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PubMed1997

QTc interval (cardiac repolarization): lengthening after meals.

Weight reduction, either by dietary or surgical means, is associated with prolongation of the heart rate corrected QT interval (QTc = QT/R-R0.5) and, on occasion, sudden death. Screening subjects with obesity before weight loss for prolonged QTc intervals is an accepted practice, although at present, there are no guidelines for whether subjects should be fasting before electrocardiogram (EKG) evaluation. The aim of this study was to test the hypothesis that EKG QTc interval duration is independent of meal ingestion. The hypothesis was tested in 11 healthy subjects who ingested a 500-kcal formula meal. A small decrease in absolute QT interval and a steady decline in R-R interval were observed for up to 60 minutes after formula ingestion. The QTc interval increased above baseline at 15 minutes (p < 0.007) after meal, a change that persisted for the 1-hour postmeal observation period. Spectral analysis of EKG R-R intervals (low-/high-frequency amplitude ratio) indicated a change in cardiac autonomic flow after meal ingestion. The QTc interval did not lengthen and R-R low-/high-frequency amplitude ratio remained unchanged in eight subjects evaluated in a similar manner but in whom isovolumic amounts of water replaced the meal. These observations suggest that (1) cardiac repolarization changes with fasting and feeding, (2) the QTc interval is influenced by meal intake, and (3) the autonomic nervous system may play a role in meal-related QTc changes. These findings have implications for the evaluation of patients with obesity before starting and during weight loss treatment.

Adult↗
PubMed2003

Immunocytochemical analysis of dentin: a double-labeling technique.

Immunocytochemical analysis is a fundamental and selective technique for identifying different molecular components of human dental structure. The hypothesis tested here is that the application of different etching solutions on dentin does not hinder collagen fibrils and proteoglycans from maintaining their immunochemical antigenicity. Human dentin disks were treated with 0.5M of EDTA, citric acid, maleic acid, or phosphoric acid (for 15 or 30 s). A double-immunolabeling technique was performed to identify, simultaneously, collagen fibrils and chondroitin sulfate. The use of different acids resulted in different degrees of labeling. Maleic and citric acids revealed a diffuse and intense labeling for both collagen fibrils and proteoglycans. The use of phosphoric acid on dentin showed a massive coagulation of the proteoglycans (15 s) or very low labeling (30 s). These data clarify that the use of acids on dentin components is able to modify their antigenicity. Moreover, the double-labeling immunocytochemical technique allows understanding of the spatial relationships between the collagen fibrils and proteoglycans of the dentin matrix.

Animals↗
PubMed2003

Immunocytochemical identification of type I collagen in acid-etched dentin.

The hypothesis tested in this study is that the application of phosphoric acid prevents collagen fibrils (CF) from maintaining their structural morphology, as assessed by their immunochemical antigenicity. Dentin was conditioned with EDTA and with 35% H3PO4 for 15, 30, and 60 s. For a control there was no treatment. A pre-embedding immunohistochemical procedure was evaluated under high-resolution SEM and a postembedding immunolocalization technique was performed on ultrathin sections at TEM level. Conditioning with EDTA resulted in a weaker labeling signal than for dentin conditioned with H3PO4. The most intense labeling was observed after dentin had been etched with H3PO4 for 15 s. The least intensive labeling was evident when the acid was applied for 30 s or for 60 s. A very weak signal was detected on the untreated dentin surface. These results provide evidence that a 15-s application of 35% H3PO4 causes mineral dissolution of the crystals enveloping the superficial CF without damaging the ultrastructure of the CF while longer applications of 35% H3PO4 cause alterations in the CF that decrease their antigenicity.

Acids↗
PubMed1991

Effects of propranolol on bone metabolism in the rat.

Propranolol, a nonspecific beta-blocker has many physiologic effects. Its effects on bone in vivo are unknown, although beta receptor sites have been found on osteoblasts. In this study, the hypothesis tested was that low doses of propranolol could alter bone properties and enhance orthotopic endochondral bone formation. In a group of nonsurgical rats, propranolol treatment increased femoral torsional strength on biomechanical testing. In the rat surgical model used, right femora were fixed to a polyethylene plate and then defects were created mid-diaphysis and subsequently filled with demineralized bone matrix. These rats (defect rats) were randomly divided into groups that were given propranolol or a saline carrier for 19 consecutive days. In the defect rats, increased trabecular femoral metaphyseal mineral apposition rates were observed in propranolol-treated groups. Densitometry and roentgenographic scoring of callus formation after 12 weeks in propranolol-treated rats revealed increased callus and bone union. The results of this study indicate that propranolol treatment can significantly affect bone properties.

Animals↗
PubMed2004

Quantitative analysis of diffusion tensor orientation: theoretical framework.

Diffusion-tensor MRI (DT-MRI) yields information about the magnitude, anisotropy, and orientation of water diffusion of brain tissues. Although white matter tractography and eigenvector color maps provide visually appealing displays of white matter tract organization, they do not easily lend themselves to quantitative and statistical analysis. In this study, a set of visual and quantitative tools for the investigation of tensor orientations in the human brain was developed. Visual tools included rose diagrams, which are spherical coordinate histograms of the major eigenvector directions, and 3D scatterplots of the major eigenvector angles. A scatter matrix of major eigenvector directions was used to describe the distribution of major eigenvectors in a defined anatomic region. A measure of eigenvector dispersion was developed to describe the degree of eigenvector coherence in the selected region. These tools were used to evaluate directional organization and the interhemispheric symmetry of DT-MRI data in five healthy human brains and two patients with infiltrative diseases of the white matter tracts. In normal anatomical white matter tracts, a high degree of directional coherence and interhemispheric symmetry was observed. The infiltrative diseases appeared to alter the eigenvector properties of affected white matter tracts, showing decreased eigenvector coherence and interhemispheric symmetry. This novel approach distills the rich, 3D information available from the diffusion tensor into a form that lends itself to quantitative analysis and statistical hypothesis testing.

Adolescent↗
PubMed2005

Ex vivo 3D diffusion tensor imaging and quantification of cardiac laminar structure.

A three-dimensional (3D) diffusion-weighted imaging (DWI) method for measuring cardiac fiber structure at high spatial resolution is presented. The method was applied to the ex vivo reconstruction of the fiber architecture of seven canine hearts. A novel hypothesis-testing method was developed and used to show that distinct populations of secondary and tertiary eigenvalues may be distinguished at reasonable confidence levels (P < or = 0.01) within the canine ventricle. Fiber inclination and sheet angles are reported as a function of transmural depth through the anterior, lateral, and posterior left ventricle (LV) free wall. Within anisotropic regions, two consistent and dominant orientations were identified, supporting published results from histological studies and providing strong evidence that the tertiary eigenvector of the diffusion tensor (DT) defines the sheet normal.

Algorithms↗
PubMedDate not supplied

Non-invasive MRS in new anticancer drug development.

In the rational development of anticancer drugs it is important to employ all the available pharmacological information. Early clinical trials provide an opportunity for hypothesis testing. MRS techniques have the potential to provide valuable data on the preclinical and clinical pharmacokinetics and pharmacodynamics of drugs non-invasively. Here we illustrate advantages and pitfalls of MRS using studies of two fluorine-containing cancer drugs: a beta,beta-difluoro analogue of the alkylating agent chlorambucil and a fluorinated derivative of the nitroimidazole misonidazole, Ro 07-0741. Limitations include signal quenching via protein binding and inadequate sensitivity for more potent drugs like beta,beta-difluorochlorambucil; but fluoromisonidazole was shown to accumulate in tumours and shows promise as a chemical probe for tumour hypoxia, detectable by 19F MRS.

Animals↗
PubMed1980

Employment activity of baccalaureate and diploma nurses.

In this study, the general hypothesis tested was that differences in rate of employment activity between baccalaureate and diploma nurses are due to effects of extraneous and intervening variables and not to intrinsic differences in the educational process. Mailed questionnaires from 1,475 nurses registered in the State of Indiana provided data on two measures of employment activity, as well as four control variables: marital status, spouse's income, presence of young children at home, and disillusionment with career. Among recent graduates, there was a negative association between possession of the baccalaureate degree and current employment status (gamma = -.359, p < .05). It was expected that holding constant the four control variables would reduce this association to or near zero. The opposite was generally the case, however; controlling for marriage, children, and disillusionment actually increased the association between type of education and employment status. Differences in employment activity between the two types of graduates therefore can not be accounted for by "traditional" variables used in the study of female labor-force participation.

Education, Nursing, Baccalaureate↗
PubMed2004

The molecular origin of the thiamine diphosphate-induced spectral bands of ThDP-dependent enzymes.

New and previously published data on a variety of ThDP-dependent enzymes such as baker's yeast transketolase, yeast pyruvate decarboxylase and pyruvate dehydrogenase from pigeon breast muscle, bovine heart, bovine kidney, Neisseria meningitidis and E. coli show their spectral sensitivity to ThDP binding. Although ThDP-induced spectral changes are different for different enzymes, their universal origin is suggested as being caused by the intrinsic absorption of the pyrimidine ring of ThDP, bound in different tautomeric forms with different enzymes. Non-enzymatic models with pyrimidine-like compounds indicate that the specific protein environment of the aminopyrimidine ring of ThDP determines its tautomeric form and therefore the changeable features of the inducible effect. A polar environment causes the prevalence of the aminopyrimidine tautomeric form (short wavelength region is affected). For stabilization of the iminopyrimidine tautomeric form (both short- and long-wavelength regions are affected) two factors appear essential: (i) a nonpolar environment and (ii) a conservative carboxyl group of a specific glutamate residue interacting with the N1' atom of the aminopyrimidine ring. The two types of optical effect depend in a different way upon the pH, in full accordance with the hypothesis tested. From these studies it is concluded that the inducible optical rotation results from interaction of the aminopyrimidine ring with its asymmetric environment and is defined by the protonation state of N1' and the 4'-nitrogen.

Animals↗
PubMed2005

Comparing protein-ligand docking programs is difficult.

There is currently great interest in comparing protein-ligand docking programs. A review of recent comparisons shows that it is difficult to draw conclusions of general applicability. Statistical hypothesis testing is required to ensure that differences in pose-prediction success rates and enrichment rates are significant. Numerical measures such as root-mean-square deviation need careful interpretation and may profitably be supplemented by interaction-based measures and visual inspection of dockings. Test sets must be of appropriate diversity and of good experimental reliability. The effects of crystal-packing interactions may be important. The method used for generating starting ligand geometries and positions may have an appreciable effect on docking results. For fair comparison, programs must be given search problems of equal complexity (e.g. binding-site regions of the same size) and approximately equal time in which to solve them. Comparisons based on rescoring require local optimization of the ligand in the space of the new objective function. Re-implementations of published scoring functions may give significantly different results from the originals. Ostensibly minor details in methodology may have a profound influence on headline success rates.

Algorithms↗
PubMed2003

Dynamic calibration and dissolved gas analysis using membrane inlet mass spectrometry for the quantification of cell respiration.

A membrane inlet mass spectrometer connected to a miniaturized reactor was applied for dynamic dissolved gas analysis. Cell samples were taken from 7 mL shake flask cultures of Corynebacterium glutamicum ATCC 13032, and transferred to the 12 mL miniaturized reactor. There, oxygen uptake and carbon dioxide and its mass isotopomer production rates were determined using a new experimental procedure and applying nonlinear model equations. A novel dynamic method for the calibration of the membrane inlet mass spectrometer using first-order dynamics was developed. To derive total dissolved concentration of all carbon dioxide species (C(T)) from dissolved carbon dioxide concentration ([CO(2)](aq)), the ratio of C(T) to [CO(2)](aq) was determined by nonlinear parameter estimation, whereas the mass transfer coefficient of CO(2) was determined by the Wilke-Chang correlation. Subsequently, the suitability of the model equations for respiration measurements was examined using residual analysis and the Jarque-Bera hypothesis test. The resulting residuals were found to be random with normal distribution, which proved the adequacy of the application of the model for cell respiration analysis. Hence, dynamic changes in respiration activities could be accurately analyzed using membrane inlet mass spectrometry with the novel calibration method.

Algorithms↗
PubMed2006

Collision-induced dissociation of protonated tetrapeptides containing beta-alanine, gamma-aminobutyric acid, epsilon-aminocaproic acid or 4-aminomethylbenzoic acid residues.

The influence of the presence and position of a single beta-alanine, gamma-aminobutyric acid, epsilon-aminocaproic acid or 4-aminomethylbenzoic acid residue on the tendency to form b(n)+ -and y(n)+ -type product ions was determined using a group of protonated tetrapeptides with general sequence XAAG, AXAG and AAXG (where X refers to the position of amino acid substitution). The hypothesis tested was that the 'alternative' amino acids would influence product ion signal intensities by inhibiting or suppressing either the nucleophilic attack or key proton transfer steps by forcing the adoption of large cyclic intermediates or blocking cyclization altogether. We found that specific b ions are diminished or eliminated completely when betaA, gammaAbu, Cap or 4AMBz residues are positioned such that they should interfere with the intramolecular nucleophilic attack step. In addition, differences in the relative proton affinities of the alternative amino acids influence the competition between complementary b(n) and y(n) ions. For both the AXAG and the XAAG series of peptides, collision-induced dissociation (CID) generated prominent b ions despite potential inhibition or suppression of intramolecular proton migration by the betaA, gammaAbu, Cap or 4AMBz residues. The prominent appearance of b ions from the AXAG and XAAG peptide is noteworthy, and suggests either that proton migration occurs through larger, 'whole' peptide cyclic intermediates or that fragmentation proceeds through a population of [M+H]+ isomers that are initially protonated at amide O atoms.

4-Aminobenzoic Acid↗
PubMed2002

Standardization using the harmonically weighted ratios: internal and external comparisons.

Standardization of rates is a basic tool for epidemiologists. The most frequently used methods are the 'direct standardization' (with summary index of comparative mortality figure, CMF) and the 'indirect standardization' (with summary index of standardized mortality ratio, SMR). The CMF facilitates a valid comparison between populations or across time periods, yet, it suffers from the problem of instability. By contrast, the SMR is stable and can be used for external comparison. However, it cannot guarantee a valid internal comparison. In this paper, the author proposes a new standardized measure, the 'harmonically weighted ratio' (HWR). The HWR can be used for external as well as internal comparisons--with the assumption of rate-ratio homogeneity, or with heterogeneity but dominance of one population over another. Simulation shows that its performance in terms of pairwise comparisons is the best among the three methods or compares favourably to that of the SMR. The author also examines the behaviours of the HWR when used for hypothesis testing (the 'HWR test'). The HWR can be considered for standardization when the purpose of the standardization is solely for comparison and when the universe of the comparisons can be clearly defined.

Adolescent↗
PubMed2002

Early selection in a randomized phase II clinical trial.

A randomized phase II clinical trial design can be employed when one wishes to be able to select one of several similar therapies or variants of a therapy for inclusion in a subsequent, definitive, phase III trial. It is not necessary in this type of trial to formally identify a superior arm using the usual parameters and stringent criteria employed for hypothesis testing. Simon, Wittes and Ellenberg have described methods and sample sizes for selecting the superior arm from among k possible arms. In this paper, we describe an approach based on statistical selection theory which allows one to potentially make a decision to end accrual to a randomized phase II trial at an interim point of the trial, and to select one of two arms as being worthy of further evaluation in a subsequent study. This method requires that an adequate gap in the number of responses between the two arms be observed at the interim point in order to limit the probability that the selected arm is actually inferior by more than an indifference amount. Published in 2002 by John Wiley & Sons, Ltd.

Clinical Trials, Phase II as Topic↗
PubMed2002

Flexible parametric proportional-hazards and proportional-odds models for censored survival data, with application to prognostic modelling and estimation of treatment effects.

Modelling of censored survival data is almost always done by Cox proportional-hazards regression. However, use of parametric models for such data may have some advantages. For example, non-proportional hazards, a potential difficulty with Cox models, may sometimes be handled in a simple way, and visualization of the hazard function is much easier. Extensions of the Weibull and log-logistic models are proposed in which natural cubic splines are used to smooth the baseline log cumulative hazard and log cumulative odds of failure functions. Further extensions to allow non-proportional effects of some or all of the covariates are introduced. A hypothesis test of the appropriateness of the scale chosen for covariate effects (such as of treatment) is proposed. The new models are applied to two data sets in cancer. The results throw interesting light on the behaviour of both the hazard function and the hazard ratio over time. The tools described here may be a step towards providing greater insight into the natural history of the disease and into possible underlying causes of clinical events. We illustrate these aspects by using the two examples in cancer.

Antineoplastic Agents↗
PubMed2005

The use of bootstrap methods for estimating sample size and analysing health-related quality of life outcomes.

Health-related quality of life (HRQoL) measures are increasingly used in trials as primary outcome measures. Investigators are now asking statisticians for advice on how to plan and analyse studies using such outcomes. HRQoL outcomes, like the SF-36, are usual measured on an ordinal scale, although most investigators assume that there exists an underlying continuous latent variable and that the actual measured outcomes (the ordered categories) reflect contiguous intervals along this continuum. The ordinal scaling of HRQoL measures means they tend to generate data that have discrete, bounded and skewed distributions. Thus, standard methods of analysis that assume Normality and constant variance may not be appropriate. For this reason, conventional statistical advice would suggest non-parametric methods be used to analyse HRQoL data. The bootstrap is one such computer intensive non-parametric method for estimating sample sizes and analysing data. We describe three methods of estimating sample sizes for two-group cross-sectional comparisons of HRQoL outcomes. We then compared the power of the three methods for a two-group cross-sectional study design using bootstrap simulation. The results showed that under the location shift alternative hypothesis, conventional methods of sample size estimation performed well, particularly Whitehead's method. Whitehead's method is recommended if the HRQoL outcome has a limited number of discrete values (<7) and/or the expected proportion of cases at either of the bounds is high. If a pilot data set is readily available then bootstrap simulation will provide a more accurate and reliable estimate, than conventional methods.Finally, we used the bootstrap for hypothesis testing and the estimation of standard errors and confidence intervals for parameters, in an example data set. We then compared and contrasted the bootstrap with standard methods of analysing HRQoL outcomes. In the data set studied, with the SF-36 outcome, the use of the bootstrap for estimating sample sizes and analysing HRQoL data produces results similar to conventional statistical methods. These results suggest that bootstrap methods are not more appropriate for analysing HRQoL outcome data than standard methods.

Adolescent↗
PubMed2005

Inferences on the common coefficient of variation.

The coefficient of variation is often used as a measure of precision and reproducibility of data in medical and biological science. This paper considers the problem of making inference about the common population coefficient of variation when it is a priori suspected that several independent samples are from populations with a common coefficient of variation. The procedures for confidence interval estimation and hypothesis testing are developed based on the concepts of generalized variables. The coverage properties of the proposed confidence intervals and type-I errors of the proposed tests are evaluated by simulation. The proposed methods are illustrated by a real life example.

Blood↗
PubMed2005

Inferences on the mean of zero-inflated lognormal data: the generalized variable approach.

This paper considers the problems of confidence interval estimation and hypothesis testing for the mean of zero-inflated lognormal data. We present an unified novel approach based on the concepts of generalized test variables and generalized pivotal quantities. Simulation results demonstrate that the coverage accuracy of proposed confidence intervals and the type I error control of the proposed exact tests are satisfactory.

Air Pollutants, Occupational↗