SEARCH · PubMed Health

Results for “sample entropy”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 307 records · Page 17Linked to original sources

PubMed1997

Adhesion of staphylococci to polymers with and without immobilized heparin in cerebrospinal fluid.

Infections of cerebrospinal fluid (CSF) shunts constitute a serious clinical problem. The role of adhesion by coagulase negative staphylococci, the most common etiological agent, was examined in vitro to polyvinyl chloride (PVC), silicone, and to PVC and silicone with end-point attached (EPA) heparin. These are flexible materials commonly used in neurosurgical implants. Bacterial adhesion was quantitated by bioluminescence. The bacterial adhesion to biomaterial surfaces increased with increasing concentrations of bacterial cells. Scatchard plot analysis showed continuous negative (concave) slopes, indicating multiple interactions between biomaterial and bacteria. The thermodynamic studies showed a positive value of the standard entropy change at 37 degrees C, which indicates that hydrophobic interactions are important in bacterial adhesion to polymers. Incubation with CSF for 1 h decreased bacterial adhesion in 75% of the samples compared to incubation in buffer. Thus, the contribution of CSF proteins, like fibronectin, for the initial bacterial adhesion might be small. Heparinization of silicone and PVC decreased the numbers of adhered bacteria by 23 to 54% and 0 to 43% compared to unheparinized surfaces. Among putative inhibitors tested, suramin, chondroitin sulfate, and fucoidan inhibited adhesion to 81 +/- 19, 78 +/- 22, and 64 +/- 7%, respectively. These findings indicate that hydrophobic interactions play an important role, and heparinization rendering the biomaterial surface hydrophilic is therefore effective to reduce bacterial adhesion. Heparinized polymers incubated with putative inhibitors may be the optimal way to prevent shunt infections.

Bacterial Adhesion↗

PubMed2006

Investigation of altered heart rate variability, nonlinear properties of heart rate signals, and organ dysfunction longitudinally over time in intensive care unit patients.

PURPOSE: To investigate longitudinally over time heart rate dynamics and relation with mortality and organ dysfunction alterations in patients admitted to a multidisciplinary intensive care unit. METHODS: Data from 53 patients were used, with heart rate recorded from monitors and analyzed on a daily basis (every morning) for 600 seconds and sampling rate at 250 Hz, from admission to the intensive care unit until final discharge from the unit. Variance, which is a measure of heart rate variability; exponent alpha2; and approximate entropy (ApEn), which assess long-range correlations and periodicity within a signal, respectively; were measured and compared with every day Sequential Organ Failure Assessment Score (SOFA) and mortality. RESULTS: Nonsurvivors had lower ApEn mean (greater periodicity in their signals) and minimum values compared to survivors (0.53 +/- 0.25 vs 0.62 +/- 0.23, P = .04; 0.24 +/- 0.23 vs 0.48 +/- 0.23, P = .01, respectively). Patients in better conditions with SOFA of less than 7 (mean value) had higher variance and ApEn (more variable, less periodic signals) than those with SOFA of 7 or higher (0.47 +/- 0.51 vs 0.10 +/- 0.65, P < .001; 0.67 +/- 0.28 vs 0.49 +/- 0.24, P < .001, respectively). The alpha2 exponent and variance were correlated with length of stay (r = 0.55, P = .02, and r = 0.53, P = .02, respectively) and minimum ApEn with mortality (r = 0.41, P = .01). CONCLUSIONS: Loss of variability and increase in periodicity in heart rate of critically ill patients are linked with parallel deterioration of organ dysfunction and high mortality.

Analysis of Variance↗

PubMed2002

Removal of mercury(II) from aqueous solutions and chlor-alkali industry wastewater using 2-mercaptobenzimidazole-clay.

The 2-mercaptobenzimidazole loaded natural clay was prepared for the removal of Hg(II) from aqueous media. Adsorption of the metal ions from aqueous solution as a function of solution concentration, agitation time, pH, temperature, ionic strength, particle size of the adsorbent and adsorbent dose was studied. The adsorption process follows a pseudo-second-order kinetics. The rate constants as a function of initial concentration and temperature were given. The adsorption of Hg(II) increased with increasing pH and reached a plateau value in the pH range 4.0-8.0. The removal of Hg(II) was found to be >99% at an initial concentration of 50 mg/l. Mercury(II) uptake was found to increase with ionic strength and temperature. Further, the adsorption of Hg(II) increased with increasing adsorbent dose and decrease with adsorbent particle size. Sorption data analysis was carried out using Langmuir and modified Langmuir isotherms for the uptake of metal ion in an initial concentration range of 50-1,000 mg/l. The significance of the two linear relationships obtained by plotting the data according to the conventional Langmuir equation is discussed in terms of the binding energies of the two population sites involved which have a widely differing affinity for Hg(II) ions. Thermodynamic parameters such as changes of free energy, enthalpy, and entropy were calculated to predict the nature of adsorption. It was found that the values of isosteric heat of adsorption were varied with surface loading. The chlor-alkali industry wastewater samples were treated by MBI-clay to demonstrate its efficiency in removing Hg(II) from wastewater.

Adsorption↗

PubMed2005

Using information theory to search for co-evolving residues in proteins.

MOTIVATION: Some functionally important protein residues are easily detected since they correspond to conserved columns in a multiple sequence alignment (MSA). However important residues may also mutate, with compensatory mutations occurring elsewhere in the protein, which serve to preserve or restore functionality. It is difficult to distinguish these co-evolving sites from other non-conserved sites. RESULTS: We used Mutual Information (MI) to identify co-evolving positions. Using in silico evolved MSAs, we examined the effects of the number of sequences, the size of amino acid alphabet and the mutation rate on two sources of background MI: finite sample size effects and phylogenetic influence. We then assessed the performance of various normalizations of MI in enhancing detection of co-evolving positions and found that normalization by the pair entropy was optimal. Real protein alignments were analyzed and co-evolving isolated pairs were often found to be in contact with each other. AVAILABILITY: All data and program files can be found at http://www.biochem.uwo.ca/cgi-bin/CDD/index.cgi

Amino Acid Sequence↗

PubMed2003

Multicanonical chain-growth algorithm.

We present a temperature-independent Monte Carlo method for the determination of the density of states of lattice proteins that combines the fast ground-state search strategy of the new pruned-enriched Rosenbluth chain-growth method and multicanonical reweighting for sampling the complete energy space. Since the density of states contains all energetic information of a statistical system, we can directly calculate the mean energy, specific heat, Helmholtz free energy, and entropy for all temperatures. We apply this method to lattice proteins consisting of hydrophobic and polar monomers, and for the examples of sequences considered, we identify the transitions between native, globule, and random coil states. Since no special properties of heteropolymers are involved in this algorithm, the method applies to polymer models as well.

Algorithms↗

PubMed2001

Continuous 24-hour intravenous infusion of recombinant human growth hormone (GH)-releasing hormone-(1-44)-amide augments pulsatile, entropic, and daily rhythmic GH secretion in postmenopausal women equally in the estrogen-withdrawn and estrogen-supplemented states.

How estrogen amplifies GH secretion in the human is not known. The present study tests the clinical hypothesis that estradiol modulates the stimulatory actions of a primary GH feedforward signal, GHRH. To this end, we investigated the ability of short-term (7- to 12-day) supplementation with oral estradiol vs. placebo to modulate basal, pulsatile, entropic, and 24-h rhythmic GH secretion driven by a continuous iv infusion of recombinant human GHRH-(1--44)-amide vs. saline in nine healthy postmenopausal women. Volunteers underwent concurrent blood sampling every 10 min for 24 h on four occasions in a prospectively randomized, single blind, within-subject cross-over design (placebo/saline, placebo/GHRH, estradiol/saline, estradiol/GHRH). Intensively sampled serum GH concentrations were quantitated by ultrasensitive chemiluminescence assay. Basal, pulsatile, entropic (feedback-sensitive), and 24-h rhythmic modes of GH secretion were appraised by deconvolution analysis, the approximate entropy (ApEn) statistic, and cosine regression, respectively. ANOVA revealed that continuous iv infusion of GHRH in the estrogen-withdrawn (control) milieu 1) amplified individual basal (P = 0.00011) and pulsatile (P < 10(-13)) GH secretion rates by 12- and 11-fold, respectively; 2) augmented GH secretory burst mass and amplitude each by 10-fold (P < 10(-11)), without altering GH secretory burst frequency, duration, or half-life; 3) increased the disorderliness (ApEn) of GH release patterns (P = 0.0000002); 4) elevated the mesor (cosine mean) and amplitude of the 24-h rhythm in serum GH concentrations by nearly 30-fold (both P < 10(-12)); 5) induced a phase advance in the clocktime of the GH zenith (P = 0.021); and 6) evoked a new 24-h rhythm in GH secretory burst mass with a maximum at 0018 h GH (P < 10(-3)), while damping the mesor of the 24-h rhythm in GH interpulse intervals (P < 0.025). Estradiol supplementation alone 1) increased the 24-h mean and integrated serum GH concentration (P = 0.047); 2) augmented GH secretory burst mass (P: = 0.025) without influencing pulse frequency, duration, half-life, or basal secretion; 2) stimulated more irregular patterns of GH release (higher ApEn; P = 0.012); and 3) elevated the 24-h rhythmic GH mesor (P = 0.0005), but not amplitude. Notably, combined stimulation of the GH axis with GHRH-(1--44)-amide and estradiol exerted no further effect beyond that evoked by GHRH alone, except for normalizing the acrophase of 24-h GH rhythmic release and elevating the postinfusion plasma insulin-like growth factor I concentration (P = 0.016). Unexpectedly, the two GHRH-infused serum GH concentration profiles monitored after placebo and estradiol pretreatment showed strongly nonrandom synchrony with a 20- to 30-min lag (P < 0.001). In summary, the present clinical investigations unmask a 3-fold (pulsatile, entropic, and daily rhythmic) similitude between the neuroregulatory actions of estradiol and GHRH in healthy postmenopausal women. However, GHRH infusion was multifold more effectual than estradiol, and only GHRH elevated nonpulsatile (basal) GH secretion, shifted the GH acrophase, and synchronized GH profiles. Given the nonadditive nature of the joint effects of estradiol and GHRH on pulsatile and entropic GH release, we hypothesize that estrogen amplifies GH secretion in part by enhancing endogenous GHRH release or actions. In addition, the distinctive ability of GHRH (but not estradiol) to increase basal (nonpulsatile) GH secretion, shift the GH acrophase and synchronize GH output patterns identifies certain divergent hypothalamo-pituitary actions of these two major GH secretagogues.

Aged↗

PubMed2000

Neuroendocrine consequences of fasting in adult male macaques: effects of recombinant rhesus macaque leptin infusion.

Fasting inhibits the gonadotropic axis and stimulates the corticotropic and somatotropic axes. Since leptin is a product of fat cells that has been implicated in the control of both reproduction and metabolism, we hypothesized that the decrease in leptin observed during fasting was responsible for these effects on reproductive and metabolic hormones. Recombinant rhesus leptin (rrhLep) produced in our laboratory was infused (100 microgram/h) into fasted adult male rhesus macaques (6-9 kg) beginning at midnight after the first missed meal and continuing until the end of the study. Bioactive luteinizing hormone (LH), testosterone, cortisol and growth hormone (GH) were measured in plasma from samples collected at 15-min intervals for the last 15 h (42-57 h) of the fast. We analyzed pulsatile LH and GH secretion by deconvolution analysis and the orderliness of pulsatile LH and GH release by the approximate entropy (ApEn) statistic. There was no difference in LH pulse frequency between control and fasted groups, but there was a significant decrease in the mean concentration of LH released (7.6 +/- 1.4 ng/ml control vs. 2.7 +/- 0.65 ng/ml fasted) that was not relieved with rrhLep infusions (2.8 +/- 0.83 ng/ml). Model-free Cluster analysis confirmed these inferences and also indicated that the peak height was lower in the fasted (4.6 +/- 1.0 ng/ml) and the fasted + rrhLep (2.85 +/- 1.0 ng/ml) groups compared to controls (16. 3 +/- 1.4 ng/ml). Testosterone levels reflected those of LH. Fasting resulted in an increase in GH secretory pulse frequency (5.3 +/- 0. 95 pulses/15 h control vs. 12.8 +/- 1.4 pulses/15 h fasted) and this increase was not affected by rrhLep infusion (12.5 +/- 1.4 pulses/15 h). In addition, fasting also increased the ApEn (decreased the orderliness) of pulsatile GH secretion, and this characteristic was not relieved with rrhLep infusions. Cortisol levels in fasted animals were 2- to 3-fold higher than those observed in control studies, and this increase was particularly pronounced at the time when the animals expected their first meal of the day. The increase in circulating cortisol observed in fasted animals was not affected by rrhLep infusion. Glucose levels at the end of the sampling period were 80 mg/dl in controls, 48 mg/dl in fasted animals and 58 mg/dl in the fasted + rrhLep group. Circulating leptin levels averaged 1.2 +/- 0.37 ng/ml in control animals, 0.7 +/- 0.2 ng/ml in fasted animals and 10.1 +/- 5.6 ng/ml in fasted animals infused with rrhLep. These studies suggest that intravenous replacement with homologous leptin does not reverse the acute changes in GH, LH and cortisol secretion observed with fasting in the adult male macaque.

Animals↗

PubMed2002

Dynamics and configurational entropy in the Lewis-Wahnström model for supercooled orthoterphenyl.

We study thermodynamic and dynamic properties of a rigid model of the fragile glass-forming liquid orthoterphenyl. This model, introduced by Lewis and Wahnström in 1993, collapses each phenyl ring to a single interaction site; the intermolecular site-site interactions are described by the Lennard-Jones potential whose parameters have been selected to reproduce some bulk properties of the orthoterphenyl molecule. A system of N=343 molecules is considered in a wide range of densities and temperatures, reaching simulation times up to 1 micros. Such long trajectories allow us to equilibrate the system at temperatures below the mode coupling temperature T(c) at which the diffusion constant reaches values of order 10(-10) cm(2)/s and thereby to sample in a significant way the potential energy landscape in the entire temperature range. Working within the inherent structures thermodynamic formalism, we present results for the temperature and density dependence of the number, depth and shape of the basins of the potential energy surface. We evaluate the total entropy of the system by thermodynamic integration from the ideal-noninteracting-gas state and the vibrational entropy approximating the basin free energy with the free energy of 6N-3 harmonic oscillators. We evaluate the configurational part of the entropy as a difference between these two contributions. We study the connection between thermodynamical and dynamical properties of the system. We confirm that the temperature dependence of the configurational entropy and of the diffusion constant, as well as the inverse of the characteristic structural relaxation time, are strongly connected in supercooled states; we demonstrate that this connection is well represented by the Adam-Gibbs relation, stating a linear relation between logD and the quantity 1/TS(c). This relation is found to hold both above and below the critical temperature T(c)-as previously found in the case of silica-supporting the hypothesis that a connection exists between the number of basins and the connectivity properties of the potential energy surface.

Journal Article↗

PubMed2004

Profound amplification of secretory-burst mass and anomalous regularity of ACTH secretory process in patients with Nelson's syndrome compared with Cushing's disease.

OBJECTIVE: As described originally, Nelson's syndrome is characterized by grossly elevated ACTH concentrations, a sellar mass and skin hyperpigmentation emerging in the course of Cushing's disease after bilateral adrenalectomy. No detailed studies have defined whether the mechanisms directing ACTH secretion differ in Nelson's syndrome and untreated Cushing's disease. PATIENTS AND METHODS: To address this pathophysiological issue, we studied nine patients fulfilling the criteria of Nelson's syndrome receiving glucocorticoid and mineralocorticoid replacement; nine patients with untreated pituitary-dependent Cushing's disease and nine gender- and age-matched controls. ACTH release was appraised by monitoring plasma ACTH concentrations in blood samples collected every 10 min for 24 h. ACTH secretion rates and endogenous decay were quantified by multiparameter deconvolution analysis. The orderliness of the ACTH release process was delineated by the approximate entropy (ApEn) statistic. Diurnal variation in ACTH secretion was appraised by cosinor analysis. RESULTS: Basal ACTH secretion was increased sixfold and pulsatile secretion ninefold in patients with Nelson's syndrome compared with Cushing's disease (P </= 0.01 and P </= 0.001, respectively). The increase in pulsatile secretion was due to an eightfold augmentation of burst mass. Event frequency was comparable in both patient groups (32 +/- 1 vs. 28 +/- 2 pulses/24 h), and higher than in normal controls (22 +/- 1 pulses/24 h, P < 0.0001). Paradoxically, the consistency of subordinate patterns of serial ACTH release, albeit disrupted in active Cushing's disease, was normal in Nelson's syndrome (P = 0.014). Normal ACTH secretory-process regularity in Nelson's syndrome was attributable to a more reproducible (lower ApEn) succession of ACTH secretory-burst mass denoting more uniform amplitude evolution over 24 h (P = 0.007, Nelson vs. Cushing). However, the quantifiable regularity of serial interburst intervals (waiting times) was unexpectedly elevated in Nelson's syndrome (P = 0.022). Nelson patients maintained a significant diurnal rhythm in ACTH release, which was marked by a 15-fold greater amplitude (P = 0.0018 vs. Cushing's) and a 4-h acrophase (maximum) delay (P = 0.037 vs. control). CONCLUSION: The present detailed analyses delineate marked ACTH secretory-burst mass amplification and (amplitude-independent) anomalous regularity of successive pulse size and timing in Nelson's syndrome compared with Cushing's disease or controls. We postulate that the foregoing novel distinctions are due to unique tumoural secretory properties, concurrently required glucocorticoid replacement and/or hypothalamic injury associated with prior radiotherapy in Nelson's syndrome.

Adrenalectomy↗

PubMed2001

Quantitative assessment of vocal development in the zebra finch using self-organizing neural networks.

To understand the mechanisms of song learning by songbirds it is necessary to have in hand tools for extracting, describing, and quantifying features of the developing vocalizations. The extremely large number of vocalizations produced by juvenile zebra finches and the variability in these vocalizations during the sensorimotor learning period preclude manual scoring methods. Here we describe an approach for classification of vocalizations produced during sensorimotor learning based on self-organizing neural networks. This approach allowed us to construct probability distributions of spectrotemporal features recorded on each day. By training the network with samples obtained across the course of vocal development in individual birds, we observed developmental trajectories of these features. The emergence of stereotypy in sequences of song elements was captured by computing the entropy in the matrices of first- and second-order transition probabilities. Self-organizing maps may assist in classifying large libraries of zebra finch vocalizations and shedding light on mechanisms of vocal development.

Aging↗

PubMed1998

Backbone and methyl dynamics of the regulatory domain of troponin C: anisotropic rotational diffusion and contribution of conformational entropy to calcium affinity.

The N-terminal domain (residues 1 to 90) of chicken skeletal troponin C (NTnC) regulates muscle contraction upon the binding of a calcium ion to each of its two calcium binding loops. In order to characterize the backbone dynamics of NTnC in the apo state (NTnC-apo), we measured and carefully analyzed 15N NMR relaxation parameters T1, T2 and NOE at 1H NMR frequencies of 500 and 600 MHz. The overall rotational correlation time of NTnC-apo at 29.6 degrees C is 4.86 (+/-0.15) ns. The experimental data indicate that the rotational diffusion of NTnC-apo is anisotropic with a diffusion anisotropy, D parallel/D perpendicular, of 1.10. Additionally, the dynamic properties of side-chains having a methyl group were derived from 2H relaxation data of CH2D groups of a partially deuterated sample. Based on the dynamic characteristics of TnC, two different levels of "fine tuning" of the calcium affinity are presented. Significantly lower backbone order parameters (S2), were observed for calcium binding site I relative to site II and the contribution of the bond vector fluctuations to the conformational entropy of sites I and II was calculated. The conformational entropy loss due to calcium binding (DeltaDeltaSp) differs by 1 kcal/mol between sites I and II. This is consistent with the different dissociation constants previously measured for sites I and II of 16 microM and 1. 7 microM, respectively. In addition to the direct role of binding loop dynamics, the side-chain methyl group dynamics play an indirect role through the energetics of the calcium-induced structural change from a closed to an open state. Our results show that the side-chains which will be exposed upon calcium binding have reduced motion in the apo state, suggesting that conformational entropic contributions can be used to offset the free energy cost of exposing hydrophobic groups. It is clear from this work that a complete determination of their dynamic characteristics is necessary in order to fully understand how TnC and other proteins are fine tuned to appropriately carry out their function.

Animals↗

PubMed2007

Estimation of absolute solvent and solvation shell entropies via permutation reduction.

Despite its prominent contribution to the free energy of solvated macromolecules such as proteins or DNA, and although principally contained within molecular dynamics simulations, the entropy of the solvation shell is inaccessible to straightforward application of established entropy estimation methods. The complication is twofold. First, the configurational space density of such systems is too complex for a sufficiently accurate fit. Second, and in contrast to the internal macromolecular dynamics, the configurational space volume explored by the diffusive motion of the solvent molecules is too large to be exhaustively sampled by current simulation techniques. Here, we develop a method to overcome the second problem and to significantly alleviate the first one. We propose to exploit the permutation symmetry of the solvent by transforming the trajectory in a way that renders established estimation methods applicable, such as the quasiharmonic approximation or principal component analysis. Our permutation-reduced approach involves a combinatorial problem, which is solved through its equivalence with the linear assignment problem, for which O(N3) methods exist. From test simulations of dense Lennard-Jones gases, enhanced convergence and improved entropy estimates are obtained. Moreover, our approach renders diffusive systems accessible to improved fit functions.

Algorithms↗

PubMed2006

Processing of ND NMR spectra sampled in polar coordinates: a simple Fourier transform instead of a reconstruction.

In order to reduce the acquisition time of multidimensional NMR spectra of biological macromolecules, projected spectra (or in other words, spectra sampled in polar coordinates) can be used. Their standard processing involves a regular FFT of the projections followed by a reconstruction, i.e. a non-linear process. In this communication, we show that a 2D discrete Fourier transform can be implemented in polar coordinates to obtain directly a frequency domain spectrum. Aliasing due to local violations of the Nyquist sampling theorem gives rise to base line ridges but the peak line-shapes are not distorted as in most reconstruction methods. The sampling scheme is not linear and the data points in the time domain should thus be weighted accordingly in the polar FT; however, artifacts can be reduced by additional data weighting of the undersampled regions. This processing does not require any parameter tuning and is straightforward to use. The algorithm written for polar sampling can be adapted to any sampling scheme and will permit to investigate better compromises in terms of experimental time and lack of artifacts.

Algorithms↗

PubMed1993

Characterization of the binding and chiral separation of D- and L-tryptophan on a high-performance immobilized human serum albumin column.

High-performance affinity chromatography was used to study the separation and binding of D- and L-tryptophan on an immobilized human serum albumin (HSA) column. Frontal analysis and zonal elution studies indicated that both D- and L-tryptophan were binding to single but distinct sites on HSA. L-Tryptophan bound to the indole site of HSA. D-Tryptophan had indirect interactions with the warfarin site of HSA but no interactions with the indole site. The association constants for the binding of D- and L-tryptophan at pH 7.4 and 25 degrees C were 0.4 x 10(4) and 2.7 x 10(4) M-1, respectively. The value of delta G for these sites ranged from -5.2 to -5.7 kcal/mol (1 cal = 4.184 J) and had a significant entropy component. The effects of varying the pH, phosphate concentration, temperature and polarity of the mobile phase on the binding of D- and L-tryptophan to HSA were examined. The role of sample size in determining peak shape and retention was also considered. From these data, general guidelines were developed for the separation of D- and L-tryptophan on immobilized HSA. Under optimized conditions the enantiomers were separated in less than 2 min with baseline resolution.

Binding, Competitive↗

PubMed2006

Analysis of biomedical signals by the lempel-Ziv complexity: the effect of finite data size.

The Lempel-Ziv (LZ) complexity and its variants are popular metrics for characterizing biological signals. Proper interpretation of such analyses, however, has not been thoroughly addressed. In this letter, we study the the effect of finite data size. We derive analytic expressions for the LZ complexity for regular and random sequences, and employ them to develop a normalization scheme. To gain further understanding, we compare the LZ complexity with the correlation entropy from chaos theory in the context of epileptic seizure detection from EEG data, and discuss advantages of the normalized LZ complexity over the correlation entropy.

Algorithms↗

PubMed1999

Tripartite neuroendocrine activation of the human growth hormone (GH) axis in women by continuous 24-hour GH-releasing peptide infusion: pulsatile, entropic, and nyctohemeral mechanisms.

Despite the discovery of potent GH-releasing peptides (GHRPs) more than 15 yr ago and the recent cloning of human, rat, and pig GHRP receptors in the hypothalamus and pituitary gland, the neuroregulatory mechanisms of action of GHRP agonists on the human hypothalamo-somatotroph unit are not well delineated. To gain such clinical insights, we evaluated the ultradian (pulsatile), entropic (pattern orderliness), and nyctohemeral GH secretory responses during continuous 24-h i.v. infusion of saline vs. the most potent clinically available hexapeptide, GHRP-2 (1 microg/kg x h) in estrogen-unreplaced (mean serum estradiol, 12 +/- 2.4 pg/mL) postmenopausal women (n = 7) in a paired, randomized design. Blood was sampled every 10 min for 24 h during infusions and was assayed by ultrasensitive GH chemiluminescence assay. Pulsatile GH secretion was quantitated by deconvolution analysis, orderliness of GH release patterns by the approximate entropy statistic, and 24-h GH rhythmicity by cosinor analysis. Statistical analysis revealed that GHRP-2 elicited a 7.7-fold increase in (24-h) mean serum (+/-SEM) GH concentrations, viz. from 0.32 +/- 0.042 (saline) to 2.4 +/- 0.34 microg/L (GHRP-2; P = 0.0006). This occurred via markedly stimulated pulsatile GH release, namely a 7.1-fold augmentation of GH secretory burst mass: 0.87 +/- 0.18 (control) vs. 6.3 +/- 1.3 microg/L (GHRP-2; P = 0.0038). Enhanced GH pulse mass reflected a commensurate 10-fold (P = 0.023) rise in GH secretory burst amplitude [maximal GH secretory rate (micrograms per L/min) attained within a secretory pulse] with no prolongation in event duration. GH burst frequency, interpulse interval, and calculated GH half-life were all invariant of GHRP-2 treatment. Concurrently, as detected in the ultrasensitive GH assay, GHRP-2 augmented deconvolution-estimated interpulse (basal) GH secretion by 4.5-fold (P = 0.025). The approximate entropy of 24-h serum GH concentration profiles rose significantly during GHRP-2 infusion; i.e. from 0.592 +/- 0.073 (saline) to 0.824 +/- 0.074 (GHRP-2; P = 0.0011), signifying more irregular or disorderly GH release patterns during secretagogue stimulation. Cosinor analysis of 24-h GH rhythms disclosed a significantly earlier (daytime) acrophase at 2138 h (+/- 140 min) during GHRP-2 stimulation vs. 0457 h (+/-42 min) during saline infusion (P = 0.013). Concomitantly, the cosinor amplitude rose 6-fold (P = 0.018), and the mesor (cosine mean) rose 5-fold (P = 0.003). Fasting (0800 h) plasma insulin-like growth factor (IGF-I) concentrations rose by -11 +/- 12 microg/L during saline infusion and by 102 +/- 18 microg/L during GHRP-2 infusion (P = 0.0036). GHRP-2 infusion did not modify (24-h pooled) serum LH, FSH, or TSH concentrations and minimally increased serum (pooled) daily PRL (6.8 +/- 0.83 vs. 12 +/- 1.2 microg/L; P < 0.05) and cortisol (5.3 +/- 0.59 to 7.0 +/- 0.74; P < 0.05) concentrations. In summary, 24-h constant iv GHRP-2 infusion in the gonadoprival female neurophysiologically activates the GH-IGF-I axis by potentiating GH secretory burst mass and amplitude by 7- to 10-fold and augmenting the basal (nonpulsatile) GH secretion by 4.5-fold. GHRP-2 action is highly selective, as it does not alter GH secretory burst frequency, interpulse interval, event duration, or GH half-life. GHRP-2 effectively elevates IGF-I concentrations, unleashes greater disorderliness of GH release patterns, and heightens the 24-h rhythmicity of GH secretion. These tripartite features of GHRP-2's action in estrogen-withdrawn (postmenopausal) women also characterize normal human puberty and/or sex steroid regulation of the GH-IGF-I axis. However, how or whether GHRP-2 interacts further with sex hormone modulation of GH neurosecretory control in older women and men is not yet known.

Aged↗

PubMed2000

Impact of age on cortisol secretory dynamics basally and as driven by nutrient-withdrawal stress.

The present study tests the clinical hypothesis that aging impairs homeostatic adaptations of cortisol secretion to stress. To this end, we implemented a short-term 3.5-day fast as an ethically acceptable metabolic stressor in eight young (ages 18-35 yr) and eight older (ages 60-72 yr) healthy men. Volunteers were studied in randomly ordered fed vs. fasting sessions. To capture the more complex dynamics of cortisol's feedback control, blood was sampled every 10 min for 24 h for later RIA of serum cortisol concentrations and quantitation of the pulsatile, entropic, and 24-h rhythmic modes of cortisol release using deconvolution analysis, the approximate entropy statistic, and cosine regression, respectively. The stress of fasting elevated the mean (24-h) serum cortisol concentration equivalently in the two age cohorts [i.e. from 7.2 +/- 0.35 to 11.6 +/- 0.71 microg/dL in young men and from 7.7 +/- 0.39 to 12.6 +/- 0.59 microg/dL in older individuals (P < 10(-7))]. The rise in integrated cortisol output was driven mechanistically by selective augmentation of cortisol secretory burst mass (P = 0.002). The resultant daily (pulsatile) cortisol secretion rate increased significantly but equally in young (from 94 +/- 6.3 to 151 +/- 15 microg/dL x day) and older (from 85 +/- 5.4 to 145 +/- 7.3 microg/dL x day) volunteers (P < 10(-4)). Nutrient restriction also prompted a marked reduction in the quantifiable regularity of (univariate) cortisol release patterns in both cohorts (P < 10(-4)). However, older men showed loss of joint synchrony of cortisol and LH secretion even in the fed state, which failed to change with metabolic stress (P < 10(-6)). In addition, older individuals maintained a premature (early-day) cortisol elevation in the fed state and unexpectedly evolved an anomalous further cortisol phase advance of 99 +/- 16 min during fasting (P < 10(-5)). Caloric deprivation in aging men also disproportionately elevated the mesor of 24-h rhythmic cortisol release (P = 10(-7)) and elicited a greater increment in the mean day-night variation in cortisol secretory-burst mass (P < 0.01 vs. young controls). Lastly, short-term caloric depletion in older subjects paradoxically normalized their age-associated suppression of the 24-h rhythm in cortisol interburst intervals. In summary, acute metabolic stress in healthy aging men (compared with young individuals) unmasks distinct, albeit complex, disruption of cortisol homeostasis. These dynamic anomalies impact the feedback-dependent and time-sensitive coupling of pulsatile and 24-h rhythmic cortisol secretion. Nutrient-withdrawal stress in the older male heightens the cortisol phase disparity already evident in fed elderly individuals. Conversely, the stress of fasting in young men paradoxically reproduces selected features of the aging unstressed (fed) cortisol axis; viz., abrogation of joint cortisol-LH synchrony and suppression of the normal diurnal variation in cortisol burst frequency. Whether fasting would unveil analogous disruption of feedback-dependent control of the corticotropic axis in healthy aging women is not yet known.

Adolescent↗

PubMed2000

Growth hormone and prolactin are secreted more irregularly in patients with Cushing's disease.

OBJECTIVE: To investigate whether the spontaneous secretion of growth hormone and prolactin in adult patients with pituitary-dependent Cushing's disease is decreased. PATIENTS: Fourteen adult patients (9 women, 5 men; age: 34 +/- 3.4 years, mean +/- SEM) with pituitary-dependent Cushing's disease and 14 controls matched for age, gender and body mass index were studied. METHODS: Blood samples were withdrawn at 10 minutes intervals starting at 0900 h for 24 h. GH and PRL release were quantified with deconvolution methods. The regularity of GH and PRL release was measured with approximate entropy statistics. RESULTS: The number of GH secretory events per 24 h was higher in patients than in controls: 19 +/- 1.3 vs. 14 +/- 1.5 peaks per 24 h, respectively (P = 0.020). GH secretion rate was about one quarter lower in patients (ns), and the 24 h secretion of PRL was unchanged. Total GH production correlated negatively with the urinary excretion of free cortisol (R = 0.729, P = 0.005) and with the plasma cortisol production rate (R = 0.613; P = 0.026). The orderliness of GH and PRL secretion was appraised with the approximate entropy statistic (ApEn). For GH secretion ApEn(1,20%) in patients was 0.952 +/- 0.084 vs. 0.404 +/- 0.047 in controls, P = 1.17 x 10-4, pointing to a markedly disordered secretion in patients. Similar results were obtained for PRL secretion: patients: 1.586 +/- 0.063 vs. 1.003 +/- 0.068 in controls, P = 3.67 x 10-5. No statistically significant differences in secretory dynamics were demonstrated between the 10 patients with a microadenoma and the four with a macroadenoma. CONCLUSION: The amount of GH released spontaneously into the circulation in adult patients with pituitary-dependent Cushing's disease is inversely related to the degree of cortisol hypersecretion. However, except for severe hypercortisolism, GH secretion is relatively preserved. In addition, secretion of GH and PRL is remarkably disordered in patients with Cushing's disease. Since we could not detect differences in GH and/or PRL secretory dynamics between patients with a microadenoma and those harboring a macroadenoma, we speculate that an intrapituitary paracrine mechanism and/or elevated cortisol feedback effects may be responsible for the evident disruption of GH and PRL secretion patterns.

Adenoma↗