Retrospective Biodosimetry of an Occupational Overexposure-Case Study.

In 2014, Health Canada was approached by the Canadian Nuclear Safety Commission to conduct biodosimetry for a possible overexposure 4 y prior to assessment. Dose estimates were determined by means of two cytogenetic assays, the dicentric chromosome assay (DCA) and translocations as measured by the fluorescent in situ hybridization (FISH). As dicentrics are considered to be unstable over time, the results of the DCA were adjusted to account for the time elapsed between the suspected exposure and sampling. The frequency of damage was then compared to Health Canada's calibration curves, respectively, to calculate dose. In addition, the translocation data were corrected for age-related increases in background. With a half-life of 36 months for dicentric chromosomes taken into consideration, the dose estimates from both assays were in agreement. Due to the uncertainty in the half-life of dicentrics, the FISH assay is considered to be more reliable as a technique for retrospective biodosimetry.

Bupivacaine inhibits endothelin-1-evoked increases in intracellular calcium in model sensory neurons.

BACKGROUND: Endothelin-1 (ET-1) induces pain-like behavior in animals and man by activating the Gq protein-coupled receptor endothelin-A (ETA ). Activation of ETA receptors on nociceptor membranes evokes intracellular calcium transients and alters membrane Na(+) and K(+) channel and TRPV1 currents, leading to neuronal hyper-excitability manifested by spontaneous and evoked pain behaviors in vivo. In addition to blocking sodium channels, local anesthetics inhibit the Gq protein-coupled signaling of several inflammatory and pro-algesic mediators. In this study, we aimed to investigate the actions of local anesthetics on ETA -mediated increases in intracellular calcium in ND7/104 model sensory neurons. METHODS: Increases in intracellular calcium were measured by the fluorescent indicator fura-2 in a sensory neuron-derived cell line (ND7/104), which endogenously expresses ETA receptors. Effects of lidocaine and bupivacaine, along with their respective membrane-impermeant derivatives QX-314, LEA-123 and LEA-124, on peak calcium responses to ET-1 were measured. RESULTS: Bupivacaine suppressed ET-1 responses in a concentration-dependent and non-competitive manner with an IC50 of 3.79 ± 1.63 mM. Bupivacaine (6 mM) reduced the Emax for ET-1 from 50.07 ± 1.91 mM to 27.30 ± 2.92 mM. The actions of bupivacaine occurred quickly and were rapidly reversible. Membrane-impermeant analogs of bupivacaine (LEA-123 and LEA-124, 6 mM) were without effect, as was lidocaine (10 mM) and its quaternary derivative QX-314 (10 mM). CONCLUSION: Bupivacaine inhibits ETA -mediated calcium transients at clinically relevant concentrations through an intracellular target. The anti-inflammatory and analgesic actions of bupivacaine may be at least partially due to its inhibitory action on Gq -coupled receptors, including ETA.

Genomic biomarkers and cellular pathways of ischemic stroke by RNA gene expression profiling.

OBJECTIVE: The objective of this study was to provide insight into the molecular mechanisms of acute ischemic cerebrovascular syndrome (AICS) through gene expression profiling and pathway analysis. METHODS: Peripheral whole blood samples were collected from 39 MRI-diagnosed patients with AICS and 25 nonstroke control subjects ≥ 18 years of age. Total RNA was extracted from whole blood stabilized in Paxgene RNA tubes, amplified, and hybridized to Illumina HumanRef-8v2 bead chips. Gene expression was compared in a univariate manner between stroke patients and control subjects using t test in GeneSpring. The significant genes were tested in a logistic regression model controlling for age, hypertension, and dyslipidemia. Inflation of type 1 error was corrected by Bonferroni and Ingenuity Systems Pathway analysis was performed. Validation was performed by QRT-PCR using Taqman gene expression assays. RESULTS: A 9-gene profile was identified in the whole blood of ischemic stroke patients using gene expression profiling. Five of these 9 genes were identified in a previously published expression profiling study of stroke and are therefore likely biomarkers of stroke. Pathway analysis revealed toll-like receptor signaling as a highly significant canonical pathway present in the peripheral whole blood of patients with AICS. CONCLUSIONS: Our study highlights the relevance of the innate immune system through toll-like receptor signaling as a mediator of response to ischemic stroke and supports the claim that gene expression profiling can be used to identify biomarkers of ischemic stroke. Further studies are needed to validate and refine these biomarkers for their diagnostic potential.

The impact of slow rewarming on inotropy, tissue metabolism, and "after drop" of body temperature in pediatric patients.

Pediatric patients undergoing surgical correction of congenital heart diseases using cardiopulmonary bypass (CPB) are subjected to hypothermia. Core temperature is cooled down to 26-28 degrees C during CPB. Postoperative hypothermia in these patients remains a source of long-intensive care unit (ICU) stay. Therefore, this study was performed to build a rewarming strategy aiming to improve the cardiac performance, minimize the early after-drop in both core and foot temperatures, and to achieve early achievement of homeostasis. Thirty pediatric patients of acyanotic congenital heart diseases were randomly allocated into one of three equal groups of 10. Group I was kept at 3 degrees C between nasopharyngeal and heater-cooler unit water temperatures during rewarming whereas group II and group III were kept at 5 degrees C and 7 degrees C, respectively. The following parameters were measured: 1) cardiac performance (cardiac index and peak velocity); 2) cumulative amrinone consumption, blood lactate levels, and total body oxygen consumption; 3) intraoperative and postoperative peak and trough core and foot temperatures; and 4) time to extubation and ICU stay. Group I patients showed statistically significant increase in cardiac index and peak velocity compared with groups II and III, at p < 0.05 and p < 0.025, respectively. Statistically, the consumption of amrinone was significantly decreased in group I compared with groups II and III, with p < 0.005 and p < 0.0005, respectively, at 6 hours postoperatively. Group I showed an insignificant increase in blood lactate level, where groups II and III showed significant increases compared with controls (p < 0.001 at 6 hours postoperatively). Intraoperatively, both trough core and peak foot temperatures of group I patients statistically were significantly higher than in group III patients at p < 0.0005 and p < 0.05, respectively. The same applies in the ICU as regards to the time to core temperature (p < 0.005) and the rate of foot warming (p < 0.01). It was found that a difference of 3 degrees C (group I) between nasopharyngeal and heater-cooler unit water temperatures during rewarming demonstrated the best outcome compared with 5 degrees C and 7 degrees C differences (groups II and III, respectively). This outcome was obvious in the following parameters: 1) the best cardiac performance (cardiac index and peak velocity); 2) the lowest values of cumulative amrinone consumption and blood lactate level; 3) the least after-drop in both core and foot temperatures; and 4) achievement of early homeostasis, shortest ICU stays, and conservation of the ICU resources.

Functional activity of CD40 antibodies correlates to the position of binding relative to CD154.

In this study we describe the characterization of a panel of 12 anti-mouse CD40 monoclonal antibodies (mAb). Characterization was performed in terms of antibody-binding site relative to the CD154 ligand, and the relationship between position and functional outcome of binding. The antibodies divided into three groups. The first were strong inhibitors of CD154 binding, and induced strong proliferative and activation signals to B cells. Two antibodies gave intermediary inhibition and comparable levels of activation. The remaining antibodies were found to bind outside the CD154 binding site and were poor inducers of B-cell activation. Data presented show a strong correlation between location of mAb binding and the resultant activation signal delivered. This correlation is shown to be independent of the isotype of the antibody involved and of its affinity. Implications of these findings are discussed.

Enhanced in vivo immune responses to bacterial lipopolysaccharide by exogenous CD40 stimulation.

The lack of specific T-cell help in immune responses to thymus-independent antigens results in weak, predominantly immunoglobulin M-mediated immunity with little or no memory. In the work presented here we show how the exogenous stimulation of CD40 by monoclonal antibodies can mimic T-cell help, resulting in enhanced immune responses which are protective against bacterial infection.

Normal and hearing-impaired word recognition scores for monosyllabic words in quiet and noise.

The effects of noise on word recognition scores were assessed with normal-hearing and hearing-impaired subjects. Fifty-one normal-hearing subjects were tested at 50 dB HL using signal-to-noise ratios (S/Ns) of 5, 10, and 15 dB. Thirty subjects with mild-to-moderate sensorineural hearing losses were tested in quiet and in noise at S/Ns of 10 dB and 15 dB. Monosyllabic words in a Multitalker Noise were selected for testing. Mean scores for the normal-hearing subjects were 45% at the 5 dB S/N, 74% at the 10 dB S/N, and 87% at the 15 dB S/N. For the hearing-impaired subjects, scores were 85% in quiet, 60% at the 15 dB S/N, and 40% at the 10 dB S/N. These results suggest that background noise which is mildly disruptive for normal hearing subjects can be highly disruptive to hearing-impaired subjects. Moreover, these findings indicate that subjects with mild-to-moderate sensorineural hearing loss require a more favourable S/N than normal listeners to achieve comparable word recognition scores. Test-retest differences for word recognition scores revealed variability that agreed closely with predictions based on the binomial distribution for both groups of subjects. Speech-in-noise abilities must be measured directly because regression equations revealed that speech-in-noise scores cannot be predicted accurately from either puretone thresholds or speech-in-quiet scores. Word recognition functions are presented from several hearing-impaired subjects and demonstrate the value of testing in noise.

X-ray diffraction studies of oxidized high-palladium alloys.

OBJECTIVE: The purpose of this study was to use x-ray diffraction (XRD) to obtain new information about the oxide layers on four representative oxidized high-palladium alloys. METHODS: Cast specimens of two Pd-Cu-Ga alloys and two Pd-Ga alloys, with both polished and etched surfaces and air-abraded surfaces, were subjected to oxidation procedures recommended by the manufacturers. The specimens were analyzed by x-ray diffraction using CuK alpha radiation, and the peaks were compared to appropriate Joint Committee on Powder Diffraction Standards (JCPDS). RESULTS: The surface preparation procedure had a profound effect on the phases present in the oxide layers. For the specimens that had been polished and etched, CuGa2O4 and beta-Ga2O3 were detected on the 79Pd-10Cu-9Ga-2Au alloy, whereas SnO2 and CuGa2O4 were detected on the 76Pd-10Cu-5.5Ga-6Sn-2Au alloy. The oxide layers on both Pd-Cu-Ga alloys contained Cu2O1 and the oxide layer on the 76Pd-10Cu-5.5Ga-6Sn-2Au alloy may contain beta-Ga2O3. The principal phase in the oxide layers on both Pd-Ga alloys that had been polished and etched was ln2O3, which exhibited extreme preferred orientation. No other phase was detected in the oxide layer on the 85Pd-10Ga-2Au-1Ag-1 ln alloy, whereas beta-Ga2O3 was found in the oxide layer on the 75Pd-6Ga-6Au-6Ag-6.5ln alloy. For the air-abraded specimens, beta-Ga2O2 was not present in the oxide layers on the Pd-Cu-Ga alloys, and beta-Ga2O3 was the major phase in the oxide layers on the Pd-Ga alloys. Palladium oxide(s) in varying amounts were detected for both surface preparations of the Pd-Cu-Ga alloys and for the air-abraded Pd-Ga alloys. Except for the 76Pd-10Cu-5.5Ga-6Sn-2Au alloy, the oxide layer caused minimal change in the lattice parameter of the palladium solid solution compared to that for the as-cast alloy. SIGNIFICANCE: Knowledge of the phases found in the oxide layers on these high-palladium alloys is of fundamental importance for interpreting differences in the adherence of dental porcelain to the metal substrates under static and dynamic conditions, and may provide guidance in the development of new high-palladium alloys with improved metal-ceramic bonding.