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PubMed2000

Comparison of dosimetry recommendations for clinical proton beams.

The formalism and data in the two most recent dosimetry recommendations for clinical proton beams, ICRU Report 59 and the forthcoming IAEA Code of Practice, are compared. Chamber calibrations in terms of air kerma and absorbed dose to water are considered, including five different cylindrical ionization chamber types commonly used in proton beam dosimetry. The methodology for both types of calibration for ionization chambers is described in ICRU Report 59. The procedure based on air kerma calibrations is compared with an alternative formalism based on IAEA Codes of Practice (TRS-277, TRS-381), modified for proton beams. The new IAEA Code of Practice is exclusively based on calibrations in terms of absorbed dose to water and a direct comparison with ICRU Report 59 recommendations is made. Common to the two formalisms are the fundamental quantities Wair and w(air) and their atmospheric conditions of applicability. The difference in the recommended values of the ratio w(air)/Wair (protons to 60Co) is as large as 2.3%. The use of Wair and w(air) values for dry air (IAEA) and for ambient air (ICRU) is a contribution to the discrepancy, and the ICRU usage is questioned. For air kerma based chamber calibrations, ICRU Report 59 does not take into account the effect of different compositions of the build-up cap and chamber wall on the calibration beam quality. For the chamber types included in the study, this introduces discrepancies of up to 1.1%. Combined with differences in the recommended basic data, discrepancies in absorbed dose determination in proton beams of up to 2.1% are found. For the absorbed dose to water based formalism, differences in the formalism, notably the omission of perturbation factors for 60Co in ICRU 59, and data yield discrepancies in calculated kQ factors, and in absorbed dose determinations, between -1.5% and +2.6%, depending on the chamber type and the proton beam quality.

Air↗
PubMed1995

A model of fluid resuscitation following burn injury: formulation and parameter estimation.

A dynamic compartmental model is developed to describe the redistribution of fluid and albumin between the circulation and the intact and injured interstitia following burn injury in humans. Transcapillary fluid and albumin exchange is described by a coupled Starling mechanism, while the effect of the burn is represented by time-dependent perturbations to all three compartments. The unknown model parameters are determined for two groups of patients, having less than and greater than 25% total body surface area burns, by statistical fitting of model predictions to patient data from two sources. The parameters include the perturbations to the fluid filtration coefficients in uninjured and injured tissue, GkF,Tl and GkF,BT, respectively, the relaxation coefficient, r, which describes the exponential decay of the perturbations, and the exudation factor, EXFAC, which relates the protein concentration in the exudate to that in the injured tissue. Perturbations to other parameters, including the membrane permeability-surface area product and the albumin reflection coefficient in the injured and uninjured tissues, are determined based on interrelationships with GkF,Tl and GkF,BT. The values of GkF,BT, when corrected for tissue destruction and decreased post-injury perfusion, are in reasonable agreement with the limited experimental data available from the literature. The model and its parameters are further validated by comparing the simulated patient responses to the clinical data used in the parameter estimation as well as to data available from two additional sources.

Body Fluid Compartments↗
PubMed2002

Electrical impedance endo-tomography: imaging tissue from inside.

This paper describes a new method for scanning the conductivity of a tissue or an organ using a multielectrode impedance probe placed at the center of the region of interest. The long-term objective of the study is the evaluation, using an urethral impedance probe, of the lesion produced by ultrasound ablathermy of localized prostate cancer. The probe consists of electrodes placed at the surface of an insulating cylinder. The injected current passes around the cylinder and spreads in the medium surrounding the probe. This paper presents the theoretical bases of this method, the calculated sensitivity distributions of electrode configurations involving a pair of diametrically opposed electrodes and an application in vitro. The experimental set-up consisted of a water tank and a 16-electrode prototype probe 50 mm in diameter. Data sets were collected in the presence of conductivity perturbations produced by small size insulators or conductors and a 7.5% constant perturbation model. The presented images, although reconstructed using a simple retro-projection algorithm, demonstrate the feasibility of the method. Improvements in data collection and image reconstruction are possible.

Electric Impedance↗
PubMed1993

Utility of the murine erythroleukemic cell (MELC) in assessing mechanisms of action of DNA-active developmental toxicants: application to 5-fluorouracil.

Murine erythroleukemic cells (MELC) exposed to 2'-deoxy-5-azacytidine (D-AZA) or to the active cyclophosphamide (CP) metabolites phosphoramide mustard (PAM) and 4-hydroxycyclophosphamide (OHCP) exhibit cell-cycle perturbations similar to those seen in limb bud nuclei of gestational day (GD) 10 CD-1 mouse embryos exposed in utero to D-AZA or CP, respectively. The similarities in response suggest MELC may be a useful model for determining mechanisms of action of DNA-active developmental toxicants. As such, we used the MELC model to investigate the mechanism of action of 5-fluorouracil (5-FU), an antimetabolite that induced in GD 14 rat fetuses an apparent S-phase accumulation in limb cells 8 hr after in utero exposure, but S-phase depletion in liver cells 24 hr postexposure. MELC timed-recovery and synchronization studies suggest that in proliferative tissues, 5-FU induces an early S-phase accumulation, followed by a synchronous, concentration-dependent delay in progression through the cell cycle. Consequently, it is the tissue-specific rate of delay, rather than different mechanisms of action, that results in apparent tissue-specific perturbations. Moreover, growth and cell-cycle data suggest that cells entering S phase (when TS activity is greatest) are the most sensitive to 5-FU toxicity. Assays of the TS activity of recovering MELC reveal that although the initial extent of TS inhibition does not appear to be concentration-dependent, the time to recovery is, suggesting that the rate of S-phase progression is closely associated with TS activity. Together, the induction of similar cell-cycle perturbations in embryonic/fetal tissues and MELC following exposure to CP (or CP metabolites), D-AZA, or 5-FU, as well as the adaptability of MELC to a variety of kinetic assays suggests that, for those developmental toxicants suspected of inducing cell-cycle perturbations in embryonic/fetal tissues, MELC may prove useful for elucidating mechanisms of action.

Animals↗
PubMed1982

Restriction of motion of protein side chains during the photocycle of bacteriorhodopsin.

Linear dichroism was measured during the photocycle of bacteriorhodopsin. The anisotropy of the sample was produced by the photoselection method. The measurements on purple membrane fragments embedded in agar gel were performed at room temperature with 200 microseconds time resolution at several wavelengths in the 240- to 550-nm spectral region. The induced anisotropy of the retinal chromophore remained constant after the formation of the photocycle intermediate M. The anisotropy was also time independent at the characteristic peaks of the UV absorption change. These experimental data suggest that the direction of the retinal transition dipole moment remains unchanged. Moreover, the affected aromatic protein side chains also do not show any rotational motion when they are in the perturbed or ground states during the photocycle. Our data render it possible to calculate the restricted range of sudden chromophore rotations that might be coupled to the appearance and decay of the M intermediate.

Bacteriorhodopsins↗
PubMedDate not supplied

NMR chemical shift mapping of the binding site of a protein proteinase inhibitor: changes in the (1)H, (13)C and (15)N NMR chemical shifts of turkey ovomucoid third domain upon binding to bovine chymotrypsin A(alpha).

The substrate-like inhibition of serine proteinases by avian ovomucoid domains has provided an excellent model for protein inhibitor-proteinase interactions of the standard type. 1H,15N and 13C NMR studies have been undertaken on complexes formed between turkey ovomucoid third domain (OMTKY3)2 and chymotrypsin A(alpha) (Ctr) in order to characterize structural changes occurring in the Ctr binding site of OMTKY3. 15N and 13C were incorporated uniformly into OMTKY3, allowing backbone resonances to be assigned for OMTKY3 in both its free and complex states. Chemical shift perturbation mapping indicates that the two regions, K13-P22 and N33-A40, are the primary sites in OMTKY3 involved in Ctr binding, in full agreement with the 12 consensus proteinase-contact residues of OMTKY3 defined previously on the basis of X-ray crystallographic and mutational analysis. Smaller chemical shift perturbations in selected other regions may result from minor structural changes on binding. Through-bond 15N-13C correlations between P1-13C' and P1'-15N in two-dimensional H(N)CO and HN(CO) NMR spectra of selectively labeled OMTKY3 complexed with Ctr indicate that the scissile peptide bond between L18 and E19 of the inhibitor is intact in the complex. The chemical shifts of the reactive site peptide bond indicate that it is predominantly trigonal, although the data are not inconsistent with a slight perturbation of the hybridization of the peptide bond toward the first tetrahedral state along the reaction coordinate.

Amino Acid Sequence↗
PubMed2001

Effect of slip on movement of body center of mass relative to base of support.

OBJECTIVE: The purpose is to investigate the effect of balance conditions and slippery perturbation on the position and velocity of the body's center of mass relative to the body's base of support. DESIGN: Twenty-two young and healthful subjects were investigated while their walk was perturbed by a soap patch applied over a force plate. A safety harness was used to prevent the subject from falling on knee or buttock. BACKGROUND: Appropriate postural response to meet physiological biomechanical requirements is mandatory in restoration of balance upon slip. METHODS: Twenty-two healthy subjects dressed with safety harness walked first without and then with slippery perturbation, guided by a metronome at 120 steps/min and 90 steps/min cadence. Data were collected from a motion analysis system and force plates. RESULTS: For slippery perturbation, the displacement and velocity of center of mass with respect to base of support became smaller from heel strike to contralateral toe off. Subject's balance condition correlated significantly to the displacement of center of mass with respect to base of support (r=-0.51 at 120 steps/min and r=-0.471 at 90 steps/min), as well as the velocity (r=-0.834 at 120 steps/min, r=-0.673 at 90 steps/min) at contralateral toe off. CONCLUSIONS: For slip during walking, smaller excursion and faster velocity of center of mass with respect to base of support were important for subjects regaining balance from heel strike to contralateral toe off. The critical time for subjects regaining stability is the first double support phase of the gait cycle. RELEVANCE: It is confirmed that two variables, the displacement and the velocity of center of mass with respect to base of support, are valuable biomechanical factors and provide quantifiable determination for investigation of the balance condition in slipping.

Accidental Falls↗
PubMed2005

8-vinyl-deoxyadenosine, an alternative fluorescent nucleoside analog to 2'-deoxyribosyl-2-aminopurine with improved properties.

We report here the synthesis and the spectroscopic characterization of 8-vinyl-deoxyadenosine (8vdA), a new fluorescent analog of deoxyadenosine. 8vdA was found to absorb and emit in the same wavelength range as 2'-deoxyribosyl-2-aminopurine (2AP), the most frequently used fluorescent nucleoside analog. Though the quantum yield of 8vdA is similar to that of 2AP, its molar absorption coefficient is about twice, enabling a more sensitive detection. Moreover, the fluorescence of 8vdA was found to be sensitive to temperature and solvent but not to pH (around neutrality) or coupling to phosphate groups. Though 8vdA is base sensitive and susceptible to depurination, the corresponding phosphoramidite was successfully prepared and incorporated in oligonucleotides of the type d(CGT TTT XNX TTT TGC) where N = 8vdA and X = A, T or C. The 8vdA-labeled oligonucleotides gave more stable duplexes than the corresponding 2AP-labeled sequences when X = A or T, indicating that 8vdA is less perturbing than 2AP and probably adopts an anti conformation to preserve the Watson-Crick H-bonding. In addition, the quantum yield of 8vdA is significantly higher than 2AP in all tested oligonucleotides in both their single strand and duplex states. The steady-state and time-resolved fluorescence parameters of 8vdA and 2AP were found to depend similarly on the nature of their flanking residues and on base pairing, suggesting that their photophysics are governed by similar mechanisms. Taken together, our data suggest that 8vdA is a non perturbing nucleoside analog that may be used with improved sensitivity for the same applications as 2AP.

Deoxyadenosines↗
PubMed2006

Three-dimensional images for electron-impact single ionization of He: complete and comprehensive (e, 2e) benchmark data.

Comprehensive fully differential cross sections for electron emission into all three spatial dimensions are presented for 1 keV and 102 eV electron-impact single ionization of helium using an advanced reaction microscope. Surprising out-of-plane contributions, traced back to an interference term in a perturbation expansion by comparison with ion-impact data, severely challenge theoretical models that accurately predict coplanar emission. The data represent the ultimate benchmark for recently developed exact theoretical descriptions of the most fundamental three-body quantum problems.

Journal Article↗
PubMed1990

Spectral weights in profile listening.

The COSS analysis suggested by Berg [B. G. Berg, J. Acoust. Soc. Am. 86, 1743-1746 (1989)] is applied to a profile listening task. The listener's task is to detect an increment in the level of the middle component of an n-component spectrum. The overall level of the components is randomly selected from a 20-dB range on each presentation; thus the detection task is essentially one of detecting a change in spectral shape. To implement the COSS analysis, a small perturbation in level is added to each component of the complex. COSS functions are generated from these perturbations, and the spectral weight that the listener assigns to each component is estimated. Data are reported for n = 3, 5, and 11 components and for perturbations with standard deviations of 0.5, 1, and 2 dB. The estimated weights are similar to those derived for an optimum detector; namely, the level at the signal component is compared with the average level of the nonsignal components. This result supports the view that profile analysis involves an across-channel comparison process. The pattern of weights also provides insight into differences among listeners. In a separate experiment, the spectral weights of a very poor profile listener are estimated, and the pattern of the weights suggests reasons for the inferior detection performance.

Adult↗
PubMed2005

Persistent nicotine treatment potentiates amplification of the dihydrofolate reductase gene in rat lung epithelial cells as a consequence of Ras activation.

Although nicotine has been suggested to promote lung carcinogenesis, the mechanism of its action in this process remains unknown. The present investigation demonstrates that the treatment of rat lung epithelial cells with nicotine for various periods differentially mobilizes multiple intracellular pathways. Protein kinase C and phosphoinositide 3-OH-kinase are transiently activated after the treatment. Also, Ras and its downstream effector ERK1/2 are activated after long term exposure to nicotine. The activation of Ras by nicotine treatment is responsible for the subsequent perturbation of the methotrexate (MTX)-mediated G1 cell cycle restriction as well as an increase in production of reactive oxygen species. When p53 expression is suppressed by introducing E6, persistent exposure to nicotine enables dihydrofolate reductase gene amplification in the presence of methotrexate (MTX) and the formation of the MTX-resistant colonies. Altering the activity of phosphoinositide 3-OH-kinase has no effect on dihydrofolate reductase amplification. However, the suppression of protein kinase C dramatically affects the colony formation in soft agar. Thus, our data suggest that persistent exposure to nicotine perturbs the G1 checkpoint and causes DNA damage through the increase of the production of reactive oxygen species. However, a third element rendered by loss of p53 is required for the initiation of the process of gene amplification. Under p53-deficient conditions, the establishment of a full oncogenic transformation, in response to long term nicotine exposure, is achieved through the cooperation of multiple signaling pathways.

Agar↗
PubMed1993

Precursor flux control through targeted chromosomal insertion of the lysine epsilon-aminotransferase (lat) gene in cephamycin C biosynthesis.

Targeted gene insertion methodology was used to study the effect of perturbing alpha-aminoadipic acid precursor flux on the overall production rate of beta-lactam biosynthesis in Streptomyces clavuligerus. A high-copy-number plasmid containing the lysine epsilon-aminotransferase gene (lat) was constructed and used to transform S. clavuligerus. The resulting recombinant strain (LHM100) contained an additional complete copy of lat located adjacent to the corresponding wild-type gene in the chromosome. Biological activity and production levels of beta-lactam antibiotics were two to five times greater than in wild-type S. clavuligerus. Although levels of lysine epsilon-aminotransferase were elevated fourfold in LHM100, the level of ACV synthetase, whose gene is located just downstream of lat, remained unchanged. These data strongly support the notion that direct perturbation of alpha-aminoadipic acid precursor flux resulted in increased antibiotic production. This strategy represents a successful application of metabolic engineering based on theoretical predictions of precursor flux in a secondary metabolic pathway.

Base Sequence↗
PubMed2001

Plasma perturbation induced by laser photodetachment.

The plasma dynamics arising from laser photodetachment is discussed herein theoretically and experimentally. The hybrid fluid-kinetic model, where the positive ions and electrons are treated by the fluid theory and the negative ions are treated within the ballistic approximation, is extended and applied to the analysis of densities perturbed by laser photodetachment. The agreement between the theory and measured data confirms the validity of the considered plasma dynamics model. This model, including the positive ion perturbation, shows a good agreement with the time evolution and the spatial distribution of perturbed electron densities which are measured by a Langmuir probe inside and outside the laser beam. From the overshoot in the time evolution of perturbed electron current in the center of the laser beam, the positive ion temperature was found to be in the range 0.1-0.25 eV, while the electron temperature changes from 0.3 to 3.2 eV.

Journal Article↗
PubMed1994

Gompertzian re-evaluation of the growth patterns of transplantable mammary tumours in sialoadenectomized mice.

The method of the recursion formula of the Gompertz function (Bassukas & Maurer-Schultze 1988) has been applied to analyse tumour growth data taken from the literature; namely the growth perturbation of transplantable mammary tumours in sialoadenectomized mice with or without subsequent epidermal growth factor substitution (results on two mouse strains, C3H or SHN, have been reported; Inui, Tsubura & Morii 1989). The recursion formula of the Gompertz function fits growth curves to all seven sets of data well (P > 0.05 for lack of fit test). The growth pattern of the tumours in the unperturbed hosts is Gompertzian and does not change if tumours are transplanted in sialoadenectomized mice, although the starting specific growth rate decreases in C3H mice. However, if sialoadenectomy is carried out after tumour inoculation, a complex alteration of the tumour growth evolves: tumour growth does not simply decelerate but it also shifts from the conventional Gompertzian to an exponential or even 'hyperexponential' growth pattern, i.e. with an accelerating specific growth rate. Some theoretical mechanisms of this alteration, as well as the differences between the present Gompertzian analysis and a previously published Verhulstian analysis of part of the same data (Leith, Harrigan & Michelson 1991), are discussed. It is concluded that the quantitative analysis of tumour growth patterns by the method of the difference equation of the Gompertz function presently applied may substantially contribute to the improvement of the interpretation of perturbations of tumour growth--irrespective of their genesis. In contrast to the application of some a priori fixed growth function, e.g. the Verhulstian one, the present method can quantitatively interpret different growth patterns and their classification on the basis of linear regression analysis.

Animals↗
PubMedDate not supplied

Acoustic measures for detecting laryngeal pathology.

Perturbations in the fundamental pitch and in the peak amplitude of the acoustic signal derived with a contact microphone system were investigated for the purpose of developing useful measures for the detection of laryngeal pathology. Sixty-three patients with various laryngeal pathologies and 31 normal subjects were studied. In 14 cases high speed motion pictures of the larynx were taken in order to examine the physiological mechanisms giving rise to the perturbations in the acoustic signal. The collected acoustic data were statistically processed, and a "critical ellipse" was computed for each subject category. The significance of the concept of a "normal standard" was discussed. It was pointed out that the physiological mechanisms for the acoustic perturbations were rather complicated and that many physiological aspects may have to be taken into account. The need for basic physiological research in relation to pathologic speech production was emphasized.

Adolescent↗
PubMed1985

Perturbation of the T4 molecule transmits a negative signal to T cells.

We investigated the functional role of the T4 molecule in the activation of T cells by OKT3. T4+ cells were induced to proliferate by OKT3 and erythrocyte rosette-negative accessory cells in the presence or absence of OKT4C, OKT4, and OKT1. OKT4C (IgG1), and not OKT4 (IgG2) or OKT1 (IgG1) inhibited proliferation when OKT4C was added during the first 24 h of cell culture. The inhibition of OKT3 activation by OKT4C did not require Ia+ accessory cells, since T4+ cells could be activated by OKT3 in the presence of Ia- U937 cells, and this activation was markedly inhibited by OKT4C. Furthermore, T4+ cells could be induced to proliferate by OKT3 covalently linked to Sepharose beads, in the absence of any accessory cells. Under these conditions, OKT4C, but not OKT4 or OKT1 significantly inhibited proliferation. These data demonstrate that at least one mechanism by which anti-T4 antibodies inhibit T cell activation is independent of any putative role of T4 molecules in the recognition of Ia on target cells. The data are compatible with the idea that perturbation of the T4 molecules can transmit a negative signal to T4+ cells.

Antibodies, Monoclonal↗
PubMed2005

Perturbation parameters associated with nonlinear responses of the head at small amplitudes.

The head-neck system has multiple degrees of freedom in both its control and response characteristics, but is often modeled as a single joint mechanical system. In this study, we have attempted to quantify the perturbation parameters that would elicit nonlinear responses in a single degree-of-freedom neuromechanical system at small amplitudes and velocities of perturbation. Twelve healthy young adults seated on a linear sled randomly received anterior-posterior sinusoidal translations with +/-15 mm and +/-25 mm peak displacements at 0.81, 1.76, and 2.25 Hz. Head angular velocity and angular position data were examined using a nonlinear phase-plane analysis. Poincare sections of the phase plane were computed and Lyapunov exponents calculated to measure divergence (chaotic behavior) or convergence (stable behavior) of system dynamics. Variability of head angular position and velocity across the entire phase plot was compared to that of the Poincare sections to quantify spatial-temporal irregularity. Multiple equilibrium points and positive Lyapunov exponents revealed chaotic behavior at 0.81 Hz at both amplitudes whereas responses at 1.76 and 2.25 Hz exhibited periodic oscillations, clustered phase points, and negative Lyapunov exponents. However, intersubject variability increased at the lowest frequency and a few subjects presented chaotic behavior at all frequencies. An inverted pendulum with position and velocity threshold nonlinearity was adopted as a simplistic model of the head and neck. Simulations with the model resulted in features similar to those observed in the experimental data. Our principal finding was that increasing the perturbation amplitude had a stabilizing effect on the behavior across frequencies. Nonlinear behaviors observed at the lowest stimulus frequency might be attributed to fluctuations in control between the multiple sensory inputs. Although this study has not conclusively pointed toward any single mechanism as responsible for the responses observed, it has revealed clear directions for further investigation. To examine if changing the sensory modalities would elicit a significant change in the nonlinear behaviors observed here, further experiments that target a patient population with some sort of sensory deficit are warranted.

Acceleration↗
PubMed1983

A noninvasive acoustic method using frequency perturbations and computer-generated vocal-tract shapes.

This study investigated improved processing of acoustic data with two adult Down's syndrome subjects. Sustained vowel samples were processed through a fast-Fourier-transform spectrum analyzer, and digital waveform data were used to obtain period-by-period measurements of the fundamental frequencies. Unusual frequency perturbation (jitter), later identified as diplophonia, was found for one of the Down's subjects. In addition, the first three formant frequencies of the vowels were determined and, utilizing an algorithm described by Ladefoged and his colleagues, computer-generated vocal-tract shapes were plotted. Differences in vocal-tract shapes, especially for the back vowels, were observed between the Down's female and the normal shape. Correlations between vocal-tract shapes of the Down's subjects and those for a normal man or woman were computed. A partial three-way factor analysis was carried out to determine those load factors or coefficients for each subject that were due to individual differences. These procedures, offering synthesized techniques portraying the interpharyngeal/oral functioning of the speech structures, may eventually have direct noninvasive diagnostic and therapeutic benefit for voice/resonance-disordered clients.

Adult↗