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PubMed1995

Optimal and practicable designs for measuring plaque pH-profiles.

The shape of the plaque pH-profile after consumption of a food item determines the food's potential caries risk. This and related facts have caused an increased interest in measurements of plaque pH-profiles during the last decade. A standard design for these measurements is to take equally spaced observations over a certain period of time. The theory of optimal experimental design gives methods for positioning the measurements of a pH-profile in an optimized way. The objective is to minimize the effort given a desired precision of the estimated profile characteristic or to maximize the precision given the number of measurements. We show that a reduction in the number of measurements up to 50 per cent or a respective improvement in precision of the estimates as compared to standardly applied designs is possible. This implies less inconvenience for the subjects and better compliance with the needs of investigation. Our study is intended to demonstrate the applicability of the theory of optimal experimental design which has the potential to improve the efficiency of medical research.

Dental Caries Susceptibility↗
PubMed1995

Unique profile of visuo-perceptual skills in a genetic syndrome.

Williams syndrome (WS) and Down syndrome (DS) are genetic disorders with characteristic neuropsychological profiles. Subjects with WS show surface similarities to subjects with right hemisphere damage (RHD) in their relative preservation of linguistic skills, their poor visuo-constructive skills, and their hierarchical processing biases. Ten adolescents and young adults with WS and nine matched subjects with DS were administered a battery of visuospatial perceptual tasks to test whether the profile of performance in WS would resemble that in RHD. It was found instead that the WS subjects showed a distinctive clustering of skills, with particular preservation of facial discrimination, but impairment of other perceptual skills. Subjects with DS showed a more homogeneous profile. The WS profile may map onto the functional dichotomy between ventral and dorsal visual pathways in the cerebral cortex.

Adolescent↗
PubMed1997

Sequence profiles of immunoglobulin and immunoglobulin-like domains.

Immunoglobulins (Ig) are highly modular proteins, consisting of variable and constant domains, which have clear, conserved sequence patterns. These sequence patterns have allowed T-cell receptor (TCR) and major histocompatibility complex (MHC) molecule domains, as well as some cell adhesion, cell surface receptor and muscle protein domains, to be identified as forming a superfamily of related proteins together with the Ig-domains. The domains of these proteins have been grouped into four sets: variable (V-set), constant-1 (C1-set), constant-2 (C2-set) and intermediate (I-set). X-ray and NMR studies have shown that these domains form a Greek-key beta-sandwich structure with the sets differing in the number of strands in the beta-sheets as well as in their sequence patterns. The conserved sequence elements in the major sets of Ig and Ig-like molecules have previously been reported as general sequence profiles. This work examines the variability within these sets. Detailed sequence profiles and consensus sequences for these sets and groups have been constructed and a novel form of presentation has been developed to overcome some of the drawbacks of current methods of presenting consensus sequences. The profiles that were constructed allow a comparison of the similarities and differences among the sets of Ig and Ig-like sequences and provide a means by which sequences can be tested for compatibility with Ig-like sequence motifs. As well, the sequence separations of the main residues in the characteristic "pin" structure of Ig-like molecules were examined for variation among the groups. From the profiles constructed here, measures of the degree of conservation within the groups of molecules were determined. These measures were used to assist in a reconsideration of possible evolutionary pathways between the major structural groups of the Ig-superfamily.

Amino Acid Sequence↗
PubMed1998

The changing nature of the protein folding transition state: implications for the shape of the free-energy profile for folding.

According to landscape theory proteins do not fold by localised pathways, but find their native conformation by a progressive organisation of an ensemble of partly folded structures down a folding funnel. Here, we use kinetics and protein engineering to investigate the shape of the free-energy profile for two-state folding, which is the macroscopic view of the funnel process for small and rapidly folding proteins. Our experiments are based mainly on structural changes of the transition state of chymotrypsin inhibitor 2 (CI2) upon destabilisation with temperature and GdnHCl. The transition state ensemble of CI2 is a localised feature in the free-energy profile that is sharply higher than the other parts of the activation barrier. The relatively fixed position of the CI2 transition state on the reaction coordinate makes it easy to characterise but contributes also to overshadow the rest of the free-energy profile, the shape of which is inaccessible for analysis. Results from mutants of CI2 and comparison with other two-state proteins, however, point at the possibility that the barrier for folding is generally broad and that localised transition states result from minor ripples in the free-energy profile. Accordingly, variabilities in the folding kinetics may not indicate different folding mechanisms, but could be accounted for by various degrees of ruggedness on top of very broad activation barriers for folding. The concept is attractive since it summarises a wide range of folding data which have previously seemed unrelated. It is also supported by theory. Consistent with experiment, broad barriers predict that new transition state ensembles are exposed upon extreme destabilisation or radical mutations.

Chymotrypsin↗
PubMed1999

A novel high-gradient permanent magnet for the profiling of planar films and coatings.

The design and construction of a low-cost, permanent magnet is described. The magnet is intended for applications which require a large static gradient, such as those for which stray field imaging or fringe field diffusometry are conventionally employed. The magnet has been designed using the scalar potential method. Particular features of the magnet include a field profile such that ||B || is constant in the horizontal plane and such that B is horizontal at the midpoint between the poles. There is a vertical, and therefore orthogonal, strong gradient, G, in ||B ||. The ratio G/ ||B || is constant within a large volume and so allows measurements at a range of gradient strengths. It is this ratio which governs the shape of the pole-pieces. The constructed magnet has a typical operating field of 0.8 T, gives a gradient of 20 Tm-1, and has a useable interpole access of 20 mm. Field plot data show values consistent with the theory. In particular ||B || has a curvature of less than +/-5 microm over a 5 x 5 mm area at the target field. The magnet is most suitable for the one-dimensional profiling of thin planar samples. As an example of the magnet's use, a profile of a sandwich structure made of several polymer layers is shown. In addition, a set of one-dimensional profiles of an alkyd coating, recorded during solvent loss and cross-linking, is presented. This example demonstrates quantitative T2 measurements at a resolution of 6.5 microm across a 70-microm-thick film.

Magnetic Resonance Spectroscopy↗
PubMed1993

Entropic profiles of DNA sequences through chaos-game-derived images.

A new method to determine entropic profiles in DNA sequences is presented. It is based on the chaos-game representation (CGR) of gene structure, a technique which produces a fractal-like picture of DNA sequences. First, the CGR image was divided into squares 4-m in size (m being the desired resolution), and the point density counted. Second, appropriate intervals were adjusted, and then a histogram of densities was prepared. Third, Shannon's formula was applied to the probability-distribution histogram, thus obtaining a new entropic estimate for DNA sequences, the histogram entropy, a measurement that goes with the level of constraints on the DNA sequence. Lastly, the entropic profile for the sequence was drawn, by considering the entropies at each resolution level, thus providing a way to summarize the complexity of large genomic regions or even entire genomes at different resolution levels. The application of the method to DNA sequences reveals that entropic profiles obtained in this way, as opposed to previously published ones, clearly discriminate between random and natural DNA sequences. Entropic profiles also show a different degree of variability within and between genomes. The results of these analyses are discussed in relation both to the genome compartmentalization in vertebrates and to the differential action of compositional and/or functional constraints on DNA sequences.

Animals↗
PubMed1995

A landscape parametric profile approach for rat brain image analysis.

This paper develops the use of the landscape parametric profile as a descriptive and interpretative method of analyzing metabolic activity data obtained by neuroimaging techniques such as 2-deoxyglucose autoradiography. The method is suggested as an initial survey-type approach that can be used to map regional activity throughout the coronal planes of a rat brain and to compare relative differences in the patterns of activity between different brains. Images are acquired using preexisting image analysis software and then transformed to landscape parametric profiles derived from each matrix array. The image profile analysis tasks are done using commercially available software for matrix computations such as MATLAB. An effective way of interpreting activity differences between brains is presented by plotting the results from a randomized blocks ANOVA significance test combined with the average profiles of different subjects within the same experimental group. The method greatly reduces the computational burden associated with image averaging and statistical comparison of brains from different subjects while preserving the richness in topographic metabolic information. One significant advantage of the method is that it results in figures that are readily depicted and interpretable in black and white.

Analysis of Variance↗
PubMed2002

Comparison of two compartmental models for describing ranitidine's plasmatic profiles.

The plasmatic profiles of 12 healthy volunteers after oral administration of ranitidine (150 mg) were studied considering two compartmental models. We observed the presence of two peaks. The proposed mechanism responsible for the existence of secondary peaks includes enterohepatic recirculation and the existence of multiple sites of absorption along the gastrointestinal tract. For characterizing the pharmacokinetic aspect of the drug, both phenomena were described using two compartmental models. We calculated the pharmacokinetic parameters and statistical tests after fitting the data of each volunteer under both models proposed. Statistically significant differences were not found in the statistical test values but existed in the area under the curve (AUC) comparing between models. To decide which of the two proposed models gave the best approximation of the physiological phenomenon undergone, we studied the pharmacokinetic of the drug in the rat, an animal without gallbladder. After oral administration of ranitidine, the plasmatic profile of the animals showed at least two peaks. Less than 0.2% of an oral dose was recovered in bile as ranitidine. Therefore, and considering the rat has no post-absorptive depot from where the drug can be released discontinuously, enterohepatic recycling does not seem to contribute significantly to the occurrence of secondary peaks in the concentration-time profiles of rats. Considering the results, we proposed that the best model able to explain the plasmatic profiles found in man and rats after oral administration of ranitidine is the one that presents multiple sites of absorption along the gastrointestinal tract. It is important to define the correct model in the calculation of the AUC and so in the value of the absolute bioavailability.

Adult↗
PubMed2002

Interferon-alpha2b secretion by adenovirus-mediated gene delivery in rat, rabbit, and chimpanzee results in similar pharmacokinetic profiles.

Gene delivery, with subsequent protein synthesis and secretion, in vivo has been proposed as an alternative way to deliver a therapeutic protein to the systemic circulation. Interferon-alpha (IFN) protein is effective in the treatment of viral and malignant diseases but has short serum half-life that requires frequent administration. An E1 region-deleted adenovirus vector encoding human IFN-alpha2b gene driven by the cytomegalovirus immediate early promoter (rAd-IFN) was generated to assess the serum concentration-time profiles of expressed IFN protein in animal models. Intravenous administration of rAd-IFN, normalized for body weight, resulted in dose-dependent serum IFN concentrations that persisted 8-40 days with similar concentration-time profiles in rats and rabbits. We sought to determine if serum concentration-time profiles in the rat and rabbit animal models would be predictive for a larger animal and would therefore be relevant models for potential dosing of human patients. Two chimpanzees (approximately 70 kg) dosed with rAd-IFN by intravenous administration normalized to body weight achieved serum IFN concentration-time profiles similar to those observed in rats and rabbits. The role of the immune response in limiting the persistence of transgene expression was highlighted by the persistence of serum IFN concentrations for over 200 days in beige/SCID immunodeficient mice. These studies suggest that serum concentration of secreted transgene products after gene delivery in small animal models may be highly predictive for larger species and will help define dosing strategies in human patients.

Adenoviridae↗
PubMed2006

The temporal profile of edema formation differs between male and female rats following diffuse traumatic brain injury.

Although female hormones are known to influence edema formation following traumatic brain injury (TBI), no studies have actually compared the temporal profile of edema formation in both male and female rats following diffuse TBI. In this study, male, female, and female ovariectomized rats were injured using the 2 m impact acceleration model of diffuse TBI. The temporal profile of brain water content was assessed over 1 week post-trauma. Male animals demonstrated increased (p < 0.05) edema at 5 hours, 24 hours, 3 days, 4 days, and 5 days after TBI with a peak at 5 hours post-injury. This time point was associated with increased blood-brain barrier (BBB) permeability. In contrast, intact females showed increased levels of edema (p < 0.05) at 5 hours, 24 hours, 3 days, and 4 days post-TBI, with a peak at 24 hours. No BBB opening was present in intact females at 5 hours. Female animals demonstrated more edema than male animals at 24 hours, but less at 5 hours, 3 days, and 5 days. Ovariectomy produced an edema profile that was similar to that observed in males. The temporal profile of edema formation after TBI seems to depend on endogenous hormone levels, a difference which may have an influence on clinical management.

Animals↗
PubMed2007

Metabolite profiling in blood plasma.

Metabolite profiling has been established as a multiparallel strategy for relative quantification of a mixture of compounds or compound classes using chromatography and universal detection technologies (gas chromatography-mass spectrometry [GC-MS], liquid chromatography-MS). Despite its origins dating back to the late 1960s, it was only in the 1980s that its use was acknowledged to diagnose metabolic disorders in men, especially for rapid screening of inborn errors. Even faster electrospray ionization-MS/MS screening methods replaced longish chromatographic methods, and method development had stopped despite its potential use for other, less imminent diseases such as likelihood assessments of type II diabetes mellitus or cardiovascular risk factor evaluation. In addition to its diagnostic use, profiling blood samples can be employed to investigate specific biochemical responses. The broader scope of analysis outweighs the disadvantages by taking compromises in method development and the reduced accuracy for specific metabolites. This chapter exemplifies the strategies in metabolite profiling by GC-MS. It gives experimental details on basic steps like blood plasma withdrawal, storage, protein precipitation, extraction, concentration, derivatization, data acquisition, raw data processing, and result data tranformation. A major difference to profiling plant tissues is that no fractionation step is utilized, enabling the analysis of primary metabolites like sugars and amino acids concomitant with lipids such as sterols and free fatty acids.

Amino Acids↗
PubMed1993

The forensic significance of various reference population databases for estimating the rarity of variable number of tandem repeat (VNTR) loci profiles.

The likelihood of occurrence of 1,964-HaeIII-generated target DNA profiles was estimated using fixed bin VNTR frequencies from various Caucasian, Black, and Hispanic databases and the product rule. The data in this study demonstrate that for forensic purposes there are smaller differences in statistical estimates of DNA profile frequencies among subgroup databases than among estimates across major population databases. This observation does not support the premise asserted by the NCR Report (1992) that the differences among subgroups within a race would be greater than between races (at least for forensic purposes). Therefore, the data do not support the need for alternative procedures, such as the ceiling principle approach (NRC Reports, 1992), for deriving statistical estimates of DNA profile frequencies. Comparisons across major population groups provide reasonable, reliable, and meaningful estimates of DNA profile frequencies without forensically significant consequences.

Black People↗
PubMed1990

Modulation of the orientational order profile of the lipid acyl chain in the L alpha phase.

The orientational order profile along the lipid acyl chain has been characterized under several different conditions of polar headgroup composition, temperature, and cholesterol content. Despite the different nature of these factors, the variation of the order is governed by two common trends. First, the relative change of order induced by the variation of these factors is always more pronounced towards the end of the chain than for the methylene groups near the interface. Second, there is, to a first approximation, a distinct correlation between the magnitude of the order parameters and the shape of the order profile. For example when the chain is highly ordered, the relative width of the order distribution is narrow indicating that the plateau region is longer. These conclusions suggest that the orientational order profile depends on only a small number of parameters and demonstrate clearly that the correlation length for changes in orientational order is much greater than one C-C bond length. Our results also show that the reduced temperature is not related in simple terms to orientational order and probably has little theoretical significance. The orientational order profiles of POPC and POPE bilayers are significantly different even when expressed in terms of reduced temperature. The behavior of POPC/cholesterol systems also indicates that the orientational order of the lipid chain and the gel-to-liquid crystalline phase transition temperature are not related in a straightforward manner.

Cell Membrane↗
PubMed1993

Interpretation of high-resolution current source density profiles: a simulation of sublaminar contributions to the visual evoked potential.

Current source density (CSD) analysis provides an index of the location, direction, and density of transmembrane currents that arise with synchronous activation of neural tissue and that generate an evoked potential profile in the extracellular medium. In neocortex and other laminated structures, a simplified, one-dimensional CSD analysis can be computed by differentiation of voltages sampled at discrete points in a linear array. One-dimensional CSD analysis is a practical and accurate method for defining both regional activity patterns and neural generators of surface-recorded evoked and event-related potentials. In computing the CSD, common practices of differentiating across spatial grids of 200 microns or more and use of spatial smoothing routines help to reduce noise, but severely limit the spatial resolution available to the analysis. High-resolution CSD procedures (i.e., 3 point differentiation using a spatial grid of 100 microns or less) are more suited to identification of processes within individual cortical laminae or sublaminae, but can magnify the contributions of computational artifacts. Despite the inclusion of independent indices of cellular activity (e.g., multiunit activity), both high- and low-resolution analyses may indicate current source and sink configurations for which there is more than one plausible physiological interpretation. In the present study we examined the resolving capacity and pitfalls of common CSD procedures using simulated ensembles of current dipoles. These were positioned and oriented to model the depolarization of lamina 4C stellate cells and thalamocortical afferents in macaque striate cortex. Empirically, the surface N40 appears in association with a CSD configuration which includes current sinks within the thalamorecipient (stellate) subdivisions of lamina 4C and a large current source extending considerably below 4C. Dipole ensemble contributions to the CSD profile were computed and compared to physiological data from this region. Small asymmetries in activation of model stellate laminae were sufficient to produce substantial open field contributions. However, the best fit with empirical CSD profile was found when the simulation included contributions from thalamocortical axons, along with both open and closed field contributions from dual stellate cell sublaminae. High-resolution CSD profiles were shown to be interpretable when computational artifacts characteristic of closed and open fields were identified using a series of differentiation grids.

Afferent Pathways↗
PubMed1989

Asymmetric velocity and acceleration profiles of human arm movements.

Displacement, velocity, acceleration and jerk (change of acceleration with time) were analyzed for arm flexion movement over a wide range of movement amplitudes and speeds. Relative time to peak velocity or relative duration of acceleration, k, was approximately 0.5 for the movements with intermediate speed (about 0.5 s in movement time), i.e., symmetric velocity and acceleration profiles. For the slow and ballistic movements, k shifted towards values below and above 0.5, respectively creating asymmetric profiles. Consistent k-dependence of movement time, peak velocity, maximum acceleration and maximum deceleration were observed. "Jerk cost", the square of the magnitude of jerk integrated over the entire movement, was calculated for each movement. A dynamic optimization technique to minimize jerk cost under the constraint on jerk input was applied to interpret the results, assuming that a major goal of skilled movements was to produce optimally smooth movements. The constrained minimum-jerk model explained speed-dependent asymmetry of the velocity and acceleration profiles. Jerk cost consumed by the movements with intermediate speed approximately satisfied minimum-cost criterion predicted by the model but was higher than the criterion for slow and ballistic movements. The results suggested that optimality criteria other than jerk cost also should be considered to predict movement profiles over the entire range of speeds.

Acceleration↗
PubMed1984

Absorption kinetics and action profiles of mixtures of short- and intermediate-acting insulins.

The effects of mixing short- and intermediate-acting insulins (lente and NPH) on plasma insulin levels and action profiles, assessed by the euglycaemic clamp technique, were studied in 10 volunteers. Four protocols were used: (1) comparison between two semi-synthetic human soluble insulins in seven subjects (0.22 IU/kg); (2) assessment of insulin levels and action profiles of lente insulin in six subjects and of NPH insulin in five subjects (0.33 IU/kg); (3) comparison between mixtures of soluble with lente insulin and soluble with NPH insulin, administered immediately after mixing, in eight subjects (0.55 IU/kg, 40% short-acting); (4) same mixtures, administered 2 days after preparation, in seven subjects. No differences in insulin levels and action profiles during the first 4 h after injection were found between both short-acting insulins and the soluble + NPH insulin mixtures. After the administration of NPH insulin, plasma insulin levels rose slightly faster in comparison with lente insulin, with no significant differences between the action profiles for either insulin. Onset of action was delayed after soluble + lente insulin, both when administered immediately after mixing and to a greater extent when stored for 2 days before administration. After the latter procedure, the onset of action was markedly retarded and only slightly faster than after lente insulin alone. We conclude, therefore, that mixing soluble with NPH insulin in a ratio of 2:3 does not affect the absorption kinetics of soluble insulin, whereas the onset of action is delayed when soluble is combined in the syringe with lente insulin, even when administered immediately after mixing.

Blood Glucose↗
PubMed1988

Use of profile analysis for the measurement of organ dimensions.

We have developed a method for measurement of organ dimension based on the use of the full width half maximum (FWHM) of profiles taken through an organ. In vitro studies were performed using a large rectangular lucite box filled with water. Five circular lucite phantoms with internal diameters of 1.4-10.2 cm and 1 elliptical phantom with dimensions 9.6 x 4.0 cm were filled with 99mTc-pertechnetate at various concentrations. Phantoms were imaged on a gamma camera at a depth of 5-25 cm in water and the FWHM calculated from horizontal profiles taken across the cylinders. The FWHM showed no variation with 99mTc concentration in the same cylinder. Phantom profiles were deconvolved with a system line spread function measured under similar conditions of scatter and depth. The correction factor to convert the deconvolved profile FWHM to true diameter was independent of cylinder depth and diameter over a range of FWHM 3-10 cm and depth 5-25 cm. The mean value for the correction factor was 1.23 +/- 0.04 for circular phantoms and 1.14 +/- 0.02 for the elliptical phantom. This technique should allow an objective and reproducible estimate of organ dimensions from planar images that is relatively independent of the depth and size of an organ.

Anatomy↗
PubMed1976

Method for the determination of mean densitometric profiles of chromosomes: application to human chromosomes stained by quinacrine mustard, ethidium bromide or by the Feulgen reaction.

When comparing the densitometric profiles of corresponding chromosomes registered from different metaphases or homologous pairs, one is always faced with the variability of their length and overall height. This makes difficult the quantitative comparison of a given chromosome treated by various staining procedures.--A simple and rapid method has been developed for normalizing the densitometric profiles and averaging them in order to obtain a "mean density pattern" of each chromosome. The analysis involves: photographic images, digitalization of the densitometric profiles and processing of the data by a mini-computer.--The method, based on a linear relationship between the area of the densitometric profiles and their length, has been applied to five human chromosomes (1, 2, 6, 12 and 16) stained by ethidium bromide, quinacrine mustard (with or without acidic hydrolysis), pararosaniline and bisaminophenyl-oxadiazole (Feulgen reaction).

Bromides↗