The prevalence of developmental dental and eruption anomalies assessed using panoramic radiographs: a retrospective study.

Developmental dental anomalies are a common finding in adolescent populations. The objective of this study was to utilize panoramic radiographs to determine the prevalence of dental anomalies and developmental disturbances in a heterogenous adolescent orthodontic patient population seeking care at a North American orthodontic residency program. A total of 1042 panoramic radiographs of 457 male and 585 female orthodontic patients aged 10 to 18 years were evaluated. Developmental and eruption anomalies were recorded and categorized, and chi-square and Fisher exact tests were used for statistical analysis. The evaluation revealed that 40.88% of patients had at least 1 anomalous finding. The most common finding overall was agenesis (12.00%), followed by deviations in eruption path (9.12%), delayed eruption (7.39%), and impaction (7.29%). There was no difference in the prevalence of having any anomalous finding or the prevalence of any specific category of anomalies based on the sex or Angle classification of the patients. Comparison of developmental dental anomalies in 3 age groups (10 to 12, 13 to 15, or 16 to 18 years) revealed no statistically significant difference in the overall prevalence of anomalous findings. Statistically significant differences for some specific categories of anomalies were explainable by correlating dental development with chronologic age, such as a greater frequency of blocked out teeth and eruption path deviation among patients aged 10 to 12 years. Black patients were found to have a significantly greater prevalence of impactions (P = 0.030), and Asian patients had a significantly greater prevalence of anomalies categorized as "other pathology," which could not be definitively diagnosed by panoramic radiograph alone (P = 0.007).

Remains of Leatherback turtles, Dermochelys coriacea, at Mid-Late Holocene archaeological sites in coastal Oman: clues of past worlds.

Small, irregular isolated bones identified as remains of leatherback turtles (Dermochelys coriacea) were recovered from Mid to Late Holocene sites at Ra's al-Hamra and Ra's al-Hadd, coastal Oman. These provide the third instance of this animal being documented from any prehistoric site anywhere, and the records provide one of the oldest, if not the oldest, dates for this distinctive chelonian-even though they do not refer to fossils. Decades of research in this region has yielded vast amounts of archeological information, including abundant evidence of intense exploitation and utilization of marine turtles from about 6,500 to 4,000 BP. During part of this period, turtle remains in human burials have been extraordinary; the turtle involved, Chelonia mydas, has been abundant in the region during modern times. Yet despite intense and varied forms of prehistoric marine resource exploitation, and major, long-term archeological work, no other turtle species has been previously authenticated from these, or other coastal sites. The documentation of remains of the largest and most distinctive of living marine turtles, D. coriacea, at Ra's al-Hamra and Ra's al-Hadd, presented herein, provide detailed information that serves as the basis for future interpretations and discussions regarding incomplete, disarticulated remains from the Mid to Late Holocene, particularly in reference to taphonomic questions and diverse environmental conditions.

Mönckeberg medial calcinosis of the infraorbital arteries: a first case report.

Mönckeberg medial calcinosis describes calcifications affecting only the tunica media of medium-sized arteries. The entity is strongly associated with chronic kidney disease and diabetes mellitus. Radiographically, medial calcinosis presents as areas of linear calcifications in soft tissue; the linear calcifications are referred to as "tram tracks," "pipe stem," "rail tracking," or "tram line" when the affected vessel is viewed longitudinally. In oral and maxillofacial radiology, it is generally an incidental finding of the facial artery. In this article, we review the literature of Mönckeberg medial calcinosis and its clinical significance related to systemic diseases; we also present a case of Mönckeberg medial calcinosis of the head and neck that affects the facial arteries, internal carotid arteries, and infraorbital arteries. We believe this is the first presentation in the literature of Mönckeberg medial calcinosis visualized in the infraorbital arteries.

Building a gold standard to construct search filters: a case study with biomarkers for oral cancer.

OBJECTIVE: To support clinical researchers, librarians and informationists may need search filters for particular tasks. Development of filters typically depends on a "gold standard" dataset. This paper describes generalizable methods for creating a gold standard to support future filter development and evaluation using oral squamous cell carcinoma (OSCC) as a case study. OSCC is the most common malignancy affecting the oral cavity. Investigation of biomarkers with potential prognostic utility is an active area of research in OSCC. The methods discussed here should be useful for designing quality search filters in similar domains. METHODS: The authors searched MEDLINE for prognostic studies of OSCC, developed annotation guidelines for screeners, ran three calibration trials before annotating the remaining body of citations, and measured inter-annotator agreement (IAA). RESULTS: We retrieved 1,818 citations. After calibration, we screened the remaining citations (n = 1,767; 97.2%); IAA was substantial (kappa = 0.76). The dataset has 497 (27.3%) citations representing OSCC studies of potential prognostic biomarkers. CONCLUSIONS: The gold standard dataset is likely to be high quality and useful for future development and evaluation of filters for OSCC studies of potential prognostic biomarkers. IMPLICATIONS: The methodology we used is generalizable to other domains requiring a reference standard to evaluate the performance of search filters. A gold standard is essential because the labels regarding relevance enable computation of diagnostic metrics, such as sensitivity and specificity. Librarians and informationists with data analysis skills could contribute to developing gold standard datasets and subsequent filters tuned for their patrons' domains of interest.

Primary glycogen-rich clear cell squamous cell carcinoma of the mandibular gingiva.

Clear cell squamous cell carcinoma (CCSCC) is a rare variant of squamous cell carcinoma, first reported by Kuo, who described 6 cases of squamous cell carcinoma of the skin of the head and neck. CCSCC is composed of cells with clear cytoplasm, which Kuo attributed to the accumulation of intracellular fluid and not the presence of glycogen, lipid, or mucin. This case describes a 59-year-old woman who presented with an exophytic, hemorrhagic lesion on the posterior mandibular gingiva of 2 months' duration. Histologic examination revealed dysplastic stratified squamous epithelium showing transition to an infiltrating tumor composed of islands of epithelial cells with clear cytoplasm. The cytoplasm stained positive with periodic acid Schiff but was diastase labile. Mucicarmine stains were negative for intracytoplasmic mucin. This is the first reported case describing primary glycogen-rich CCSCC of the mandibular gingiva.

Virtual reality goes to war: a brief review of the future of military behavioral healthcare.

Numerous reports indicate that the incidence of posttraumatic stress disorder (PTSD) in returning OEF/OIF military personnel is creating a significant healthcare challenge. These findings have served to motivate research on how to better develop and disseminate evidence-based treatments for PTSD. Virtual Reality delivered exposure therapy for PTSD has been previously used with reports of positive outcomes. This article details how virtual reality applications are being designed and implemented across various points in the military deployment cycle to prevent, identify and treat combat-related PTSD in OIF/OEF Service Members and Veterans. The summarized projects in these areas have been developed at the University of Southern California Institute for Creative Technologies, a U.S. Army University Affiliated Research Center, and this paper will detail efforts to use virtual reality to deliver exposure therapy, assess PTSD and cognitive function and provide stress resilience training prior to deployment.

Stochastic simulation and analysis of biomolecular reaction networks.

BACKGROUND: In recent years, several stochastic simulation algorithms have been developed to generate Monte Carlo trajectories that describe the time evolution of the behavior of biomolecular reaction networks. However, the effects of various stochastic simulation and data analysis conditions on the observed dynamics of complex biomolecular reaction networks have not received much attention. In order to investigate these issues, we employed a a software package developed in out group, called Biomolecular Network Simulator (BNS), to simulate and analyze the behavior of such systems. The behavior of a hypothetical two gene in vitro transcription-translation reaction network is investigated using the Gillespie exact stochastic algorithm to illustrate some of the factors that influence the analysis and interpretation of these data. RESULTS: Specific issues affecting the analysis and interpretation of simulation data are investigated, including: (1) the effect of time interval on data presentation and time-weighted averaging of molecule numbers, (2) effect of time averaging interval on reaction rate analysis, (3) effect of number of simulations on precision of model predictions, and (4) implications of stochastic simulations on optimization procedures. CONCLUSION: The two main factors affecting the analysis of stochastic simulations are: (1) the selection of time intervals to compute or average state variables and (2) the number of simulations generated to evaluate the system behavior.

Calculating arterial pressure-based cardiac output using a novel measurement and analysis method.

Work on applying physical and physiological principles for determining cardiac output by analysis of pressure measurements has been pursued for decades. Reference measurements for this kind of cardiac output analysis rely on the pulmonary artery catheter (PAC), considered the clinical gold standard for cardiac output monitoring. Recent advances in signal processing, as well as applied information on the relationships that enable arterial pulse pressure to be used to determine stroke volume, have led to the development of a novel system that can continuously measure cardiac output from an arterial pressure waveform that does not require an external calibration reference method. There are significant challenges in applying statistical- and signal-processing practices to the analysis of complex physiological waveforms. This paper reviews the historical basis for measuring flow from the analysis of pressure in a vessel, establishes the physiological and mathematical basis for this new system and describes its performance under various physiological conditions.

Variability of DNA microarray gene expression profiles in cultured rat primary hepatocytes.

DNA microarray is a powerful tool in biomedical research. However, transcriptomic profiling using DNA microarray is subject to many variations including biological variability. To evaluate the different sources of variation in mRNA gene expression profiles, gene expression profiles were monitored using the Affymetrix RatTox U34 arrays in cultured primary hepatocytes derived from six rats over a 26 hour period at 6 time points (0 h, 2h, 5h, 8h, 14 h and 26 h) with two replicate arrays at each time point for each animal. In addition, the impact of sample size on the variability of differentially expressed gene lists and the consistency of biological responses were also investigated. Excellent intra-animal reproducibility was obtained at all time points with 0 out of 370 present probe sets across all time points showing significant difference between the 2 replicate arrays (3-way ANOVA, p

Integrating time-course microarray gene expression profiles with cytotoxicity for identification of biomarkers in primary rat hepatocytes exposed to cadmium.

MOTIVATION: DNA microarrays can provide information about the expression levels of thousands of genes simultaneously at the transcriptomic level, while conventional cell viability and cytotoxicity measurement methods provide information about the biological functions at the cellular level. Integrating these data at different levels provides a promising approach for evaluating or predicting how cells respond to chemical exposure. It is important to investigate the multi-scale biological system in a systematic way to better understand the gene regulation networks and signal transduction pathways involved in the cellular responses to environmental factors. RESULTS: Primary rat hepatocytes were exposed to cadmium acetate at 0, 1.25 and 2 microM. mRNA expression profiles at 0, 3, 6, 12 and 24 h were measured using the Affymetrix RatTox U34 GeneChip arrays. Simultaneously, cytotoxicity was assessed by lactase dehydrogenase leakage assay. Gene expression profiles at different time points were used to evaluate cytotoxicity at subsequent time points using partial least squares, and it was found that gene expression profiles at 0 h had the best prediction accuracy for the cytotoxicity observed at 12 h. Some biomarkers whose expression profiles showed strong relationship with cytotoxicity were identified and the underlying pathways were reconstructed to illustrate how hepatocytes respond to cadmium exposure. Permutation studies were also applied to assess the reliability of the predictive models. AVAILABILITY: Matlab source code is available upon request and DNA microarray data are available at GEO (http://www.ncbi.nlm.nih.gov/geo).

Halogenated aliphatic toxicity QSARs employing metabolite descriptors.

The toxic effects from exposure to halogenated hydrocarbons (HAs), which are produced in large amounts and used in a variety of applications, are well-known. Previously, QSARs for the toxicity of a series of HAs in vitro have been studied extensively. In this work, using a composite toxicity metric calculated from a set of five in vitro hepatotoxicity endpoints determined for 20 HAs, we find that QSARs derived using quantum descriptors calculated from the neutral HA species are statistically similar to QSARs calculated from HA metabolites. In most cases, QSARs derived using descriptors calculated from both neutral HAs and metabolites are statistically superior to those derived using either neutral-HA descriptors or metabolite descriptors. However, to properly utilize metabolite descriptors, multiple QSARs, each of which utilizes a set of HAs that form unique metabolites, must be derived and toxicity values calculated therefrom must be averaged. These average toxicity values agree better with experiment than those calculated from the neutral-HA QSARs.

Tailored gene array databases: applications in mechanistic toxicology.

MOTIVATION: The development of an annotated global database suitable for a wide range of investigations is a challenging and labor-intensive task. Thus, the development of databases tailored for specific applications remains necessary. For example, in the field of toxicology, no annotated gene array databases are now available that may assist in the correlation of changes in gene activity to cellular functions and processes associated with the toxic response. RESULTS: As an example of a tailored annotated database, an attempt was made to systematize available biological information on genes present on the Affymetrix Rat Toxicology U34 GeneChip, with a focus on how the gene products relate to liver cells and their response to chemical toxins. The information collected was imbedded in a local relational database to analyze data obtained in toxicological gene array experiments with hydrazine-exposed hepatocytes. The advantages and benefits of the tailored database in the biological interpretation of the results are demonstrated.

A theoretical model for simulating the outcome of mechanism based in vitro toxicity testing strategies.

In order to investigate the fundamental principles that influence the optimal selection of toxicity test methods for the evaluation of chemical hazards, it is useful to have a design model to explore possible alternative testing strategies. In general, our lack of detailed knowledge of the mechanisms of toxicity (including not only the early events in the interaction of chemicals with biological systems, but the sequence of events that lead to experimentally measurable toxicity) limits the development of realistic dynamic models of the toxicological process for individual chemicals. We report here the development of a theoretical model that includes two independent hypothetical mechanisms of toxicity. The mechanisms are designed to be qualitatively similar to known mechanisms of action. The model is exercised to simulate the experimental data that would be obtained for a collection of "test" and "validation" chemicals using a single or a combination of two toxicity tests. The data generated are used to evaluate the "relevance" of the testing strategy based on the two proposed in vitro toxicity tests.

Involvement of apoptosis in hydrazine induced toxicity in rat primary hepatocytes.

The current study was undertaken to investigate the role of apoptosis in hydrazine induced hepatotoxicity. Hepatocytes were exposed to hydrazinium nitrate (HzN) at two doses (50 and 75 mM) for 2 h then placed in fresh HzN-free media and cultured for an additional 24 h. Post-exposure, cell viability was evaluated at several time points by lactate dehydrogenase (LDH) leakage and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction. Markers of apoptosis (mitochondrial membrane potential, annexin binding, DNA fragmentation, caspase activation, and cytochrome c release) were measured 24 h post-exposure. The viability data showed time dependent increase in LDH leakage at 75 mM of HzN, with only a slight increase at 50 mM. MTT reduction showed a decrease in mitochondrial activity at both doses immediately after the 2 h continuous exposure. However, MTT reduction returned to normal at 50 mM while at 75 mM, MTT reduction initially recovered but then deteriorated to approximately 50% of controls at 24 h post-exposure. Based on viability data, exposure to 50 mM HzN for 2 h is a marginally toxic dose while 75 mM is a significantly toxic dose. The results for apoptosis biomarkers showed a reduction in mitochondrial membrane potential, an increase in annexin binding, an increase in total caspase activity, moderate activation of caspase-3, and release of cytochrome c. However, the appearance of DNA fragmentation in HzN exposed cells was very low compared to positive controls (cadmium and cyclosporine). The possibility that HzN induces apoptosis without the involvement of DNA fragmentation can not be ruled out. The present results, overall, suggest that apoptosis may be a contributing factor in acute HzN toxicity.

Incorporation of protein-binding kinetics and carrier-mediated membrane transport into a model of chemical kinetics in the isolated perfused rat liver.

Nonlinear processes present difficult problems in extrapolating toxicological kinetics from one dose or species to another. A model that includes the details of these processes will aid in identifying those conditions under which a linear extrapolation is not valid. Previously, a kinetic model of the perfused rat liver system was presented that included the effects of equilibrium protein binding, diffusion-based and saturable membrane transport, metabolism, and biliary excretion. This model has been extended here to account for two complex processes. First, the kinetics of chemical association and dissociation from binding sites in various compartments are explicitly included to allow for the possibility that the binding of the compound is not in equilibrium. Second, mediated transport via a simple four-state carrier in the membrane has been included at both the sinusoidal and biliary membranes of the liver cell. This enables inclusion of carrier-specific transport processes (such as selective transport against a concentration gradient) in modeling the kinetics in perfused rat liver experiments. Simulations demonstrating the effects of each of these processes on observable state variables have been conducted. Physiological conditions that elicit nonlinear behavior have been identified.

Cellular toxicity of hydrazine in primary rat hepatocytes.

Hydrazine (HzN) is an aircraft fuel and propellant used by the U.S. Air Force. The current study was undertaken to evaluate the acute toxicity of HzN in primary rat hepatocytes in vitro with reference to oxidative stress. The effects of short-term exposure (4 h) of hepatocytes to HzN were investigated with reference to viability, mitochondrial function, and biomarkers of oxidative stress. The viability data showed an increase in lactate dehydrogenase leakage and a decrease in mitochondrial activity with increasing concentration of HzN. The results of studies of oxidative stress biomarkers showed a depletion of reduced glutathione (GSH) and an increase in oxidized GSH, increased reactive oxygen species generation, lipid peroxidation, and reduced catalase activity. Furthermore, depletion of GSH and catalase activity in hepatocytes by buthionine sulfoximine and 3-amino triazole, respectively, prior to exposure to HzN, increased its toxicity. The results suggest that acute HzN-induced cytotoxicity in rat hepatocytes is likely to be mediated through oxidative stress.

Effect of cadmium on bromosulfophthalein kinetics in the isolated perfused rat liver system.

Bromosulfophthalein (BSP) is a relatively nontoxic organic anion used as an in vivo indicator of liver performance. Elimination of BSP via the biliary system following iv injection requires dissociation from albumin in plasma, translocation across the sinusoidal membrane, conjugation with glutathione within the hepatocyte, translocation across the bile canalicular membrane, and excretion in bile. The effects of cadmium (Cd), anin vivo hepatotoxicant in rats, on BSP kinetics in the isolated perfused rat liver (IPRL) were studied to investigate the interaction between liver toxicity and BSP kinetics. Livers were isolated from male Fisher 344 rats. After a 30-min period for acclimation to the IPRL system, livers were dosed with Cd (as cadmium acetate), in the presence of 0.25% bovine serum albumin, to give initial concentrations of 10 and 100 microM. Sixty min after Cd dosing, the IPRL system was dosed with BSP to give an initial concentration of 150 microM and the elimination kinetics of BSP from the perfusion medium were monitored. Cadmium concentrations in livers at the end of the experiments were 60 +/- 4 and 680 +/- 210 micro mol/kg for the 10 and 100 microM doses, respectively. Exposure to 10 microM Cd for 60 min resulted in a reduction in bile flow, no significant effect on lactate dehydrogenase (LDH) leakage, and slight effects on BSP clearance. Similar studies following exposure to 100 microM Cd showed a dramatic decrease in bile flow with complete cholestasis 60 min after Cd addition. LDH leakage into perfusion medium at the end of the experiment was less than 10%, indicating that Cd affected bile production well before the liver showed significant signs of necrosis. Clearance of BSP from the perfusion medium was dramatically reduced. Taken together, the data indicate that Cd has a significant effect on the kinetics of BSP in the IPRL and the dominant effects were mediated through the cholestatic effect of Cd.