from only one solving process. The evolution of any original signal can be analysed. The nonlinear solution is obtained by the implicit scheme via a fast linear solver. The numerical model is validated by comparison to analytical data. Numerical experiments are presented and commented. The effect of the initial pulse shape on the evolution of the pressure waveform is especially analysed.

Journal Article↗
PubMed2003

[Influence of initial chirp on the evolution of spectra].

The influence of dispersion and nonlinearity on the spectra was analysed. The nonlinear Schrödinger equation was solved numerically in the frequency domain. The effect of the initial chirp on the spectra of different formats was simulated. It was found that the influence of the initial chirp on the spectra changed with different formats. The positive initial chirps make spectra spreading and negative initial chirps have little influence upon spectra for Gauss pulses. For super Gauss pulses, the spectra have some side tails, which cause energy loss, but the initial chirp has very little effect on the spectra. The initial chirps have a great influence on the spectra for soliton pulse, especially for high order soliton, which suggests that initial chirp must be decreased for stable pulse transmission.

English Abstract↗
PubMed2004

Nonlinear complexity and spectral analyses of heart rate variability in medicated and unmedicated patients with schizophrenia.

OBJECTIVE: Heart rate variability (HRV) reflects functioning of the autonomic nervous system and possibly also regulation by the neural limbic system, abnormalities of which have both figured prominently in various etiological models of schizophrenia, particularly those that address patients' vulnerability to stress in connection to psychosis onset and exacerbation. This study provides data on cardiac functioning in a sample of schizophrenia patients that were either medication free or on atypical antipsychotics, as well as cardiac data on matched healthy controls. We included a medication-free group to investigate whether abnormalities in HRV previously reported in the literature and associated with atypical antipsychotics were solely the effect of medications or whether they might be a feature of the illness (or psychosis) itself. METHOD: We collected 24-hour ECGs on 19 patients and 24 controls. Of the patients, 9 were medication free and 10 were on atypical antipsychotics. All subject groups were matched for age and gender. Patient groups showed equivalent symptom severity and type, as well as duration of illness. We analyzed the data using nonlinear complexity (symbolic dynamic) HRV analyses as well as standard and relative spectral analyses. RESULTS: For the medication-free patients as compared to the healthy controls, our data show decreased R-R intervals during sleep, and abnormal suppression of all frequency ranges, but particularly the low frequency range, which persisted even after adjusting the spectral data for the mean R-R interval. This effect was exacerbated for patients on atypical antipsychotics. Likewise, nonlinear complexity analysis showed significantly impaired HRV for medication-free patients that was exacerbated in the patients on atypical antipsychotics. CONCLUSIONS: Altogether, the data suggest a pattern of significantly decreased cardiac vagal function of patients with schizophrenia as compared to healthy controls, apart from and beyond any differences due to medication side effects. The data additionally confirm earlier reports of a deleterious effect of atypical antipsychotics on HRV, which may exacerbate an underlying vulnerability in patients. These results support previous evidence that autonomic abnormalities may be a core feature of the illness (or psychosis), and that an even more conservative approach to cardiac risk in schizophrenia than previously thought may therefore be clinically appropriate.

Adult↗
PubMed2025

No More Free Lunch: Challenges to Mendelian Randomization Due to Sample Selection and Complex Methods.

Mendelian randomization (MR) is increasingly used in epidemiological studies to investigate causal relationships. MR depends on 3 fundamental instrumental variable assumptions: relevance, independence, and exclusion restriction. Studies often assume that MR mitigates bias from confounding due to the random allocation of genetic variants at conception. In this perspective, using causal directed acyclic graphs, we discuss several scenarios where biases in MR analyses may arise due to the nature of the data or methods being used. These include (1) collider bias due to the nonrandom selection of participants into study populations used for conducting genome-wide association studies (GWAS), (2) indirect genetic effects arising from population-based GWAS rather than within-family studies, and (3) collider bias due to gene-environment interaction effects on the exposure in nonlinear MR analyses. We provide practical considerations for examining and reducing these biases in MR analyses.

Humans↗
PubMed1998

Evaluation of the effect on heart rate variability of some agents acting at the beta-adrenoceptor using nonlinear scatterplot and sequence methods.

There is evidence that the processes regulating heart rate variability (HRV) reflect nonlinear complexity and show "chaotic" determinism. Data analyses using nonlinear methods may therefore reveal patterns not apparent with the standard methods for HRV analysis. We have consequently used two nonlinear methods, the Poincaré plot (scatterplot) and cardiac sequence (quadrant) analysis, in addition to the standard time-domain summary statistics, during a normal volunteer investigation of the effects on HRV of some agents acting at the cardiac beta-adrenoceptor. Under double-blind and randomized conditions (Latin square design), 25 normal volunteers received placebo, salbutamol 8 mg (beta 2-adrenoceptor partial agonist), pindolol 10 mg (beta 2-adrenoceptor partial agonist), or atenolol 50 mg (beta 1-adrenoceptor antagonist). Single oral doses of medication (at weekly intervals) were administered at 22:30 hours, with sleeping heart rates recorded overnight. The long-term (SDNN, SDANN) and short-term (rMSSD) time-domain summary statistics were reduced by salbutamol 8 mg and increased by atenolol 50 mg compared with placebo. The reductions in both SDNN and SDANN were greater after salbutamol 8 mg compared with pindolol 10 mg. The reduced HRV after pindolol 10 mg differed from the increased HRV following atenolol 50 mg. The Poincaré plot, constructed by plotting each RR interval against the preceding RR interval, was measured using a reproducible computerized method. Scatterplot length and area were reduced by salbutamol 8 mg and increased by atenolol 50 mg compared with placebo; scatterplot length and area were lower after pindolol 10 mg compared with atenolol 50 mg. Geometric analysis of the scatterplots allowed width assessment (i.e., dispersion) at fixed RR intervals. At the higher percentiles (i.e., 90% of scatterplot length: low HR), salbutamol 8 mg reduced and atenolol 50 mg increased dispersion; at lower percentiles (i.e., 10%, 25%, and 50% length), atenolol 50 mg and pindolol 10 mg increased dispersion compared with placebo and salbutamol 8 mg. Cardiac sequence analysis (differences between three adjacent beats; delta RR vs. delta RRn + 1) was used to assess the short-term patterns of cardiac acceleration and deceleration. Four patterns were identified: +/+ (a lengthening sequencing), +/- or -/+ (balanced sequences), and finally -/- (a shortening sequence). Cardiac acceleration episodes (i.e., number of times delta RR and delta RRn + 1 were both changed) were increased in quadrants -/- and +/+ following pindolol 10 mg and salbutamol 8 mg; the beat-to-beat difference (delta RRn + 1) was reduced after salbutamol 8 mg compared with the three other groups. These results demonstrated a shift towards sympathetic dominance (beta-adrenoceptor partial agonist salbutamol 8 mg) or parasympathetic dominance (beta 1-adrenoceptor antagonist atenolol 50 mg); pindolol 10 mg exhibited HR-dependent effects, reducing HRV at low but increasing variability at high prevailing heart rates. These nonlinear methods appear to be valuable tools to investigate HRV in health and to study the implications of perturbation of HRV with drug therapy in disease states.

Adrenergic beta-Agonists↗
PubMed1999

A pharmacokinetic model for tenidap in normal volunteers and rheumatoid arthritis patients.

PURPOSE: To develop a pharmacokinetic model for tenidap and to identify important relationships between the pharmacokinetic parameters and available covariates. METHODS: Plasma concentration data from several phase I and phase II studies were used to develop a pharmacokinetic model for tenidap, a novel anti-rheumatic drug. An appropriate pharmacokinetic model was selected on the basis of individual nonlinear regression analyses and an EM algorithm was used to perform a nonlinear mixed-effects analysis. Scatter plots of posterior individual pharmacokinetic parameters were used to identify possible covariate effects. RESULTS: Predicted responses were in good agreement with the observed data. A bi-exponential model with zero order absorption was subsequently used to develop the mixed-effects model. Covariate relationships selected on the basis of differences in the objective function, although statistically significant, were not particularly strong. CONCLUSIONS: The pharmacokinetics of tenidap can be described by a bi-exponential model with zero order absorption. Based on differences in the log-likelihood, significant covariate-parameter relationships were identified between smoking and CL, and between gender and Vss and CLd. Simulated sparse data analyses indicated that the model would be robust for the analysis of sparse data generated in observational studies.

Adult↗
PubMedDate not supplied

[Formation and stability of dissipative structures].

The nonlinear interaction of the disturbed wave packet modes has been analysed within nonlinear parabolic equation. There has also been designed the approach to a limit cycle regime of an isolated mode, the analytical stability criterion of the obtained solutions having separated the existance spheres of isolated and multimode regimes. Stochastization and self-organization processes taking place during the formation of dissipative structures have been studied by methods of random function theory.

Biophysical Phenomena↗
PubMed2006

Stability of dynamic trunk movement.

STUDY DESIGN: Nonlinear systems analyses of trunk kinematics were performed to estimate control of dynamic stability during repetitive flexion and extension movements. OBJECTIVE: Determine whether movement pace and movement direction of dynamic trunk flexion and extension influence control of local dynamic stability. SUMMARY OF BACKGROUND DATA: Spinal stability has been previously characterized in static, but not in dynamic movements. Biomechanical models make inferences about static spinal stability, but existing analyses provide limited insight into stability of dynamic movement. Stability during dynamic movements can be estimated from Lyapunov analyses of empirical data. METHODS: There were 20 healthy subjects who performed repetitive trunk flexion and extension movements at 20 and 40 cycles per minute. Maximum Lyapunov exponents describing the expansion of the kinematic state-space were calculated from the measured trunk kinematics to estimate stability of the dynamic system. RESULTS: The complexity of torso movement dynamics required at least 5 embedded dimensions, which suggests that stability components of lumbar lordosis may be empirically measurable in addition to global stability of trunk dynamics. Repeated trajectories from fast paced movements diverged more quickly than slower movement, indicating that local dynamic stability is limited in fast movements. Movements in the midsagittal plane showed higher multidimensional kinematic divergence than asymmetric movements. CONCLUSION: Nonlinear dynamic systems analyses were successfully applied to empirically measured data, which were used to characterize the neuromuscular control of stability during repetitive dynamic trunk movements. Movement pace and movement direction influenced the control of spinal stability. These stability assessment techniques are recommended for improved workplace design and the clinical assessment of spinal stability in patients with low back pain.

Adult↗