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PubMed2004

A theoretical and experimental analysis of formulation and device parameters affecting solution MDI size distributions.

The influence of formulation and device configurations on the initial droplet and residual particle size distribution from solution MDIs was theoretically and experimentally examined. Aerodynamic size distribution tests were conducted to characterize the size distribution of the residual particles formed when a solution MDI is actuated. The measured size distributions were approximately log-normally distributed, and did not show evidence of a secondary large particle mode. Theoretical relationships were developed to relate the residual particle size distribution to the initial size distribution of the atomized droplets. The residual particle size distribution was shown to be proportional to the nonvolatile concentration to the one-third power. Ethanol concentration, propellant type, valve size, and actuator orifice diameter were all shown to affect the initial droplet size distribution. Deposition of drug in the mouthpiece and USP inlet affect the measured size distribution during aerodynamic particle size measurements. Although there is a significant increase in the size of initial droplets as ethanol concentration increases, there is only a minor increase in the size of the residual particles measured when the USP Inlet is used due to size dependent deposition in the USP inlet and actuator mouthpiece. Vapor pressure was shown to explain only part of the differences in the size of the atomized droplets for various formulations. Theoretical and empirical equations were developed that make it possible to predict the residual particle size distribution for solution MDIs.

Chemistry, Pharmaceutical↗

PubMed2000

Male-male competition and large size mating advantage in European earwigs, Forficula auricularia.

European earwigs are sexually dimorphic in forceps shape and length. Male forceps are thought to be weapons in male contests for access to females, but recent findings suggest that females choose males on the basis of their forceps length. I investigated sexual selection on forceps length and body size and the occurrence of male-male competition. When I controlled for forceps length experimentally and statistically, relatively heavy males had greater copulation success than relatively light males. When I controlled for body size, males with relatively longer forceps had no tendency for greater copulation success than males with shorter forceps. Relatively heavy males more often took over copulations from smaller males than vice versa. Male contests were important for the outcome of mate competition, as males commonly interrupted and took over copulations. My results therefore suggest that intrasexual selection is significant in competition for copulations in male earwigs, and acts on body size. This contrasts with previous findings, which have shown intersexual selection on forceps length to be important. However, both modes of sexual selection may be acting through a two-stage process, where male-male competition first determines which males have access to females, and then through female choice among available males. Morphological measurements supported the conclusion that forceps length and body size are male secondary sexual characters, as these characters had large variance and skewed distributions in males, but were normally distributed in females. Copyright 2000 The Association for the Study of Animal Behaviour.

Journal Article↗

PubMed2002

QTL analysis for grain protein content using SSR markers and validation studies using NILs in bread wheat.

QTL interval mapping for grain protein content (GPC) in bread wheat was conducted for the first time, using a framework map based on a mapping population, which was available in the form of 100 recombinant inbred lines (RILs). The data on GPC for QTL mapping was recorded by growing the RILs in five different environments representing three wheat growing locations from Northern India; one of these locations was repeated for 3 years. Distribution of GPC values followed normal distributions in all the environments, which could be explained by significant g x e interactions observed through analyses of variances, which also gave significant effects due to genotypes and environments. Thirteen (13) QTLs were identified in individual environments following three methods (single-marker analysis or SMA, simple interval mapping or SIM and composite interval mapping or CIM) and using LOD scores that ranged from 2.5 to 6.5. Threshold LOD scores (ranging from 3.05 to 3.57), worked out and used in each case, however, detected only seven of the above 13 QTLs. Only four (QGpc.ccsu-2B.1; QGpc.ccsu-2D.1; QGpc.ccsu-3D.1 and QGpc.ccsu-7A.1) of these QTLs were identified either in more than one location or following one more method other than CIM; another QTL (QGpc.ccsu-3D.2), which was identified using means for all the environments, was also considered to be important. These five QTLs have been recommended for marker-assisted selection (MAS). The QTLs identified as above were also validated using ten NILs derived from three crosses. Five of the ten NILs possessed 38 introgressed segments from 16 chromosomes and carried 42 of the 173 markers that were mapped. All the seven QTLs were associated with one or more of the markers carried by the above introgressed segments, thus validating the corresponding markers. More markers associated with many more QTLs to be identified should become available in the future by effective MAS for GPC improvement.

Analysis of Variance↗

PubMed2005

Thyroid hormone reference intervals in an ambulatory Arab population on the Abbott Architect i2000 immunoassay analyzer.

BACKGROUND: Considerable differences in reference intervals for FT4 and TSH have been reported between countries. Method related differences in the distribution of free thyroxine (FT4) have also been reported. The aim of this study was to establish reference intervals for thyrotrophin (TSH) and FT4 in an ambulatory adult (16-75 y) Arab population attending a general practice clinic using the Abbott Architect i2000 immunoassay analyzer. METHODS: TSH and FT4 results from 959 consecutive ambulatory Arab subjects were available. After excluding data sets from pregnant women, patients with known and newly diagnosed thyroid disease, individuals taking medication that may affect TSH and FT4 and individuals with acute illness, 742 data sets were available for analysis. A 2-way between-groups ANOVA was conducted to explore the impact of age and gender on TSH and FT4. RESULTS: TSH showed a non-Gaussian distribution, FT4 showed a near normal distribution. There was no significant main effect on FT4 and TSH for age and gender. The interaction effect of age and gender also did not reach significance. The 95% reference intervals were: TSH 0.30-4.32 mU/l and FT4 9.8-18.6 pmol/l. The reference intervals for TSH and FT4 determined in this study differed from those reported from other countries using the same analytical platform and from the 99% reference intervals, provided by the manufacturer. CONCLUSIONS: These differences in reference intervals in different populations may affect patient management. The data reported reemphasize that each laboratory should determine population and method-specific reference intervals.

Adolescent↗

PubMed2005

The relationship between number of striae of Retzius and their periodicity in imbricational enamel formation.

Imbricational crown formation times (ICFTs) estimated from the number of perikymata on tooth surfaces are error-prone because the number of days between adjacent perikymata varies across individuals and species, and is only visible within tooth microstructure. We investigated striae of Retzius (SR) numbers (analogous to perikymata numbers), SR periodicities (days between SR or perikymata), and ICFTs for a mandibular canine sample (n=49) from medieval Denmark. We tested the relationship between SR number and periodicity to determine whether regression formulae could be produced that would allow periodicity (and ICFTs) to be determined from surface perikymata numbers. Periodicities (range=7-11 days, mode=8) and SR numbers (range=142-257, mean=190.3, s.d.=27.5) were normally distributed; ICFTs were non-normal (mean=1,594 days, s.d.=65.7). We tested periodicity as a quadratic, linear, and log-log transform linear function of SR number and found an inverse relationship (quadratic: R2=0.9504; linear: R2=0.9138; log-log transform: R2=0.9418; all p<0.001) that allowed estimation of periodicity from SR or perikymata numbers in this population and tooth type. If periodicity and SR number are inversely related in other hominin taxa, studies that have estimated ICFT by multiplying perikymata number by a human modal periodicity value or made inferences about development based only on perikymata numbers may have introduced substantial error into their ICFT estimates and life history inferences. The inverse relationship is similar to that predicted by a model of SR formation in which the ICFT for a given tooth type and population is held constant and all combinations of periodicity and SR number result in the same ICFT. However, we found that lower periodicities had longer ICFTs and higher periodicities had shorter ICFTs than the model predicted, suggesting that the model may not reflect the real process, or that there are other factors (e.g., sample size, misclassification, sexual dimorphism) also affecting the relationship between periodicity and SR number.

Adolescent↗

PubMed2001

Estimation of width of narrow molecular-weight distributions by size-exclusion chromatography with concentration and light scattering detection.

A new method for the estimation of the weight-to-number-average molecular-weight ratio, Mw/Mn of polymers with a narrow molecular-weight distribution, approximated by log-normal distribution, is proposed using size-exclusion chromatography (SEC) with concentration and light-scattering detectors. From experimental data, the Mw/Mn ratios are calculated by two procedures: one using the concentration and light-scattering elution curve for the polymer measured, and the other based on the concentration elution curve and calibration line for a wide range of molecular masses. An iteration method has been developed making the two Mw/Mn ratios converge. The method was applied to a series of narrow molecular-weight distribution polystyrene standards.

Calibration↗

PubMed2003

The balance between pleiotropic mutation and selection, when alleles have discrete effects.

The theory of pleiotropic mutation and selection is investigated and developed for a large population of asexual organisms. Members of the population are subject to stabilising selection on Omega phenotypic characters, which each independently affect fitness. Pleiotropy is incorporated into the model by allowing each mutation to simultaneously affect all characters. To expose differences with continuous-allele models, the characters are taken to originate from discrete-effect alleles and thus have discrete genotypic effects. Each character can take the values nxDelta where n=0,+/-1,+/-2, em leader, and the splitting in character effects, Delta, is a parameter of the model. When the distribution of mutant effects is normally distributed around the parental value, and Delta is large, a "stepwise" model of mutation arises, where only adjacent trait effects are accessible from a single mutation. The present work is primarily concerned with the opposite limit, where Delta is small and many different trait effects are accessible from a single mutation. In contrast to what has been established for continuous-effect models, discrete-effect models do not yield a singular equilibrium distribution of genotypic effects for any value of Omega. Instead, for different values of Omega, the equilibrium frequencies of trait values have very different dependencies on Delta. For Omega=1 and 2, decreasing Delta broadens the width of the frequency distribution and hence increases the equilibrium level of polymorphism. For all sufficiently large values of Omega, however, decreasing Delta decreases the width of the frequency distribution and the equilibrium level of polymorphism. The connection with continuous trait models follows when the limit Delta-->0 is considered, and a singular probability density of trait values is obtained for all sufficiently large Omega.

Alleles↗

PubMed1997

Effect of different sampling techniques on odds ratio estimates using hospital-based cases and controls.

Potential biases introduced by the use of hospital admission records have rarely been discussed in the veterinary literature. Veterinary Medical Teaching Hospital (VMTH) patient records kept at the University of California, Davis (UCD) School of Veterinary Medicine provide a unique opportunity to perform in-depth analyses on the effect of different control selection (sampling) techniques on odds ratio (OR) estimates for disease risk factors in a retrospective case-control study. Horses with Corynebacterium pseudotuberculosis abscesses (134) and the (secondary) study base population (source for controls) were identified, and a 'gold standard' OR for each category of the factors admission type, age, breed and sex was derived. Example data were used to calculate sampling ratios (SRs), defined as the ratio between any sample proportion (of an arbitrary risk factor) and the study base proportion for this risk factor. Sampling ratios different from 1.0 introduced biases into the observed OR estimates, when compared with the 'gold standard' OR. Three randomized samples (simple random, stratified random, systematic sampling), one matched (on date of admission) and three different diagnosis samples ('colic', 'cuts and lacerations', 'fractures') were selected from the study base, and the SRs for all categories of the four factors were derived. The matched and two different disease samples ('colic' and 'fractures') had especially wide ranges of observed SRs (and large errors in the OR estimates), whereas simple random and systematic sampling had comparably narrow ranges (less biased OR estimates). For the three randomized sampling techniques under study, repeated sampling was used to derive SR distributions. The SRs were approximately normally distributed. Analysis of variance and covariance showed that simple random and systematic sampling provided SR distributions with means closest to 1.0 (expected value) and small standard deviations. The OR estimates obtained from records selected by these two sampling techniques therefore were least biased. The findings demonstrate the importance of selecting appropriate sampling techniques in addition to properly defining the study (base) population. Sampling design introduces uncertainty into the OR estimates. The direction of the bias, however, depends on the OR between factor and disease in the source population (the 'gold standard'), and on the direction and magnitude of the SR. When combining the results from single and repeated sampling we conclude that sampling design is most influential on the range of the observed SRs (single samples), on the absolute deviation of the SR from 1.0 (expressed as SR delta Mean) and on the SR standard deviation (SD) (repeated sampling).

Animals↗

PubMed1987

An explanatory hypothesis for early- and late-effect parameter values in the LQ model.

The isoeffect equation derived from the linear-quadratic (LQ) model of cell survival contains linear and quadratic terms in dose. Experimental studies have shown that higher-order terms may also be present. These terms have been previously attributed to the fact that the LQ model may be the first two terms in a power series approximation to a more complex model. This study shows that higher-order terms are introduced as a result of heterogeneity in the response of the cell population being irradiated. This heterogeneity is modeled by assuming that the parameters alpha and beta in the LQ model are distributed according to a bivariate normal distribution. Using this distribution, the expected value of cell survival contains third- and fourth-order terms in dose. These terms result in the previously observed downward curvature of Fe plots. Furthermore, these higher-order terms introduce bias in the estimated values of alpha and beta, if only the linear and quadratic terms of the LQ model are used, and higher-order terms are ignored. The bias is such that the estimated value of alpha/beta is substantially increased. Thus the higher values of alpha/beta observed for early effects as compared to late effects may be due to greater heterogeneity of response in early-responding tissues than in later-responding tissues. This differential effect is maintained even if the two cell populations have the same average values of alpha and beta.

Cell Cycle↗

PubMed1998

Spindle disturbances induced by benzo[a]pyrene and 7, 12-dimethylbenz[a]anthracene in a Chinese hamster cell line (V79-MZ) and the stability of the numerical chromosome aberrations that follow.

We previously reported that benzo[a]pyrene (BP) and 7, 12-dimethylbenz[a]anthracene (DMBA) induce aneuploidy and polyploidy, respectively, in the Chinese hamster cell line V79-MZ in the absence of S9 mix. In the present study we investigated the effect of BP and DMBA on the mitotic spindle. BP caused incomplete spindle formation and DMBA inhibited spindle formation completely. The combined results indicate that incomplete spindles caused by BP resulted in aneuploidy, and the absence of spindle formation caused by DMBA resulted in polyploidy. The induced polyploidy was stable for several serial passages in fresh medium. BP and DMBA induced different chromosome number distributions. After BP treatment, the normal distribution of chromosome number was restored in 4 days. After DMBA treatment, on the other hand, a tetraploid peak was maintained for 2 months following an initial transient broad distribution of chromosome number after 1 day. The results suggest that different mechanisms were involved in the induction of numerical aberrations by BP and DMBA. Furthermore the induction of numerical aberrations by BP and DMBA was reproducible over 5 months of passages. In four clones tested, the frequency of cells with the modal chromosome number in control cultures gradually decreased from 82% on the average just after cloning to 62% 5 months later. BP and DMBA induced characteristic ploidy changes following succeeding cell passages for up to 5 months, indicating that the ability to respond to BP and DMBA was stable for that period of time. Because these findings were specific to V79-MZ cells, this cell line might be a good tool for studying chemicals that induce numerical chromosome aberrations.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2005

AFM characterization of dendrimer-stabilized platinum nanoparticles.

This work describes the use of atomic force microscopy (AFM) to measure the size of dendrimer-stabilized Pt nanoparticles (Pt DNs) deposited from aqueous solutions onto mica surfaces. Despite considerable previous work in this area, we do not fully understand the mechanisms by which PAMAM dendrimers template the formation of Pt DNs. In particular, Pt DN sizes measured by high-resolution transmission electron microscopy (HRTEM) are reported to be larger than expected if one assumes that each PAMAM molecule templates one spherical Pt nanoparticle. AFM provides a vertical height measurement that complements the lateral dimension measurement from HRTEM. We show that AFM height measurements can distinguish between "empty" PAMAM and Pt DNs. If the complexation of Pt precursor with PAMAM is prematurely terminated, AFM images and feature height distributions show evidence of arrested precipitation of Pt colloids. In contrast, sufficient Pt-PAMAM complexation time leads to AFM images and height distributions that have relatively narrow, normal distributions with mean values that increase with the nominal Pt:PAMAM ratio. The surface density of features in AFM images suggest that these Pt DNs reside on the mica surface as two-dimensional surface aggregates. These observations are consistent with an intradendrimer templating mechanism for Pt DNs. However, we cannot determine if the mechanism obeys a fixed loading law because we do not have definitive information about Pt DN shape. A second peak in the Pt DN height distribution appears when the Pt loading exceeds about 66% of PAMAM's theoretical capacity for Pt. Excluding these secondary particles, the dependence of mean feature height on the Pt:PAMAM ratio follows a power-law relationship. Also considering the magnitudes of the measured mean height values, the data suggest that Pt DNs exist as ramified, noncompact aggregates of Pt atoms interspersed within the PAMAM framework.

Journal Article↗

PubMed1998

Evaluation of in vitro chemosensitivity of antitumor drugs using the MTT assay in fresh human breast cancer.

Practical criteria were developed in this paper for the purpose of evaluating chemosensitivity of fresh human breast cancer by the MTT assay. The survival rates at maximum inhibition (Imax %) and the concentrations of drugs which caused fifty percent reduction in absorbance compared to baseline values (IC50) of 175 samples of 10 anti-tumor drugs were evaluated by logistic analyses of the dose-response curves. Distributions of Imax% appeared as normal curves, while those of the IC50 significantly deviated from normal distribution (p < 0.0001). We assessed the in vitro chemosensitivity by comparing the Imax % of each drug on individual samples with the mean Imax % + SD which was obtained from the Imax% of 175 samples. If the individual Imax % > mean Imax % + SD. we thought the tumor sample was resistant to this drug. If the Imax % < or = mean Imax % + SD, we would compare its IC50 with Q50 which was used as a cutoff point for in vitro chemosensitivity of anti-tumor drugs. The in vitro chemosensitivity could be graded as sensitive (Q1-Q25), intermediate (Q26-Q75), and resistant (Q76-Q100) by means of percentile method. If the individual IC50 > or = Q76, the tumor sample would be defined as resistant. If the individual IC50 < or = Q25, it would be defined as sensitive. In the range of Q26-Q75, we used Q50 as a cutoff point between relative sensitivity and relative resistance. Preliminary results showed that the in vitro chemosensitivity to different anti-tumor drugs determined by these criteria were consistent with the clinical response in 83 advanced breast cancer patients.

Antineoplastic Agents↗

PubMed2003

A tobit variance-component method for linkage analysis of censored trait data.

Variance-component (VC) methods are flexible and powerful procedures for the mapping of genes that influence quantitative traits. However, traditional VC methods make the critical assumption that the quantitative-trait data within a family either follow or can be transformed to follow a multivariate normal distribution. Violation of the multivariate normality assumption can occur if trait data are censored at some threshold value. Trait censoring can arise in a variety of ways, including assay limitation or confounding due to medication. Valid linkage analyses of censored data require the development of a modified VC method that directly models the censoring event. Here, we present such a model, which we call the "tobit VC method." Using simulation studies, we compare and contrast the performance of the traditional and tobit VC methods for linkage analysis of censored trait data. For the simulation settings that we considered, our results suggest that (1) analyses of censored data by using the traditional VC method lead to severe bias in parameter estimates and a modest increase in false-positive linkage findings, (2) analyses with the tobit VC method lead to unbiased parameter estimates and type I error rates that reflect nominal levels, and (3) the tobit VC method has a modest increase in linkage power as compared with the traditional VC method. We also apply the tobit VC method to censored data from the Finland-United States Investigation of Non-Insulin-Dependent Diabetes Mellitus Genetics study and provide two examples in which the tobit VC method yields noticeably different results as compared with the traditional method.

Analysis of Variance↗

PubMed2002

Linear modes of gene expression determined by independent component analysis.

MOTIVATION: The expression of genes is controlled by specific combinations of cellular variables. We applied Independent Component Analysis (ICA) to gene expression data, deriving a linear model based on hidden variables, which we term 'expression modes'. The expression of each gene is a linear function of the expression modes, where, according to the ICA model, the linear influences of different modes show a minimal statistical dependence, and their distributions deviate sharply from the normal distribution. RESULTS: Studying cell cycle-related gene expression in yeast, we found that the dominant expression modes could be related to distinct biological functions, such as phases of the cell cycle or the mating response. Analysis of human lymphocytes revealed modes that were related to characteristic differences between cell types. With both data sets, the linear influences of the dominant modes showed distributions with large tails, indicating the existence of specifically up- and downregulated target genes. The expression modes and their influences can be used to visualize the samples and genes in low-dimensional spaces. A projection to expression modes helps to highlight particular biological functions, to reduce noise, and to compress the data in a biologically sensible way.

Algorithms↗

PubMed1999

Decreased apoptosis as a mechanism for hepatomegaly in streptozotocin-induced diabetic rats.

Insulin-dependent diabetes mellitus in both humans and animals leads to structural and functional changes including hepatomegaly. This study examined hypertrophy, hyperplasia, and apoptosis, three basic aspects of tissue growth, in livers of Sprague-Dawley and Wistar rats made diabetic by iv injection of streptozotocin 8, 30, or 90 days previously. Immunohistochemical measurement of proliferating cell nuclear antigen revealed that hepatic DNA labeling indices were similar in normal control animals and diabetic rats 30 or 90 days post diabetic induction, but were reduced to 45 to 50% of control in insulin-treated diabetic animals, perhaps due to altered receptor activity or to partial insulin resistance, as reported previously. Flow cytometry indicated a 613% increase in diploid hepatocytes in the livers of diabetic rats 30 days after the onset of diabetes, compared to control. Diabetic livers contained 29% fewer tetraploid cells, 81% fewer octaploid cells, and 20% more binucleated hepatocytes than normal controls. At 90 days, the overall smaller size of hepatocytes in diabetic tissue was evidenced by more cells per area. Insulin treatment prevented some of these changes, but did not restore ploidy to a normal distribution. Mitosis, while 300% of normal at 8 days after streptozotocin injection, was reduced to 25% of normal after 90 days of diabetes. The morphological evidence of apoptosis was decreased by 23% to 76% in the diabetic liver, and was reversed but not normalized by insulin treatment. This study indicates that the hepatomegaly observed in streptozotocin-induced experimental diabetes may be due primarily to early hyperplasia, and later decreased apoptosis.

Animals↗

PubMed2005

Expression of RCAS1 in female genital organs.

Receptor-binding antigen expressed on a human uterine adenocarcinoma cell line, SiSo (RCAS1), has been reported to be a prognostic factor of various malignant tumors, and it has also been proven to induce apoptosis of lymphoid cells. However, its normal distribution and function have not yet been elucidated. The purpose of this study was to disclose the distribution of RCAS1 expression in normal female genital organs. Immunohistochemical staining using anti-RCAS1 and anti-MIB-1 antibodies was performed on 123 surgical specimens of a histologically normal uterus, ovary, or fallopian tube from 66 patients, and the apoptotic index was determined. In uterine cervical glands, the expression of RCAS1 was seen in 93% of the cases, and it was mainly localized in the superficial cervical glands. Near the areas of squamous metaplasia, RCAS1 was strongly expressed in all samples. In the uterine cervical squamous epithelium, RCAS1 was seen in 84% of cases. In the uterine corpus, RCAS1 was seen in 87% of all cases, and it was mainly expressed in the endometrial glands of basalis layer. There was significant positive correlation between age and RCAS1 expression, but no significant difference was found regarding the endometrial status and RCAS1 expression in endometrium. No significant correlation was found between RCAS1 expression and MIB-1 index/apoptotic index. RCAS1 may affect these metaplastic processes and tumor progression.

Adult↗

PubMed2002

The timing of sequences of saccades in visual search.

According to the LATER model (linear approach to thresholds with ergodic rate), the latency of a single saccade in response to target appearance can be understood as a decision process, which is subject to (i) variations in the rate of (visual) information processing; and (ii) the threshold for the decision. We tested whether the LATER model can also be applied to the sequences of saccades in a multiple fixation search, during which latencies of second and subsequent saccades are typically shorter than that of the initial saccade. We found that the distributions of the reciprocal latencies for later saccades, unlike those of the first saccade, are highly asymmetrical, much like a gamma distribution. This suggests that the normal distribution of the rate r, which the LATER model assumes, is not appropriate to describe the rate distributions of subsequent saccades in a scanning sequence. By contrast, the gamma distribution is also appropriate to describe the distribution of reciprocal latencies for the first saccade. The change of the gamma distribution parameters as a function of the ordinal number of the saccade suggests a lowering of the threshold for second and later saccades, as well as a reduction in the number of target elements analysed.

Humans↗

PubMed2005

Intrinsically anomalous roughness of admissible crack traces in concrete.

We study the roughness of postmortem cracks in concrete plates of different size. We find that the set of admissible crack paths exhibits an intrinsically anomalous roughness; nevertheless, any individual crack trace in concrete is essentially self-affine. We also find that both the local and the global amplitudes of crack traces are distributed according to a log-logistic distribution characterized by the same scaling exponent, whereas the mean-square width distribution is best fitted by the Pearson distribution, while the log-normal distribution also provides quite good adjustments and cannot be clearly rejected.

Journal Article↗