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Results for “nonlinear analyses”

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PubMed1997

Clinical implications of maximal respiratory pressure determinations for individuals with Duchenne muscular dystrophy.

OBJECTIVE: To analyze the relationship between disease progression, pulmonary volumes, respiratory muscle strength (maximum inspiratory [MIP] and expiratory [MEP] pressure), and arterial blood gases for patients with Duchenne muscular dystrophy (DMD). DESIGN: An inception cohort study of pulmonary volumes, MIPs, and MEPs, correlated with age and PaCO2 levels and with each other using linear and nonlinear regression analyses. SETTING: Outpatient clinic. PATIENTS: Fifty-two consecutive DMD patients who presented for regular evaluations at a regional DMD center. RESULTS: Maximum expiratory pressures were 47.7% +/- 10.9% of normal in the 167- to 14-year-old patients and decreased linearly thereafter (MEP% = -2.7 x age +73.8; p < .001). Declines in MEP also correlated linearly with expiratory reserve volume (p < .001) and inversely with residual volume (p < .001). By contrast, MIP was 66.3% +/- 19.0% in the 357- to 14-year-old patients and then declined to 30.2% +/- 19.5% after age 14. No linear relationships were found with age but declines did correlate linearly with inspiratory reserve volume (p < .001) and total lung capacity (p < .001). PaCO2 elevations correlated best with decreases in MIP (p < .0001) and appeared when MIP was below 30cmH2O. CONCLUSIONS: Lung volume changes in DMD patients correlate with respiratory muscle weakness, and although inspiratory muscle dysfunction plays a key role in the development of chronic ventilatory insufficiency, reductions in expiratory muscle strength are the first signs of dysfunction and lead to the first episodes of respiratory failure.

Adolescent↗

PubMed2002

Cadmium transport through type II alveolar cell monolayers: contribution of transcellular and paracellular pathways in the rat ATII and the human A549 cells.

Cadmium (CD) transport in alveolar type II (ATII) cells has been studied using two in vitro models widely used to investigate lung function: primary cultures of rat ATII cells and the human cell line A549. Nonlinear regression analyses of the uptake time-course of (109)Cd revealed: a zero-time accumulation, a fast process of accumulation which proceeds within minutes, and a much slower process which takes hours. This three-step mechanism was characterized by different parameter values under dishes-or filter-growth conditions. A higher initial uptake rate (v(i)) and equilibrium accumulation (A(max)) of (109)Cd were found in the rat ATII cells; these differences were not related to a higher level of adsorption onto the external surface of the cell membrane. Specific transport systems of similar capacity but different affinity (threefold higher in rat cells) were characterized. A significant transepithelial transport of (109)Cd, with similar P(coeff) in both cell models, could not be exclusively related to cellular metal release. Results on 3H-mannitol permeability together with (109)Cd efflux data strongly suggest a greater contribution of the paracellular pathways in Cd transport through A549 cell monolayers. These differences in transport properties between the two lung cell models may modify the dose-response curve for Cd toxicity.

Absorption↗

PubMed1998

Viscoelastic stress analysis of thermally compatible and incompatible metal-ceramic systems.

OBJECTIVE: The purpose of this study was to analyze transient and residual midpoint deflections and stresses in metal-opaque porcelain-body porcelain systems with matched and mismatched thermal contraction coefficients. METHODS: Calculations and measurements were made for seven trimaterial strips that covered a wide range of thermal contraction mismatches among constituent materials. Midpoint deflections were measured in a beam-bending viscometer during slow cooling from an initial temperature of 700 degrees C. Linear regression analysis with a correlation coefficient of 0.950 was used to compare measured and calculated residual midpoint deflections. Stress relaxation data were fit to a three-term exponential series by nonlinear regression analyses with correlation ratios ranging from 0.9972 to 0.9999. RESULTS: While finite element analyses correctly predicted the general shape of the deflection behavior as a function of temperature for all combinations, the best agreement between measured mean residual midpoint deflections and calculated values (+250 microns vs. +268 microns) was obtained for strips composed of a Au-Pd alloy (alpha m = 13.5 ppm/ degree C) with a medium expansion opaque porcelain (alpha o = 13.3 ppm/degree C) and a high expansion body porcelain (alpha B = 14.4 ppm/degree C). The highest calculated residual tensile stress of +26 MPa at the surface of body porcelain was associated with the 0.5-mm-thick Ni-Cr-Be alloy strip (alpha m = 15.1 ppm/degree C) with medium expansion porcelains (alpha o = 13.5 ppm/degree C and alpha B = 13.9 ppm/degree C). The smallest measured residual deflection (+10 microns) was also associated with this combination. The results of this study indicated that metal-ceramic strips are sensitive indicators of stress development caused by a thermal contraction mismatch; however, the magnitudes of the residual deflections do not necessarily correlate with the stress magnitudes in the ceramic. SIGNIFICANCE: Currently there are no U.S. or international standards that define the maximum difference in thermal contraction coefficients that can exist between a metal and its ceramic veneer without causing transient failures of ceramic during cooling or delayed failures in ceramic because of high residual tensile stresses. The present research represents a major step in understanding the various factors that influence the development of transient and residual stresses. A knowledge of the effects of process variables on stress development is necessary for selection of potentially successful metal-ceramic systems and for optimizing the design of dental prostheses.

Aluminum Oxide↗

PubMed1998

Biomechanical response of the passive human knee joint under anterior-posterior forces.

OBJECTIVE: To investigate the detailed biomechanics of the passive tibiofemoral knee joints in full extension under anterior/posterior drawer forces of up to 400 N. DESIGN: A nonlinear three-dimensional finite element model of the entire human tibiofemoral joint consisting of bony structures, their articular cartilage layers, menisci, and four principal ligaments was utilized. BACKGROUND: The mechanics of the knee joint, specially under drawer forces, have extensively been investigated. Despite all these works, the detailed joint biomechanics, specially the role of boundary conditions, load transmission through menisci/articular cartilage layers, and coupling between menisci and cruciate ligaments are not yet quantified. METHODS: Nonlinear elastostatic analyses were carried out considering the tibiofemoral joint at full extension under anterior and posterior loads of up to 400 N applied either to the tibial or the femoral shaft. Cases with various boundary conditions, cruciate ligament deficiency (anterior or posterior), and total unilateral meniscectomy (medial or lateral) were analysed. RESULTS: In addition to the total primary anterior-posterior motion of about 9 mm at +/-400 N, significant coupled external tibial rotations of about 9 degrees and 10 degrees were computed under 400 N femoral posterior and anterior forces, respectively. The response was influenced by the manner of loading and boundary conditions. The anterior cruciate ligament and posterior cruciate ligament were the primary restraints to femoral posterior and anterior drawer forces, respectively. Section of either of these ligaments drastically increased the joint anterior-posterior motion. In the absence of cruciates, the collaterals became the primary restraints in both anterior-posterior forces. In this case, the tibial plateaus, specially the medial one in the anterior cruciate ligament-deficient joint, experienced much larger compressive forces. In addition to causing an increase in joint primary anterior-posterior laxity and anterior cruciate ligament forces, medial meniscectomy substantially increased coupled tibial external rotation, forces on the lateral plateau, and stresses in the articular cartilage of the lateral plateau. RELEVANCE: Our results suggest an increased role for the medial meniscus in the anterior cruciate ligament-deficient joint. Lateral meniscectomy had much smaller effects on results than the medial one. The success of any anterior cruciate ligament replacement or meniscal transplantation in the restoration of the joint stability and the protection of the articular cartilage against excessive stresses depends on the coupling between the anterior cruciate ligament and medial meniscus. Absence of any of these components would drastically influence the joint response.

Journal Article↗

PubMed1998

Isolation and characterization of a monoclonal anti-quadruplex DNA antibody from autoimmune "viable motheaten" mice.

A cell line that produces an autoantibody specific for DNA quadruplex structures has been isolated and cloned from a hybridoma library derived from 3-month-old nonimmunized autoimmune, immunodeficient "viable motheaten" mice. This antibody has been tested extensively in vitro and found to bind specifically to DNA quadruplex structures formed by two biologically relevant sequence motifs. Scatchard and nonlinear regression analyses using both one- and two-site models were used to derive association constants for the antibody-DNA binding reactions. In both cases, quadruplexes had higher association constants than triplex and duplex molecules. The anti-quadruplex antibody binds to the quadruplex formed by the promoter-region-derived oligonucleotide d(CGCG4GCG) (Ka = 3.3 x 10(6) M-1), and has enhanced affinity for telomere-derived quadruplexes formed by the oligonucleotides d(TG4) and d(T2G4T2G4T2G4T2G4) (Ka = 5.38 x 10(6) and 1.66 x 10(7) M-1, respectively). The antibody binds both types of quadruplexes but has preferential affinity for the parallel four-stranded structure. In vitro radioimmunofilter binding experiments demonstrated that purified anti-DNA quadruplex antibodies from anti-quadruplex antibody-producing tissue culture supernatants have at least 10-fold higher affinity for quadruplexes than for triplex and duplex DNA structures of similar base composition and length. The antibody binds intramolecular DNA triplexes formed by d(G4T3G4T3C4) and d(C4T3G4T3G4), and the duplex d(CGCGCGCGCG)2 with an affinities of 6. 76 x 10(5), 5.59 x 10(5), and 8.26 x 10(5) M-1, respectively. Competition experiments showed that melted quadruplexes are not effective competitors for antibody binding when compared to native structures, confirming that the quadruplex is bound structure-specifically. To our knowledge, this is the first immunological reagent known to specifically recognize quadruplex structures. Subsequent sequence analysis demonstrates homologies between the antibody complementarity determining regions and sequences from Myb family telomere binding proteins, which are hypothesized to control cell aging via telomeric DNA interactions. The presence of this antibody in the autoimmune repertoire suggests a possible linkage between autoimmunity, telomeric DNA binding proteins, and aging.

Animals↗

PubMed2006

Joint action of benzoxazinone derivatives and phenolic acids.

The joint action of binary and ternary mixtures of benzoxazinone derivatives and phenolic acids was studied using the additive dose model (ADM) as reference model. The activity of fixed-ratio mixtures of phenolic acids [ferulic acid (FA), p-coumaric acid (CA), vanillic acid (VA), and p-hydroxybenzoic acid (HBA)] and benzoxazinone derivatives [2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one (DIMBOA), 6-methoxybenzoxazolin-2-one (MBOA), benzoxazolin-2-one (BOA), 2-aminophenol (AP), and N-(2-hydroxyphenyl)acetamide (HPAA)] on Lolium perenne and Myosotis arvensis root growth was assessed in Petri dishes. Root length was recorded 6 days after seeding, and EC(50) and EC(90) values were estimated using nonlinear regression analyses. The benzoxazinone derivatives were found to be more phytotoxic than the phenolic acids, particularly on M. arvensis. Binary mixtures of phenolic acids responded predominantly additively on both plant species. Deviations from additivity were species-specific with antagonistic responses on L. perenne and synergistic responses on M. arvensis. Similarly, binary mixtures of benzoxazinone derivatives also followed the ADM, although synergistic responses were observed for BOA + AP and BOA + HPAA. Binary and ternary mixtures of benzoxazinone derivatives and phenolic acids responded primarily antagonistically; however, a significant synergistic performance was observed with DIMBOA + FA and DIMBOA + VA on L. perenne. These results do not support the assumption that allelopathic effects of wheat can be attributed to synergistic effects of otherwise weakly active allelopathic compounds, and it is suggested that future research be directed toward identifying and studying the effects of other potential allelochemicals including the degradation products of the most abundant wheat allelochemicals.

Acids, Carbocyclic↗

PubMed1994

Pharmacokinetics and pharmacodynamics of a new cardiotonic vasodilator agent, 349U85, in normal subjects.

OBJECTIVE: To assess the pharmacodynamics and pharmacokinetics of single oral doses of a new vasodilator-cardiotonic agent, 349U85 hydrochloride [6-piperidino-2(1H)-quinolinone hydrochloride], in healthy male subjects. METHODS: This randomized, parallel, double-blind, placebo-controlled, dose escalation trial was conducted at a university-based clinical research center among 27 healthy male subjects. Data measurements used in the study included cardiac index, supine and standing blood pressure, 24-hour ambulatory electrocardiography, and 12-lead electrocardiography. RESULTS: Doses from 2 mg to 250 mg were well tolerated. Cardiac index, supine heart rate, and orthostatic hypotension, indicators of inotropic, chronotropic, and vasodilator effects, respectively, correlated to plasma concentrations of 349U85 and of its metabolite, 661U88. Results suggest that 349U85 may be more responsible for inotropic effects, whereas 661U88 may be more responsible for vasodilatory and chronotropic effects. These results are consistent with the preclinical pharmacologic profile for these two compounds. Headache, orthostatic dizziness, and hypotension tended to occur more frequently at higher doses and were temporally related to drug administration. Pharmacokinetic analyses indicate nonlinearity of 349U85 and 661U88, suggestive of saturation of metabolism and large interindividual variability in maximum plasma drug concentration and area under the plasma concentration-time curve. The source of the variability is not known. The time to maximum distribution was approximately 0.7 hours for both 349U85 and 661U88; the terminal elimination half-life was 1 hour for 349U85 and 3 hours for 661U88. Holter monitoring revealed asymptomatic increases in ventricular and supraventricular ectopic activity in some volunteers; ectopy appeared to be related to the dose of 349U85 and generally occurred at higher doses.

Adult↗

PubMed2004

Alcohol intake and 8-year weight gain in women: a prospective study.

OBJECTIVE: To examine prospectively the relationship between alcohol and 8-year weight gain in women. RESEARCH METHODS AND PROCEDURES: A prospective study of 49,324 women 27 to 44 years old who did not have a history of cardiovascular disease, cancer, or diabetes, who were not pregnant during the study period, and who reported weights in 1991 and 1999. RESULTS: In cross-sectional analyses, there was a significant inverse relationship between alcohol and BMI even after adjustment for dietary factors and a wide range of confounders. In multivariate prospective analyses, a nonlinear relationship was seen between alcohol and weight gain (>or=5 kg) in all women. Compared with nondrinkers, the adjusted relative odds [95% confidence interval (CI)] of weight gain according to grams per day were 0.94 (0.89, 0.99) for those consuming 0.1 to 4.9 g/d, 0.92 (0.85,0.99) for 5 to 14.9 g/d, 0.86 (0.76, 0.78) for 15 to 29.9 g/d, and 1.07 (0.89,1.28) for those consuming 30+ g/d (p < 0.0001 for quadratic trend). Women who continued to drink heavily and those who became heavy drinkers showed similar increased odds of weight gain. The increased odds of weight gain associated with heavy drinking (30+ g/d) were most marked in the younger women (<35 years) (odds ratio 1.64; 5% CI 1.03 to 2.61). In African-American women, light drinking was associated with increased odds of weight gain compared with nondrinkers (odds ratio = 2.43; 95% CI 1.22 to 4.82). DISCUSSION: Our data suggest that light to moderate drinking (up to 30 g/d) is not associated with weight gain in women except possibly in African-American women. Heavier drinking may promote weight gain in women.

Adult↗

PubMed2003

Population pharmacokinetics of platinum after nedaplatin administration and model validation in adult patients.

AIMS: The pharmacokinetics of unbound platinum after administration of an anticancer drug nedaplatin, cis-diammineglycolateplatinum were examined using population analysis. The relevant covariates and the extent of inter- and intra-individual variability were evaluated. METHODS: In order to clarify the pharmacokinetic profile of nedaplatin, unbound platinum concentrations (789 points) in plasma after intravenous infusion of nedaplatin were obtained from 183 courses for 141 patients. Plasma concentration data were analysed by nonlinear mixed effect modelling using NONMEM to evaluate the population mean parameters and variances for inter- and intra-individual random effects. The final population model was validated by parameter sensitivity analysis using objective function mapping, the bootstrap resampling and a data-splitting technique, i.e. the Jackknife method, and the predictive performance of the final model was evaluated. RESULTS: A two-compartment pharmacokinetic model with zero-order input and first order elimination described the current data well. The significant covariates were creatinine clearance (CLcr) for clearance of platinum (CL) [population mean [95% confidence interval (CI)] CL (l h(-1)) = 4.47 (3.27, 5.67) + 0.0738 (0.0581, 0.0896) x CLcr (CLcr: ml min(-1))] and body weight (BW: kg) for volume of distribution of platinum (Vc) [Vc (l) = 12.0 (7.5, 16.5) + 0.163 (0.081, 0.246) x BW]. Inter-individual variations (CV%, 95% CI) for CL and Vc were 25.5% (20.7, 29.6) and 21.4% (17.0, 24.1), respectively, and intra-individual variation (CV%, 95% CI) was 12.6% (10.5, 14.4). The effects of pretreatment with nedaplatin or other platinum agents on clearance and volume of distribution were also tested, but no significant effect was found. The relationship between the observed and predicted unbound platinum concentration by empirical Bayesian prediction showed good correlation with no bias, suggesting that the final model explains well the observed data in the patients. The mean prediction error and root mean square prediction error (95% CI) were - 0.0164 micro g ml(-1) (- 0.4379, 0.4051) and 0.2155 micro g ml(-1) (not calculable, 0.6523), respectively. The values of mean, standard error and 95% CI for objective function mapping, the bootstrap resampling, the Jackknife estimates and the final model coincided well. CONCLUSIONS: A population pharmacokinetic model was developed for unbound platinum after intravenous infusion of nedaplatin. Only creatinine clearance was found to be a significant covariate of clearance, and BW was found to be a significant covariate of volume of distribution. These population pharmacokinetic estimates are useful for setting initial dosing of nedaplatin using its population mean and can also be used for setting appropriate dosage regimens using empirical Bayesian forecasting.

Adult↗

PubMed2003

[The psychometric quality of the Nottingham Health Profile (NHP) in the general population].

The Nottingham Health Profile (NHP) is a questionnaire that assesses health related quality of life. The aim of this paper is to test the psychometric quality of the instrument based on a subject sample which is representative for the German population. The sample consisted of 1996 persons with ages between 18 and 92 years. They were asked to fill in several questionnaires including the NHP. The results show that the NHP does not differentiate between subjects in the range of low and medium levels of complaints. Only one half of the subject sample agreed to at least one of the 38 items. All six subscales showed significant age and sex effects which were proved with nonlinear regression analyses. The validity was assessed through correlations with other health related questionnaires. It can be concluded that the use of the NHP cannot be recommended when studies in the general population are conducted.

Adult↗

PubMed2003

Cisapride: a potential model substrate to assess cytochrome P4503A4 activity in vivo.

OBJECTIVES: Cisapride was compared with midazolam in vivo to determine its potential applicability as a cytochrome P450 (CYP) 3A4 "probe." As well, we evaluated whether cisapride was transported by P-glycoprotein. METHODS: Bidirectional transport assays were conducted in LLC-PK1 cells and the derivative cell line L-MDR1 to determine whether cisapride was a substrate for P-glycoprotein. A pharmacokinetic study was also conducted in 17 healthy adults (n = 8 women) who received intravenous midazolam (0.025 mg/kg), oral midazolam (0.15 mg/kg), and oral cisapride (0.07 mg/kg) in a randomized crossover design. Plasma concentrations were quantitated from repeated after-dosing blood samples by HPLC with ultraviolet detection for midazolam and HPLC with tandem mass spectrometry detection for cisapride and norcisapride. Pharmacokinetic parameters were determined by noncompartmental methods. Both linear and nonlinear regression analyses were used to examine the association between the apparent plasma clearance of midazolam and cisapride and the cisapride/norcisapride plasma concentration ratios. RESULTS: Although not a substrate for P-glycoprotein, cisapride inhibited P-glycoprotein with an apparent inhibition constant (K(i)) of 16.1 micromol/L. Linear correlations between cisapride clearance and both intravenous and oral midazolam clearance (P =.01, r(2) = 0.43 and P =.001, r(2) = 0.46, respectively) were found. Cisapride/norcisapride plasma concentration ratios at 8 hours (P =.001, r(2) = 0.90) and 12 hours (P =.001, r(2) = 0.96), as well as cisapride plasma concentrations at these time points, were shown to accurately predict the area under the plasma concentration versus time curve for cisapride. CONCLUSIONS: CYP3A4 activity reflected by the total body clearance after oral administration of cisapride should be independent of transport by P-glycoprotein. Concordance between the pharmacokinetics for cisapride and midazolam support the applicability of oral cisapride as a pharmacologic substrate to assess total CYP3A4 activity in vivo. Cisapride plasma concentration ratios at 8 or 12 hours after a single oral cisapride dose may prove useful as a single-point determination to reflect the area under the plasma concentration versus time curve and the plasma clearance of cisapride and, as well, total CYP3A4 activity in vivo.

ATP Binding Cassette Transporter, Subfamily B↗

PubMedDate not supplied

Pathological analysis of myocardial cell under ventricular tachycardia and fibrillation based on symbolic dynamics.

Ventricular fibrillation (VF) is one of the most serious malignant arrhythmias usually resulting from immediate degeneration of ventricular tachycardia (VT). In order to analyse the nonlinear dynamics of the cardiac micro-mechanism under VT and VT rhythm, at the cellular level, myocardial cell action potentials are investigated under different rhythm, normal sinus rhythm, VT and VT. On the basis of nonlinear chaotic theory and symbolic dynamics, we put forward new definitions, complexity rate, etc, and obtained some useful properties for cellular electrophysiological analysis. The results of the experiments and computation show that the myocardial cellular signals under VT and VF rhythm are different kinds of chaotic signals in that the cardiac chaos attractor under VF is higher than that under VT. The analytical complexity theory has been promising in the clinical application.

Action Potentials↗

PubMed2002

PLS-QSAR of the adult and developmental toxicity of chemicals to Hydra attenuata.

Autocorrelation descriptors encoding lipophilicity, molar refractivity, the H-bonding acceptor and donor ability of the molecules and also indicator variables were used to describe 30 organic chemicals characterized by their adult and developmental toxicities to Hydra attenuata. A PLS regression analysis was successfully employed to derive a QSAR model allowing the simulation of both endpoints. Comparisons were made with orthogonal regression analysis and different nonlinear regression analyses.

Age Factors↗

PubMed1993

Application of neural networks in the QSAR analysis of percent effect biological data: comparison with adaptive least squares and nonlinear regression analysis.

Artificial neural networks (ANN) can be used for the direct QSAR analysis of percent effect biological data, thus avoiding the bias introduced by arbitrarily chosen classes and the loss of information due to prior classification. For two data sets the ANN results are compared with those obtained by adaptive least squares and nonlinear regression analyses. In comparison with the other methods the neural network shows higher predictive power and does not require an explicit equation relating the observed effect to physicochemical descriptors.

Animals↗

PubMed1995

[Empty body weight gain, protein, fat and energy deposit and utilization of metabolizable energy for energy deposit in black and white bulls. 2. Protein, fat and energy deposit].

The protein, fat and energy deposition determined in 6 series of individual feeding experiments with different energy supply on slaughter steps (altogether 458 animals) and whole body analysis were generalized in this publication on nonlinear regression analyses. The protein deposition per kg empty body weight gain is influenced by empty body weight, it takes off with increase of the empty body weight. At low empty body weight (100-200 kg) the protein deposition per kg empty body weight gain is small increased with increasing of empty body weight gain, at high empty body weight it is reduced continuously. The fat deposition per kg empty body weight gain increases progressively with the empty body weight and with the empty body weight gain respectively. The energy deposition per kg empty body weight gain increases with increase of empty body weight and of empty body weight gain. It showed the same development like the fat deposition. The protein, fat and energy deposition per kg live weight gain are calculated and tabulated in dependence on the live weight and the live weight gain.

Animals↗

PubMed2002

The impact of possible modifications to the DS86 dosimetry on neutron risk and relative biological effectiveness.

The current DS86 dosimetry system for the Japanese bomb survivors indicates that neutron doses were so low that they prevent the direct derivation of any useful estimates of neutron risk. However, the large body of thermal neutron activation measurements carried out over many years in Hiroshima and Nagasaki appear to indicate that current DS86 neutron doses may have been significantly underestimated in Hiroshima. An earlier companion paper has provided an update of neutron activation measurements. While a large body of data appears to support a significant increase, there is ongoing debate and review regarding its validity. However, as yet, there are no detailed, peer-reviewed, published refutations of the neutron activation data which appear to support an increase in neutron doses. In this paper, we consider the impact of possible future revisions in the DS86 dosimetry on radiation risk estimates. We consider the extreme range of possibilities from maintaining the existing DS86 values, to changes in neutron doses in accord with the majority of existing neutron activation data. We have used the latest cancer incidence data and cancer mortality data for the A-bomb survivors, and neutron doses have been modified using a neutron revision factor (NRF) in line with the latest thermal neutron activation measurements in Hiroshima. In contrast to previous analyses, a nonlinear relationship between log(NRF) and slant range has been used which better represents the data beyond slant ranges of approximately 1 km. The impact on the evaluation of neutron relative biological effectiveness (RBE) and gamma radiation risk estimates has been assessed. While DS86 neutron doses are too low to allow any useful direct evaluation of neutron risk or neutron RBE, it becomes possible to derive more meaningful values if neutron doses are increased in Hiroshima in line with the broad range of thermal neutron activation measurements. The uncertainties are smallest for the cancer incidence data. The best estimates of neutron RBE give upper 95% confidence limits of about 6 for all solid tumours for the incidence data and about 28 for the mortality data. The uncertainties in neutron RBE for leukaemia incidence are larger, and estimation at doses below about 0.1 Gy is not possible. There is no significant change in the excess relative risk for gamma radiation for all solid tumours taken together, compared with the current DS86 dosimetry. The results preclude neutron RBE values significantly greater than the current ICRP radiation weighting factors, which range between 5 and 20, depending on energy. Whether or not the Japanese bomb survivors can indeed form the basis for useful, directly determined neutron risks clearly depends on the veracity of existing neutron activation data. This is currently the subject of careful international scrutiny and the outcome is eagerly awaited.

Animals↗

PubMed1999

Analysis of the inhibition of N-nitroso-dimethylamine activation in the liver by N-nitro-dimethylamine using a new non-linear statistical method.

N-nitro-dimethylamine (NTDMA) is carcinogenic to rats: it induces nasal cavity tumours. It can be demethylated to N-nitromethylamine and formaldehyde and reduced to N-nitroso-dimethylamine (NDMA): a potent liver carcinogen and also of the nasal cavity if activation in the liver is blocked. To explain the mechanism of NTDMA carcinogenicity we compared its demethylation with that of NDMA in liver microsomes from female and male rats, untreated, fasted or treated with ethanol to induce cytochrome P450 2E1 (CYP2E1). Kinetic parameters were analysed by nonlinear statistical methods, which yielded unbiased parameter estimates for the calculated Km and Vmax values. Km for both compounds was very similar in females (24-47 microM) whereas Vmax for NTDMA was consistently higher than for NDMA as substrate: 1.07-4.70 nmol formaldehyde/mg microsomal protein x min and 0.52-2.76 nmol, respectively. In liver microsomes from induced male rats NTDMA was found to be a much more effective inhibitor of NDMA activation (KEI 39.6-73.6 microM) than NDMA of NTDMA demethylation (KEI 224-286 microM). Nasal microsomes can demethylate both NDMA and NTDMA but the kinetics are vastly different. NTDMA is demethylated at a linear rate and approximately 10-fold more effectively than NDMA. The mechanism of carcinogenicity of ingested NTDMA, we propose, is a partial reduction to NDMA in the liver and inhibition of NDMA activation in the liver by residual NTDMA, which enables NDMA to reach the nasal mucosa where it is activated to DNA-alkylating species and the observed tumours are formed.

Animals↗

PubMed2003

An evaluation of local item dependencies in the Medical Council of Canada Qualifying Examination Part I.

PURPOSE: This study investigates (a) whether items within the Multiple-Choice Questions component of the Medical Council of Canada's Qualifying Examination Part I exhibit local dependencies and (b) potential sources of such dependencies. METHOD: The dimensionality of each of six discipline-based subtests was assessed based on exploratory nonlinear factor analyses. A standardized Fisher's z statistic was used to test residual item correlations for local item dependencies. The characteristics of pairs of items flagged as possibly locally dependent were reviewed. RESULTS: Some items in the Pediatrics and Public Medicine/Community Health subtests are locally dependent; these tend to be the more difficult items on the subtests. DISCUSSION: While these results are encouraging, the possible causes and potential impacts of any local dependencies should be investigated further.

Canada↗