Recent developments in the investigation of thyroid regulation and thyroid carcinogenesis

This review covers new mechanistic information spanning the past 10 years relevant to normal and abnormal thyroid growth and function that may assist in the risk assessment of chemicals inducing thyroid follicular cell neoplasia. Recent studies have shown that thyroid regulation occurs via a complex interactive network mediated through several different messenger systems. Increased thyroid-stimulating hormone (TSH) levels activate the signal transduction pathways to stimulate growth and differentiation of the follicular cell. The important role of TSH in growth as well as in function helps to explain how disruptions in the thyroid-pituitary axis may influence thyroid neoplasia in rodents. New investigations that couple mechanistic studies with information from animal cancer bioassays (e. g., sulfamethazine studies) confirm the linkage between prolonged disruption of the thyroid-pituitary axis and thyroid neoplasia. New initiation/promotion studies in rodents also support the concept that chronic stimulation of the thyroid induced by goitrogens can result in thyroid tumors. Some of these studies confirm previous suggestions regarding the importance of chemically induced thyroid peroxidase inhibition and the inhibition of 3,3',5, 5'-tetraiodothyronine (T4, thyroxine) deiodinases on disruption of the thyroid-pituitary axis leading to thyroid neoplasia. Some comparative physiologic and mechanistic data highlight certain differences between rodents and humans that could be expected to confer an increased vulnerability of rodents to chronic hypersecretion of TSH. New data from epidemiologic and molecular genetic studies in humans contribute further to an understanding of thyroid neoplasia. Acute exposure to ionizing radiation, especially in childhood, remains the only verified cause of thyroid carcinogenesis in humans. Iodine deficiency studies as a whole remain inconclusive, even though several new studies in humans examine the role of dietary iodine deficiency in thyroid cancer. Specific alterations in gene expression have been identified in human thyroid neoplasia, linked to tumor phenotype, and thus oncogene activation and tumor-suppressor gene inactivation may also be factors in the development and progression of thyroid cancer in humans. An analysis by the U.S. EPA Risk Assessment Forum, prepared as a draft report in 1988 and completed in 1997, focused on the use of a threshold for risk assessment of thyroid follicular tumors. New studies, involving several chemicals, provide further support that there will be no antithyroid activity until critical intracellular concentrations are reached. Thus, for chemically induced thyroid neoplasia linked to disruptions in the thyroid-pituitary axis, a practical threshold for thyroid cancer would be expected. More information on thyroid autoregulation, the role of oncogene mutations and growth factors, and studies directly linking persistently high TSH levels with the sequential cellular development of thyroid follicular cell neoplasia would provide further confirmation.     

Prenatal diagnosis of trisomy 13 on fetal cells obtained from maternal blood after minor enrichment

In a pilot study to establish fetal nucleated red blood cell (NRBC) detection in maternal blood, trisomy 13 was diagnosed by FISH analysis at 11 weeks' gestation. The NRBCs were detected after a single-step ficoll density gradient enrichment. In blood samples taken both before and after CVS, 52 and 80 NRBCs, respectively, were found to be positive for fetal haemoglobin. In 47 per cent of these cells, FISH analysis for X and Y chromosomes confirmed the fetal sex. Moreover, 48 per cent of these NRBCs showed three fluorescent signals for a chromosome 13 probe, which confirmed the diagnosis of trisomy 13, previously detected at CVS karyotyping. This is the first report of non-invasive prenatal diagnosis of trisomy 13, i.e., pre-CVS, in the first trimester. The high number of fetal NRBCs detected indicates a connection with aneuploidy, probably due to early impairment of the feto-maternal barrier.     

What do we mean by “catalytic activity”?

The relative reactivities of the lower alkanes in hydrogenolysis on a Pt/Al₂O₃ catalyst depend on the H₂ pressure used, as do those of a Ru/Al₂O₃ catalyst, pretreated in various ways, for propane hydrogenolysis. Apparent activation energies also vary with H₂ pressure. No single rate measurement adequately represents catalytic activity, which is properly defined as the rateconstant for the slow step.     

A usability evaluation of medical software at an expert conference setting

Introduction

A usability test was employed to evaluate two medical software applications at an expert conference setting. One software application is a medical diagnostic tool (electrocardiogram [ECG] viewer) and the other is a medical research tool (electrode misplacement simulator [EMS]). These novel applications have yet to be adopted by the healthcare domain, thus, (1) we wanted to determine the potential user acceptance of these applications and (2) we wanted to determine the feasibility of evaluating medical diagnostic and medical research software at a conference setting as opposed to the conventional laboratory setting.

Methods

The medical diagnostic tool (ECG viewer) was evaluated using seven delegates and the medical research tool (EMS) was evaluated using 17 delegates that were recruited at the 2010 International Conference on Computing in Cardiology. Each delegate/participant was required to use the software and undertake a set of predefined tasks during the session breaks at the conference. User interactions with the software were recorded using screen-recording software. The ‘think-aloud’ protocol was also used to elicit verbal feedback from the participants whilst they attempted the pre-defined tasks. Before and after each session, participants completed a pre-test and a post-test questionnaire respectively.

Results

The average duration of a usability session at the conference was 34.69 min (SD = 10.28). However, taking into account that 10 min was dedicated to the pre-test and post-test questionnaires, the average time dedication to user interaction of the medical software was 24.69 min (SD = 10.28). Given we have shown that usability data can be collected at conferences, this paper details the advantages of conference-based usability studies over the laboratory-based approach. For example, given delegates gather at one geographical location, a conference-based usability evaluation facilitates recruitment of a convenient sample of international subject experts. This would otherwise be very expensive to arrange. A conference-based approach also allows for data to be collected over a few days as opposed to months by avoiding administration duties normally involved in laboratory based approach, e.g. mailing invitation letters as part of a recruitment campaign.Following analysis of the user video recordings, 41 (previously unknown) use errors were identified in the advanced ECG viewer and 29 were identified in the EMS application. All use errors were given a consensus severity rating from two independent usability experts. Out of a rating scale of 4 (where 1 = cosmetic and 4 = critical), the average severity rating for the ECG viewer was 2.24 (SD = 1.09) and the average severity rating for the EMS application was 2.34 (SD = 0.97). We were also able to extract task completion rates and times from the video recordings to determine the effectiveness of the software applications. For example, six out of seven tasks were completed by all participants when using both applications. This statistic alone suggests both applications already have a high degree of usability. As well as extracting data from the video recordings, we were also able to extract data from the questionnaires. Using a semantic differential scale (where 1 = poor and 5 = excellent), delegates highly rated the ‘responsiveness’, ‘usefulness’, ‘learnability’ and the ‘look and feel’ of both applications.

Conclusion

This study has shown the potential user acceptance and user-friendliness of the novel EMS and the ECG viewer applications within the healthcare domain. It has also shown that both medical diagnostic software and medical research software can be evaluated for their usability at an expert conference setting. The primary advantage of a conference-based usability evaluation over a laboratory-based evaluation is the high concentration of experts at one location, which is convenient, less time consuming and less expensive.     

Serotonin and serotonin receptors in the central auditory system

Single channel currents were activated by GABA (0.5 to 5 microM) in cell-attached and inside-out patches from cells in the dentate gyrus of rat hippocampal slices. The currents reversed at the chloride equilibrium potential and were blocked by bicuculline (100 microM). Several different kinds of channel were seen: high conductance and low conductance, rectifying and "nonrectifying." Channels had multiple conductance states. The open probability (Po) of channels was greater at depolarized than at hyperpolarized potentials and the relationship between Po and potential could be fitted with a Boltzmann equation with equivalent valency (z) of 1. The combination of outward rectification and potential-dependent open probability gave very little chloride current at hyperpolarized potentials but steeply increasing current with depolarization, useful properties for a tonic inhibitory mechanism.     

Development and characterization of a purified diet to identify obesity-susceptible and resistant rat populations

A purified moderately high fat diet has been developed to examine diet-induced obesity in rats. Male Sprague-Dawley rats were fed this or an AIN-76A diet for 15 wk and energy metabolism indices were monitored. Food intake, body weight and water balance indices were recorded on a weekly or daily basis. Over the 15-wk period, rats fed the experimental diet diverged into two groups differing in the rate of body weight gain. Animals were labeled as "gainers" or "resisters" depending on their susceptibility to obesity. Following the dietary period, rats were decapitated and trunk blood was collected for glucose and insulin measurements. Gainers consumed slightly more energy than resisters over the experimental period (P < 0.05), but due to greater fecal energy loss, absorbed energy did not differ. Hence gainers became obese without significantly altered energy retention. Urinary creatinine, urea nitrogen and water balance were not different between the groups and consequently could not explain body weight differences. Further, gainers had significantly greater plasma glucose concentration than controls, indicating a potential for these animals to become diabetic. Results suggest metabolic differences must account for the divergence in weight gain observed in the two groups. The dietary model characterized in this study should provide a useful tool to study diet-induced obesity and to determine its underlying mechanism.     

Apolipoprotein E*3-Leiden transgenic mice as a test model for hypolipidaemic drugs

PURPOSE: We report an investigation into the distribution of proteoglycans (PGs) in normal, organ-cultured and dextran-treated human corneas. METHODS: Immunogold labeling was carried out at the electron microscope level to localize keratan sulphate (KS), chondroitin sulphate (CS), and heparan sulphate (HS) PGs. RESULTS: High levels of labeling for CS was found in the epithelium, endothelium, and keratocytes, with light labelling present in the basement membranes and the corneal stroma. Labeling for HS was present in the epithelium, endothelium, and keratocytes, with intense labeling present at the endothelium/Descemet's membrane interface and the epithelium/Bowman's layer interface. Large filaments were also observed in these regions in cuprolinic blue-stained specimens. Keratan sulphate was present at high levels in the stroma and the basement membranes with low levels present within the keratocytes, epithelium, and endothelium. The pattern of KS labeling along the collagen fibrils in the stroma sometimes showed evidence of periodicity. Organ-cultured corneas had extensive collagen-free "lakes," the interior of which immunolabeled positively for KS and showed staining with cuprolinic blue. The lakes were greatly reduced in the dextran-treated samples. CONCLUSION: This investigation determined the ultrastructural distribution of KS, CS, and HS PGs in human cornea and showed that organ culture is associated with a change in distribution of stromal PGs.     

Voltammetric determination of the synthetic pyrethroid insecticide tetramethrin in acetonitrile

The synthetic pyrethroid insecticide tetramethrin may be reduced reversibly (E°' = -1.650 V vs Ag/Ag(+)) in acetonitrile at hanging mercury drop electrodes (HMDE) and glassy carbon electrodes. On the voltammetric time scale, the initial electron-transfer process involves the reversible formation of a radical anion. Data obtained from electron paramagnetic resonance spectroscopy indicate that the unpaired electron of the radical is located within the phthalimide system of the molecule. The radical anion may be further reduced at very negative applied potentials with the number of processes being dependent on the nature of the voltammetric technique. The detection limit (3σ) for the determination of tetramethrin in acetonitrile at a glassy carbon electrode, using differential pulse voltammetry, was found to be 2.1 × 10(-6) M. At a HMDE the detection limit is lower, having a value of 9.6 × 10(-7) M. The limit of determination (10σ) at a glassy carbon electrode is 3.5 × 10(-6) M and at a HMDE is 3.0 × 10(-6) M. Tetramethrin was selectively determined in an insecticide formulation, at a glassy carbon electrode using differential pulse voltammetry, at a concentration (w/v) of 0.34 ± 0.02%. The determined concentration is in good agreement with the stated value of 0.350 ± 0.018% (w/v).     

Corrective classification: Learning from data imperfections with aggressive and diverse classifier ensembling

Learning from imperfect (noisy) information sources is a challenging and reality issue for many data mining applications. Common practices include data quality enhancement by applying data preprocessing techniques or employing robust learning algorithms to avoid developing overly complicated structures that overfit the noise. The essential goal is to reduce noise impact and eventually enhance the learners built from noise-corrupted data. In this paper, we propose a novel corrective classification (C2) design, which incorporates data cleansing, error correction, Bootstrap sampling and classifier ensembling for effective learning from noisy data sources. C2 differs from existing classifier ensembling or robust learning algorithms in two aspects. On one hand, a set of diverse base learners of C2 constituting the ensemble are constructed via a Bootstrap sampling process; on the other hand, C2 further improves each base learner by unifying error detection, correction and data cleansing to reduce noise impact. Being corrective, the classifier ensemble is built from data preprocessed/corrected by the data cleansing and correcting modules. Experimental comparisons demonstrate that C2 is not only more accurate than the learner built from original noisy sources, but also more reliable than Bagging [4] or aggressive classifier ensemble (ACE) [56], which are two degenerated components/variants of C2. The comparisons also indicate that C2 is more stable than Boosting and DECORATE, which are two state-of-the-art ensembling methods. For real-world imperfect information sources (i.e. noisy training and/or test data), C2 is able to deliver more accurate and reliable prediction models than its other peers can offer.