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Lack of genotoxicity of formocresol, paramonochlorophenol, and calcium hydroxide on mammalian cells by comet assay.

Formocresol, paramonochlorophenol, and calcium hydroxide are widely used in dentistry because of their antibacterial activities in root canal disinfection. However, the results of genotoxicity studies using these materials are inconsistent in literature. The goal of this study was to examine the genotoxic potential of formocresol, paramonochlorophenol, and calcium hydroxide using mouse lymphoma cells and human fibroblasts cells in vitro by the comet assay. Data were assessed by Kruskal-Wallis nonparametric test. The results showed that all compounds tested did not cause DNA damage for the tail moment or tail intensity parameters. These findings suggest that formocresol, paramonochlorophenol, and calcium hydroxide do not promote DNA damage in mammalian cells and that the comet assay is a suitable tool to investigate genotoxicity.

Analysis of Variance↗

A simple nonparametric test for linkage with sib-pair censored event time observations.

Consider the case that individual phenotype and genotype observations were collected from a large or moderate number of pedigrees. Some of the pedigrees have multi-generation nuclear families. For each nuclear family, the phenotype trait value of each sibling is the time to onset for a specific event (e.g., disease). Often, this event time may be right censored, that is, an individual is event-free at the study examination time point. In this article, we propose a purely nonparametric test for testing if the distribution of a Haseman-Elston distance measure between two siblings' event times is independent of their mean genetic sharing identical by descent at a genetic marker based on such incomplete observations from all the nuclear families. The new test can be implemented easily and is illustrated with a data set from the Genetic Analysis Workshop 12. The validity of the new test is examined via a simulation study.

Genetic Linkage↗

Pharmacokinetic-pharmacodynamic model for educational simulations.

Pharmacokinetic-pharmacodynamic (PK-PD) models play an important role in educational simulations. The parameters of PK-PD models described in the scientific literature are obtained from studies in which the drug concentrations and the drug-effect data are measured simultaneously. Simultaneous PK-PD studies cannot be expected to incorporate all possible combinations of drugs and patient physiology that are desired for educational simulations. To solve this problem, we elaborate on the traditional simultaneous PK-PD model, creating a new model that accepts parameter data from different, more readily available, nonsimultaneous pharmacologic studies. These data are incorporated in the model using a novel estimation procedure for the parameters kc0 and EC50. A sensitivity analysis of the parameter estimation procedure confirms that the time of peak effect following a bolus and the dose-response curve are accurately reflected by the new model. It also demonstrates how inconsistencies among the different parameter sets affect simulation of the recovery phase. The model is extended to incorporate any monotonic parametric or nonparametric dose-response curve. For the neuromuscular relaxant vecuronium, we demonstrate that data from different pharmacologic studies are available, and that the described estimation procedure leads to parameter estimates that are within the standard deviations of the parameters determined in a simultaneous PK-PD study.

Computer Simulation↗

Nonparametric estimation for the three-stage irreversible illness-death model.

In this paper, we present new nonparametric estimators of the stage-occupation probabilities in the three-stage irreversible illness-death model. These estimators use a fractional risk set and a reweighting approach and are valid under stage-dependent censoring. Using a simulated data set, we compare the behavior of our estimators with previously proposed estimators. We also apply our estimators to data on time to Pneumocystis pneumonia and death obtained from an AIDS cohort study.

AIDS-Related Opportunistic Infections↗

Micronucleus investigation of alcoholic patients with oral carcinomas.

The micronucleus test (MN) is used as an indicator of genotoxic exposition, since it is associated with chromosome aberrations. An increased mutation rate in oral squamous cells, indicated by an increased MN frequency, is also related to the development of oral carcinomas. We evaluated the frequencies of MN and other metanucleated anomalies in the buccal squamous cells of 30 alcoholics with oral or oropharyngeal carcinomas, and compared them to a control group of abstinent health individuals. Microscopic examination was made of 2000 cells per individual from each of three distinct areas of the mouth: around the lesion (A), opposite to the lesion (B) and in the upper gingival-labial gutter (C); C was used as a control region because of low tumor frequency. There was a seven-fold increase in MN frequency in region B, a three-fold increase in region A and a two-fold, though nonsignificant, increase in C; indicating a gradient of frequencies towards carcinogenesis: C --> A --> B. Comparisons of frequencies of various types of metanucleated cells: binucleated, karyorrhexis (KR), karyolysis (KL) and broken egg (BE) in patients and controls showed, with few exceptions, highly significant differences. This gave us a better understanding of the dynamics of this squamous epithelium, supporting a more efficient biomonitor based on these various metanucleated anomalies: the repair index RI=(KL+KR)/(MN+BE). Also, the apparently contradictory results from regression analysis revealed that the MN frequency decreased with age and alcohol consumption, probably because of slow cell proliferation, and consequently led to a loss of homeostasis due to aging. In addition, in the analysis of nonparametric variables only one CAGE question was significant, confirming the effect of alcohol. In conclusion, the MN test and the repair index could be used for monitoring clinical evolution, by means of intra- and inter-individual cellular comparisons, in subjects with healed or surgically removed tumors or leukoplastic lesions, after chemo- or radiotherapeutic treatments.

Adult↗

Nonparametric linkage analysis between schizophrenia and candidate genes of dopaminergic and serotonergic systems.

BACKGROUND: Alterations in dopaminergic and serotonergic systems have been implicated in the pathophysiology of schizophrenia for many years. This study was performed to assess the possible involvement of the dopamine receptor genes D2 (DRD2), D3, D4, serotonin receptor genes 1Da, 1Db, and 2A in the etiology of schizophrenia. METHODS: We examined 33 multiplex schizophrenic families from Portugal. RESULTS: Linkage analysis performed by GENEHUNTER showed nonsignificant linkage for these genes. A maximum nonparametric linkage score of 1.635 (P=.032) at DRD2 gene was observed, and this finding suggests DRD2 gene for further studies. CONCLUSION: the polymorphisms studied at dopamine receptor genes D3, D4, serotonin receptor genes 1Da, 1Db, and 2A do not have a major effect in susceptibility to schizophrenia in a Portuguese population.

Chromosomes, Human, Pair 13↗

A second-generation genome screen for linkage to type 1 diabetes in a Bedouin Arab family.

IDDM17 on chromosome 10 was identified in an initial genome screen of 13 members (10 affected) of a large Bedouin Arab family that had 19 relatives affected with type 1 diabetes. Two more children have now been diagnosed with the disease. A second genome screen with 45 members (17 affected members, spouses, and offspring; 382 markers) was performed. A parallel version of Genehunter was used for parametric and nonparametric linkage analyses. The nonparametric linkage analysis (NPL) confirmed the IDDM17 locus (NPL = 3.79; P = 0.001) with a prominent LOD (logarithm of the odds = 2.38) peak. These results demonstrate the strong potential of genetically homogenous, extended families for mapping genes that contribute to a complex disease.

Arabs↗

Probabilities of identity-by-descent patterns in sibships when the parents are not genotyped.

An assumption-free algorithm has been applied to compute the probabilities of all possible identity-by-descent (IBD) configurations when the parents have not been genotyped. These probabilities can be used to determine the amount of information that a particular sibship will bring to a nonparametric linkage analysis. It is shown that the number of possible configurations can be extremely large even when the markers are closely spaced and are rather polymorphic. Further, it is not always possible to reduce this number to a manageable one simply by consideration of the relative probabilities of the configurations.

Algorithms↗

A nonparametric estimator of survival functions for arbitrarily truncated and censored data.

It is well-known that the nonparametric maximum likelihood estimator (NPMLE) may severely under-estimate the survival function with left truncated data. Based on the Nelson estimator (for right censored data) and self-consistency we suggest a nonparametric estimator of the survival function, the iterative Nelson estimator (INE), for arbitrarily truncated and censored data, where only few nonparametric estimators are available. By simulation we show that the INE does well in overcoming the under-estimation of the survival function from the NPMLE for left-truncated and interval-censored data. An interesting application of the INE is as a diagnostic tool for other estimators, such as the monotone MLE or parametric MLEs. The methodology is illustrated by application to two real world problems: the Channing House and the Massachusetts Health Care Panel Study data sets.

Epidemiologic Methods↗

Study of myographic signals from sternomastoid muscle in patients with chronic obstructive pulmonary disease.

Analysis of the respiratory muscle activity is a promising technique for diagnosis of respiratory diseases, such as chronic obstructive pulmonary disease (COPD). The sternomastoid muscle (SMM) was selected to study the activity of respiratory muscles due to its accessibility in order to define a noninvasive analysis. The aims of this work are two: analyze the relationship between the SMM function and pulmonary obstruction, and study the influence of spectral estimator on frequency parameters related with the muscle activity. For the first goal, we propose the analysis of vibromyographic and electromyographic signals from the SMM to study the muscle function during two ventilatory tests. Activity of SMM was found by means of several indexes: root-mean-square (rms) values, mean and median frequencies, and ratio between high and low-frequency components. For the second goal, spectral analysis was performed by means of nonparametric methods: Correlogram and Welch periodogram, and parametric methods: autoregressive (AR), moving average (MA), and ARMA models. It is deduced that these indexes show muscle activity and certain fatigue of the SMM, whose muscle function depends on the level of pulmonary obstruction, and they depend a lot of spectral estimator being the more suitable an AR model with high order.

Aged↗

A genome-wide linkage and association study using COGA data.

BACKGROUND: Genome-wide association will soon be available to use as an adjunct to traditional linkage analysis. We studied alcoholism in 119 families collected by the Collaborative Study on the Genetics of Alcoholism and made available in Genetic Analysis Workshop 14, using genome-wide linkage and association analyses. METHODS: Genome-wide linkage analysis was first performed using microsatellite markers and a region with the strongest linkage evidence was further analyzed using single-nucleotide polymorphisms (SNPs). Family based genome-wide association test was also conducted using the SNPs. RESULTS: Nonparametric linkage analysis revealed weak linkage evidence on chromosome 7, and association analysis identified SNP tsc0515272 on chromosome 3 as significantly associated with alcoholism. CONCLUSION: Linkage analysis may require large sample sizes and high quality genotyping and marker maps to adequately improve power, while association analysis could hold more promise in efforts to identify variants responsible for complex traits.

Alcoholism↗

Genomic-assisted prediction of genetic value with semiparametric procedures.

Semiparametric procedures for prediction of total genetic value for quantitative traits, which make use of phenotypic and genomic data simultaneously, are presented. The methods focus on the treatment of massive information provided by, e.g., single-nucleotide polymorphisms. It is argued that standard parametric methods for quantitative genetic analysis cannot handle the multiplicity of potential interactions arising in models with, e.g., hundreds of thousands of markers, and that most of the assumptions required for an orthogonal decomposition of variance are violated in artificial and natural populations. This makes nonparametric procedures attractive. Kernel regression and reproducing kernel Hilbert spaces regression procedures are embedded into standard mixed-effects linear models, retaining additive genetic effects under multivariate normality for operational reasons. Inferential procedures are presented, and some extensions are suggested. An example is presented, illustrating the potential of the methodology. Implementations can be carried out after modification of standard software developed by animal breeders for likelihood-based or Bayesian analysis.

Algorithms↗

The effect of acid primer or conventional acid etching on microleakage in a photoactivated sealant.

PURPOSE: The purpose of this study was to examine differences in microleakage in extracted human teeth when placing sealants using conventional acid etching or an acidic primer resin. METHODS: Three experimental groupings were used: group 1--conventional acid etching with placement of light-cured sealant; group 2--application of acidic primer resin (Prompt-L-Pop) and light curing, followed by sealant placement; group 3--similar to group 2, but acidic primer and sealant were photocured after placement of sealant. Teeth were thermocycled, stained, sectioned and examined for marginal microleakage. RESULTS: In group 1, 94% of the enamel-sealant interfaces were free of microleakage. For groups 2 and 3, only 28% showed no leakage, with most leakage occurring at both margin and base areas. Nonparametric data analysis indicated acid etching demonstrated significantly lower microleakage than either treatment using the acidic primer resin (P<.001) and that leakage scores in the acidic primer groups were identical (P=.4011). CONCLUSIONS: Use of this specific acidic resin primer in lieu of conventional acid etching (whether cured prior to or subsequent to sealant placement) demonstrated greater incidence of microleakage and would not be advocated over traditional etching procedures.

Acid Etching, Dental↗

Effect of sucralose--alone or bulked with maltodextrin and/or dextrose--on plaque pH in humans.

Sucralose is a safe, intensely sweet, noncaloric sucrose derivative that has been shown to be noncariogenic. The purpose of the present study was to compare the effects on plaque pH in vivo of sucralose in iced tea (alone or bulked with maltodextrin or with maltodextrin/dextrose) with sucrose in iced tea. Fourteen subjects, with DMFT > 7 and an acidogenic plaque, participated in the study. Plaque pH response to one of five solutions: unsweetened tea, tea with sucralose (final concentration 0.007% by weight), tea with sucralose/maltodextrin (final concentrations 0.007% and 0.59% by weight, respectively), tea with sucralose/maltodextrin/dextrose (final concentrations 0.007, 0.018 and 0.57% by weight, respectively) and tea with sucrose (final concentration 4.7% by weight); was assessed in five experimental sessions. All solutions, except the unsweetened tea, had a sweetness equivalent to 2 teaspoons of sucrose in 6 OZ of beverage. Using a touch electrode, plaque pH was measured at baseline and at specific time intervals up to 60 min after rinsing with the test solution for 1 min. Comparisons between groups were done for minimum pH, delta pH, and area under the pH curve (AUC), by using the nonparametric Friedman's test and the Wilcoxon signed rank test. Rinsing with tea and sucrose resulted in significantly lower minimum pH, higher delta pH and larger AUC than rinsing with the solutions containing sucralose. It can be concluded that sucralose alone or in combination with maltodextrin or with maltodextrin/dextrose is significantly less acidogenic than sucrose when used as a sweetener in iced tea.

Adult↗

The impact of redefining affection status for alcoholism on affected-sib-pair analysis.

The analysis of a complex disease such as alcohol dependence requires a more precise definition of affection status. Collaborative Study on the Genetics of Alcoholism (COGA) provided a variety of qualitative and quantitative measures as well as genotype information, in addition to two criteria of affection status. To identify two groups of phenotypically "more homogeneous" individuals among alcoholics (COGA criterion), we redefined affection status by using cluster analysis and classification and regression tree, incorporating some important covariates such as event related potentials, monoamine oxidase B activity, status of smoking, age of onset, three variables of personality assessed with the Tridimensional Personality Questionnaire and three latent class variables. With redefined affection status, we repeated nonparametric analysis by three sib pair analysis programs (SIBPAL, SIBPAIR, and BETA) using nine candidate DNA markers identified by Reich et al. [1998] and Long et al. [1998]. The goals of our analysis are 1) to confirm previous results for these nine markers with redefined affection status and 2) to compare the performance from these three programs.

Adolescent↗

Deconvolution of infrequently sampled data for the estimation of growth hormone secretion.

In this paper, the deconvolution of infrequently and nonuniformly sampled data is addressed. A nonparametric technique is worked out that provides a smooth estimate of the unknown input signal and takes into account nonnegativity constraints. In spite of the size of the problem, efficient algorithms for solving the constrained optimization problem and computing confidence intervals are proposed. The new technique is used to estimate growth hormone (GH) secretion after repeated GH-releasing hormone (GHRH) administration from samples of blood concentration.

Adult↗

[The effect of adenosine receptor agonists on the normal cerebral blood flow and in subsequent ischemia].

Nonconformity of arterial pressure (AP) and cerebral blood flow (CBF) to the normal distribution necessitates the use of nonparametric criteria. Cerebroprotective doses of adenosine and cyclohexyladenosine significantly decrease AP and reduce (or virtually do not change) CBF. In conditions of following occlusion of carotid arteries AP is lower and CBF is somewhat better or the same as in the control (ischemia). Changes in CBF can be only an additional contribution to the high cerebroprotective effect of the A-receptor agonists.

Adenosine↗

Nonparametric methods for analyzing replication origins in genomewide data.

Due to the advent of high-throughput genomic technology, it has become possible to monitor cellular activities on a genomewide basis. With these new methods, scientists can begin to address important biological questions. One such question involves the identification of replication origins, which are regions in the chromosomes where DNA replication is initiated. One hypothesis is that their locations are nonrandom throughout the genome. In this article, we analyze data from a recent yeast study in which candidate replication origins were profiled using cDNA microarrays to test this hypothesis. We find no evidence for such clustering.

DNA, Complementary↗