Neutron Rem Detector Response Changes due to Activation of Components.

The relative response of neutron rem detectors has previously been shown to increase after prolonged exposure to a neutron flux. This increase has been referred to as the "soak factor." The cause of the increased response has been previously unexplained. This note reports on a search for the underlying cause of the increased response. Testing involved gamma-ray spectroscopy of activated neutron rem detector components and testing of instrument response at various rates of neutron flux and accumulated fluence. The proposed primary cause of the increased response is activation of copper in the brass collar at the fill end of the gas-filled detector tube. This component allows for attachment of the extension housing on the tube containing BF3 or He gas. Under a neutron flux, some of this copper activates to Cu. In addition, Mn was detected in activated components but does not seem to be a significant contributor to the detector response. Cadmium isotopes did not appear to be significant. The activated component causes an increase in indicated neutron dose rate due to decay photons from activated components. Photons normally have little impact on neutron rem detector readings because the electrical pulses produced in the probes are below the lower-level discriminator. However, the photon pulses do impact the overall count rate when they occur simultaneously with normally uncounted, lower amplitude, wall-effect neutron pulses.

An evaluation of selected (Q)SARs/expert systems for predicting skin sensitisation potential.

Predictive testing to characterise substances for their skin sensitisation potential has historically been based on animal models such as the Local Lymph Node Assay (LLNA) and the Guinea Pig Maximisation Test (GPMT). In recent years, EU regulations, have provided a strong incentive to develop non-animal alternatives, such as expert systems software. Here we selected three different types of expert systems: VEGA (statistical), Derek Nexus (knowledge-based) and TIMES-SS (hybrid), and evaluated their performance using two large sets of animal data: one set of 1249 substances from eChemportal and a second set of 515 substances from NICEATM. A model was considered successful at predicting skin sensitisation potential if it had at least the same balanced accuracy as the LLNA and the GPMT had in predicting the other outcomes, which ranged from 79% to 86%. We found that the highest balanced accuracy of any of the expert systems evaluated was 65% when making global predictions. For substances within the domain of TIMES-SS, however, balanced accuracies for the two datasets were found to be 79% and 82%. In those cases where a chemical was within the TIMES-SS domain, the TIMES-SS skin sensitisation hazard prediction had the same confidence as the result from LLNA or GPMT.

Riboflavin induces Metarhizium spp. to produce conidia with elevated tolerance to UV-B, and upregulates photolyases, laccases and polyketide synthases genes.

AIMS: The effect of nutritional supplementation of two Metarhizium species with riboflavin (Rb) during production of conidia was evaluated on (i) conidial tolerance (based on germination) to UV-B radiation and on (ii) conidial expression following UV-B irradiation, of enzymes known to be active in photoreactivation, viz., photolyase (Phr), laccase (Lac) and polyketide synthase (Pks). METHODS AND RESULTS: Metarhizium acridum (ARSEF 324) and Metarhizium robertsii (ARSEF 2575) were grown either on (i) potato dextrose agar medium (PDA), (ii) PDA supplemented with 1% yeast extract (PDAY), (iii) PDA supplemented with Rb (PDA+Rb), or (iv) PDAY supplemented with Rb (PDAY+Rb). Resulting conidia were exposed to 866·7 mW m-2 of UV-B Quaite-weighted irradiance to total doses of 3·9 or 6·24 kJ m-2 . Some conidia also were exposed to 16 klux of white light (WL) after being irradiated, or not, with UV-B to investigate the role of possible photoreactivation. Relative germination of conidia produced on PDA+Rb (regardless Rb concentration) or on PDAY and exposed to UV-B was higher compared to conidia cultivated on PDA without Rb supplement, or to conidia suspended in Rb solution immediately prior to UV-B exposure. The expression of MaLac3 and MaPks2 for M. acridum, as well as MrPhr2, MrLac1, MrLac2 and MrLac3 for M. robertsii was higher when the isolates were cultivated on PDA+Rb and exposed to UV-B followed by exposure to WL, or exposed to WL only. CONCLUSIONS: Rb in culture medium increases the UV-B tolerance of M. robertsii and M. acridum conidia, and which may be related to increased expression of Phr, Lac and Pks genes in these conidia. SIGNIFICANCE AND IMPACT OF THE STUDY: The enhanced UV-B tolerance of Metarhizium spp. conidia produced on Rb-enriched media may improve the effectiveness of these fungi in biological control programs.

Cigarette smoking is associated with an altered vaginal tract metabolomic profile.

Cigarette smoking has been associated with both the diagnosis of bacterial vaginosis (BV) and a vaginal microbiota lacking protective Lactobacillus spp. As the mechanism linking smoking with vaginal microbiota and BV is unclear, we sought to compare the vaginal metabolomes of smokers and non-smokers (17 smokers/19 non-smokers). Metabolomic profiles were determined by gas and liquid chromatography mass spectrometry in a cross-sectional study. Analysis of the 16S rRNA gene populations revealed samples clustered into three community state types (CSTs) ---- CST-I (L. crispatus-dominated), CST-III (L. iners-dominated) or CST-IV (low-Lactobacillus). We identified 607 metabolites, including 12 that differed significantly (q-value < 0.05) between smokers and non-smokers. Nicotine, and the breakdown metabolites cotinine and hydroxycotinine were substantially higher in smokers, as expected. Among women categorized to CST-IV, biogenic amines, including agmatine, cadaverine, putrescine, tryptamine and tyramine were substantially higher in smokers, while dipeptides were lower in smokers. These biogenic amines are known to affect the virulence of infective pathogens and contribute to vaginal malodor. Our data suggest that cigarette smoking is associated with differences in important vaginal metabolites, and women who smoke, and particularly women who are also depauperate for Lactobacillus spp., may have increased susceptibilities to urogenital infections and increased malodor.

The impact of electrolyte on the adsorption of the anionic surfactant methyl ester sulfonate at the air-solution interface: Surface multilayer formation.

The methyl ester sulfonates represent a promising group of anionic surfactants which have the potential for improved performance and biocompatibility in a range of applications. Their solution properties, in particular their tolerance to hard water, suggests that surface ordering may occur in the presence of multi-valent counterion. Understanding their adsorption properties in a range of different circumstances is key to the exploitation of their potential. Neutron reflectivity and surface tension have been used to characterise the adsorption at the air-aqueous solution interface of the anionic surfactant sodium tetradecanoic 2-sulfo 1-methyl ester, C14MES, in the absence of electrolyte and in the presence of mono, di, and tri-valent counterions, Na+, Ca2+, and Al3+. In particular the emphasis has been on exploring the tendency to form layered structures at the interface. In the absence of electrolyte and in the presence of NaCl and CaCl2 and AlCl3 at low concentrations monolayer adsorption is observed, and the addition of electrolyte results in enhanced adsorption. In the presence of NaCl and CaCl2 only monolayer adsorption is observed. However at higher AlCl3 concentrations surface multilayer formation is observed, in which the number of bilayers at the surface depends upon the surfactant and AlCl3 concentrations.

Hyperspectral data processing improves PpIX contrast during fluorescence guided surgery of human brain tumors.

Fluorescence guided surgery (FGS) using aminolevulinic-acid (ALA) induced protoporphyrin IX (PpIX) provides intraoperative visual contrast between normal and malignant tissue during resection of high grade gliomas. However, maps of the PpIX biodistribution within the surgical field based on either visual perception or the raw fluorescence emissions can be masked by background signals or distorted by variations in tissue optical properties. This study evaluates the impact of algorithmic processing of hyperspectral imaging acquisitions on the sensitivity and contrast of PpIX maps. Measurements in tissue-simulating phantoms showed that (I) spectral fitting enhanced PpIX sensitivity compared with visible or integrated fluorescence, (II) confidence-filtering automatically determined the lower limit of detection based on the strength of the PpIX spectral signature in the collected emission spectrum (0.014-0.041 µg/ml in phantoms), and (III) optical-property corrected PpIX estimates were more highly correlated with independent probe measurements (r = 0.98) than with spectral fitting alone (r = 0.91) or integrated fluorescence (r = 0.82). Application to in vivo case examples from clinical neurosurgeries revealed changes to the localization and contrast of PpIX maps, making concentrations accessible that were not visually apparent. Adoption of these methods has the potential to maintain sensitive and accurate visualization of PpIX contrast over the course of surgery.

The implantation effect: delay in seizure occurrence with implantation of intracranial electrodes.

OBJECTIVE: A transient decrease in seizure frequency has been identified during therapeutic brain stimulation trials with stimulator in patients in the inactive sham group. This study was performed to examine whether the implantation of intracranial electrodes decreases seizure occurrence and explores factors that may be associated. METHODS: A retrospective review of 193 patients was performed, all evaluated with both scalp video EEG monitoring and intracranial EEG (iEEG) monitoring. Data about the number of seizures per day during the monitoring period, the number of days until the first seizure, anti-epileptic drugs (AEDs), pain medications, types of implanted electrodes, and anesthetic agents were reviewed. We conducted a repeated measure analysis for counted data using generalized estimating equations with a log-link function and adjustment for number of days and anti-epileptic medication load on the previous day to compare seizure frequencies between scalp and iEEG monitoring. RESULTS: The time to the first seizure was significantly prolonged during iEEG monitoring as compared to scalp monitoring after correction for AED withdrawal (hazard ratio: 0.81, CI 0.69-0.96). During scalp video EEG monitoring, patients experienced an average of 1.09 seizures/day vs 1.27 seizures/day during iEEG monitoring (P=.066). There was no significant difference in seizure frequency in patients that received craniotomy vs burr holes only for intracranial implantation. An increasing number of electrodes implanted increased the delay to seizures (P=.01). Of all anesthetic agents used, desflurane seemed to have an anticonvulsive effect compared to other anesthetics (P=.006). Pain medication did not influence delay to seizures. SIGNIFICANCE: Seizures are delayed during iEEG as opposed to scalp monitoring illustrating the "implantation effect" previously observed. Surgical planning should account for longer monitoring periods, particularly when using larger intracranial arrays.

Mechanism-Based QSAR Modeling of Skin Sensitization.

Many chemicals can induce skin sensitization, and there is a pressing need for non-animal methods to give a quantitative indication of potency. Using two large published data sets of skin sensitizers, we have allocated each sensitizing chemical to one of 10 mechanistic categories and then developed good QSAR models for the seven categories that have a sufficient number of chemicals to allow modeling. Both internal and external validation checks showed that each model had good predictivity.

Infrared lidar observations of stratospheric aerosols.

We observed the stratospheric aerosol layer at 34° north latitude with a photon-counting 1574 nm lidar on three occasions in 2011. During all of the observations, we also operated a nearby 523.5 nm micropulse lidar and acquired National Weather Service upper air data. We analyzed the lidar data to find scattering ratio profiles and the integrated aerosol backscatter at both wavelengths and then calculated the color ratio and wavelength exponent for lidar backscattering from the stratospheric aerosols. The visible-light integrated backscatter values of the layer were in the range 2.8-3.5×10⁻4 sr⁻¹ and the infrared integrated backscatter values ranged from 2.4 to 3.7×10⁻5 sr⁻¹. The wavelength exponent was determined to be 1.9±0.2.

TIMES-SS--recent refinements resulting from an industrial skin sensitisation consortium.

The TImes MEtabolism Simulator platform for predicting Skin Sensitisation (TIMES-SS) is a hybrid expert system, first developed at Bourgas University using funding and data from a consortium of industry and regulators. TIMES-SS encodes structure-toxicity and structure-skin metabolism relationships through a number of transformations, some of which are underpinned by mechanistic 3D QSARs. The model estimates semi-quantitative skin sensitisation potency classes and has been developed with the aim of minimising animal testing, and also to be scientifically valid in accordance with the OECD principles for (Q)SAR validation. In 2007 an external validation exercise was undertaken to fully address these principles. In 2010, a new industry consortium was established to coordinate research efforts in three specific areas: refinement of abiotic reactions in the skin (namely autoxidation) in the skin, refinement of the manner in which chemical reactivity was captured in terms of structure-toxicity rules (inclusion of alert reliability parameters) and defining the domain based on the underlying experimental data (study of discrepancies between local lymph node assay Local Lymph Node Assay (LLNA) and Guinea Pig Maximisation Test (GPMT)). The present paper summarises the progress of these activities and explains how the insights derived have been translated into refinements, resulting in increased confidence and transparency in the robustness of the TIMES-SS predictions.

Electrophilic reactivity and skin sensitization potency of SNAr electrophiles.

We published in 2011 a quantitative mechanistic model (QMM) for skin sensitization potency of SNAr electrophiles in the mouse local lymph node assay (LLNA). In this model, potency was correlated with a combination of σ* for the leaving group and the total σ(-) values of the other substituents in the aromatic ring. Shortly afterward Natsch et al. published a kinetic study in which rate constants were determined for reactions of SNAr electrophiles with the cysteine-based peptide Ac-RFAACAA (Cys-peptide) that is used in the direct peptide reactivity assay (DPRA), and correlations were sought between these rate constants and sensitization potency in the LLNA. These two publications together have enabled the present study, aiming to develop a linear free energy relationship (LFER) correlating Cys-peptide reactivity with a reactivity parameter (RP) based on a combination of σ* and σ(-) substituent constants and, by analyzing differences between the QMM based on RP and the QMM based on Cys-peptide rate constants, to gain further insights into the underlying chemistry of skin sensitization. For the 2,4-dinitro-X-subsituted benzenes (DNXB), the rate constants of Natsch et al. are well correlated with the reactivity parameter used in our earlier work, with two outliers. These are the compounds with X = F and X = SCN, which are both substantially more reactive toward Cys-peptide than predicted from comparison of their RP values with those of the other DNXB compounds. These two compounds are both negative outliers from a correlation of sensitization potency with experimental rate constants, but fit well to the correlation of sensitization potency with RP values. With these two compounds excluded, sensitization potency is well correlated with the experimental rate constants for the DNXB compounds (X = SO3(-), I, Br, Cl) together with 2,4-dichloro-1-nitrobenzene and 1,3,4,5-tetrachloro-2,6-dicyanobenzene. The regression equation is pEC3 = 0.88 log k + 4.03, R(2) = 0.966. The implication of DNFB being an outlier is that the model Cys-peptide nucleophile is substantially more sterically hindered than the cutaneous nucleophile(s) involved in the sensitization process. The pattern seen with 2,4-dinitrothiocyanatobenzene suggests that this compound reacts as an SNAr electrophile in the sensitization process, but by a different pathway, acting as a CN transfer agent, with the model Cys-peptide. For two further compounds, 2,4,6-trinitrochlorobenzene and 2,4,6-trinitrobenzenesulfonate, the Cys-peptide rate constants are well predicted by the reactivity parameter based on displacement of the Cl or SO3(-) substituent, but their sensitization potency is underestimated by both the Cys-peptide rate constant and this reactivity parameter. However, potency of these two compounds is well predicted by a reactivity parameter calculated on the basis of displacement of the 2-nitro group. This is interpreted as a case of sensitization being driven by the thermodynamically favored rather than the kinetically favored reaction product.

Predicting skin sensitization potency for Michael acceptors in the LLNA using quantum mechanics calculations.

This study outlines the development of a series of quantitative mechanistic models enabling skin sensitization potency in the LLNA to be predicted for direct acting Michael acceptors. These models utilized several computational descriptors based on knowledge of the Michael addition reaction mechanism. The key descriptor was calculated using density functional theory and modeled the stability of the reaction intermediate. A second descriptor relating to the available surface area at the site of the reaction was also found to be important. Several poorly predicted compounds were identified, and in all cases, these could be rationalized mechanistically. The analysis of these compounds allowed a well-defined mechanistically driven applicability domain to be developed. The study showed that in silico quantitative mechanistic models, with a well-defined applicability domain, can be used to predict skin sensitization potency in the LLNA. The approach presented has the potential to be of use as part of a weight of evidence approach for predicting skin sensitization without the use of animals in risk assessment.

Aquatic toxicity of cationic surfactants to Daphnia magna.

Quantitative structure-activity relationship (QSAR) modelling of aquatic toxicity for cationic surfactants has received limited attention despite the fact that surfactants of this type are generally more toxic than predicted by general narcosis or polar narcosis equations. Here we report measurement of log P for three types of aromatic quaternary ammonium halides at sub-micellar concentrations, refinement of earlier rules for log P calculation, and development of a hydrophobicity based QSAR, using both calculated and measured log P values, for the aquatic toxicity of quaternary ammonium halides to Daphnia magna. The QSAR for cationics has a substantially larger intercept than the log P-based QSARs for nonionic and anionic surfactants. This is rationalised in terms of the head group interactions with membrane phospholipid in a two-dimensional partitioning model. The effect of the positive nitrogen on the log P contributions of methylene groups along alkyl chains varies, depending on the other groups bonded to the positive nitrogen. We propose a mechanistic explanation, but until these effects can be put on a more predictable quantitative basis it is recommended that, for quaternaries other than the three types discussed here, calculated log P values should not be relied on and experimental values should be determined, e.g. for prediction of toxicity by the QSAR equation reported here.

Is diacetyl a respiratory sensitizer? A reconsideration using QSAR, QMM, and competition experiments.

Concerns have been raised that diacetyl (DA) might be a respiratory sensitizer based on its LUMO energy similar to that of the respiratory allergen toluene-2,4-diisocyanate (TDI) and results of a local lymph node assay (LLNA) that reported an EC3 of 1.9%. To better understand the concerns, we performed a systematic literature review and experimental competition reactions between DA and TDI. The experimental evidence demonstrates that DA is at least 400-fold less reactive than TDI. The literature review finds evidence that the EC3 for DA is actually >11%. We conclude that DA is unlikely to have significant respiratory sensitization potential.

Development of mechanism-based structural alerts for respiratory sensitization hazard identification.

This study outlines how mechanistic organic chemistry related to covalent bond formation can be used to rationalize the ability of low molecular weight chemicals to cause respiratory sensitization. The results of an analysis of 104 chemicals which have been reported to cause respiratory sensitization in humans showed that most of the sensitizing chemicals could be distinguished from 82 control chemicals for which no clinical reports of respiratory sensitization exist. This study resulted in the development of a set of mechanism-based structural alerts for chemicals with the potential to cause respiratory sensitization. Their potential for use in a predictive algorithm for this purpose alongside an externally validated quantitative structure-activity relationship model is discussed.

A spectrally constrained dual-band normalization technique for protoporphyrin IX quantification in fluorescence-guided surgery.

We report a dual-band normalization technique for in vivo quantification of the metabolic biomarker, protoporphyrin IX (PpIX), during brain tumor resection procedures. The accuracy of the approach was optimized in tissue simulating phantoms with varying absorption and scattering properties, validated with fluorimetric assessments on ex vivo brain tissue, and tested on human data acquired in vivo during fluorescence-guided surgery of brain tumors. The results demonstrate that the dual-band normalization technique allows PpIX concentrations to be accurately quantified by correction with reflectance data recorded and integrated within only two narrow wavelength intervals. The simplicity of the method lends itself to the enticing prospect that the method could be applicable to wide-field applications in quantitative fluorescence imaging and dosimetry in photodynamic therapy.

Pollen counts and suicide rates. Association not replicated.

OBJECTIVE: To replicate a previously reported association between pollen counts and county suicide rates in the continental United States, across space and time. METHOD: The authors evaluated the relationship between airborne pollen counts and suicide rates in 42 counties of the continental United States, containing a pollen-counting station participating in the Aeroallergen Monitoring Network in the United States (N = 120,076 suicides), considering years' quarter, age group, sex, race, rural/urban location, number of local psychiatrists, and median household income, from 1999 to 2002. The county-level effects were broken into between-county and within-county. RESULTS: No within-county effects were found. Between-county effects for grass and ragweed pollen on suicide rates lost statistical significance after adjustment for median income, number of psychiatrists, and urban vs. rural location. CONCLUSION: Future research is necessary to reappraise the previously reported relationship between pollen levels and suicide rates that may have been driven by socioeconomic confounders.

Analytic expression of fluorescence ratio detection correlates with depth in multi-spectral sub-surface imaging.

Here we derived analytical solutions to diffuse light transport in biological tissue based on spectral deformation of diffused near-infrared measurements. These solutions provide a closed-form mathematical expression which predicts that the depth of a fluorescent molecule distribution is linearly related to the logarithm of the ratio of fluorescence at two different wavelengths. The slope and intercept values of the equation depend on the intrinsic values of absorption and reduced scattering of tissue. This linear behavior occurs if the following two conditions are satisfied: the depth is beyond a few millimeters and the tissue is relatively homogeneous. We present experimental measurements acquired with a broad-beam non-contact multi-spectral fluorescence imaging system using a hemoglobin-containing diffusive phantom. Preliminary results confirm that a significant correlation exists between the predicted depth of a distribution of protoporphyrin IX molecules and the measured ratio of fluorescence at two different wavelengths. These results suggest that depth assessment of fluorescence contrast can be achieved in fluorescence-guided surgery to allow improved intra-operative delineation of tumor margins.

Chemistry-based risk assessment for skin sensitization: quantitative mechanistic modeling for the S(N)Ar domain.

There is a strong impetus to develop nonanimal based methods to predict skin sensitization potency. An approach based on physical organic chemistry, whereby chemicals are classified into reaction mechanistic domains and quantitative models or read-across methods are derived for each domain, has been the basis of several recent publications. This article is concerned with the S(N)Ar reaction mechanistic domain. Electrophiles able to react by the S(N)Ar mechanism have long been recognized as skin sensitizers and have been used extensively in research studies on the biology of skin sensitization. Although qualitative discriminant analysis approaches have been developed for estimating the sensitization potential for S(N)Ar electrophiles on a yes/no qualitative basis, no quantitative mechanistic model (QMM) has so far been developed for this domain. Here, we derive a QMM that correlates skin sensitization potency, quantified by murine local lymph node assay (LLNA) EC3 data on a range of S(N)Ar electrophiles. It is based on the Hammett σ(-) values for the activating groups and the Taft σ* value for the leaving group. The model takes the form pEC3=2.48 Σσ(-) + 0.60 σ* - 4.51. This QMM, generated from mouse LLNA data, provides a reactivity parameter 2.48 Σσ(-) + 0.60 σ*, which was applied to a set of 20 compounds for which guinea pig test results were available in the literature and was found to successfully discriminate the sensitizers from the nonsensitizers. The reactivity parameter correctly predicted a known human sensitizer 2,4-dichloropyrimidine. New LLNA data on two further S(N)Ar electrophiles are consistent with the QMM.