Calculating all multiple parameter solutions of ODE models to avoid biological misinterpretations.

Biological system's dynamics are increasingly studied with nonlinear ordinary differential equations, whose parameters are estimated from input/output experimental data. Structural identifiability analysis addresses the theoretical question whether the inverse problem of recovering the unknown parameters from noise-free data is uniquely solvable (global), or if there is a finite (local), or an infinite number (non identifiable) of parameter values that generate identical input/output trajectories. In contrast, practical identifiability analysis aims to assess whether the experimental data provide information on the parameter estimates in terms of precision and accuracy.

Modeling Pathological Hemodynamic Responses to the Valsalva Maneuver.

The Valsalva maneuver (VM) consisting in a forced expiration against closed airways is one of the most popular clinical tests of the autonomic nervous system function. When properly performed by a healthy subject, it features four characteristic phases of arterial blood pressure (BP) and heart rate (HR) variations, based on the magnitude of which the autonomic function may be assessed qualitatively and quantitatively. In patients with some disorders or in healthy patients subject to specific conditions, the pattern of BP and HR changes during the execution of the Valsalva maneuver may, however, differ from the typical sinusoidal-like pattern.

Mathematical modelling of cardiovascular response to the Valsalva manoeuvre.

The Valsalva manoeuvre (VM) used for clinical autonomic testing results in a complex cardiovascular response with a concomitant action of several regulatory mechanisms whose nonlinear interactions are difficult to analyse without the aid of a mathematical model. The article presents a new non-pulsatile compartmental model of the human cardiovascular system with a variable intrathoracic pressure enabling the simulation of the haemodynamic response to the VM. The model is based on physiological data and includes three baroreflex mechanisms acting on heart rate, systemic resistance and venous unstressed volume.

Prevalence of Cardiovascular Autonomic Neuropathy in a Cohort of Patients With Newly Diagnosed Type 2 Diabetes: The Verona Newly Diagnosed Type 2 Diabetes Study (VNDS).

Objective: Cardiovascular autonomic diabetic neuropathy (CAN) is a serious complication of diabetes. No reliable data on the prevalence of CAN among patients with newly diagnosed type 2 diabetes are available. Therefore, the aim of this study was to estimate the prevalence of CAN among patients with newly diagnosed type 2 diabetes.

Modeling glucose and free fatty acid kinetics during insulin-modified intravenous glucose tolerance test in healthy humans: role of counterregulatory response.

Insulin administration during insulin-modified intravenous glucose tolerance test (IM-IVGTT) can induce transient hypoglycemia in healthy insulin-sensitive subjects. This triggers counterregulatory reflex (CRR) responses, which influence the kinetics of glucose and nonesterified fatty acids (NEFA), and undermines the accuracy of mathematical modeling methods that do not explicitly account for CRR. The aim of this study is to evaluate mathematical models of glucose and NEFA kinetics against experimental data in the presence or absence of CRR.

A regional blood flow model for glucose and insulin kinetics during hemodialysis.

The distribution and elimination of a bolus of glucose injected during hemodialysis (HD) was examined using a distributed double-pool regional blood flow model. Intracorporeal glucose disposal was assumed as insulin-independent (λ) in the central high-flow compartment comprising blood, brain, and internal organs, including pancreatic insulin secretion (a, C1) and hepatic insulin clearance (α). Insulin-dependent (γ) glucose utilization was allocated to the low-flow system comprising muscle, skin, and bone.

Cats differ from other species in their cytokine and antioxidant enzyme response when developing obesity.

Objectives: Obese cats show many similarities to obese people, including insulin resistance and an increased diabetes risk. However, atherosclerosis and cardiovascular disease are not seen in cats. In people, they are associated with the development of an inflammatory response, which, we hypothesized, does not occur in cats.

Evaluation of long-term glucose homeostasis in lean and obese cats by use of continuous glucose monitoring.

Objective: To evaluate intraday and interday variations in glucose concentrations in cats and to test the utility of a continuous glucose monitoring system (CGMS).

Animals: 6 lean and 8 long-term (> 5 years) obese cats.

Procedures: Blood glucose concentrations were measured during the course of 156 hours by use of a laboratory hexokinase-based reference method and a handheld glucometer.

Insulinogenic index in non-diabetics during haemodialysis.

Background: The aim of this study was to analyse whether the insulin to glucose relationship following an intravenous glucose load in non-diabetic patients delivered during haemodialysis was affected by extracorporeal clearance and whether this relationship could be determined by an abridged sampling protocol.

Methods: Studies were done during routine haemodialysis following the infusion of 0.5 g glucose per kilogram body mass.

Intracorporeal glucose disposal during hemodialysis after a standardized glucose load.

The aim of this study was to quantify intracorporeal clearance and disposal of glucose after the administration of a standardized glucose load during regular hemodialysis done in stable and non-diabetic patients and to account for effects of extracorporeal clearance. A standardized load of glucose was administered approximately 30 min after starting hemodialysis with a constant dialysate glucose of 5.0 +/- 0.

Dissociated effects of glucose-dependent insulinotropic polypeptide vs glucagon-like peptide-1 on beta-cell secretion and insulin clearance in mice.

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) potently augment insulin response to glucose. It is less known what their effects are insulin clearance, which also contributes to peripheral hyperinsulinemia observed after administration of incretins together with glucose. The aims of this study were the quantification of C-peptide secretion and the evaluation of insulin clearance after administration of GIP with glucose.

Importance of glycemic control on the course of glomerular filtration rate in type 2 diabetes with hypertension and microalbuminuria under tight blood pressure control.

Background And Aims: To evaluate the role of glycemic control on the evolution of glomerular filtration rate (GFR) in type 2 diabetes (T2DM) with mild-moderate hypertension under tight blood pressure control, and to address the current controversy whether diabetic nephropathy worsens, independently of blood pressure, proportionally to HbA1c at any physiological level or only when HbA1c is above a 7.5-8% threshold.

Methods And Results: T2DM (N=127) during early stage diabetic nephropathy characterized by microalbuminuria were followed during a 2 year multicenter study.

Model-based assessment of insulin sensitivity of glucose disposal and endogenous glucose production from double-tracer oral glucose tolerance test.

A new mathematical model of short-term glucose regulation by insulin is proposed to exploit the oral glucose tolerance test (OGTT), which is commonly used for clinical diagnosis of glucose intolerance and diabetes. Contributions of endogenous and exogenous sources to measured plasma glucose concentrations have been separated by means of additional oral administration and constant intravenous infusion of glucose labeled with two different tracers. Twelve type 2 diabetic patients (7 males and 5 females) and 10 control subjects (5 males and 5 females) with normal glucose tolerance and matched body mass index (BMI) participated in this study.

A new equation for estimating renal function using age, body weight and serum creatinine.

Background: Many formulas have been developed to estimate glomerular filtration rate (GFR). The aim of our study was to propose a new, more reliable equation.

Methods: The study considered 530 subjects (training sample) with M/F 280/250, age 57.

The role of endocrine counterregulation for estimating insulin sensitivity from intravenous glucose tolerance tests.

Context: During insulin-modified frequently sampled iv glucose tolerance tests (IM-FSIGT), which allow assessment of insulin action, plasma glucose can markedly decrease.

Objective: This study aimed to assess the counterregulatory impact of the insulin-induced fall of glucose on minimal model-derived indices of insulin sensitivity (S(I)) and glucose effectiveness.

Participants: Thirteen nondiabetic volunteers (seven males, six females, aged 26 +/- 1 yr, body mass index 22.

Local influence analysis when interfacing toxicokinetic and proportional hazard models.

We present a local influence analysis to assigned model quantities in the context of a dose-response analysis of cancer mortality in relation to estimated absorbed dose of dioxin. The risk estimation is performed using dioxin dose as a time-dependent explanatory variable in a proportional hazard model. The dioxin dose is computed using a toxicokinetic model, which depends on some factors, such as assigned constants and estimated parameters.

Modeling population kinetics of free fatty acids in isolated rat hepatocytes using Markov Chain Monte Carlo.

The aim of this study is the characterization, by means of mathematical models, of the activity of isolated hepatic rat cells as regards the conversion of free fatty acids (FFA) to ketone bodies (KB). A new physiologically based compartmental model of FFA metabolism is used within a context of population pharmacokinetics. This analysis is based on a hierarchical model, that differs from standard model formulations, to account for the fact that some data sets belong to the same animal but have been collected under different experimental conditions.

Multidisciplinary modelling of biomedical systems.

This paper describes general principles and example results of a new software tool being developed for physiologically-based modelling of biomedical systems within a multidisciplinary framework. The aim is to overcome some limitations of currently available software designed either for general purpose or for highly specialised modelling applications. In fact, general purpose tools usually impose explicit coding of mathematical model equations or non-intuitive system representations, whereas specialised software use domain-specific notations that allow efficient and convenient model building only for special classes of systems.

Basal and dynamic proinsulin-insulin relationship to assess beta-cell function during OGTT in metabolic disorders.

The fasting proinsulin-to-insulin ratio is a currently used marker of beta-cell dysfunction. This ratio is calculated at the basal condition, but its behavior in dynamic conditions, i.e.

Population toxicokinetic analysis of 2,3,7,8-tetrachlorodibenzo-p-dioxin using Bayesian techniques.

Understanding the kinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) concentrations in humans is an important step for TCDD cancer risk assessment. In this paper longitudinal series of serum TCDD concentration measurements on U.S.