Biomedical subjects

K Thomaseth

Publications and source records attributed to K Thomaseth.

31 records · Page 2Linked to original sources

PubMed1996

Integrated mathematical model to assess beta-cell activity during the oral glucose test.

A model describing beta-cell secretion during an oral glucose tolerance test (OGTT) is introduced. The aim was to quantify beta-cell activity in different pathologies by analyzing peripheral concentration data of insulin, C-peptide, and islet amyloid polypeptide (IAPP). Insulin appearance in periphery is given by the fraction of C-peptide secretion, CPS(t), which accounts for liver degradation. A novelty of this study is the inclusion of IAPP delivery assumed proportional to CPS(t). Although IAPP fractional clearance is estimated in every subject, the clearances of insulin and C-peptide are assigned from a wide set of previous independent studies. Sensitivity analysis was performed to quantify the "error" in the estimated variables due to these assignments. All parameters relating to beta-cell secretion increased in the glucose-intolerant states [integrated CPS(t)=56 +/- 8 nmol/l in 180 min vs. 32 +/- 3 of controls, P<0.05; total IAPP delivery= 83 +/- 21 pmol/l in 180 min vs. 41 +/- 6, P<0.05]. Elevated plasma IAPP concentration of the patients was due to augmented secretion since IAPP clearance was found to be even slightly greater than in controls, (0.053 +/- 0.011 vs. 0.034 +/- 0.004 min-1) and markedly lower than that of insulin (0.14 +/- 0.02, P<0.01). In conclusion, the model introduced here allows the characterization of beta-cell secretory parameters during a simple test such as OGTT.

Amyloid↗

PubMed1996

Power spectral analysis of heart rate in hyperthyroidism.

The aim of the present study was to evaluate the impact of hyperthyroidism on the cardiovascular system by separately analyzing the sympathetic and parasympathetic influences on heart rate. Heart rate variability was evaluated by autoregressive power spectral analysis. This method allows a reliable quantification of the low frequency (LF) and high frequency (HF) components of the heart rate power spectral density; these are considered to be under mainly sympathetic and pure parasympathetic control, respectively. In 10 newly diagnosed untreated hyperthyroid patients with Graves' disease, we analyzed power spectral density of heart rate cyclic variations at rest, while lying, and while standing. In addition, heart rate variations during deep breathing, lying and standing, and Valsalva's maneuver were analyzed. The results were compared to those obtained from 10 age-, sex-, and body mass index-matched control subjects. In 8 hyperthyroid patients, the same evaluation was repeated after the induction of stable euthyroidism by methimazole. Heart rate power spectral analysis showed a sharp reduction of HF components in hyperthyroid subjects compared to controls [lying, 13.3 +/- 4.1 vs. 32.0 +/- 5.6 normalized units (NU; P < 0.01); standing, 6.0 +/- 2.7 vs. 15.0 +/- 4.0 NU (P < 0.01); mean +/- SEM]. On the other hand components were comparable in the 2 groups (lying, 64.0 +/- 6.9 vs. 62.0 +/- 6.5 NU; standing, 77.0 +/- 6.5 vs. 78.0 +/- 5.4 NU). Hence, the LF/HF ratio, which is considered an index of sympathovagal balance, was increased in hyperthyroid subjects while both lying (11.3 +/- 4.5 vs. 3.5 +/- 1.1; P < 0.05) and standing (54.0 +/- 12.6 vs. 9.8 +/- 2.6; P < 0.02). This parameter was positively correlated with both T3 (r = 0.61; P < 0.05) and free T4 (r = 0.63; P < 0.05) serum levels. Among traditional cardiovascular autonomic tests, the reflex response of heart rate during lying to standing was significantly lower in hyperthyroid patients than in controls (1.12 +/- 0.03 vs. 1.31 +/- 0.04; P < 0.002). No statistically significant difference in reflex responses between the two groups was found in deep breathing or Valsalva's maneuver. In the 8 patients reexamined after methimazole treatment, we observed complete normalization of altered cardiovascular parameters, with slight predominance of the vagal component compared with controls. These results suggest that thyroid hormone excess may determine reduced parasympathetic activity and, thus, a relative hypersympathetic tone.

Adolescent↗

PubMed1996

Plasma clearance rate of 51Cr-EDTA provides a precise and convenient technique for measurement of glomerular filtration rate in diabetic humans.

It has not yet been fully clarified whether the plasma or renal clearance approach is the most reliable to investigate GFR in humans. The study presented here aimed to compare plasma decay with renal clearance of 51Cr-EDTA in 27 diabetic patients with patterns of renal function broadly dispersed in a wide range of values. Moreover, the comparison was also performed with renal clearance of nonlabeled iothalamate in a subgroup of 17 patients. A biexponential function was found to fulfill statistical and heuristic criteria for the modeling analysis of plasma 51Cr-EDTA decay with 19 samples after bolus intravenous 51Cr-EDTA injection. Individual GFR values from 51Cr-EDTA plasma clearance highly correlated with those from renal clearance (r2 = 0.977, P < 0.0001), but resulted on average about 2.5 mL.min-1.1.73 m-2 higher (66.8 +/- 6.5 mL.min-1.1.73 m-2 (mean +/- SE) versus 64.3 +/- 6.4, P < 0.02). This difference remained relatively constant from patients with normal renal function to those with impaired renal function, suggesting that the plasma clearance is slightly less accurate than renal clearance approach because of a constant extrarenal clearance rate. In the subgroup studied, a similar difference was found between GFR values from 51Cr-EDTA plasma clearance (84.7 +/- 7.3) and renal clearance of iothalamate (82.8 +/- 7.3), although not statistically significant (P = 0.4). Individual GFR values well correlated (r2 = 0.913, P < 0.0001). The precision and reproducibility of the experimental approaches were assessed by comparing three coefficients of variation: (1) CVb of the bolus injection, because of measurement errors; (2) CVc of the continuous infusion, which additionally includes errors of urine volume measurement and physiological variability in the same day; and (3) CVr of repeated measurements by using bolus injection, which also accounts for physiological variability in different days. CVc of iothalamate and 51Cr-EDTA infusions were 7.5 +/- 1.9% and 7.4 +/- 1.2% respectively. CVb and CVr of bolus injection of 51Cr-EDTA were 2.6 +/- 0.3% and 3.5 +/- 0.8% respectively. CVb and CVr of bolus injection of 51Cr-EDTA, but not CVc of iothalamate and 51Cr-EDTA infusions were twofold to tenfold lower than the percent yearly change reported in IDDM and NIDDM patients. More particularly, CVr was significantly less than CVc. In order to make the test less cumbersome, a reduced sampling schedule with seven samples was designed and validated. GFR measured with seven samples was 66.1 +/- 6.4 (P = 0.1 when compared with the full 19-sample schedule) with a CVb of 3.5 +/- 0.5%. This seven-sample protocol was not different from that obtained with the previously described simplified method of Brøchner-Mortensen (63.9 +/- 6.8, P = 0.16), yet yielding a statistically more accurate estimate (coefficient of variation for Brøchner-Mortensen method = 12.1 +/- 2.9, P = 0.004). Moreover, only bolus injection, along with modeling analysis of plasma clearance rate, allows the accurate measurement of the extracellular fluid volume, an important parameter in diabetic patients. It was concluded that the reduced seven-plasma sample protocol is able to detect as small as 4 to 5% changes per year in a single patient. Moreover, it provides precise and accurate estimate of GFR in diabetic patients with hyperfiltration, who are postulated to be at higher risk to develop renal damage.

Chromium Radioisotopes↗

PubMed1996

On-line urea kinetics in haemodiafiltration.

BACKGROUND: Calculation of Kt/V and assessment of nutrition have so far been dependent upon off-line urea measurements of blood or dialysate samples. Here we describe a biosensor for on-line urea measurement during haemodiafiltration. Methods. The biosensor consisted of a cartridge containing covalently linked urease placed between two conductivity cells. The biosensor was placed on the outlet line of a haemofilter in series with a dialyser in order to obtain an aliquot of plasma ultrafiltrate for on-line measurement of urea. RESULTS: Urea nitrogen concentrations were highly correlated to the difference (Delta) in conductivity measured by the two conductivity cells both in aqueous solutions (in-vitro studies, y=-6. 676+32.12x, R2=0.998, P<0.0001) and in ultrafiltrates (ex-vivo studies, y=-637+32.01x, R2=0.98, P<0.00001). Delta conductivity was highly reproducible (% variation: ).8-5.3%) and stable (maximal % variation at 150 mg/dl after 100 min. 0.9+/-0.3 vs initial values). The intradialytic plasma water urea profile was obtained in 10 haemodialysis patients. To study recirculation, the plasma water urea profile was analysed before and 3 min after stopping the dialysate flow. The pre- and post-stopped flow ratio (1.21+/-0.1, mean+/-1 SD) was superimposable to conventional blood sampling data (opposite arm venous arterial: 1.22+/-0.11) and allowed correction for recirculation. A novel approach to urea kinetic modelling was described and used to reliably project end-dialysis and post-dialysis rebound urea concentration as early as 90 min. Projected (29.2+/-10.4 g) or measured (29.8+/-10.5 g) net urea removal was highly correlated with the amount of urea collected in the total spent dialysate (29.7+/-10.6 g) (R2=0.99, R2=0.97 respectively). CONCLUSIONS: These results indicate that on-line, real-time analysis of urea kinetics may provide information on delivery of adequate dialysis in high-efficiency techniques.

Adult↗

PubMed1995

Analysis of errors due to assigned model constants in pharmacokinetic calculations based on functional optimization.

Mathematical models in pharmacokinetic studies frequently include, in addition to model parameters that are estimated from experimental data, model constants that are directly measured or derived from standardized, anthropometric formulae. Although these assigned constants are usually considered as error-free, uncertainties in their values affect the estimation precision of the remaining model parameters as well as the reliability of other derived quantities such as predictions of drug concentration levels or prescriptions of drug dosage. The present paper addresses the problem of quantifying the effects of errors in assigned model constants on the outcome of pharmacokinetic calculations. The error analysis is performed starting from the general assumption that the optimization of some objective function, such as encountered in parameter estimation, is involved. The proposed approach is based on the linearization of theoretical conditions that must be satisfied by the optimal solution of the problems. It requires quite complex mathematical calculations which can be however performed automatically by specific software based on symbolic computer algebra. Examples of applications are reported showing the usefulness of this kind of error analysis, in particular for detecting potentially critical error sources in the modeling of physiological systems and for suggesting improvements to experimental protocols for increasing the confidence in diagnostic and therapeutic decisions.

Administration, Oral↗

PubMed1994

PANSYM: a symbolic equation generator for mathematical modelling, analysis and control of metabolic and pharmacokinetic systems.

Software is presented for automatic generation of first-order ordinary differential equations (ODE) that arise from lumped parameter representations of metabolic and pharmacokinetic systems. The definition of system structures is accomplished by fractional transfer rates between state variables, together with input/output equations and initial conditions of state variables. General non-linear mathematical expressions can be assigned to all structure definition items. The software parses and interprets the system definitions and generates symbolically the mathematical expression of the model's set of ODE. In addition, symbolic derivatives of state equations are determined with respect to model parameters, state variables and external inputs. These derivatives represent the constituents of systems of sensitivity-differential and adjoint-differential equations that arise in identification and optimal control problems. Finally, output routines generate source code that, once compiled and linked to simulation programs, allows efficient numerical integration of the system of ODE. This software has been developed in PROLOG on Macintosh computers and has been extensively used with the programming environment MATLAB. Possible applications of this software include model building, sensitivity analysis, identification, optimal experiment design and numerical solution of optimal control problems.

Computer Simulation↗

PubMed1994

Role of islet amyloid polypeptide secretion in insulin-resistant humans.

Although it is generally accepted that islet amyloid polypeptide is cosecreted with insulin, relatively few data on its kinetics are available. We therefore studied the dynamics of islet amyloid polypeptide release following oral and frequently sampled intravenous glucose tolerance tests in comparison to insulin and C-peptide using mathematical model techniques in 14 control subjects, 10 obese and 11 hypertensive patients. The fractional clearance rate of islet amyloid polypeptide (0.034 +/- 0.004 min-1 in control subjects, 0.058 +/- 0.008 in the obese and 0.050 +/- 0.008 in the hypertensive patients) was significantly different (p < 0.01) in each group compared with that of insulin (0.14 +/- 0.03 min-1) and similar to that of C-peptide (0.061 +/- 0.007 min-1), at least in the insulin-resistant subjects. Based on the insulin sensitivity index derived from the minimal model analysis of intravenous glucose tolerance test data, both the hypertensive (2.4 +/- 0.4 min-1/(microU/ml); p < 0.0005) and the obese (2.7 +/- 0.5; p < 0.001) patients demonstrated severe insulin resistance compared to control subjects (8.1 +/- 1.3). Marked insulin hypersecretion was found in the hypertensive (57.6 +/- 5.2 nmol.l-1 in 180 min; p < 0.001) and obese (60.8 +/- 10.1; p < 0.003) patients in comparison with control subjects (32.4 +/- 3.2). The release of islet amyloid polypeptide was significantly higher in the hypertensive (83.1 +/- 16.6 pmol/l in 180 min; p < 0.02) and obese (78.6 +/- 13.1; p < 0.005) patients than in control subjects (40.5 +/- 6.4). No correlation was found between islet amyloid polypeptide release and the insulin sensitivity index in any group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1993

Role of hyperglycemia and insulin resistance in determining sodium retention in non-insulin-dependent diabetes.

Sodium retention has been advocated to give rise to hypertension in humans. Increases in blood glucose and insulin concentrations ensue in the stimulation of sodium reabsorption by the kidney. Although the combined occurrence of hyperglycemia and hyperinsulinemia, frequently secondary to insulin resistance with regard to carbohydrate metabolism, is a hallmark of non-insulin dependent diabetes (NIDDM), the role of these abnormalities in determining an impaired natriuresis in NIDDM is not yet fully understood. We studied sodium homeostasis in 14 control subjects and 59 NIDDM normotensive, normoalbuminuric patients who were divided into two groups with markedly impaired (Group 2 NIDDM: 30) and less severely impaired (Group 1 NIDDM: 29) insulin sensitivity during euglycemic-hyperinsulinemic (80 to 90 microU/ml plasma insulin) clamp. A hyperglycemic (9 mmol/liter plasma glucose)--nearly euinsulinemic (20 to 40 microU/ml plasma insulin) clamp was also performed in the same 14 controls and in two cohorts of 22 Group 2 and 17 Group 1 NIDDM patients. The two groups of patients had similar overnight fasting glucose levels (Group 1 NIDDM vs. Group 2 NIDDM: 176 +/- 13 vs. 185 +/- 15 mg/dl, mean +/- SE). Conversely, overnight fasting plasma insulin was significantly higher in Group 2 NIDDM than in Group 1 NIDDM patients (Group 1 NIDDM vs. Group 2 NIDDM: 12 +/- 3 vs. 18 +/- 3 microU/ml, P < 0.05). Both NIDDM Groups had higher plasma glucose and insulin than controls (75 +/- 4 mg/dl and 6 +/- 3 microU/ml). Blood pressure levels and albumin excretion rates were slightly but significantly higher in Group 2 NIDDM, but not in Group 1 NIDDM patients, than in controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1992

Power spectral analysis of heart-rate variations improves assessment of diabetic cardiac autonomic neuropathy.

Power spectral analysis (PSA) of heart-rate variations has recently proved a useful tool in evaluating cardiovascular autonomic activity. It offers the possibility of examining both the functioning of parasympathetic and sympathetic pathways through breakdown into two frequency bands, and of their effects on heart-rate cyclic variability. We applied an autoregressive model for PSA to study overall autonomic tone in 20 male age-matched control subjects and 53 insulin-dependent (type I) diabetic subjects, subdivided into three groups of 20, 15, and 18, each group presenting different degrees of autonomic involvement. We found that: 1) power spectrum density (PSD) values at high-frequency bands (parasympathetic dependent) were similar in diabetic subjects without cardiac autonomic neuropathy (CAN) and in control subjects, but differed significantly from diabetic subjects with mild CAN and severe CAN, both standing and lying; 2) PSD values at low frequency (mainly sympathetic dependent) were similar, or slightly different, in diabetic subjects without CAN and in control subjects, but differed significantly from diabetic subjects with mild and severe CAN, both standing and lying; 3) as an expression of parasympathetic versus sympathetic coherence, correlations, both standing and lying, existed between PSD values at low- and high-frequency bands in control and diabetic subjects without CAN, but not in diabetic subjects with CAN; and 4) different degrees of correlation characterized the PSD values of high and low frequencies versus traditional cardiovascular test values in the diabetic subjects. The best correlation was between PSD low-frequency values and the lying-to-standing maneuver.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1990

Heart rate spectral analysis for assessing autonomic regulation in diabetic patients.

Spectral analysis of the R-R variability signal has been used for assessing the autonomic regulation of heart rate in control subjects and in diabetic patients affected by autonomic neuropathy. Modifications of the parasympathetic-sympathetic balance following postural changes, as observed in normal subjects, were not significant in autonomic patients. In addition, the overall reduction of power occurring in diabetics at all frequencies indicates the impairment of both autonomic components.

Diabetes Mellitus↗

PubMedDate not supplied

OPSEG: a general routine for smoothing and interpolating discrete biological data.

The optimal segments technique is a new approach to smoothing and interpolating between small numbers of discrete biological data. This method balances the degree of smoothness against the expected error of the observed data. The OPSEG computer program searches for the set of smoothed data points which will match the overall difference between the smoothed and observed data to an a priori estimate of the measurement error. The smoothed curve is described as a series of linked individual line segments. This approach is useful for the analysis of biological signals such as plasma measurements of hormone and metabolite concentration and has been applied to the development of assay standard curves.

Biometry↗

PubMedDate not supplied

Generalized sensitivity functions in physiological system identification.

Parameters of physiological models are commonly associated in an input-output experiment with a specific pattern of the system response. This association is often made on an intuitive basis by traditional sensitivity analysis, i.e., by inspecting the variations of model output trajectories with respect to parameter variations. However, this approach provides limited information since, for instance, it ignores correlation among parameters. The aim of this study is to propose a new set of sensitivity functions, called the generalized sensitivity functions (GSF), for the analysis of input-output identification experiments. GSF are based on information theoretical criteria and provide, as compared to traditional sensitivity analysis, a more accurate picture on the information content of measured outputs on individual model parameters at different times. Case studies are presented on an input-output model and on two structural circulatory and respiratory models. GSF allow the definition of relevant time intervals for the identification of specific parameters and improve the understanding of the role played by specific model parameters in describing experimental data.

Animals↗

PubMedDate not supplied

Evaluation of the vagal-sympathetic interaction in diabetics with autonomic neuropathy through power spectrum density analysis of the heart rate. A critical revision of the natural history of diabetic autonomic neuropathy is possible.

In this paper we apply spectral analysis methods to heart rate variability to assess the autonomic nervous system activity in normal subjects and in patients affected by different degrees of diabetic autonomic neuropathy. The current opinion, based on different clinical tests, is that parasympathetic impairment occurs earlier in autonomic dysfunctions. However, the use of power spectrum density analysis based on a single parameter (heart rate) suggests a simultaneous involvement of parasympathetic and sympathetic pathways leading to the conclusion that perhaps the natural history of diabetic autonomic neuropathy should be substantially rewritten.

Autonomic Nervous System Diseases↗