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Differentiation trajectories in normal and malignant cells.

We discuss a model for the organization of differentiation paths within the vector spaces of the cell genome. It is conjectured that the nuclear vesicle apparatus participates in the coordination of genes along nuclear trajectories directing cell commitment to terminal maturation. In this scenario, nuclear (onco)genes are interpreted as regulators of transcriptional exchanges among spatially correlated genes. The paper digresses on events leading to anachronistic acquisition of immortal growth by normally dependent cells as well as on the time and path dependent incidence of cancer, in vivo. Albeit the mathematico-physical foundations have been largely ignored, the basic ideas were derived from order-disorder transitions in chaotic systems whose dynamics are not pervasively random. The paper ends with a brief note on tumor heterogeneity, seen as a logistic phenomenon complementing the interpretation offered by (1).

Animals↗

Development of auditory brainstem evoked potentials in newborn infants: a three-channel Lissajous' trajectory study.

Auditory brainstem evoked potentials (ABEP) were recorded from 50 newborns (35-43 weeks gestational age), using three orthogonal differential electrode pairs, in addition to the widely used vertex-mastoid derivation. Potentials were evoked by alternating polarity, 75 dBnHL clicks presented monaurally at a rate of 10/s. From the records of the three orthogonal electrode pairs (nasion-inion; vertex-spinous cervical process VII; left-right mastoids), Three-channel Lissajous' trajectories (3CLT) were derived and analyzed. 3CLT point-by-point, as well as segmental descriptors were compared with peak latencies of the vertex-mastoid derivation. Point-by-point 3CLT descriptors included apex amplitude, latency and orientation. Segmental descriptors included planar segment beginning latencies, duration and orientation. The interpretation of these results in relation to developmental aspects of the auditory system, as well as to the question of ABEP generators, is enhanced by using 3CLT descriptors of ABEP, which are more comprehensive than their single-channel counterparts. 3CLT apices correlated well with the Vertex-Mastoid defined peaks. Both peak and apex latency changes indicate that at the developmental stages surveyed in this study, development takes place in the more central portions of the pathway, whereas the peripheral portion is already relatively mature. The results also indicate a maturational change in the relative contributions of constituent generators of ABEP components.

Brain Stem↗

Effects of myelin or cell body brainstem lesions on 3-channel Lissajous' trajectories of feline auditory brainstem evoked potentials.

Auditory brainstem evoked potentials (ABEP) were recorded from 16 awake cats to obtain 3-Channel Lissajous' Trajectories (3CLTs) using three orthogonal differential electrode configurations (nasion-midline nuchal ridge, left-right mastoids, vertex-midline under the mandible). Potentials, evoked by monaural 80 dBnHL (re, human threshold) clicks, were studied before, and up to 7 weeks after inducing neuronal lesions localized to the cochlear nucleus (CN) or the superior olivary complex (SOC), or myelin lesions localized to the fibers of the trapezoid body connecting these two structures. Neuronal lesions were induced by injection of kainic acid (KA), while myelin lesions were induced by injection of L-alpha-lysophosphatidylcholine (LPC). With CN neuronal lesions the major changes in 3CLT were in the time domain of 'b', 'c' and 'd' (components P2, P3 and P4 of single-channel ABEP). With SOC neuronal lesions the major changes were in 'c' and 'd' of 3CLT (P3 and P4 of ABEP). With trapezoid body lesions the major change was in 'c' (P3 of ABEP). The results are compatible with the peripheral generation of the first ABEP components (P1a and P1b). The second component (P2) is generated by ipsilateral CN neurones and their outputs. The third component (P3) is generated primarily by ipsilateral SOC neurones and their outputs, with the ipsilateral CN providing input. The The fourth component (P4) is generated bilaterally by the SOC neurones and their outputs, receiving their inputs from ipsilateral CN. The fifth ABEP component (P5) is generated by structures central to the SOCs and their immediate outputs. Neither focal neuronal nor myelin lesions were sufficient to produce obliteration of any component, consistent with a set of generators for each of the ABEP components, consisting of both cell bodies and their output fibers, that is distributed spatially in the brainstem.

Animals↗

Critical ages in brainstem development revealed by neonatal 3-channel Lissajous' trajectory of auditory brainstem evoked potentials.

Auditory brainstem evoked potentials (ABEPs) were recorded from 91 newborns from 7 age groups between 26 to 43 weeks of gestation. In addition to the widely used vertex-mastoid derivation, potentials were recorded from three orthogonal electrode configurations, and represented in 3 dimensional voltage-space as three-channel Lissajous' trajectories (3CLTs). ABEPs were evoked by alternating polarity, monaural 75 dBnHL clicks presented at rates of 10/s, 55/s and 80/s. Potentials were also recorded to 45 dBnHL and 15 dBnHL clicks presented at 10/s. 3CLT point by point (apex latencies, amplitudes and orientation) as well as planar segment (planar segment position and duration) descriptors, along with peak latencies of the vertex-mastoid peaks, were followed for effects of age, stimulus intensity and rate. ABEPs began to appear consistently at 29 weeks of gestation to high stimulus intensities, with a rapid decrease of ABEP thresholds up to 34 weeks. At 35 weeks, thresholds stabilized approximately at adult values. The results indicate a significant effect of stimulus rate and intensity as well as of gestational age group on apex latencies. The findings also showed changes in apex orientations associated with stimulus rate and intensity interacting with gestational age. 3CLT descriptors enhanced the understanding of these results in relation to developmental and maturational aspects of the auditory system. The results may be explained by maturational change in relative contributions of constituents of the complex ABEP generators.

Analysis of Variance↗

Three-channel Lissajous' trajectory of the binaural interaction components of human auditory middle-latency evoked potentials.

Three-channel Lissajous' trajectories (3-CLTs) of the binaural interaction component (BI) of auditory middle latency evoked potentials (AMLEPs) were derived from 14 normally hearing adults by subtracting the response to binaural clicks from the algebraic sum of monaural responses. AMLEPs were recorded in response to 65 dB nHL, rarefaction clicks, presented at a rate of 3.3/s. A normative set of BI 3-CLT measures was calculated and compared with the corresponding measures of simultaneously recorded, single-channel vertex-left mastoid and vertex-neck derivations of BI and of AMLEP to binaural stimulation (B). 3-CLT measures included: apex latency, amplitude and orientation, as well as planar segment duration, orientation, size and shape. The results showed seven main apices and associated planar segments ('Be', 'Bf', 'Bg', 'Bh', 'Bi1', 'Bi2' and 'Bj') in the 3-CLT of BI. Apex latencies of the BI 3-CLT were comparable to peak latencies of the vertex-left mastoid and vertex-neck AMLEP and BI records, both in their absolute values and in intersubject variability. Durations of BI planar segments were approximately 5.0 ms. Apex amplitudes of BI 3-CLT were larger than the respective peak amplitudes of the vertex-mastoid and vertex-neck BI records, while their intersubject variabilities were comparable. The lateralization of BI components may indicate asymmetric processing of binaural auditory input, or may be connected with anatomical asymmetry such as skull thickness. Preliminary analyses did not reveal a clear correlation between the lateralization of the BI component 'Bi2' and the handedness of the subject. We suggest that BI components of AMLEP may be associated with the primary auditory cortex and subcortical ascending structures.

Acoustic Stimulation↗

Intra- and extra-uterine development of neonatal 3-channel Lissajous' trajectory of auditory brainstem evoked potentials.

This study compared intra- and extra-uterine maturation of the auditory pathway, using auditory brainstem evoked potentials (ABEPs), recorded with three orthogonal differential electrode configurations. From the three records of each subject, 3-channel Lissajous' trajectories (3CLTs) were derived and analyzed. 107 newborns were compared at the same gestational and post-conceptional (gestational+postnatal) age, from 29 weeks (wks) up to 43 wks. In addition, we explored the effects and neurophysiological consequences of early exposure to extra-uterine life, on the peripheral and central portions of the auditory pathway. Our findings indicate that exposure of premature infants to the extra-uterine environment is associated with advanced peripheral development, but slower central conduction compared to intra-uterine development.

Analysis of Variance↗

Intermediate representations in the formation of arm trajectories.

Psychophysical evidence shows that the planning of an arm trajectory is specified by the central nervous system in extrinsic coordinates. The complex issue of translating the planning of arm movements into muscle forces is discussed in relation to the recent discovery of structures in the brainstem and in the spinal cord. These structures represent discrete maps of motor behavior. Remarkably, the force outputs, produced by activating different zones of the map, sum vectorially. This vectorial combination of motor outputs is a mechanism for producing a vast repertoire of motor behaviors in a simple fashion.

Animals↗

A new system for three-dimensional kinematic trajectory acquisition and analysis--I. The application of an ultrasonic technique to human gait analysis.

This paper discusses some techniques of kinematics analysis, and describes a new system for movement recording and analysis. The new system, which is inexpensive and easy to use, consists mainly of some ultrasonic wave transmitters, receivers, a distributive multiprocessor system and software. The system can record kinematics parameters of anatomical landmarks (e.g. space coordinates, movement trajectories and angles of hips, knees and ankles). Such a system, combined with foot pressure equipment and a force plate, forms an advanced gait analysis system.

Algorithms↗

A new system for three-dimensional kinematic trajectory acquisition and analysis--II. Digital orthogonal integration phase-detection technique.

This paper describes a new technique for phase detection of multichannel ultrasonic signals. This technique is called digital orthogonal integration phase detection, and it has been applied in a new gait analysis system for multipoint kinematic trajectory acquisition and analysis. It is also suitable for separating different signals from a narrow bandwidth frequency range.

Biophysics↗

Reliability of trajectory identification for cosmic heavy ions and cytogenetic effects of their passage through plant seeds.

The potentially specific importance of the study of heavy ions from galactic cosmic rays for the understanding of radiation protection in manned spaceflight continues to stimulate spaceflight experiments in order to investigate the radiobiological properties of these ions. Chromosome aberrations as an expression of a direct assault on the genome are of particular interest in view of carcinogenesis as the primary radiation risk for man in space. An essential technical ingredient of such spaceflight experiments is the visual nuclear track detector which permits identification of those biological test organisms which have been affected by cosmic heavy ions. We describe such a technique and report on an analysis of the qualitative and quantitative reliability of this identification of particle trajectories in layers of biological test organisms. The incidence of chromosome aberrations in cells of lettuce seeds, Lactuca sativa, exposed during the Kosmos 1887 mission, was determined for seeds hit by cosmic heavy ions. In those seeds the incidence of both single and multiple chromosome aberrations was enhanced.

Chromosome Aberrations↗

Tractography to depict three layers of visual field trajectories to the calcarine gyri.

PURPOSE: Fiber-tracking by diffusion tensor magnetic resonance imaging (DT-MRI) is currently the only noninvasive in vivo method for white matter fiber-tracking in the human brain. We used this method in attempts to visualize the optic radiation and to examine the clinical applicability of this technique. DESIGN: Observational case series. METHODS: DT-MRI scans for fiber-tracking were obtained in five healthy volunteers by use of a whole-body, 1.5 Tesla imager. DT-MRI data were transferred to an off-line workstation; PRIDE software was used for image analysis. We constructed 3 diopters fiber trajectories by tracking the direction of the fastest diffusion from the lateral geniculate nucleus, and then selected tracts on the basis of anatomical knowledge of the optic radiation. RESULTS: Our method successfully reconstructed the macroscopic 3 diopters architecture of the three major groups of optic radiation in all subjects. Meyer's loop depicted by tractography was located more posterior than the known anatomical locations, although our results on the central and posterior bundles were in good agreement with them. DT-MRI scanning required 7 minutes; preliminary images of the optic radiation could be obtained in approximately 20 minutes. CONCLUSIONS: Fiber-tracking enabled us to obtain information quickly on the 3 diopters course of the optic radiation in vivo. The finding that the fiber-tracking method underestimates the anterior extent of the optic radiations could prove to be an important limitation in the utility of this technique for preoperative planning. The time required for data acquisition and processing makes this method acceptable for routine clinical use.

Adult↗

Age trajectories of grip strength: cross-sectional and longitudinal data among 8,342 Danes aged 46 to 102.

PURPOSE: The purpose is to study the age trajectory of hand-grip strength after the age of 45 years. METHODS: In this study, we use data from three large nationwide population-based surveys of Danes aged 45 to 102 years with a total of 8342 participants with grip-strength measurements and up to 4 years of follow-up. Grip strength was measured by using a portable hand dynamometer. RESULTS: Grip strength declines throughout life for both males and females, but among the oldest women, the longitudinal curve reaches a horizontal plateau. The course of the decline is estimated by using full information in the longitudinal data and is found to be almost linear in the age span of 50 to 85 years. In this age span, mean annual grip-strength loss is estimated to be 0.59 (0.02) (SE) kg for men and 0.31 (0.01) kg for women. CONCLUSION: This study confirms the previously reported grip-strength decline with increasing age. Estimates were obtained by using full-information methods from large population-representative studies. Equations of expected grip strength, as well as tables with sex-, age-, and height-stratified reference data, provide an opportunity to include grip-strength measurement in clinical care in similar populations.

Aged↗

Individual trajectories in stress covary with immunity during recovery from cancer diagnosis and treatments.

Research connects stressful events with altered immune regulation, but the role of subjective stress is uncertain. Using a longitudinal design, we provide a statistically powerful test of the relationship between subjective stress (perceived stress, emotional distress) and immunity (T cell blastogenesis, natural killer cell cytotoxicity, [NKCC]) as individuals adjust to a severe stressor, a cancer diagnosis and its treatments. Women with regional breast cancer (N=113) were assessed at diagnosis/surgery and reassessed 4, 8, 12, and 18 months later. Latent growth curve analysis tested two hypotheses: (1) initial levels of subjective stress will correlate inversely with initial levels of immunity, and (2) rate of change in subjective stress will correlate inversely with rate of change in immunity. As predicted by Hypothesis 1, participants with high initial subjective stress showed poor initial blastogenesis. As predicted by Hypothesis 2, participants exhibiting an early, rapid decline in subjective stress also showed rapid improvement in NKCC. Follow-up analyses revealed perceived stress to be strongly related to immune function, while emotional distress was not. This is the first study to investigate trajectories in stress and immunity during recovery from a major stressor. Results imply that NK and T cells are sensitive to different aspects of the stress response. While T cell blastogenesis correlated with initial (peak) subjective stress, NKCC correlated with change (improvement) in subjective stress. These data highlight the importance of subjective stress, particularly stress appraisals, in the immune response to a major stressor.

Adaptation, Psychological↗

Modifying center of mass trajectory during sit-to-stand tasks redistributes the mechanical demand across the lower extremity joints.

OBJECTIVE: Sit-to-stand tasks are commonly facilitated by modifying the initial position of the center of mass relative to the feet. It was hypothesized that modifications in the center of mass trajectory during sit-to-stand tasks altered the total body momentum at seat departure and redistributed the lower extremity net joint moments. DESIGN: Between-task within-subject comparison was employed using a robust statistical method to accommodate for small sample size. METHODS: Six individuals performed four sit-to-stand tasks with systematic modifications in the initial center of mass position by varying the orientation of the lower extremity segments. The momentum of the center of mass and lower extremity net joint moments were quantified and compared. RESULTS: Reducing the horizontal center of mass displacement significantly reduced horizontal total body momentum required at seat departure. Sit-to-stand tasks initiated with more horizontal shank and thigh positions required significantly greater knee and hip extensor net joint moments than those with more vertical shank and thigh positions. Sit-to-stand tasks initiated with vertical shank positions also required significantly greater hip extensor net joint moments as compared to those with more horizontal shank orientations. INTERPRETATION: When changes in initial center of mass position are made, alteration in center of mass horizontal momentum and the orientation of the lower extremity segments relative to the reaction force are observed. Consequently, mechanical demand imposed on the ankle, knee, and hip joint is redistributed. The magnitude of the net joint moments is dependent on the segment orientation, the reaction force, and the adjacent net joint moment.

Adaptation, Physiological↗

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

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

Journal Article↗

Ejection mechanics and trajectory of the ascospores of Gibberella zeae (anamorph Fuarium graminearum).

Since wind speed drops to zero at a surface, forced ejection should facilitate spore dispersal. But for tiny spores, with low mass relative to surface area, high ejection speed yields only a short range trajectory, so pernicious is their drag. Thus, achieving high speeds requires prodigious accelerations. In the ascomycete Gibberella zeae, we determined the launch speed and kinetic energy of ascospores shot from perithecia, and the source and magnitude of the pressure driving the launch. We asked whether the pressure inside the ascus suffices to account for launch speed and energy. Launch speed was 34.5 ms-1, requiring a pressure of 1.54 MPa and an acceleration of 870,000 g--the highest acceleration reported in a biological system. This analysis allows us to discount the major sugar component of the epiplasmic fluid, mannitol, as having a key role in driving discharge, and supports the role of potassium ion flux in the mechanism.

Gibberella↗

The cost and cost trajectory of genome sequencing and bioinformatics analysis for Indigenous children with suspected rare diseases.

PURPOSE: Indigenous peoples are underrepresented in reference genome libraries. Consequently, rare disease diagnosis may require bespoke bioinformatics analyses of genome sequences. Establishing diagnostic cost is crucial to support policy development for equitable diagnosis of rare diseases. We estimated the cost and cost trajectory of diagnostic genome sequencing and bioinformatics for Indigenous participants with suspected rare diseases. METHODS: We conducted a microcosting study of Indigenous children and their families receiving genome sequencing through Canada's Silent Genomes Project. Invoice data informed the costs of genome sequencing. We conducted a time-and-motion study for bioinformatics analyses, including labor, computing, and data storage costs. RESULTS: With standard bioinformatics, costs ranged from C$3645 (SD: 455) for singletons to C$7402 (SD: 566) for trios. With advanced, bespoke bioinformatics, costs ranged from C$5344 (SD: 634) for singletons to C$9760 (SD: 822) for trios. Genome sequencing was a primary cost driver; however, sequencing costs decreased by 61% over 4 years. Bioinformatics costs ranged from 21.3% to 58.3% of the total costs. The time required for bioinformatics ranged from 71 hours to 215 hours for standard and advanced analyses, respectively. CONCLUSION: Genome sequencing costs decreased over time. Bioinformatics is a significant cost driver, particularly for bespoke analyses arising from nonrepresentative reference libraries.

Humans↗

Trajectory of prehospital delay in patients with acute myocardial infarction in the Japanese health care system.

OBJECTIVE: The purpose of this study was to understand the trajectory of prehospital delay in patients with acute myocardial infarction (AMI) in the Japanese health care system, which offers patients a choice between seeking treatment in a neighborhood clinic/small hospital (clinic group) or a large hospital with comprehensive cardiac services, including a cardiac catheterization laboratory (hospital group). METHODS: In this cross sectional study, 155 consecutive patients admitted with AMI to one of 5 urban hospitals in Japan were interviewed within 7 days after admission. RESULTS: The median total prehospital delay time in the clinic group (n=84) was significantly longer than the hospital group (n=71) (6 h and 48 min vs 2 h and 9 min, p<.001). Patients with severe chest pain were significantly less likely to seek treatment at a clinic/small hospital than at a large hospital compared to patients with mild or moderate symptoms (OR 0.85, 95% CI: 0.75, 0.97). Patients who did not interpret their symptoms as cardiac in origin were significantly more likely to seek treatment at a clinic/small hospital than at a large hospital compared to patients who interpreted their symptoms as cardiac in origin (OR 3.32, 95% CI: 1.56, 7.10). After controlling for demographic and medical history, patients in the clinic group were 3.69 times (95% CI: 1.28, 10.66) less likely to receive any reperfusion therapy compared to patients in the hospital group. CONCLUSIONS: Findings support the need for public education in Japan that focuses on the appropriate response to AMI symptoms. Moreover, regional AMI networks need to be instituted to provide for early transfer for PCI from clinic/small hospitals to tertiary centers.

Aged↗