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PubMed2000

Assessment of insulin secretion in relatives of patients with type 2 (non-insulin-dependent) diabetes mellitus: evidence of early beta-cell dysfunction.

To examine beta-cell function in glucose-tolerant offspring of type 2 diabetic families, 41 insulin-resistant (hyperinsulinemic-euglycemic clamp, P < .001) first-degree relatives and 32 controls underwent oral (OGTT) and intravenous (IVGTT) glucose tolerance tests and a constant intravenous glucose infusion (4.0 or 4.5 mg/kg/min) with blood sampling every minute for insulin determinations. Insulin concentration time-series were analyzed with complementary mathematical models (deconvolution and autocorrelation analysis, approximate entropy [ApEn], and coefficient of variation [CV] for a 6-point moving average, together with a combined index for regularity and stationarity [RaS] based on the last 2 measures). During the OGTT, the area under the curve (AUC) for plasma glucose was moderately (11%) but significantly (P < .01) elevated in the relatives despite a trend for increased serum insulin (AUC, P = .14). The acute-phase serum insulin response (IVGTT) did not differ between groups (2,055 +/- 330 v 1,766 +/- 229 pmol/L x 10 min, P = .84) but was inappropriately low (individually, P < .05 v control group) for the degree of insulin resistance in 16 relatives. Deconvolution analysis of the insulin time-series did not uncover differences in either the intersecretory pulse interval (5.8 +/- 0.2 v5.7 +/- 0.2 min/pulse) or the fractional secretory burst amplitude (133% +/- 10% v 116% +/- 7% over basal) between the 2 groups. Similarly, significant autocorrelation coefficients were observed in a comparable number of relatives and control subjects (P = .74). In contrast, the RaS index was significantly higher (ie, insulin time-series was more irregular and nonstationary) in the relatives (0.221 +/- 0.194) than in the controls (-0.318 +/- 0.176, P < .05), primarily attributed to the pattern of insulin secretion in relatives with a strong genetic burden. In conclusion, nonstationary and disorderly insulin secretion patterns during glucose stimulation and a low acute-phase serum insulin response associated with significant insulin resistance suggest early beta-cell regulatory dysfunction in individuals genetically predisposed to type 2 diabetes mellitus prior to any evident alterations in insulin secretory burst frequency or mass.

Adult↗
PubMed2004

Connection between the observable and centroid structural properties of a quantum fluid: application to liquid para-hydrogen.

It is shown that the discrepancy between path integral Monte Carlo [M. Zoppi et al., Phys. Rev. B 65, 092204 (2002)] and path integral centroid molecular dynamics [F. J. Bermejo et al., Phys. Rev. Lett. 84, 5359 (2000)] calculations of the static structure factor of liquid para-hydrogen can be explained based on a deconvolution equation connecting centroid and physical radial distribution functions. An explicit expression for the kernel of the deconvolution equation has been obtained using functional derivative techniques. In the superposition approximation, this kernel is given by the functional derivative of the effective potential with respect to the pairwise classical potential. Results of path integral Monte Carlo calculations for the radial distribution function and the static structure factor of liquid para-hydrogen are presented.

Journal Article↗
PubMed2000

Biosynthesis and structural composition of gap junction intercellular membrane channels.

Gap junction channels assemble as dodecameric complexes, in which a hexameric connexon (hemichannel) in one plasma membrane docks end-to-end with a connexon in the membrane of a closely apposed cell to provide direct cell-to-cell communication. Synthesis, assembly, and trafficking of the gap junction channel subunit proteins referred to as connexins, largely appear to follow the general secretory pathway for membrane proteins. The connexin subunits can assemble into homo-, as well as distinct hetero-oligomeric connexons. Assembly appears to be based on specific signals located within the connexin polypeptides. Plaque formation by the clustering of gap junction channels in the plane of the membrane, as well as channel degradation are poorly understood processes that are topics of current research. Recently, we tagged connexins with the autofluorescent reporter green fluorescent protein (GFP), and its cyan (CFP), and yellow (YFP) color variants and combined this reporter technology with single, and dual-color, high resolution deconvolution microscopy, computational volume rendering, and time-lapse microscopy to examine the detailed organization, structural composition, and dynamics of gap junctions in live cells. This technology provided for the first time a realistic, three-dimensional impression of gap junctions as they appear in the plasma membranes of adjoining cells, and revealed an excitingly detailed structural organization of gap junctions never seen before in live cells. Here, I summarize recent progress in areas encompassing the synthesis, assembly and structural composition of gap junctions with a special emphasis on the recent results we obtained using cell-free translation/ membrane-protein translocation, and autofluorescent reporters in combination with live-cell deconvolution microscopy.

Animals↗
PubMed2003

A multi-mechanistic drug release approach in a bead dosage form and in vitro/in vivo correlations.

An in vitro/in vivo relationship of a combined multi-mechanistic dosage form has now been established in the literature. In our previous study, we successfully prepared a combination of immediate release, enteric coated, and controlled-release (CR) beads and mathematically modeled in vitro and in vivo drug release characteristics of the combination based on the release profiles of individual beads. The objective of the present study is to develop in vitro/in vivo correlations (IVIVC) for three individual beads and the combination using theophylline as a model drug and the beagle dog as an animal model. In the study, an IVIVC correlation is estimated by two-stage procedures: deconvolution followed by comparison of the fraction of drug absorbed to the fraction of drug dissolved. The Wagner-Nelson mass balance method was used to deconvolute plasma drug concentration-time curves. In vitro, a two-stage medium (0.1 N HCl and pH 6.5 phosphate buffer) was used for the dissolution test; a 2h first stage (acidic) was selected based on the average gastric emptying time in a fasted dog. In vivo, t(lag) was used for the gastric emptying process for enteric coated beads and the combination, which contains enteric coated beads. A time-scaling technique was used to consider the rate difference between in vitro dissolution and in vivo absorption in the process of IVIVC. As shown in the results, a point-to-point correlation was established for each formulation. The linear regression analysis of the correlation was r2>0.99 for all three individual beads and 0.97 for the combined bead dosage form. The results suggest level A IVIVCs indicating an appropriateness for the in vitro and in vivo models used in this study.

Administration, Oral↗
PubMed1976

The construction and use of nomograms for cerebral blood flow calculation using a 133Xe inhalation technique.

Measurement of cerebral blood flow (CBF) using a 133Xe inhalation technique requires monitoring the clearance rate of the radioisotope from the head using externally situated detectors and also from arterial blood using a detector to monitor the expired air activity. The end-tidal concentration function is assumed to be proportional to the arterial concentration function and this has to be deconvoluted from the clearance functions obtained from the head to enable CBF to be calculated. A digital computer is generally considered to be essential for this. In this paper a procedure using three-dimensional nomograms is derived and tested. It is shown that results obtained using the nomograms do not differ significantly from results obtained using a full deconvolution procedure, and so it is not essential to use a computer to calculate CBF by the inhalation technique.

Cerebrovascular Circulation↗
PubMed1996

Imaging laser heated subsurface chromophores in biological materials: determination of lateral physical dimensions.

We describe a non-contact method using infrared radiometry to determine lateral physical dimensions of laser heated subsurface chromophores in biological materials. An imaging equation is derived that relates measured radiometric temperature change to the reduced two-dimensional temperature increase of laser heated chromophores. From measured images of radiometric temperature change, the lateral physical dimensions of chromophores positioned in an in vitro model of human skin are determined by deconvolution of the derived imaging equation using a non-negative constrained conjugate gradient algorithm. Conditions for optimum spatial resolution are found by analysis of a derived radiometric transfer function and correspond to superficial chromophores and/or weak infrared absorption in a laser irradiated biological material. Analysis indicates that if the infrared attenuation coefficient is sufficiently small (i.e., less than 10mm-1), infrared radiometry in combination with a deconvolution algorithm allows estimation of lateral physical dimensions of laser heated subsurface chromophores in human skin.

Algorithms↗
PubMed2005

Reassessing the clinical efficacy of two MR quantitative DSC PWI CBF algorithms following cross-calibration with PET images.

Clinical cerebral blood flow (CBF) maps generated through dynamic- susceptibility contrast (DSC) magnetic resonance (MR) perfusion imaging are currently cross-calibrated with PET studies. The cross-calibration is achieved by rescaling the MR CBF values so that normal white matter CBF corresponds to 22 ml/100 g/min. Examples are provided in this paper to show how this rescaling procedure changes both the clinical interpretation of CBF maps and the manner by which the performance of a given deconvolution algorithm should be assessed. (i) Singular-value decomposition-based (SVD) algorithms produce absolute CBF estimates that are inherently under-estimated for all tissue mean transit times (MTT) but, after rescaling, will generate CBF maps that are over-estimated for MTT >4.8 s. (ii) In principle, frequency-domain modelling techniques are expected to be inherently less sensitive to contrast recirculation biases than the time-domain SVD algorithms. However, it is shown that both CBF algorithms become greatly less sensitive to distortions from recirculation after clinical cross-calibration through rescaling has been performed. It is concluded that, when rescaling procedures are employed, it is relatively more important to develop deconvolution algorithms that produce CBF estimates with accuracies that vary little with MTT than to produce algorithms that provide inherently more accurate CBF estimates, but whose relative accuracy varies significantly with MTT.

Algorithms↗
PubMed2006

Resolution enhancement in digital x-ray imaging.

We have developed a restoration method for radiographs that enhances image sharpness and reveals bone microstructures that were initially hidden in the soft-tissue glare. The method is two fold: the image is first deconvolved using the Richardson-Lucy algorithm and is then divided with a signal modelling the soft-tissue distribution to increase the overall contrast. Each step has its own merits but the power of the restoration method lies in their combination. The originality of the method is its reliance on a priori information at each step in the processing. We have measured and modelled analytically the point-spread function of a low-dose gas microstrip x-ray detector at several beam energies. We measured the relationship between the local image intensity and the noise variance for these images. The soft-tissue signal was also modelled using a minimum-curvature filtering technique. These results were then combined into an image deconvolution procedure that uses wavelet filtering to reduce restoration noise while keeping the enhanced small-scale features. The method was applied successfully to images of a human-torso phantom and improved the contrast of small details on the bones and in the soft tissues. We measured a mean 54% increase in signal to noise ratio and a mean 105% increase in contrast to noise ratio in the 70 and 140 kVp images we analysed. The method was designed to facilitate the analysis of radiographs by relying on two levels of visual inspection. The contrast of the full image is first enhanced by division with the signal modelling the soft-tissue distribution. Based on the result, a radiologist might decide to zoom in on a given image section. The full restoration method is then applied to that region of interest. Indeed, full image deconvolution is often unnecessary since enhanced small-scale details are not visible at large scale; only the section of interest is processed which is more efficient.

Algorithms↗
PubMed2001

Numerical selection of optimal tumor imaging agents with application to engineered antibodies.

Three analytic indicators were used to compare five members of a monoclonal antibody (Mab) family. The cognates consisted of the genetically engineered intact chimeric IgGI (cT84.66) and related engineered fragments [scFv, diabody, minibody, F(ab')2] reactive against the same epitope of carcinoembryonic antigen (CEA). All analyses were based on radioiodinated Mabs targeting to colorectal xenografts of LS174T tumors in nude mice. Affinity constants were evaluated initially. A second indicator was the imaging figure of merit (IFOM) which determines how rapidly a statistically significant tumor image can be acquired. Finally, deconvolution was used to determine tumor temporal response to an arterial bolus. This last analysis gave the possible tumor accumulation in the absence of normal tissue sequestration. Affinities were all in excess of 10(8) M-1 and were highest for the divalent Mabs. Using the IFOM criterion, an 131I label was best suited as a radiolabel for the intact (IgG) T84.66, while an 123I label indicated optimal imaging with either minibody or F(ab')2. Deconvolution analyses showed that divalent members behaved similarly while the univalent member (scFv) had a tumor residence time smaller by an order of magnitude. The diabody had the largest impulse response function, but renal uptake may limit its present usefulness.

Animals↗
PubMedDate not supplied

Application of curve fitting in thin-layer chromatography-flame ionization detection analysis of the carbohydrate fraction in marine mucilage and marine snow samples from Italian seas.

This paper presents a thin-layer chromatographic-flame ionization detection (TLC-FID) procedure to characterize the carbohydrate fraction of marine mucilage and marine snow samples from the Italian Seas. The identification of the different carbohydrate subfractions is supported by the application of a deconvolution procedure based on a new mathematical function for describing chromatographic peaks and enhancing their resolution. The joint-approach TLC-FID analysis and deconvolution procedure allows for the characterization of the carbohydrate fraction of the marine samples in a single step without using the different derivatization procedures requested by the most common gas chromatography and high-performance liquid chromatographic methods for carbohydrate analysis. In fact, the results obtained by the TLC-FID procedure show that different neutral, uronic acid, and aminosugar subfractions can be present simultaneously in these samples. Moreover, the results support some hypotheses about the causes of the presence of mucilages in the Italian Seas.

Journal Article↗
PubMed2001

Four-dimensional dielectric property image obtained from electron spectroscopic imaging series.

We have demonstrated a new quantitative method to characterize two-dimensional distributions of energy-dependent dielectric function of materials from low loss electron spectroscopic image (ESI) series. Two problems associated with extracted image-spectrum from the low-loss image series, under-sampling and loss of energy resolution, were overcome by using fast Fourier transformation (FFT) interpolation and maximum entropy deconvolution method. In this study, Black Diamond/Si3N4/SiO2/Si-substrate dielectric layer designed for copper metallization was used as the sample. We show that the reconstructed (FFT interpolated and maximum entropy deconvoluted) image-spectrum obtained from ESI series images can be quantified with the same accuracy as conventional electron energy-loss spectroscopy spectra. Since the analysis of the dielectric function is sensitive to the local thickness of the specimen using Kramers-Kronig analysis, we also developed a new method to quantitatively determine the dielectric constant for low-k materials. We have determined the thickness of the Black Diamond using the extrapolated thickness method from the materials of known dielectric constants. Using Kramers-Kronig formula, the dielectric function map can be deduced from two-dimensional reconstructed single scattering spectra with providing the information of thickness. We proposed a four-dimensional data presentation for revealing the uniformity of the energy dependent property. The accuracy of our methods depends on the thickness determination and on the quality of the reconstructed spectra from the image series.

Journal Article↗
PubMed2003

The study of Al-L23 ELNES with resolution-enhancement software and first-principles calculation.

Resolution-enhancement software and first-principles calculation for electron energy-loss spectroscopy (EELS) were applied for the study of aluminium (Al) coordination in alumina. Al-L23 energy-loss near-edge structures (ELNES) of alpha- and gamma-aluminas were observed using a field-emission transmission electron microscope and advanced software for EELS. The inherent energy resolution of a cold field-emission gun (FEG) of approximately 0.3 eV was realized using drift-correction software. The energy spread of the cold FEG was deconvoluted by means of maximum-entropy or Richardson-Lucy algorithms and the energy resolution of the deconvoluted spectrum became comparable with that obtained using a monochromator, whose energy resolution was < 0.2 eV. Fine structures in Al L23-edge were observed, such as 0.5 eV splitting between L3 and L2 peaks in alpha-alumina (i.e. spin-orbit splitting). The difference in Al coordination was clearly observed in Al-L23 ELNES and the major structures near the threshold were assigned using first-principles calculations.

Journal Article↗
PubMed2002

Analysis of the glow curves obtained from LiF:Mg,Cu,Na,Si TL material using the general order kinetics model.

Three-dimensional thermoluminescence (TL) spectra based on temperature, wavelength and intensity for newly developed LiF:Mg,Cu,Na,Si TL material at the Korea Atomic Energy Research Institute (KAERI) were measured and analysed. The glow curves were obtained by integration of luminescence intensity over all wavelengths at each temperature, and various trapping parameters related to the traps were determined by analysing these curves. A computerised glow curve deconvolution (CGCD) method which was based on the general order kinetics (GOK) model was used for the glow curve analysis. The glow curves of LiF:Mg,Cu,Na,Si TL material were deconvoluted to six isolated glow curves which have peak temperatures at 333, 374, 426, 466, 483 and 516 K. The main glow peak of peak temperature at 466 K had activation energy of 2.06 eV and a kinetic order of 1.05. This TL material was also found to have three recombination centres, 1.80 eV, 2.88 eV and 3.27 eV by analysis of the TL spectra.

Copper↗
PubMed2006

Discrimination of photon from proton irradiation using glow curve feature extraction and vector analysis.

Two types of thermoluminescence dosemeters (TLDs), the Harshaw LiF:Mg,Ti (TLD-100) and CaF(2):Tm (TLD-300) were investigated for their glow curve response to separate photon and proton irradiations. The TLDs were exposed to gamma irradiation from a (137)Cs source and proton irradiation using a positive ion accelerator. The glow curve peak structure for each individual TLD exposure was deconvolved to obtain peak height, width, and position. Simulated mixed-field glow curves were obtained by superposition of the experimentally obtained single field exposures. Feature vectors were composed of two kinds of features: those from deconvolution and those taken in the neighbourhood of several glow curve peaks. The inner product of the feature vectors was used to discriminate among the pure photon, pure proton and simulated mixed-field irradiations. In the pure cases, identification of radiation types is both straightforward and effective. Mixed-field discrimination did not succeed using deconvolution features, but the peak-neighbourhood features proved to discriminate reliably.

Algorithms↗
PubMed1994

Prolactin secretion and sleep.

To clarify the relationship between prolactin (PRL) secretion and sleep, three experimental procedures were employed and secretory rates were estimated from plasma levels using a deconvolution procedure. Eight healthy young men participated in two 24-hour studies, one using normal night sleep and one using delayed sleep, to determine the influence of sleep as a whole on the PRL rhythm. Another group of 24 subjects underwent a 1-night study to investigate the relationship between PRL secretion and the internal sleep structure. The influence of sleep quality was studied in two more groups of eight subjects. Secretory rates were calculated by deconvolution from plasma PRL measured at 10-minute intervals. Sleep was recorded polygraphically in all experiments. PRL secretory pulses occurred throughout the 24-hour cycle without significant variation in frequency, but with enhanced pulse amplitude for both night and day sleep periods. Sleep onset was rapidly followed by an increase in secretion, and awakenings coincided with an immediate offset of active secretion. Analyzing the association between secretory pulses and sleep stages demonstrated that PRL secretory rate is low at the time of rapid eye movement sleep onset. Sleep quality appeared not to affect the PRL secretory profile. These results confirmed that PRL secretion is enhanced during the whole sleep period, as inferred from plasma levels. Considering secretory pulses provides a precise determination of the temporal relations between PRL and sleep structure and demonstrates that occasionally poor sleep does not influence PRL secretion in normal humans.

Adult↗
PubMed1998

Buccal absorption of etomidate from a solid formulation in dogs.

UNLABELLED: Etomidate is typically administered i.v. for the induction of general anesthesia. We believe that oral transmucosal absorption may extend etomidate's use to premedication and conscious sedation. Our objective was to study the oral mucosal absorption kinetics and bioavailability of etomidate in a solid dose form in dogs. A solid dose form containing 50 mg of etomidate in sorbitol for buccal administration was prepared. Each dog was administered both i.v. etomidate and buccal etomidate on separate days. Serum etomidate concentrations after i.v. administration were fit to a two-compartment pharmacokinetic model. The rates at which etomidate enters the systemic circulation via buccal mucosal absorption were calculated from serum concentrations from mucosal and i.v. administrations using model-dependent constrained numerical deconvolution. The apparent permeability coefficient and bioavailability were also determined. The mean (+/- SD) maximal serum etomidate concentration after buccal mucosal absorption from the 50-mg dose unit was 239 +/- 79 ng/mL. The time to reach maximal serum concentration was 12.5 +/- 1.8 min. Peak absorption rate of etomidate into the systemic circulation was 832 +/- 417 microg/min. For all dogs, 90% or more of the absorption via buccal mucosa took place during the period in which the drug was in contact with the mucosa (15 min). The apparent transbuccal mucosal permeability coefficient was 9.1 +/- 4.2 x 10(-4) cm/s, higher than values of any other compounds examined. Bioavailability calculated using the area under the serum etomidate concentration versus time curve method and the deconvolution method was 13.6% +/- 10.7% and 16.6% +/- 7.6%, respectively. In conclusion, etomidate is highly permeable through the canine buccal mucosa. IMPLICATIONS: Etomidate is highly permeable through the canine buccal mucosa. Both the onset and the termination of buccal mucosal absorption of etomidate are rapid, which suggests that titratable delivery of etomidate may be possible by buccal administration.

Absorption↗
PubMed1994

Pharmacokinetics of alfentanil after epidural administration. Investigation of systemic absorption kinetics with a stable isotope method.

BACKGROUND: The effects of epidurally administered alfentanil may be due in part to its uptake into the systemic circulation. Therefore we examined the systemic absorption kinetics after epidural injection of alfentanil. METHODS: Pharmacokinetics were determined using a stable isotope method in ten patients, undergoing lower abdominal surgery under general anesthesia. After epidural injection of 0.68 mg deuterium-labeled alfentanil (alfentanil-d5), 1 mg unlabeled alfentanil was administered over 1 h by an intravenous infusion. Blood samples were collected for 12 h. Concentrations of alfentanil and alfentanil-d5 were measured by a combination of gas chromatography and mass fragmentography. The systemic absorption profiles of alfentanil-d5 were determined by deconvolution of the plasma alfentanil-d5 concentrations with the biexponential unit disposition functions, derived from the intravenous data. In addition, data were analyzed by moment analysis. RESULTS: The mean (+/- SD) steady-state volume of distribution, total plasma clearance, elimination half-life and mean residence time, derived from the unlabeled alfentanil concentration-time data, were 43.2 +/- 19.5 1,418 +/- 129 ml/min, 119 +/- 34 min, and 103 +/- 26 min, respectively. The absorption of alfentanil-d5 was monophasic in most patients. The mean systemic availability and mean absorption time derived from the deconvolution data were 100 +/- 17% and 114 +/- 24 min. The values determined by moment analysis were 107 +/- 18% and 112 +/- 36 min, respectively. CONCLUSIONS: After epidural administration alfentanil is slowly absorbed into the general circulation. Resulting plasma concentrations are very low and do not contribute appreciably to the systemic opioid effect.

Absorption↗
PubMed1995

Biopharmaceutics of a new transdermal fentanyl device.

BACKGROUND: Compared with conventional routes of delivering potent analgesics to postoperative patients, transdermal administration of fentanyl offers the advantages of simplicity and noninvasive delivery. The only available form of transdermal fentanyl, the Duragesic system, has been implicated in preventable patient deaths when used for postoperative analgesia and is contraindicated in the management of postoperative pain. We examined the biopharmaceutics of a new transdermal fentanyl device developed by Cygnus and intended for use as a postoperative analgesic to see whether the new formulation offers pharmacokinetic advantages that might permit safe use in postoperative patients. METHODS: We studied 15 consenting male adult surgical patients. Patients received 650 or 750 micrograms intravenous fentanyl as part of the induction of anesthesia. Plasma fentanyl concentrations were measured over the following 24-h period. On the first postoperative day, 24 h after the intravenous dose of fentanyl, a transdermal fentanyl device was placed on the upper torso of the patient for 24 h and then removed. Plasma fentanyl concentrations were measured for 72 h after application of the transdermal fentanyl device. From the concentration versus time profile for the 24 h after intravenous fentanyl administration we determined each patient's clearance and unit disposition function by moment analysis and constrained numeric deconvolution, respectively. From the concentration versus time profile for the 72 h after application of the transdermal device we determined the amount of fentanyl absorbed and the rate of absorption, again by moment analysis and constrained numeric deconvolution. The residual fentanyl in the transdermal fentanyl device was measured, permitting calculation of the absolute bioavailability of transdermally administered fentanyl. RESULTS: Of the 14 subjects who received transdermal fentanyl, 3 had clinically significant fentanyl toxicity, mandating early removal of the device. The range during the plateau from 12 to 24 h in subjects still wearing the device was 0.34-6.75 ng/ml, a 20-fold range in concentration. In subjects wearing the device for 24 h, the terminal half-life of fentanyl after removal of the device was 16 h. The bioavailability of transdermally administered fentanyl was 63 +/- 35% coefficient of variation. The rate of fentanyl absorption from 12-24 h ranged from 10 to 230 micrograms/h in subjects still wearing the device. In two subjects, the rate within the first 6 h briefly exceeded 300 micrograms/h. Both of these subjects demonstrated fentanyl toxicity, requiring early removal of the device. CONCLUSIONS: The Cygnus transdermal fentanyl device shows great variability in the rate of fentanyl absorption, resulting in highly variable plasma fentanyl concentrations. Some persons may rapidly absorb fentanyl from the device in the first few hours after application, leading to fentanyl toxicity. The variability in effect of the Cygnus transdermal fentanyl device is appreciably greater than that reported for the currently available Duragesic transdermal fentanyl device, which is contraindicated for postoperative analgesia.

Administration, Cutaneous↗