A gender-moderated model of family relationships and adolescent adjustment.

The objective of this study was to explain why adolescent girls with conduct problems (CP) are more at risk than boys to develop emotional distress (ED) in a sample composed of Israeli-born and immigrant youth from Ethiopia and the former Soviet Union (n = 305, ages 14-18). We tested a structural equation model and found a very good fit to the data for both immigrant and nonimmigrant groups. The hypothesized effects of gender, CP, and parent-child relationships on ED were significant, whereas the effect of family discord was mediated by parent-child relationships. Subsequently, we used multiple-group analyses to test the two interaction hypotheses. We found significantly higher associations between CP and family discord and between ED and negative parent-child relationships in girls compared to boys.     

On the use of Monte Carlo-derived dosimetric data in the estimation of patient dose from CT examinations

The purpose of this work was to investigate the applicability and appropriateness of Monte Carlo-derived normalized data to provide accurate estimations of patient dose from computed tomography (CT) exposures. Monte Carlo methodology and mathematical anthropomorphic phantoms were used to simulate standard patient CT examinations of the head, thorax, abdomen, and trunk performed on a multislice CT scanner. Phantoms were generated to simulate the average adult individual and two individuals with different body sizes. Normalized dose values for all radiosensitive organs and normalized effective dose values were calculated for standard axial and spiral CT examinations. Discrepancies in CT dosimetry using Monte Carlo-derived coefficients originating from the use of: (a) Conversion coefficients derived for axial CT exposures, (b) a mathematical anthropomorphic phantom of standard body size to derive conversion coefficients, and (c) data derived for a specific CT scanner to estimate patient dose from CT examinations performed on a different scanner, were separately evaluated. The percentage differences between the normalized organ dose values derived for contiguous axial scans and the corresponding values derived for spiral scans with pitch = 1 and the same total scanning length were up to 10%, while the corresponding percentage differences in normalized effective dose values were less than 0.7% for all standard CT examinations. The normalized organ dose values for standard spiral CT examinations with pitch 0.5-1.5 were found to differ from the corresponding values derived for contiguous axial scans divided by the pitch, by less than 14% while the corresponding percentage differences in normalized effective dose values were less than 1% for all standard CT examinations. Normalized effective dose values for the standard contiguous axial CT examinations derived by Monte Carlo simulation were found to considerably decrease with increasing body size of the mathematical phantom used. When the body-mass index was increased from 23.0 to 32.7 kg/m2 discrepancies in patient effective dose were up to 34%. The error in estimating effective dose from a CT exposure performed on a specific CT scanner using Monte Carlo data derived for a different CT scanner was estimated to be up to 25%. A simple method was proposed and validated for the determination of scanner-specific normalized dosimetric data from data derived from Monte Carlo simulation of a specific scanner. In conclusion, computed tomography dose index (CTDI) to effective dose conversion coefficients derived by Monte Carlo simulation of axial CT scans may provide a good approximation of corresponding coefficients applicable in helical scans. However, the use of Monte Carlo conversion coefficients for the estimation of patient dose from a CT examination involves a remarkable inaccuracy when the body size of the mathematical anthropomorphic phantom used in Monte Carlo simulation differs from the body of the patient. Therefore, separate sets of Monte Carlo dosimetric CT data shall be generated for different patient body sizes. Besides calculation of different sets of Monte Carlo data for each commercially available scanner is not necessary, since scanner specific data may be derived with acceptable accuracy from the Monte Carlo data calculated for a specific scanner appropriately modified for the different CTDI(W)/CTDI(air) ratio.     

The determination of effective antiviral doses using a computer program for sigmoid dose-response curves

A computer program was designed to construct best fit sigmoid dose-response curves for determination of the dose required to reduce the yield of virus by 50%, effective antiviral dose (ED50). A single antiviral agent, 9-beta-D-arabinofuranosyladenine, was examined for effectiveness against four strains of herpes simplex virus type 1. The resulting ED50 values were compared with those obtained by probit analysis. The statistical parameters obtained from sigmoid curve fit program were utilized to evaluate statistical differences between ED50 values for resistant and sensitive virus strains and to evaluate the goodness-of-fit of the regression line to the data. In addition, using this analytical method, it was shown that a change in one experimental variable, i.e., multiplicity of infection, in the yield reduction assay significantly affected the apparent ED50 value. The computer program was easily utilized for analysis of data obtained from both plaque reduction and yield reduction assays and generated the parameters necessary for statistical comparison of relative antiviral activity of any antiviral agent.     

Sublinear response in lacZ mutant frequency of Muta™Mouse spermatogonial stem cells after low dose subchronic exposure to N‐ethyl‐N‐nitrosourea

The transgenic rodent mutation assay was used to compare the dose–response relationship of lacZ mutant frequency (MF) in spermatogonial stem cells exposed acutely or subchronically to N‐ethyl‐N‐nitrosourea (ENU). Muta^?Mouse males were exposed orally to 0, 25, 50, or 100 mg/kg ENU for acute exposures and 0, 1, 2, or 5 mg/(kg day) for 28‐day subchronic exposures. LacZ MF was measured in sperm collected 70 days post‐exposure to target spermatogonial stem cells. Dose–response data were fit to linear, quadratic, exponential, or power models. Acute exposure resulted in a dose‐dependent increase in MF that was significant (P < 0.05) at all doses tested and was best described by a quadratic dose–response model that was linear in the low dose range. In contrast, similar total doses fragmented over a 28‐day subchronic exposure only resulted in a significant increase in lacZ MF at the highest dose tested. Therefore, the subchronic no observable genotoxic effect level (NOGEL) was 2 mg/(kg day) (or 56 mg/kg total dose). The subchronic dose–response was best described by the exponential and power models, which were sublinear in the low dose range. Benchmark dose lower confidence limits (BMDLs) for acute and subchronic exposure were 3.0 and 1.0 mg/(kg day) (or 27.4 mg/kg total dose), respectively. These findings are supportive of a saturable DNA repair mechanism as the mutagenic mode of action for ENU in spermatogonia and imply that sufficiently low exposures would not cause appreciable genotoxic effects over background. This may have important implications for the quantitative risk assessment of germ cell mutagens. Environ. Mol. Mutagen. 56:347–355, 2015. © 2015 The Authors. Environmental and Molecular Mutagenesis Published by Wiley Periodicals, Inc.     

Analyses of carcinogenesis dose-response relations with dichotomous data: implications for carcinogenic risk assessment

Dose-response data from experimental and epidemiologic carcinogenicity studies were analyzed in attempts to resolve basic questions in extrapolating from high to low doses and assessing human risk. Four models (Weibull, Mantel-Bryan, Marshall-Groer, and Mancuso-Stewart) were fit to 46 sets of experimental and 4 sets of epidemiologic data by maximizing the likelihood function with a Rosenbrock hill-climbing algorithm. The models were compared as to their adequacy in describing the data and analyzed to determine the effect of carcinogen and breeding category, species, and spontaneous tumor incidence. The shapes of the dose-response curves were analyzed, and errors in risk estimation from linear extrapolation through the origin were calculated. All models were shown to fit the data and to be comparable in accuracy. The dose-response curves were generally "stretched out," particularly for outbred strains, with one or two orders of magnitude of dose increase required to increase the proportion of tumor responders from 10% to 70%. Linear extrapolation through the origin generally underestimated the response at low doses, frequently by several orders of magnitude. The power dependence of tumor incidence on dose was generally found to be of the order of unity, substantially less than assumed in most mathematical models.     

Complex segregation analysis of obsessive-compulsive disorder in 141 families of eating disorder probands, with and without obsessive-compulsive disorder

Probands affected with eating disorders (ED) present a higher number of relatives affected with obsessive-compulsive disorders/tic disorders than a comparison population. Therefore, we hypothesized that ED and obsessive-compulsive disorder (OCD) might share the same biological liability, and that a single major gene might account for that liability. We tested this hypothesis by applying a complex segregation analysis to 141 families of probands affected with ED (89 with anorexia nervosa, restricting and binge-eating types, 52 with bulimia nervosa). Given the hypothesized relationship between OCD and genetic spectrum disorders, we considered these diagnoses as affected phenotype in relatives. In Italian ED families, ED and OCD followed a Mendelian dominant model of transmission. When probands were divided according to co-diagnosis of OCD, best fit in the subgroup of families of 114 probands without OCD co-diagnosis was for a Mendelian dominant model of transmission whereas a Mendelian additive model of transmission represented best fit in the subgroup of families of 27 probands with an OCD co-diagnosis. Genetic transmission was not shown in those families where the only affected phenotype was ED. The existence of a Mendelian mode of genetic transmission within ED families supports the hypothesis that a common genetic liability could account for both ED and OCD.     

Estimation of parameters of dose-volume models and their confidence limits

Predictions of the normal-tissue complication probability (NTCP) for the ranking of treatment plans are based on fits of dose-volume models to clinical and/or experimental data. In the literature several different fit methods are used. In this work frequently used methods and techniques to fit NTCP models to dose response data for establishing dose-volume effects, are discussed. The techniques are tested for their usability with dose-volume data and NTCP models. Different methods to estimate the confidence intervals of the model parameters are part of this study. From a critical-volume (CV) model with biologically realistic parameters a primary dataset was generated, serving as the reference for this study and describable by the NTCP model. The CV model was fitted to this dataset. From the resulting parameters and the CV model, 1000 secondary datasets were generated by Monte Carlo simulation. All secondary datasets were fitted to obtain 1000 parameter sets of the CV model. Thus the 'real' spread in fit results due to statistical spreading in the data is obtained and has been compared with estimates of the confidence intervals obtained by different methods applied to the primary dataset. The confidence limits of the parameters of one dataset were estimated using the methods, employing the covariance matrix, the jackknife method and directly from the likelihood landscape. These results were compared with the spread of the parameters, obtained from the secondary parameter sets. For the estimation of confidence intervals on NTCP predictions, three methods were tested. Firstly, propagation of errors using the covariance matrix was used. Secondly, the meaning of the width of a bundle of curves that resulted from parameters that were within the one standard deviation region in the likelihood space was investigated. Thirdly, many parameter sets and their likelihood were used to create a likelihood-weighted probability distribution of the NTCP. It is concluded that for the type of dose response data used here, only a full likelihood analysis will produce reliable results. The often-used approximations, such as the usage of the covariance matrix, produce inconsistent confidence limits on both the parameter sets and the resulting NTCP values.     

Central axis depth dose curve for electron beams.

In this article an analytical equation for electron depth dose is proposed electron energies from 6-20 MeV. The equation contains four parameters and it fits the build-up region, fall-off region as well as the bremsstrahlung background region. The calculated values from this equation fit within 1,5% of the measured data in the build-up region and in the fall-off region within 0,5 mm for the energy range 5-10 MeV and within 1 mm for the range 12-20 MeV. This equation can be applied beyond the practical range.     

Polymer gel dosimetry using x-ray computed tomography: a feasibility study

A new three-dimensional dosimetry technique using x-ray computed tomography (CT) to analyse polymer gels is proposed. The CT imaging is sensitive to radiation-induced density changes that occur within irradiated polyacrylamide gel (PAG). In this preliminary study, a CT imaging protocol is developed to optimize CT images of PAG; the response of PAG CT number to dose (N(CT)-dose response) and the reproducibility of the response are investigated, and the use of CT to analyse PAG is compared with MRI. Experiments were conducted using two 1.5 l cylindrical PAG phantoms (3% acrylamide, 3% bis and 5% gelatin by weight), one irradiated with four intersecting 10 MV photon beams and the other with 10 sets of 6 MV parallel opposed circular radiosurgery fields. The final imaging protocol involves using optimum CT parameters (120 kVp and 200 mAs for our GE HiSpeed CT/i scanner), image averaging and background subtraction. The N(CT)-dose response is reproducible, linear up to 800-1000 cGy and is relatively insensitive to the gel temperature during imaging. The dose resolution is approximately 50 cGy for an image thickness of 10 mm. Despite the low dose resolution, preliminary results indicate that this CT technique provides accurate localization of high dose gradients such as those observed in stereotactic radiosurgery. Thus, given the availability and speed of CT scanners, the technique has the potential to be a valuable and practical 3D dose verification tool in radiation therapy.     

Fitting biological equations to data using non-parametric methods

Simulated experimental data were generated for these equations: a straight line, the integrated Michaelis-Menten equation, plus a linear term, the Hill equation, a two-exponential function and a double Michaelis-Menten equation. The equations were fitted to the data using (i) least-squares and (ii) non-parametric methods. The precision and accuracy of the parameter estimates obtained by each method were compared and the methods assessed. For several of the equations, non-parametric methods provided robust techniques for parameter estimation. For the remainder, the results were poor. The reasons for this are discussed.     

A rigorous multiple independent binding site model for determining cell-based equilibrium dissociation constants

A new 4-parameter nonlinear equation based on the standard multiple independent binding site model (MIBS) is presented for fitting cell-based ligand titration data in order to calculate the ligand/cell receptor equilibrium dissociation constant and the number of receptors/cell. The most commonly used linear (Scatchard Plot) or nonlinear 2-parameter model (a single binding site model found in commercial programs like Prism(R)) used for analysis of ligand/receptor binding data assumes only the K(D) influences the shape of the titration curve. We demonstrate using simulated data sets that, depending upon the cell surface receptor expression level, the number of cells titrated, and the magnitude of the K(D) being measured, this assumption of always being under K(D)-controlled conditions can be erroneous and can lead to unreliable estimates for the binding parameters. We also compare and contrast the fitting of simulated data sets to the commonly used cell-based binding equation versus our more rigorous 4-parameter nonlinear MIBS model. It is shown through these simulations that the new 4-parameter MIBS model, when used for cell-based titrations under optimal conditions, yields highly accurate estimates of all binding parameters and hence should be the preferred model to fit cell-based experimental nonlinear titration data.     

Dose‐response analysis of bromate‐induced DNA damage and mutagenicity is consistent with low‐dose linear,nonthreshold processes

Mutagenic agents have long been inferred to act through low‐dose linear, nonthreshold processes. However, there is debate about this assumption, with various studies interpreting datasets as showing thresholds for DNA damage and mutation. We have applied rigorous statistical analyses to investigate the shape of dose‐response relationships for a series of in vitro and in vivo genotoxicity studies using potassium bromate (KBrO₃), a water ozonation byproduct that is bioactivated to a reactive species causing oxidative damage to DNA. We analyzed studies of KBrO₃ genotoxicity where no‐effect/threshold levels were reported as well as other representative datasets. In all cases, the data were consistent with low‐dose linear models. In the majority of cases, the data were fit either by a linear (straight line) model or a model which was linear at low doses and showed a saturation‐like downward curvature at high doses. Other datasets with apparent upward curvature were still adequately represented by models that were linear at low dose. Sensitivity analysis of datasets showing upward curvature revealed that both low‐dose linear and nonlinear models provide adequate fits. Additionally, a simple biochemical model of selected key processes in bromate‐induced DNA damage was developed and illustrated a situation where response for early primary events suggested an apparent threshold while downstream events were linear. Overall, the statistical analyses of DNA damage and mutations induced by KBrO₃ are consistent with a low‐dose linear response and do not provide convincing evidence for the presence of a threshold. Environ. Mol. Mutagen., 2013. © 2012 Wiley Periodicals, Inc.     

Fitting the linear-quadratic model to detailed data sets for different dose ranges

Survival curve behaviour and degree of correspondence between the linear-quadratic (LQ) model and experimental data in an extensive dose range for high dose rates were analysed. Detailed clonogenic assays with irradiation given in 0.5 Gy increments and a total dose range varying from 10.5 to 16 Gy were performed. The cell lines investigated were: CHOAA8 (Chinese hamster fibroblast cells), U373MG (human glioblastoma cells), CP3 and DU145 (human prostate carcinoma cell lines). The analyses were based on chi2-statistics and Monte Carlo simulation of the experiments. A decline of LQ fit quality at very low doses (<2 Gy) is observed. This result can be explained by the hypersensitive effect observed in CHOAA8, U373MG and DU145 data and an adaptive-type response in the CP3 cell line. A clear improvement of the fit is discerned by removing the low dose data points. The fit worsening at high doses also shows that LQ cannot explain this region. This shows that the LQ model fits better the middle dose region of the survival curve. The analysis conducted in our study reveals a dose dependency of the LQ fit in different cell lines.     

进化策略,进化规划在医用非线性曲线拟合中的应用

作者提出医用非线性曲线拟合的进化策略，进化规划方法并以Ｇ ａｍｍａ曲线，指数－对数曲线，指数曲线为例，测试了该类方法的效果，结果表明其性能良好，可望成为各类医用非线性曲线拟合的有效工具。     

GafChromic EBT film dosimetry with flatbed CCD scanner: a novel background correction method and full dose uncertainty analysis

Film dosimetry using radiochromic EBT film in combination with a flatbed charge coupled device scanner is a useful method both for two-dimensional verification of intensity-modulated radiation treatment plans and for general quality assurance of treatment planning systems and linear accelerators. Unfortunately, the response over the scanner area is nonuniform, and when not corrected for, this results in a systematic error in the measured dose which is both dose and position dependent. In this study a novel method for background correction is presented. The method is based on the subtraction of a correction matrix, a matrix that is based on scans of films that are irradiated to nine dose levels in the range 0.08-2.93 Gy. Because the response of the film is dependent on the film's orientation with respect to the scanner, correction matrices for both landscape oriented and portrait oriented scans were made. In addition to the background correction method, a full dose uncertainty analysis of the film dosimetry procedure was performed. This analysis takes into account the fit uncertainty of the calibration curve, the variation in response for different film sheets, the nonuniformity after background correction, and the noise in the scanned films. The film analysis was performed for film pieces of size 16 x 16 cm, all with the same lot number, and all irradiations were done perpendicular onto the films. The results show that the 2-sigma dose uncertainty at 2 Gy is about 5% and 3.5% for landscape and portrait scans, respectively. The uncertainty gradually increases as the dose decreases, but at 1 Gy the 2-sigma dose uncertainty is still as good as 6% and 4% for landscape and portrait scans, respectively. The study shows that film dosimetry using GafChromic EBT film, an Epson Expression 1680 Professional scanner and a dedicated background correction technique gives precise and accurate results. For the purpose of dosimetric verification, the calculated dose distribution can be compared with the film-measured dose distribution using a dose constraint of 4% (relative to the measured dose) for doses between 1 and 3 Gy. At lower doses, the dose constraint must be relaxed.     

A Monte Carlo and physical phantom evaluation of quantitative In-111 SPECT

Accurate estimation of the 3D in vivo activity distribution is important for dose estimation in targeted radionuclide therapy (TRT). Although SPECT can potentially provide such estimates, SPECT without compensation for image degrading factors is not quantitatively accurate. In this work, we evaluated quantitative SPECT (QSPECT) reconstruction methods that include compensation for various physical effects. Experimental projection data were obtained using a GE VH/Hawkeye system and an RSD torso phantom. Known activities of In-111 chloride were placed in the lungs, liver, heart, background and two spherical compartments with inner diameters of 22 mm and 34 mm. The 3D NCAT phantom with organ activities based on clinically derived In-111 ibritumomab tiuxetan data was used for the Monte Carlo (MC) simulation studies. Low-noise projection data were simulated using previously validated MC simulation methods. Fifty sets of noisy projections with realistic count levels were generated. Reconstructions were performed using the OS-EM algorithm with various combinations of attenuation (A), scatter (S), geometric response (G), collimator-detector response (D) and partial volume compensation (PVC). The QSPECT images from the various combinations of compensations were evaluated in terms of the accuracy and precision of the estimates of the total activity in each organ. For experimental data, the errors in organ activities for ADS and PVC compensation were less than 6.5% except the smaller sphere (-11.9%). For the noisy simulated data, the errors in organ activity for ADS compensation were less than 5.5% except the lungs (20.9%) and blood vessels (15.2%). Errors for other combinations of compensations were significantly (A, AS) or somewhat (AGS) larger. With added PVC, the error in the organ activities improved slightly except for the lungs (11.5%) and blood vessels (3.6%) where the improvement was more substantial. The standard deviation/mean ratios were all less than 1.5%. We conclude that QSPECT methods with appropriate compensations provided accurate In-111 organ activity estimates. For the collimator used, AGS was almost as good as ADS and may be preferable due to the reduced reconstruction time. PVC was important for small structures such as tumours or for organs in close proximity to regions with high activity. The improved quantitative accuracy from QSPECT methods has the potential for improving organ dose estimations in TRT.     

Interaction of gastrin I, secretin, and cholecystokinin on gallbladder smooth muscle.

The effect of cholecystokinin (CCK), the octapeptide of cholecystokinin (CCK-OP), gastrin I, and secretin was studied on guinea pig gallbladder smooth muscle in vitro. Both CCK and CCK-OP stimulated gallbladder contraction, with CCK-OP being more potent. Gastrin I, over a wide dose range, had no effect on gallbladder contractility. Secretin alone also showed no effect on gallbladder smooth muscle but in combination with CCK-OP it produced a noncompetitive type of inhibition. Michaelis-Menten kinetics showed the calculated maximum response of the secretin plus CCK-OP interaction to be less than with CCK-OP alone. There was no change in the dose required to achieve half-maximal response, D50. These studies indicate that: a) CCK-OP has a greater effect on gallbladder contractility than CCK, b) gastrin I has no effect on gallbladder muscle tone, and c) secretin acts as a noncompetitive antagonist of CCK-OP. These findings suggest that gallbladder motor function may be determined in part by the interaction of secretin and CCK rather than solely in response to CCK.     

Normalized glandular dose (DgN) coefficients for flat-panel CT breast imaging

The development of new digital mammography techniques such as dual-energy imaging, tomosynthesis and CT breast imaging will require investigation of optimal camera design parameters and optimal imaging acquisition parameters. In optimizing these acquisition protocols and imaging systems it is important to have knowledge of the radiation dose to the breast. This study presents a methodology for estimating the normalized glandular dose to the uncompressed breast using the geometry proposed for flat-panel CT breast imaging. The simulation uses the GEANT 3 Monte Carlo code to model x-ray transport and absorption within the breast phantom. The Monte Carlo software was validated for breast dosimetry by comparing results of the normalized glandular dose (DgN) values of the compressed breast to those reported in the literature. The normalized glandular dose was then estimated for a range of breast diameters from 10 cm to 18 cm using an uncompressed breast model with a homogeneous composition of adipose and glandular tissue, and for monoenergetic x-rays from 10 keV to 120 keV. These data were fit providing expressions for the normalized glandular dose. Using these expressions for the DgN coefficients and input variables such as the diameter, height and composition of the breast phantom, the mean glandular dose for any spectra can be estimated. A computer program to provide normalized glandular dose values has been made available online. In addition, figures displaying energy deposition maps are presented to better understand the spatial distribution of dose in CT breast imaging.     

Comparative studies on tree pollen allergens. XI. Trials on the regulation of IgE response in mice using modified birch pollen allergens

The major allergen of birch pollen, BV45, was isolated and conjugated to 2-o-methoxy polyethylene glycol-4,6-dichloro-5-triazine (mPEG). The molecular-weight variant of 6,000 daltons of the activated mPEG was used in an antigen-specific regulation of IgE response. In these studies 200 genetically high IgE responders (CBA/Ca) female mice were intradermally immunized by the purified BV45, with the use of various adjuvants. Four different sets of experiments were made. In the first experiment 50 mice were immunized on days 1 and 15 with BV45. This was followed by another booster dose of the native BV45 or the modified mPEG-BV45 in Freund's incomplete adjuvants (FIA) on day 72. In the 2nd experiment, a similar procedure was performed except that booster doses were injected on day 135. Subsequently on day 136, BV45/FIA was intradermally injected. In the 3rd and 4th sets of experiments, 2 groups of 50 mice were daily immunized by intraperitoneal injections of 10 successive doses of BV45. On day 33 a dose of BV45 or mPEG-BV45 respectively, was intraperitoneally injected in each mouse. This injection was followed by other 10 successive doses of BV45. In experiment 3 no adjuvants were used, and in experiment 4 aluminium hydroxide gel was used as adjuvant. The mice immune response was assessed by analyses of the serum IgG and IgE levels. In all experiments higher IgG concentrations were shown for the immunized mice as compared to the non-treated control animals. Administration of booster doses of BV45 or mPEG-BV45 induced increases in the IgG levels.(ABSTRACT TRUNCATED AT 250 WORDS)