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PubMed1997

Angiotensin II affects basal, pulsatile, and glucose-stimulated insulin secretion in humans.

Angiotensin II (Ang II) modulates the tissue response to insulin (insulin sensitivity), but the effect of Ang II on the secretion of insulin has not been investigated thus far. Nineteen healthy volunteers (17 male; mean age, 26+/-1 years) were studied. In a double-blind, randomized, placebo-controlled study, seven volunteers were allocated on three occasions in random order after an overnight fast to three interventions: (1) solvent (placebo) infusion; (2) infusion of 1.0 ng Ang II x kg(-1) x min(-1) (subpressor dose); and (3) infusion of 5.0 ng Ang II x kg(-1) x min(-1) (pressor dose). Frequent blood samples (each minute) were obtained for estimation of plasma insulin concentrations over a period of 120 minutes to assess basal and pulsatile insulin secretion. In an ancillary study, plasma glucose and insulin levels were measured after an oral glucose tolerance test while solvent (placebo) or Ang II was infused in 12 fasting healthy volunteers. Plasma insulin concentrations were measured immunoenzymatically (enzyme-linked immunosorbent assay). Insulin secretion pulses were analyzed with the deconvolution technique, and the regularity of insulin secretion was analyzed with the approximate entropy technique. Plasma insulin half-life was assessed using the hyperinsulinemic euglycemic clamp method. The pressor dose of Ang II reduced total, basal, and pulsatile insulin secretion, and this effect was highly significant (P<.01). The subpressor dose tended to suppress insulin secretion. The burst frequency (number of peaks) and the regularity of insulin secretion were not affected by administration of Ang II. After the oral glucose load, the insulinemic response was significantly lower and plasma glucose concentrations were significantly higher with infusion of Ang II compared with placebo. Ang II affects both the basal (nonpulsatile) and the pulsatile component of spontaneous insulin secretion and the glucose-stimulated insulin secretion in humans. This observation is of potential interest with respect to the interaction of Ang II and insulin, eg, in the genesis of hyperinsulinemia and hypertension.

Adult↗

PubMed2002

A method for measuring oxygen distributions in tissue using frequency domain phosphorometry.

Phosphorescence lifetime of phosphors dissolved in biological fluids is dependent on the local oxygen concentration. When phosphor is added to the blood in vivo there is a distribution of lifetimes due to the distribution of oxygen concentrations in the blood of the sampled tissue volume. The distribution of oxygen can be assessed non-invasively and in practically real-time using frequency domain time-resolved phosphorometry. Here we describe a multi-frequency system for measurements of oxygen distributions in tissue in vivo.

Entropy↗

PubMed1996

Control of pulsatile and tonic parathyroid hormone secretion by ionized calcium.

To investigate the effect of changes in ionized calcium on instantaneous PTH secretion, we examined seven young healthy volunteers by 1-min blood sampling under conditions of normo-, hypo-, and hypercalcemia. After a baseline period of 75 min, ambient ionized calcium was either increased or decreased by 0.2 mmol/L for 105 min by clamped infusion of calcium gluconate or sodium citrate. The characteristics of PTH secretion were analyzed by a deconvolution technique, accounting for subject-specific plasma PTH disappearance half-life, as measured during the first 15 min of calcium infusion (range, 2.04-2.93 min). The process regularity of pulsatile PTH secretion was evaluated by an approximate entropy statistic. Under baseline conditions, 32% of total PTH secretion was released in a pulsatile fashion, with a burst frequency of 6.9 +/- 0.8 h-1 and a PTH mass per burst of 2.6 +/- 0.9 pmol/L. The remaining 68% of total secretion was attributed to tonic hormone release. During the initial 30 min of induced hypocalcemia, pulsatile secretion increased by 1140%, whereas tonic secretion did not change. The preferential increase in pulsatile PTH secretion was mediated by a combined rise in burst frequency and mass released per burst. During subsequent steady state hypocalcemia, the tonic secretion rate increased (255% of baseline), whereas burst frequency and burst mass decreased (to 103% and 189% of the baseline values), restoring the baseline ratio of tonic to pulsatile PTH secretion. The regularity of PTH release increased during steady state hypocalcemia. During hypercalcemia, tonic secretion, burst mass, and burst frequency decreased by 75%, 82%, and 32%, respectively, and remained constant throughout the clamp period. We conclude that acute hypocalcemia elicits an immediate pulsatile and a delayed tonic secretory response of the parathyroid gland with increased regularity of PTH release. Acute hypercalcemia suppresses both the pulsatile and the tonic component of PTH secretion.

Adult↗

PubMed2005

Calculation of the Entropy of Lattice Polymer Models from Monte Carlo Trajectories.

While lattice models are used extensively for macromolecules (synthetic polymers proteins, etc), calculation of the absolute entropy, S, and the free energy, F, from a given Monte Carlo (MC) trajectory is not straightforward. Recently we have developed the hypothetical scanning MC (HSMC) method for calculating S and F of fluids. Here we extend HSMC to self-avoiding walks on a square lattice and discuss its wide applicability to complex polymer lattice models. HSMC is independent of existing techniques and thus constitutes an independent research tool; it provides rigorous upper and lower bounds for F, which can be obtained from a very small sample and even from a single chain conformation.

Journal Article↗

PubMed1973

A thermodynamic analysis of mitotic spindle equilibrium at active metaphase.

The mitotic apparatus of first-division metaphase eggs of the sea urchin Strongylocentrotus drobachiensis was observed by means of polarization microscopy under controlled temperature conditions. Eggs were fertilized and grown at two temperature extremes in order to produce two different sizes of available spindle pool. Slow division time allowed successive samples of such cells to be observed at the same point in metaphase but at different equilibrium temperatures, yielding curves of metaphase equilibrium birefringence vs. observational temperature. Using the plateau value of birefringence at higher temperatures as a measure of total available spindle pool and the observed birefringence at lower temperatures as a measure of polymerized material at equilibrium, the spindle protein association was evaluated according to the method of Inoué. Both pool conditions produced linear van't Hoff functions. Analysis of these functions yielded enthalpy and entropy changes of +55-65 kcal/mol and +197-233 entropy units (eu), respectively. These values for active mitotic metaphase are quite comparable to those obtained by Inoué and co-workers for arrested meiotic metaphase cells. When other equilibrium treatments were considered, the best fit to the experimental data was still that of Inoué, a treatment which theoretically involves first-order polymerization and dissociation kinetics. Treatment of metaphase cells with D(2)O by direct immersion drove the equilibrium to completion regardless of temperature, attaining or exceeding a birefringence value equal to the cell's characteristic pool size; perfusion with D(2)O appeared to erase the original temperature-determined pool size differences for the two growth conditions, attaining a maximum value characteristic of the larger pool condition. These data confirm Inoué's earlier contention that D(2)O treatment can modify the available spindle pool.

Animals↗

PubMed2004

Advanced search algorithms for information-theoretic learning with kernel-based estimators.

Recent publications have proposed various information-theoretic learning (ITL) criteria based on Renyi's quadratic entropy with nonparametric kernel-based density estimation as alternative performance metrics for both supervised and unsupervised adaptive system training. These metrics, based on entropy and mutual information, take into account higher order statistics unlike the mean-square error (MSE) criterion. The drawback of these information-based metrics is the increased computational complexity, which underscores the importance of efficient training algorithms. In this paper, we examine familiar advanced-parameter search algorithms and propose modifications to allow training of systems with these ITL criteria. The well known algorithms tailored here for ITL include various improved gradient-descent methods, conjugate gradient approaches, and the Levenberg-Marquardt (LM) algorithm. Sample problems and metrics are presented to illustrate the computational efficiency attained by employing the proposed algorithms.

Algorithms↗

PubMed1995

Increased disorderliness and amplified basal and pulsatile aldosterone secretion in patients with primary aldosteronism.

To investigate the pathophysiology of altered aldosterone secretion in patients with primary aldosteronism, the pulsatile mode of in vivo aldosterone and cortisol release was examined by quantitative deconvolution analysis in 5 normal subjects (controls) and 10 patients with aldosterone-producing adenomas (APA) under conditions of sodium (150 meq/day) balance. Episodic release of aldosterone and cortisol was assessed by sampling blood at 10-min intervals for 24 h. A waveform-independent deconvolution algorithm was used to calculate endogenous aldosterone and cortisol secretion rates on a sample by sample basis in each subject. There were no differences in the number of aldosterone or cortisol secretory bursts per day or their mean interpulse intervals between normal subjects and patients with primary aldosteronism. A 24-h rhythmicity in serum aldosterone concentrations was maintained in APA patients. Patients with primary aldosteronism had significantly higher (P < 0.01) aldosterone mean secretory rates, mean mass of aldosterone secreted per burst, maximal aldosterone secretion rates attained within each burst, and mean basal (nadir) aldosterone secretion rates. A recently introduced regularity statistic, approximate entropy (ApEn), was used to test for orderliness (small ApEn) vs. randomness (large ApEn) in the aldosterone time series. ApEn was significantly larger for the APA patients (1.433 +/- 0.148) than for normal subjects (0.306 +/- 0.098; P < 0.001), with complete group segmentation yielding 100% sensitivity and specificity. In contrast, a scale-invariant form of this measure, normalized ApEn, showed no significant distinction between tumoral and normal aldosterone release patterns. These ApEn findings taken together are consistent with the deconvolution results from an entirely distinct perspective, reinforcing an amplitude difference, but no frequency difference, between normal subjects and APA patients. Unexpectedly, patients with APA had significantly lower mean cortisol secretory rates, reduced cortisol secretory burst mass, and attenuated maximal cortisol secretory rates than normal subjects (P < 0.01). Plasma cortisol and aldosterone concentrations in patients remained positively correlated over short time lags. In summary, the present findings demonstrate that in normal subjects and patients with APA, both aldosterone and cortisol are secreted in a burst-like mode. The presence of substantial basal aldosterone release and increased irregularity of serial aldosterone concentrations distinguishes APA from normal subjects.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed1987

Assessment of analgesia by evoked cerebral potential measurements in humans.

This paper gives a brief account of new methods for the evaluation of pain and analgesia in healthy male volunteers by use of evoked cerebral potentials. In pain research, the so-called late components with latencies between 100 and 400 ms are usually used, but these potentials are non-specific, depending on a variety of factors e.g. on the activity of the ongoing electroencephalogram (EEG) on the subject's arousal/attention mechanisms, on the novelty of the stimulus and on its painfulness. Therefore, if evoked cerebral potentials in response to phasic pain stimuli are to be evaluated quantitatively, constant experimental conditions are essential, including subject selection to obtain as uniform a sample of volunteers as possible. Latency variation in evoked potential components in single studies makes signal averaging methods rather inaccurate to predict the effects of weak analgesics upon cerebral potentials in relation to time. Therefore single trial studies have been performed using transformation of post-stimulus EEG activity in terms of frequency. Because of the short duration of the evoked potentials, various parametric spectral estimators have been investigated for their advantages in EEG analysis. Frequency transformation of stimulus-induced cerebral activity by means of the maximum entropy method gives an enormous increase in the power in the 2-4 Hz frequency band with a very constantly located maximum. Examples are given showing that in this way it might be possible to monitor the time course of efficacy of even so-called weak analgesics.

Brain↗

PubMed2000

Prediction and significance of the temporal pattern of hormone secretion in disease states.

Comparison of the temporal pattern of hormone secretion in health and disease reveals distinct differences in many systems. Analysis of these visually apparent differences conventionally rests on computer-assisted programs based on either model assumptions, or estimations of hormonal decay rates or threshold values, all of which may not accurately reflect physiological and/or pathophysiological states. Only recently have new methods evolved which are independent of preexisting knowledge of the system under study. Apart from the widely used approximate entropy statistic (ApEn), a measure for the regularity of a time-series, artificial neural networks are able to capture temporal structures in endocrine rhythms without any previous assumptions. In particular, non-linear dynamical systems may be delineated and separated from random behaviour. This is achieved by mapping complex input data to a given complex output by propagating data from the input layer to the output layer through a larger number of interconnections, so-called hidden layers. The networks are capable to extract relevant features from training samples and store this information in the distributed structure of interconnections. Using this approach on growth hormone (GH) rhythms of healthy controls, fasted healthy subjects, untreated acromegalic patients and acromegalics under octreotide suppressive therapy we were recently able to demonstrate the power of this approach to differentiate the temporal pattern of GH secretion following normalization of the data for absolute amplitudes. In a second approach we were able to significantly reduce the number of data points required to characterize the temporal structure of these rhythms. This latter quality of the networks may help to transfer analysis of changes in the temporal pattern of hormone secretion on a more routine basis.

Human Growth Hormone↗

PubMed2005

Structural changes induced by lattice-electron interactions: SiO2 stishovite and FeTiO3 ilmenite.

The bright source and highly collimated beam of synchrotron radiation offers many advantages for single-crystal structure analysis under non-ambient conditions. The structure changes induced by the lattice-electron interaction under high pressure have been investigated using a diamond anvil pressure cell. The pressure dependence of electron density distributions around atoms is elucidated by a single-crystal diffraction study using deformation electron density analysis and the maximum entropy method. In order to understand the bonding electrons under pressure, diffraction intensity measurements of FeTiO3 ilmenite and gamma-SiO2 stishovite single crystals at high pressures were made using synchrotron radiation. Both diffraction studies describe the electron density distribution including bonding electrons and provide the effective charge of the cations. In both cases the valence electrons are more localized around the cations with increasing pressure. This is consistent with molecular orbital calculations, proving that the bonding electron density becomes smaller with pressure. The thermal displacement parameters of both samples are reduced with increasing pressure.

Journal Article↗

PubMed1998

Assessment of hepatitis C virus sequence complexity by electrophoretic mobilities of both single-and double-stranded DNAs.

To assess genetic variation in hepatitis C virus (HCV) sequences accurately, we optimized a method for identifying distinct viral clones without determining the nucleotide sequence of each clone. Twelve serum samples were obtained from seven individuals soon after they acquired HCV during a prospective study, and a 452-bp fragment from the E2 region was amplified by reverse transcriptase PCR and cloned. Thirty-three cloned cDNAs representing each specimen were assessed by a method that combined heteroduplex analysis (HDA) and a single-stranded conformational polymorphism (SSCP) method to determine the number of clonotypes (electrophoretically indistinguishable cloned cDNAs) as a measure of genetic complexity (this combined method is referred to herein as the HDA+SSCP method). We calculated Shannon entropy, incorporating the number and distribution of clonotypes into a single quantifier of complexity. These measures were evaluated for their correlation with nucleotide sequence diversity. Blinded analysis revealed that the sensitivity (ability to detect variants) and specificity (avoidance of false detection) of the HDA+SSCP method were very high. The genetic distance (mean +/- standard deviation) between indistinguishable cloned cDNAs (intraclonotype diversity) was 0.6% +/- 0.9%, and 98.7% of cDNAs differed by <2%, while the mean distance between cloned cDNAs with different patterns was 4.0% +/- 3.2%. The sensitivity of the HDA+SSCP method compared favorably with either HDA or the SSCP method alone, which resulted in intraclonotype diversities of 1.6% +/- 1.8% and 3.5% +/- 3.4%, respectively. The number of clonotypes correlated strongly with genetic diversity (R2, 0.93), but this correlation fell off sharply when fewer clones were assessed. This HDA+SSCP method accurately reflected nucleotide sequence diversity among a large number of viral cDNA clones, which should enhance analyses to determine the effects of viral diversity on HCV-associated disease. If sequence diversity becomes recognized as an important parameter for staging or monitoring of HCV infection, this method should be practical enough for use in laboratories that perform nucleic acid testing.

Cloning, Molecular↗

PubMed2001

Excluded volume in protein side-chain packing.

The excluded volume occupied by protein side-chains and the requirement of high packing density in the protein interior should severely limit the number of side-chain conformations compatible with a given native backbone. To examine the relationship between side-chain geometry and side-chain packing, we use an all-atom Monte Carlo simulation to sample the large space of side-chain conformations. We study three models of excluded volume and use umbrella sampling to effectively explore the entire space. We find that while excluded volume constraints reduce the size of conformational space by many orders of magnitude, the number of allowed conformations is still large. An average repacked conformation has 20 % of its chi angles in a non-native state, a marked reduction from the expected 67 % in the absence of excluded volume. Interestingly, well-packed conformations with up to 50 % non-native chi angles exist. The repacked conformations have native packing density as measured by a standard Voronoi procedure. Entropy is distributed non-uniformly over positions, and we partially explain the observed distribution using rotamer probabilities derived from the Protein Data Bank database. In several cases, native rotamers that occur infrequently in the database are seen with high probability in our simulation, indicating that sequence-specific excluded volume interactions can stabilize rotamers that are rare for a given backbone. In spite of our finding that 65 % of the native rotamers and 85 % of chi(1) angles can be predicted correctly on the basis of excluded volume only, 95 % of positions can accommodate more than one rotamer in simulation. We estimate that, in order to quench the side-chain entropy observed in the presence of excluded volume interactions, other interactions (hydrophobic, polar, electrostatic) must provide an additional stabilization of at least 0.6 kT per residue in order to single out the native state.

Algorithms↗

PubMed2000

Image registration by maximization of combined mutual information and gradient information.

Mutual information has developed into an accurate measure for rigid and affine monomodality and multimodality image registration. The robustness of the measure is questionable, however. A possible reason for this is the absence of spatial information in the measure. The present paper proposes to include spatial information by combining mutual information with a term based on the image gradient of the images to be registered. The gradient term not only seeks to align locations of high gradient magnitude, but also aims for a similar orientation of the gradients at these locations. Results of combining both standard mutual information as well as a normalized measure are presented for rigid registration of three-dimensional clinical images [magnetic resonance (MR), computed tomography (CT), and positron emission tomography (PET)]. The results indicate that the combined measures yield a better registration function does mutual information or normalized mutual information per se. The registration functions are less sensitive to low sampling resolution, do not contain incorrect global maxima that are sometimes found in the mutual information function, and interpolation-induced local minima can be reduced. These characteristics yield the promise of more robust registration measures. The accuracy of the combined measures is similar to that of mutual information-based methods.

Entropy↗

PubMed1979

The binding of phenprocoumon to human plasma proteins.

By in vitro experiments with equilibrium dialysis and 5 micrograms PPC per ml an average of 99.7 +/- 0.2% was bound to serum proteins. The binding in a solution with the albumin concentration which was present in the serum samples did not differ from this binding or from the binding in plasma where coagulation was prevented with either heparin or citrate. The binding constant in albumin solutions at 37 degrees was 4.5 +/- 0.31/mol x 10(-5) and an average of 1.16 +/- 0.04 primary binding sites was found. The association constant for the PPC albumin interaction was temperature dependent and the results of thermodynamic calculations suggested a combined ionic and non-polar type of binding as the change in enthalpy contributed with 40% of change in free energy. A large positive entropy change was found (15.79 Kcal/mol/degree K). The addition of phytomenadione to albumin solutions and of menadione to plasma caused a considerable decrease in the protein bound fraction of PPC, indicating the relevance of a study concerning the possible clinical consequences of these interactions.

4-Hydroxycoumarins↗

PubMed1990

The spatial metric of brain underlying the temporal metric of EEG and thought.

Multiplying memory span by mental speed, we obtain the information entropy of short-term memory capacity, which is rate-limiting for cognitive functions and corresponds with EEG power spectral density. From psychometric and EEG data follows a fundamental of about 3.14 Hz. The number of harmonics (n = 1, 2,...,9) is identical with memory span, and the eigenvalues of the EEG impulse response are represented by the zero-crossings up to the convolved fundamental, the P300. The difference T of 4.42 ms between the 8th and the 9th harmonic is the smallest time window of conscious information processing. Shannon's sampling theorem allows the replacement of any band-limited signal by m discrete sequences of T without loss of any information. Brain architecture can be understood in terms of sequences of delaying chains. Acting as a wavefront tracking array, scaled in relation of mT and in such a way also expressing the metric of eigenvalues, widths of orientation columns match with phase reversal after a zero-crossing and lengths of dendritic trees with run-length of travelling harmonics.

Brain↗

PubMed1998

DNA quantification as a prognostic factor in gastric adenocarcinoma.

OBJECTIVE: To determine if DNA quantification, studied in cytologic samples obtained by fiberendoscopy, has predictive value in gastric adenocarcinoma. The survival times of patients in whom the tumor was the cause of death were considered variables of interest. STUDY DESIGN: Twenty-nine patients with gastric cancer, diagnosed by cytology, endoscopy and microbiopsy, were selected. The study was done over more than 10 years. Smears were stained with progressive hematoxylin and processed by computer for DNA evaluation by image cytometry. RESULTS: Four different types of histograms that directly relate to tumoral malignancy were obtained. These histograms were characterized by the value of entropy. We established four grades of aggressiveness. Then we obtained two large groups: high and low grade of malignancy. We studied the survival times in both groups and constructed a Kaplan-Meier survival curve for the high grade of malignancy group. We confirmed the results statistically and found that there was a significant relationship, with P < .05. CONCLUSION: The use of DNA quantification by image cytometry is strongly advised in daily surgery as a prognostic indicator of survival time in gastric adenocarcinoma patients.

Adenocarcinoma↗

PubMed1991

Formulas for threshold computations.

Given a continuous variable S, which density functions on two subgroups omega + and omega - of a population omega are known (with for instance a higher mean value on omega + than on omega -), we first define two strategies for classification in these groups; the first one (MWC) consists in determining a threshold alpha such that classifying in omega + when S greater than or equal to alpha, in omega - otherwise, leads to the highest percentage of well-classed elements. The second one consists in choosing the most probable group, given the observed value of S. We give mathematical formulas for the thresholds involved in these two strategies when the density functions, determined by the application of the maximum entropy principle, are those of normal distributions. These formulas prove that the two considered strategies are frequently equivalent, and we give simpler formulas when the partial variances of S on omega + and omega - are unknown or approximately equal. All the formulas are adapted to the case where a cost coefficient is introduced to display the unequal seriousness of the two possible errors (misclassification in omega + or omega -). Then we consider an example, where we see that the computed thresholds can be graphically validated from empirical curves and have the same performances on the learning sample and on a test sample.

Analysis of Variance↗

PubMed2005

Improved side-chain modeling for protein-protein docking.

Success in high-resolution protein-protein docking requires accurate modeling of side-chain conformations at the interface. Most current methods either leave side chains fixed in the conformations observed in the unbound protein structures or allow the side chains to sample a set of discrete rotamer conformations. Here we describe a rapid and efficient method for sampling off-rotamer side-chain conformations by torsion space minimization during protein-protein docking starting from discrete rotamer libraries supplemented with side-chain conformations taken from the unbound structures, and show that the new method improves side-chain modeling and increases the energetic discrimination between good and bad models. Analysis of the distribution of side-chain interaction energies within and between the two protein partners shows that the new method leads to more native-like distributions of interaction energies and that the neglect of side-chain entropy produces a small but measurable increase in the number of residues whose interaction energy cannot compensate for the entropic cost of side-chain freezing at the interface. The power of the method is highlighted by a number of predictions of unprecedented accuracy in the recent CAPRI (Critical Assessment of PRedicted Interactions) blind test of protein-protein docking methods.

Models, Molecular↗