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[Asynchrony of ventricular contraction and relaxation--pathophysiologically recognized phenomenon, now can be clinically assessed].

When regional myocardial dysfunction is present, the physiological pattern of ventricular filling and contraction is impaired. During acute coronary occlusion, characteristic changes are observed in the ischemic myocardial segment: the amplitude of the systolic wall thickening is reduced (hypokinesia), then virtually absent (akinesia) and finally replaced by a paradoxical outward motion (dyskinesia). The maximum amplitude is reached in early diastole ("post-ejection thickening"). Since hyperkinesis develops in the normal region, the ischemic and the normal region contract asynchronously. Experimentally left ventricular asynchrony can be detected by means of subendo- and subepicardially implanted ultrasonic crystals ("sonomicrometry") or by the analysis of the phase difference of the first Fourier harmonic of dysfunctional versus control myocardial wall motion. In the clinical setting, digitized cineventriculography, radionuclide angiography and digitized M-mode echocardiography were used to assess left ventricular asynchrony in patients with coronary artery disease and hypertrophic cardiomyopathy. However, these imaging modalities are time-consuming and require complicated off-line analysis. Tissue Doppler echocardiography (TDE) is a new ultrasound modality that is based on color Doppler principles and allows for quantification of myocardial wall motion velocity by detection of consecutive phase shifts of the ultrasound signal reflected from the myocardium. The Doppler signals are displayed as a color or pulsed Doppler image by rejecting low-amplitude echoes from the blood pool due to changes in thresholding and filtering algorithms. In addition, the ability to measure low velocity is improved in the TDE system so that the lowest measurable velocity is 0.2 cm/s, a velocity level associated with cardiac tissue motion (Table 1). Due to its high temporal and spatial resolution, TDE provides valuable information on regional myocardial wall motion during different intervals of the cardiac cycle. In healthy subjects, patients with coronary artery disease and patients with hypertrophic cardiomyopathy, tissue Doppler echocardiography was used to assess myocardial synchrony/asynchrony on a 2-fold temporal and spatial analysis. Peak myocardial velocities in different myocardial regions were detected during rapid ejection, isovolumic relaxation, rapid filling and atrial contraction (Figure 1). In the apical view, during the isovolumic relaxation time (IVRT) healthy subjects showed slow, synchronous outward motion of the septum and the lateral wall with homogeneous color-encoding (blue/green, Figure 2). Analysis of peak velocities revealed low, negative velocities in both the septum and the lateral wall (Figure 3). In patients with a significant luminal narrowing of the LAD myocardial asynchrony was detected during the isovolumic relaxation period: while the septum was moving inwards (red color-encoding with low, positive velocities), the lateral wall was moving outwards (blue/green encoding, low, negative velocities). A representative example of a patient with CAD is given in Figure 4. The M-mode analysis of the abnormally contracting interventricular septum reveals positive peak tissue velocities during the isovolumic relaxation period (Figure 5). In hypertrophic cardiomyopathy, TDE was able to detect an abnormal inward motion of the interventricular septum during IVRT and a delay in the onset of rapid filling (Figure 6). Thus, tissue Doppler echocardiography is a feasible method for the on-line detection of myocardial asynchrony. Sensitivity and specificity of the findings have to be explored in further, prospectively randomized trials.

Cardiomyopathy, Hypertrophic↗

Evaluation of global and regional left ventricular function using technetium-99m sestamibi ECG-gated single-photon emission tomography.

We evaluated a method for the assessment of left ventricular (LV) function with technetium-99m sestamibi ECG-gated single-photon emission tomography (GSPET). GSPET was performed at rest in 21 patients. Images were reconstructed to obtain end-diastolic (ED) and end-systolic (ES) images. Endocardial and epicardial edges of the left ventricle for the ED and ES images were defined using the gradient images and the algorithm developed. LV wall thickness was measured for the mid-ventricular slices of ED and ES images at 10 degrees intervals. The systolic thickening (ST) and the LV ejection fraction [LVEF(GSPECT)] could be determined. These values were compared with the LV ejection fraction (LVEF) estimated using the gated blood pool method. There was a linear correlation between LVEF and ST (r=0.79), and LVEF and LVEF(GSPET) (r=0.87). Histograms of LV thicknesses were generated. Agreement for evaluation of regional wall motion between the method using histograms of LV thicknesses and the gated blood pool study was 92.8% (kappa=0.75). It is concluded that with an appropriate method for LV edge detection, GSPET with 99mTc-labelled perfusion agents is of use for simultaneous evaluation of myocardial perfusion and assessment of LV function.

Electrocardiography↗

Magnetocardiographic QT dispersion during cardiovascular autonomic function tests.

QT dispersion is considered to reflect nonhomogeneity of ventricular repolarization. The autonomic nervous system modulates QT interval duration, but the effect may not be spatially homogenous. Magnetocardiography (MCG) registers the weak magnetic fields generated by myocardial electric currents with high localizing accuracy. We studied the effects of rapid cardiovascular autonomic nervous adjustment on QT dispersion in MCG. Ten healthy male volunteers were monitored during deep breathing, the Valsalva maneuver, sustained handgrip, hyperventilation, the cold pressor test and mental stress. 67 MCG channels and 12 ECG leads were recorded simultaneously. A computer algorithm was used for QT interval measurements. QT dispersion was defined as maximum - minimum or standard deviation of the QTpeak and QTend intervals. In MCG the QT(end) dispersion increased during deep inspiration compared with deep expiration (96+/-19 ms v. 73+/-27 ms, p = 0.05). Magnetic QT dispersion tended to increase during the bradycardia phase of the Valsalva maneuver, but the change was obvious only for QT(end) (55+/-26 ms v. 76+/-29 ms, p<0.05). Other tests had no significant effect on QT dispersion, not even the cold pressor test, although it causes strong sympathetic activation. Magnetic and electric QT(peak) and QT(end) intervals correlated closely (r = 0.93 and 0.91), whereas the QT dispersion measures showed no correlation. In conclusion, magnetic QT dispersion is not modified by rapid changes in autonomic tone, but maneuvers involving deep respiratory efforts and changes in ventricular loading affect QT dispersion measurements.

Adult↗

A computer reconstruction of the entire coronary arterial tree based on detailed morphometric data.

A rigorous analysis of blood flow must be based on the branching pattern and vascular geometry of the full vascular circuit of interest. It is experimentally difficult to reconstruct the entire vascular circuit of any organ because of the enormity of the vessels. The objective of the present study was to develop a novel method for the reconstruction of the full coronary vascular tree from partial measurements. Our method includes the use of data on those parts of the tree that are measured to extrapolate the data on those parts that are missing. Specifically, a two-step approach was employed in the reconstruction of the entire coronary arterial tree down to the capillary level. Vessels > 40 microm were reconstructed from cast data while vessels < 40 microm were reconstructed from histological data. The cast data were reconstructed one-bifurcation at a time while histological data were reconstructed one-sub-tree at a time by "cutting" and "pasting" of data from measured to missing vessels. The reconstruction algorithm yielded a full arterial tree down to the first capillary bifurcation with 1.9, 2.04 and 1.15 million vessel segments for the right coronary artery (RCA), left anterior descending (LAD) and left circumflex (LCx) trees, respectively. The node-to-node connectivity along with the diameter and length of every vessel segment was determined. Once the full tree was reconstructed, we automated the assignment of order numbers, according to the diameter-defined Strahler system, to every vessel segment in the tree. Consequently, the diameters, lengths, number of vessels, segments-per-element ratio, connectivity and longitudinal matrices were determined for every order number. The present model establishes a morphological foundation for future analysis of blood flow in the coronary circulation.

Algorithms↗

Non-parametric detection of temporal order across pairwise measurements of time delays.

Neuronal synchronization is often associated with small time delays, and these delays can change as a function of stimulus properties. Investigation of time delays can be cumbersome if the activity of a large number of neurons is recorded simultaneously and neuronal synchronization is measured in a pairwise manner (such as the cross-correlation histograms) because the number of pairwise measurements increases quadratically. Here, a non-parametric statistical test is proposed with which one can investigate (i) the consistency of the delays across a large number of pairwise measurements and (ii) the consistency of the changes in the time delays as a function of experimental conditions. The test can be classified as non-parametric because it takes into account only the directions of the delays and thus, does not make assumptions about the distributions and the variances of the measurement errors.

Algorithms↗

A program package for self-assessment and examination in biochemistry.

A BASIC program has been developed for self-evaluation and testing of an individual's knowledge of main categories in biochemistry. The computer tests permit sequential or random distribution of items, random distribution of answers in each item at each new run, effective feedback control with the student, use of a program clock to determine different time allowance, precise and quick analysis and grading of student's answer thus saving the time and labour of examiners. Editing, deleting and appending of new items is easily achieved. Information is obtained for verifying the quality of the test itself. Examination versions of tests in ten categories have been combined into an annual computer test in biochemistry.

Algorithms↗

Simulation of the spatial distribution of muscle fibres in human muscles.

A composite muscle cross section model was simulated on a VAX 780 computer. The various motor unit territories in the cross section area were circular, partially overlapping each other. The radii of the territories of the motor units, their centres, and the number of muscle fibres in each motor unit were treated as random variables. Two different models were generated, one with a uniform distribution of the fibres in the motor unit territories, and the other with a normal distribution of the fibres. An algorithm for simulation of fibre density measurements was written, and the effects of varying the parameters of the model on fibre density measurements were investigated. The results of the computer simulation were in agreement with analytical and laboratory findings.

Computers↗

Model control of image processing: pupillometry.

Smart instruments require on-line computers, special purpose hardware, or both. A pupillometer is described that relies only on a general purpose microcomputer with a frame grabber to process infrared video camera pictures of the human eye. An essential feature of the instrument is that a top-down model controls the image processing algorithms. The model generates regions of interest, ROIs, positioned from knowledge of anatomy and optics of the eye and information from previously analyzed frames. Within these adaptively controlled ROIs, fast, run-time algorithms automatically calculate local thresholds, area measurements, moments for centroid position information, and use pyramiding to shorten calculation time for large pupils. Outputs are precise measurements of pupil size and eye position in real time, with adequate bandwidth for most purposes.

Artificial Intelligence↗

Optical detection of high-grade cervical intraepithelial neoplasia in vivo: results of a 604-patient study.

OBJECTIVE: The purpose of this study was to assess the in vivo optical detection of high-grade cervical intraepithelial neoplasia (2/3+) on the whole cervix with a noncontact, spectroscopic device. STUDY DESIGN: Cervical scanning devices collected intrinsic fluorescence and broadband white light spectra and video images from 604 women during routine colposcopy examinations at 6 clinical centers. A statistically significant dataset was developed of intrinsic fluorescence and white light-induced cervical tissue spectra that was correlated to expert histopathologic determination. On the basis of a retrospective analysis of the acquired data, a classification algorithm was developed, validated, and optimized. RESULTS: Intrinsic fluorescence, backscattered white light, and video imaging each contribute complementary information to diagnostic algorithms for high-grade cervical neoplasia. More than 10000 measurements that were made on colposcopically identified tissue from >500 subjects were the basis for algorithm training and testing. Algorithm performance demonstrated a sensitivity of approximately 90%. This performance was confirmed by various training methods. With the use of a multivariate classification algorithm, optical detection is predicted to detect 33% more high-grade cervical intraepithelial neoplasia (2/3+) than colposcopy alone. CONCLUSION: Full cervix optical interrogation for the detection of high-grade cervical intraepithelial neoplasia is feasible and appears capable of detecting more high-grade cervical intraepithelial neoplasia than colposcopy alone. With the use of this classification algorithm, a multisite, randomized controlled trial is underway that compares the combination of optical detection and colposcopy versus colposcopy alone.

Adolescent↗

Encoding of diffusion and T1 in the CPMG echo shape: single-shot D and T1 measurements in grossly inhomogeneous fields.

We present a new approach of NMR measurements in the presence of grossly inhomogeneous fields where information is encoded in the echo shape of CPMG trains. The method is based on sequences that consist of an initial encoding sequence that generates echoes with contributions from at least two different coherence pathways that are then both refocused many times by a long string of closely spaced identical pulses. The generated echoes quickly assume an asymptotic shape that encodes the information of interest. High signal-to-noise ratios can be achieved by averaging the large number of echoes. We demonstrate this approach with different implementations of the measurements of longitudinal relaxation time, T(1), and diffusion coefficient, D. It is shown that the method can be used for novel single-shot measurements.

Algorithms↗

Testing and mapping non-stationarity in animal behavioral processes: a case study on an individual female bean weevil.

Statistical analysis based on two characteristics of a small-world network, and on Lempel-Ziv's measure of Kolmogorov-Chaitin's algorithmic complexity are first proposed to scan through an individual behavioral sequence for possible existence of non-stationarity. Due to fixed window width, these tests have drawbacks in mapping out regions of non-stationarity. A non-parametric approach based on sparse coding schemes is employed to segment the whole behavioral sequence into unequal length segments, thus resultant avoiding further efforts for grouping. Then attempts are made to entangle the resultant segmentation with other non-local behavioral patterns onto such sequence to ascertain that the non-stationarity corresponds to a sequence of different categories of underlying driving force. It is of potential importance that this segmentation, represented by a hierarchy of code sequences, provides a natural platform for detecting intrinsically coherent behavioral patterns based on continuously recorded data. Illustrations throughout the developments are made exclusively on data encoded from a nearly 4-h video-recording of a female bean weevil's behavior.

Algorithms↗

Genetic influences on dynamic complexity of brain oscillations.

Human electroencephalogram (EEG) consists of complex aperiodic oscillations that are assumed to indicate underlying neural dynamics such as the number and degree of independence of oscillating neuronal networks. EEG complexity can be estimated using measures derived from nonlinear dynamic systems theory. Variations in such measures have been shown to be associated with normal individual differences in cognition and some neuropsychiatric disorders. Despite the increasing use of EEG complexity measures for the study of normal and abnormal brain functioning, little is known about genetic and environmental influences on these measures. Using the pointwise dimension (PD2) algorithm, this study assessed heritability of EEG complexity at rest in a sample of 214 young female twins consisting of 51 monozygotic (MZ) and 56 dizygotic (DZ) pairs. In MZ twins, intrapair correlations were high and statistically significant; in DZ twins, correlations were substantially smaller. Genetic analyses using linear structural equation modeling revealed high and significant heritability of EEG complexity: 62-68% in the eyes-closed condition, and 46-60% in the eyes-open condition. Results suggest that individual differences in the complexity of resting electrocortical dynamics are largely determined by genetic factors. Neurophysiological mechanisms mediating genetic variation in EEG complexity may include the degree of structural connectivity and functional differentiation among cortical neuronal assemblies.

Adolescent↗

Development and evaluation of an automated atlas-based image analysis method for microPET studies of the rat brain.

An automated method for placement of 3D rat brain atlas-derived volumes of interest (VOIs) onto PET studies has been designed and evaluated. VOIs representing major structures of the rat brain were defined on a set of digitized cryosectioned images of the rat brain. For VOI placement, each PET study was registered with a synthetic PET target constructed from the VOI template. Registration was accomplished with an automated algorithm that maximized the mutual information content of the image volumes. The accuracy and precision of this method for VOI placement was determined using datasets from PET studies of the striatal dopamine and hippocampal serotonin systems. Each evaluated PET study could be registered to at least one synthetic PET target without obvious failure. Registration was critically dependent upon the initial position of the PET study relative to the synthetic PET target, but not dependent on the amount of synthetic PET target smoothing. An evaluation algorithm showed that resultant radioactivity concentration measurements of selected brain structures had errors=2% due to misalignment with the corresponding VOI. Further, radioligand binding values calculated from these measurements were found to be more precise than those calculated from measurements obtained with manually drawn regions of interest (ROIs). Overall, evaluation results demonstrated that this atlas-derived VOI method can be used to obtain unbiased measurements of radioactivity concentration from PET studies. Its automated features, and applicability to different radioligands and brain regions, will facilitate quantitative rat brain PET assessment procedures.

Animals↗

HIV vaccine development by computer assisted design: the GAIA vaccine.

The design of epitope-driven vaccines that address the global variability of HIV has been significantly hampered by concerns about conservation of the vaccine epitopes across clades of HIV. We developed two computer-driven methods for improving epitope-driven HIV vaccines: the Epi-Assembler, which derives representative or "immunogenic consensus sequence" (ICS) epitopes from multiple viral variants, and VaccineCAD, which reduces junctional immunogenicity when epitopes are aligned in a string-of-beads format for insertion in a DNA expression vector. In this study, we report on 20 ICS HIV-1 peptides. The core 9-mer contained in these consensus peptides was conserved in 105-2250 individual HIV-1 strains. Nineteen of the 20 ICS epitopes (95%) evaluated in this study were confirmed in ELISpot assays using peripheral blood monocytes obtained from 13 healthy HIV-1 infected subjects. Twenty-five ICS peptides (all 20 of the peptides evaluated in this study and 5 additional ICS epitopes) were then aligned in a pseudoprotein string using "VaccineCAD", an epitope alignment tool that eliminates immunogenicity created by the junctions between the epitopes. Reordering the construct reduced the immunogenicity of the junctions between epitopes as measured by EpiMatrix, an epitope mapping algorithm. The reordered construct was also a more effective immunogen in vivo when tested in HLA-DR transgenic mice. These data confirm the utility of bioinformatics tools to design novel vaccines containing "immunogenic consensus sequence" T cell epitopes for a globally relevant vaccine against HIV.

AIDS Vaccines↗

Determination of confidence intervals of metabolic fluxes estimated from stable isotope measurements.

Metabolic fluxes, estimated from stable isotope studies, provide a key to quantifying physiology in fields ranging from metabolic engineering to the analysis of human metabolic diseases. A serious drawback of the flux estimation method in current use is that it does not produce confidence limits for the estimated fluxes. Without this information it is difficult to interpret flux results and expand the physiological significance of flux studies. To address this shortcoming we derived analytical expressions of flux sensitivities with respect to isotope measurements and measurement errors. These tools allow the determination of local statistical properties of fluxes and relative importance of measurements. Furthermore, we developed an efficient algorithm to determine accurate flux confidence intervals and demonstrated that confidence intervals obtained with this method closely approximate true flux uncertainty. In contrast, confidence intervals approximated from local estimates of standard deviations are inappropriate due to inherent system nonlinearities. We applied these methods to analyze the statistical significance and confidence of estimated gluconeogenesis fluxes from human studies with [U-13C]glucose as tracer and found true limits for flux estimation in specific human isotopic protocols.

Blood Glucose↗

A new method for extracting cable parameters from input impedance data.

We establish conditions under which the input impedance and its first two derivatives, evaluated at the origin, uniquely determine the axial resistance, membrane capacitance, and membrane conductance of a finite uniform cable with one sealed end. We argue that these impedance data are readily available to the experimentalist and we demonstrate the recovery of a cable's electrical parameters from synthetic noisy measurements.

Algorithms↗

Age-related decline in striatal volume in monkeys as measured by magnetic resonance imaging.

Age-related declines in striatal markers for the dopamine system have been demonstrated in several species. The current study investigated structural changes during aging in the rhesus monkey striatum. Male monkeys were studied using a volumetric spoiled gradient recall (SPGR) magnetic resonance imaging protocol. The caudate nucleus and putamen were segmented by manual tracing using landmarks made in the orthogonal planes. The whole brain volume (defined as volume of gray and white matter plus cerebrospinal fluid in ventricles and sulci) was measured using a semi-automated algorithm. There was no correlation between age and whole brain volume. There were age-related declines in normalized (i.e. brain region/whole brain volume) caudate nucleus and putamen volumes. Monkeys in the young group (n = 7, 39-45 months old) had larger volumes of both the caudate nucleus and putamen than animals in the middle-age (n = 5, 120-180 months) or old (n = 7, 291-360 months) groups. The current results provide normative data to assess potential interventions (e.g. caloric restriction) in the aging process.

Aging↗