Analysis of immune cell populations in atrial myocardium of patients with atrial fibrillation or sinus rhythm.

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia and despite obvious clinical importance remains its pathogenesis only partially explained. A relation between inflammation and AF has been suggested by findings of increased inflammatory markers in AF patients. OBJECTIVE: The goal of this study was to characterize morphologically and functionally CD45-positive inflammatory cell populations in atrial myocardium of patients with AF as compared to sinus rhythm (SR). METHODS: We examined 46 subjects (19 with AF, and 27 in SR) undergoing coronary bypass or valve surgery. Peroperative bioptic samples of the left and the right atrial tissue were examined using immunohistochemistry. RESULTS: The number of CD3+ T-lymphocytes and CD68-KP1+ cells were elevated in the left atrial myocardium of patients with AF compared to those in SR. Immune cell infiltration of LA was related to the rhythm, but not to age, body size, LA size, mitral regurgitation grade, type of surgery, systemic markers of inflammation or presence of diabetes or hypertension. Most of CD68-KP1+ cells corresponded to dendritic cell population based on their morphology and immunoreactivity for DC-SIGN. The numbers of mast cells and CD20+ B-lymphocytes did not differ between AF and SR patients. No foci of inflammation were detected in any sample. CONCLUSIONS: An immunohistochemical analysis of samples from patients undergoing open heart surgery showed moderate and site-specific increase of inflammatory cells in the atrial myocardium of patients with AF compared to those in SR, with prevailing population of monocyte-macrophage lineage. These cells and their cytokine products may play a role in atrial remodeling and AF persistence.

Intelligent Soft Computing on Forex: Exchange Rates Forecasting with Hybrid Radial Basis Neural Network.

This paper deals with application of quantitative soft computing prediction models into financial area as reliable and accurate prediction models can be very helpful in management decision-making process. The authors suggest a new hybrid neural network which is a combination of the standard RBF neural network, a genetic algorithm, and a moving average. The moving average is supposed to enhance the outputs of the network using the error part of the original neural network. Authors test the suggested model on high-frequency time series data of USD/CAD and examine the ability to forecast exchange rate values for the horizon of one day. To determine the forecasting efficiency, they perform a comparative statistical out-of-sample analysis of the tested model with autoregressive models and the standard neural network. They also incorporate genetic algorithm as an optimizing technique for adapting parameters of ANN which is then compared with standard backpropagation and backpropagation combined with K-means clustering algorithm. Finally, the authors find out that their suggested hybrid neural network is able to produce more accurate forecasts than the standard models and can be helpful in eliminating the risk of making the bad decision in decision-making process.

A physiological view and structures of mean residence times.

The author's previous theoretical study described the determination of a physiologically realistic structure of a mean residence time of an intravenously administered drug (Durisová 2012). This study continues previous work and the aim is to determine physiologically realistic structures of mean residence times of a drug administered either orally (MRTpo) or intramuscularly (MRTim). The determinations are based on the following assumption: a cardiopulmonary, portal, portal-venous, hepatic-portal subsystem, and a subsystem that mathematically represents non-eliminating tissues can be considered to be most important in terms of their impact on MRTpo and MRTim. If drug fate and disposition is a linear process, the used method allows developing mathematical models without any prior knowledge or hypothesis concerning drug fate and disposition. This is a great advantage of the method considered here when compared with compartment methods. The research presented in this study was aimed at contributing to the knowledge base of physiological origins of mean residence times.

Physiologically based structure of mean residence time.

A mean residence time (MRT) is an important pharmacokinetic parameter. To the author's knowledge, however, a physiologically based structure of MRT (thereafter MRT structure) has not been published so far. Primarily this is because MRT structures cannot be identified by traditional pharmacokinetic methods used for the determination of MRT. Therefore, tools from the theory of linear dynamic systems were used for the structural identification of MRT in this study. The MRT structure identified is physiologically meaningful. Accordingly, it seems that the MRT structure identified may contribute to already established knowledge about MRT.

Novel approach to bioequivalence assessment based on physiologically motivated model.

The study was conducted to exemplify an approach capable of obtaining a new insight into bioequivalence (BE) assessment, by the use of a physiologically motivated model. Data from an oral BE study of two piroxicam (PXM) products was used as an example. The BE study was carried out with 24 healthy European subjects according to a two-sequence crossover-randomized design. The test and reference formulations were a PXM generic formulation (LaborMed Pharma, Romania) and Feldene (Pfizer, USA), respectively. Plasma concentrations of PXM were monitored by a validated high-performance liquid chromatography over a period of 144 h after administration. After the structure of the optimal model was selected, parameters that characterized the whole-body disposition behavior of PXM in the subjects were derived. The paired Student's t-test and Wilkoxon's test were performed on the derived parameters. The null hypothesis of no differences in the parameters of the whole-body disposition behavior of PXM related to the test and reference product was not rejected at 5% level of significance. This result suggested that the compared products were bioequivalent and could be used interchangeably in clinical setting. The presented approach might show a new way, worth incorporating in future BE guidelines.

Computer controlled sequential simulation method: reconsidering evaluation of measurements from frequently sampled intravenous glucose tolerance test.

This work describes quantification of regulatory mechanisms glucose-insulin, using data from a frequently sampled intravenous glucose tolerance test (FSIVGTT) and a mechanistically motivated model with time delays. FSIVGTT was performed on 14 young healthy volunteers. The constructed model computationally takes into account the form of the short-time glucose infusion used. Estimated model parameters are used to derive relationships quantifying the following mechanisms of regulatory systems glucose-insulin of the volunteers enrolled: (1) glucose uptake by body cells; (2) cessation (suppression) of glucose output from liver; (3) glucose clearance. The model presented correctly approximates initial peaks and subsequent waves in plasma glucose concentration-time profiles after the glucose infusion. These results indicate that the model presented is an appropriate tool for assessing glucose behavior during a FSIVGTT.

Physiologically motivated time-delay model to account for mechanisms underlying enterohepatic circulation of piroxicam in human beings.

The study was conducted to formulate a physiologically motivated time-delay (PM TD) mathematical model for human beings, which incorporates disintegration of a drug formulation, dissolution, discontinuous gastric emptying and enterohepatic circulation (EHC) of a drug. Piroxicam, administered to 24 European, healthy individuals in 20 mg capsules Feldene Pfizer, was used as a model drug. Plasma was analysed for piroxicam by a validated high-performance liquid chromatography method. The PM TD mathematical model was developed using measured plasma piroxicam concentration-time profiles of the individuals and tools of a computationally efficient mathematical analysis and modeling, based on the theory of linear dynamic systems. The constructed model was capable of (i) quantifying different fractions of the piroxicam dose sequentially disposable for absorption and (ii) estimating time delays between time when the piroxicam dose reaches stomach and time when individual of fractions of the piroxicam dose is disposable for absorption. The model verification was performed through a formal proof, based on comparisons of observed and model-predicted plasma piroxicam concentration-time profiles. The model verification showed an adequate model performance and agreement between the compared profiles. Accordingly, it confirmed that the developed model was an appropriate representative of the piroxicam fate in the individuals enrolled. The presented model provides valuable information on factors that control dynamic mechanisms of EHC, that is, information unobtainable with the models proposed for the EHC analysis previously.

Estimation of influence of gastric emptying on shape of glucose concentration-time profile measured in oral glucose tolerance test.

AIMS: To develop a model for simulations of processes in the oral glucose tolerance test (OGTT), using tools of the theory of dynamic systems. METHODS: Frequent sampling OGTT was performed in 13 healthy subjects (6 males and 7 females). Subsequently, employing glucose and insulin concentration-time profiles of the subjects, the model was developed. RESULTS: In all subjects the model was able to simulate influences of the insulin plasma concentration and gastric emptying rate on glucose concentration and to determine time profiles of glucose fractions retained in stomach. CONCLUSIONS: The approach presented represents an opportunity for building models for data analyses in OGTT.

New mathematical methods in pharmacokinetic modeling.

In recent years, several new methods for the mathematical modeling have gradually emerged in pharmacokinetics, and the development of pharmacokinetic models based on these methods has become one of the most rapidly growing and exciting application-oriented sub-disciplines of the mathematical modeling. The goals of our MiniReview are twofold: i) to briefly outline fundamental ideas of some new modeling methods that have not been widely utilized in pharmacokinetics as yet, i.e. the methods based on the following concepts: linear time-invariant dynamic system, artificial-neural-network, fuzzy-logic, and fractal; ii) to arouse the interest of pharmacological, toxicological, and pharmaceutical scientists in the given methods, by sketching some application examples which indicate the good performance and perspective of these methods in solving pharmacokinetic problems.

Modeling behavior of protein C during and after subcutaneous administration.

Protein C is an important blood factor protein that regulates the blood coagulation process. Deficiency of protein C can lead to excessive coagulation that results in lack of tissue oxygenation, causing conditions such as deep vein thrombosis, pulmonary embolism, and stroke. Human protein C has been approved as a treatment for congenital protein C deficiency; however, the therapy requires frequent injections, due to the short residence time of the protein. Subcutaneous administration has been examined as an alternative to increase residence time and decrease injection frequency, thereby creating a more patient-friendly dosing regimen. In order to design an efficient injection or infusion protocol for subcutaneously administered proteins, it is important to accurately model the behavior (absorption, distribution, elimination) of these proteins in the body. However, several factors involved in a subcutaneous injection of the protein make modeling this behavior a challenging task. For example, absorption of the drug from the subcutaneous site into the blood stream can be variable depending on the site of injection, physical activity of the patient, etc. Furthermore, degradation of the protein can occur at the site of injection and further modify its absorption. The objective of this work was to demonstrate the utility of frequency response modeling as an alternative method to analyze the behavior of subcutaneously administered protein C. The results of our study indicate that if the dose range yielding the constant clearance of protein C is identified for the patient, models of that type, as presented in our study, can be used to adjust optimal dosing of protein C necessary to reach prescribed levels of the protein in this patient at desired time points, both specified by treatment requirements.

System-approach methods for modeling and testing similarity of in vitro dissolutions of drug dosage formulations.

System-approach based modeling methods are used to model dynamic systems describing in vitro dissolutions of drug dosage formulations. Employing the models of these systems, model-dependent criteria are proposed for testing similarity between in vitro dissolutions of different drug dosage formulations. The criteria proposed are exemplified and compared with the criterion called the similarity factor f(2), commonly used in the field of biomedicine. Advantages of the criteria proposed over this factor are presented.

A system-approach method for the adjustment of time-varying continuous drug infusion in individual patients: a simulation study.

The aim of this simulation study was to present a system-approach method for adjustment of continuous drug infusions at time-varying rates, aimed at achieving and then maintaining required drug concentration-time profiles in patients. The method presented can be used for safe and cost-effective individualization of drug dosing by computer-controlled infusion pumps. Utilization of this method is exemplified by simulation experiments, aimed at adjusting continuous infusions of Factor VIII (FVIII) at time-varying rates, which would theoretically yield required concentration-time profiles of FVIII in hemophilia A patients over several days.