GM-CSF and IL-4 are not involved in IVIG-mediated amelioration of ITP in mice: a role for IL-11 cannot be ruled out.

Previously, we have reported that interleukin (IL)-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-11, but not IL-33, are up-regulated in two strains of mice with immune thrombocytopenia (ITP) that are responsive to intravenous immunoglobulin (IVIg) treatment. Previously, IL-4 was ruled out in the mechanism of IVIg; however, other publications have suggested this cytokine as a major player in the mechanism of IVIg action. Thus, we sought to further investigate a role for IL-4 and, in addition, GM-CSF and IL-11 in the mechanism of action of IVIg using a murine model of ITP. A passive platelet antibody model was used to generate ITP in IL-4 receptor knock-out (IL-4R-/- ), IL-11 receptor knock-out (IL-11Rα-/- ) and GM-CSF knock-out (Csf2-/- ) mice. We also used a neutralizing antibody to IL-11 and recombinant human IL-11 (rhIL-11) in addition to depleting basophils in vivo to study the effect of IVIg to ameliorate ITP. Our results showed that basophils, IL-4 and GM-CSF were unimportant in both ITP induction and its amelioration by IVIg. The role of IL-11 in these processes was less clear. Even though IL-11Rα-/- mice with ITP responded to IVIg similarly to wild-type (WT) mice, treatment of ITP WT mice with rhIL-11 instead of IVIg showed an increase in platelet numbers and WT mice administered anti-IL-11 showed a significant reduction in the ability of IVIg to ameliorate the ITP. Our findings indicate that neither IL-4, basophils or GM-CSF have roles in IVIg amelioration of ITP; however, a role for IL-11 requires further study.

Differential effects of phototherapy, adalimumab and betamethasone-calcipotriol on effector and regulatory T cells in psoriasis.

BACKGROUND: Psoriasis is a chronic T-cell-mediated skin disease with marked social and economic burdens. Current treatments are unsatisfactory, with unpredictable remission times and incompletely understood modes of action. Recent advances in our understanding of the pathogenesis of psoriasis have identified the imbalance between CD4+ T effector cells, particularly the T helper (Th)17 subset, and regulatory T cells (Tregs) as key to the development of psoriatic lesions, and therefore a novel therapeutic target. OBJECTIVES: To quantify in patients the effects of three commonly used psoriasis treatment modalities on the Th1, Th2, Th17 and Treg subsets, and to test whether any change correlates with clinical response. METHODS: Flow cytometry was used to enumerate Th1, Th2, Th17 and Treg subsets in blood and skin of patients with psoriasis before and after receiving any of the following treatments: narrowband ultraviolet B (NB-UVB), adalimumab and topical betamethasone-calcipotriol combination (Dovobet® ) RESULTS: All patients responded clinically to the treatments. NB-UVB significantly increased the numbers of circulating and skin Tregs, while, by contrast, adalimumab reduced Th17 cells in these compartments, and Dovobet had dual effects by both increasing Tregs and reducing Th17 cells. CONCLUSIONS: The differential effects reported here for the above-mentioned treatment modalities could be exploited to optimize or design therapeutic strategies to overcome the inflammatory drivers more effectively and restore the Th17-Treg balance in psoriasis.

Bubble-detector measurements of neutron radiation in the international space station: ISS-34 to ISS-37.

Bubble detectors have been used to characterise the neutron dose and energy spectrum in several modules of the International Space Station (ISS) as part of an ongoing radiation survey. A series of experiments was performed during the ISS-34, ISS-35, ISS-36 and ISS-37 missions between December 2012 and October 2013. The Radi-N2 experiment, a repeat of the 2009 Radi-N investigation, included measurements in four modules of the US orbital segment: Columbus, the Japanese experiment module, the US laboratory and Node 2. The Radi-N2 dose and spectral measurements are not significantly different from the Radi-N results collected in the same ISS locations, despite the large difference in solar activity between 2009 and 2013. Parallel experiments using a second set of detectors in the Russian segment of the ISS included the first characterisation of the neutron spectrum inside the tissue-equivalent Matroshka-R phantom. These data suggest that the dose inside the phantom is ∼70% of the dose at its surface, while the spectrum inside the phantom contains a larger fraction of high-energy neutrons than the spectrum outside the phantom. The phantom results are supported by Monte Carlo simulations that provide good agreement with the empirical data.

Bubble-detector measurements in the Russian segment of the International Space Station during 2009-12.

Measurements using bubble detectors have been performed in order to characterise the neutron dose and energy spectrum in the Russian segment of the International Space Station (ISS). Experiments using bubble dosemeters and a bubble-detector spectrometer, a set of six detectors with different energy thresholds that is used to determine the neutron spectrum, were performed during the ISS-22 (2009) to ISS-33 (2012) missions. The spectrometric measurements are in good agreement with earlier data, exhibiting expected features of the neutron energy spectrum in space. Experiments using a hydrogenous radiation shield show that the neutron dose can be reduced by shielding, with a reduction similar to that determined in earlier measurements using bubble detectors. The bubble-detector data are compared with measurements performed on the ISS using other instruments and are correlated with potential influencing factors such as the ISS altitude and the solar activity. Surprisingly, these influences do not seem to have a strong effect on the neutron dose or energy spectrum inside the ISS.

T cell participation in autoreactivity to NC16a epitopes in bullous pemphigoid.

Bullous pemphigoid is a blistering skin disease characterized by autoantibodies against the NC16a domain of bullous pemphigoid 180. This study was performed to characterize and map the fine specificity of T cell responses to NC16a. Peripheral blood mononuclear cells (PBMC) from a total of 28 bullous pemphigoid patients and 14 matched controls were tested for proliferative and cytokine responses to recombinant NC16a and a complete panel of 21 overlapping peptides spanning this region of BP180. Proliferative responses to NC16A and the peptide panel in the patients with active disease were similar in frequency and magnitude to those in healthy donors, and included late responses typical of naive cells in approximately 60% of each group. Interleukin (IL)-4 responses were slightly stronger for six peptides, and significantly stronger for Nc16a, in patients than in controls. Factor analysis identified factors that separate responses to the peptide panel discretely into IL-4, T helper type 2 (Th2) pattern, interferon (IFN)-γ, Th1 pattern and IL-10 or transforming growth factor [TGF-ß, regulatory T cell (Treg )] pattern. Factors segregating IL-10 versus IFN-γ were predicted by active blistering or remission, and TGF-ß or IL-10 versus IFN-γ by age. Finally, we confirmed a significant up-regulation of IgE responses to BP180 in the patients with pemphigoid. This shows the complexity of T cell phenotype and fine autoreactive specificity in responses to NC16A, in patients and in normal controls. Important disease-associated factors determine the balance of cytokine responses. Of these, specific IL-4 and IgE responses show the strongest associations with pemphigoid, pointing to an important contribution by Th2 cytokines to pathogenesis.

Aircrew radiation dose estimates during recent solar particle events and the effect of particle anisotropy.

A model was developed using a Monte-Carlo radiation transport code, MCNPX, to estimate the additional radiation exposure to aircrew members during solar particle events. The model transports an extrapolated particle spectrum based on satellite measurements through the atmosphere to aircraft altitudes. This code produces the estimated flux at a specific altitude where radiation dose conversion coefficients are applied to convert the particle flux into effective and ambient dose-equivalent rates. A cut-off rigidity model accounts for the shielding effects of the Earth's magnetic field. Comparisons were made between the model predictions and actual flight measurements taken with various types of instruments used to measure the mixed radiation field during ground level enhancements (GLEs) 60 and 65. An anisotropy analysis that uses neutron monitor responses and the pitch angle distribution of energetic solar particles was used to identify particle anisotropy for a solar event in December 2006. In anticipation of future commercial use, a computer code has been developed to implement the radiation dose assessment model for routine analysis.

Predominance of activated, clonally expanded T helper type 17 cells within the CD4+ T cell population in psoriatic lesions.

Recent evidence points to the T helper type 17 (Th17) subset as key in the pathogenesis of psoriasis, but cells of this type in lesions remain to be fully characterized. Here we isolated, enumerated, functionally tested and clonotyped the CD4(+) Th cell population ex vivo from lesional biopsies and paired peripheral blood samples from psoriasis patients. Th17 cells were over-represented dramatically in lesions from all patients, representing 49-93% of CD4(+) Th cells compared with 3-18% in blood. Most lesional Th17 cells produced interleukin (IL)-17A ex vivo without further stimulation and expressed the CD45RO(+) phenotype characteristic of activated or memory cells. There was no increase in 'natural' [CD25(hi) forkhead box protein 3 (FoxP3(+))] regulatory T cells in lesions versus peripheral blood, but there was enrichment of 'induced' IL-10(+) regulatory T cell numbers in biopsies from some patients. The lesional Th17 cells exhibited a bias in T cell receptor Vß chain usage, suggestive of specific expansion by antigen. The therapeutic challenge is to overcome the dominance of overwhelming numbers of such antigen-specific Th17 cells in psoriatic lesions.

Measurements of the neutron dose and energy spectrum on the International Space Station during expeditions ISS-16 to ISS-21.

As part of the international Matroshka-R and Radi-N experiments, bubble detectors have been used on board the ISS in order to characterise the neutron dose and the energy spectrum of neutrons. Experiments using bubble dosemeters inside a tissue-equivalent phantom were performed during the ISS-16, ISS-18 and ISS-19 expeditions. During the ISS-20 and ISS-21 missions, the bubble dosemeters were supplemented by a bubble-detector spectrometer, a set of six detectors that was used to determine the neutron energy spectrum at various locations inside the ISS. The temperature-compensated spectrometer set used is the first to be developed specifically for space applications and its development is described in this paper. Results of the dose measurements indicate that the dose received at two different depths inside the phantom is not significantly different, suggesting that bubble detectors worn by a person provide an accurate reading of the dose received inside the body. The energy spectra measured using the spectrometer are in good agreement with previous measurements and do not show a strong dependence on the precise location inside the station. To aid the understanding of the bubble-detector response to charged particles in the space environment, calculations have been performed using a Monte-Carlo code, together with data collected on the ISS. These calculations indicate that charged particles contribute <2% to the bubble count on the ISS, and can therefore be considered as negligible for bubble-detector measurements in space.

Review of bubble detector response characteristics and results from space.

A passive neutron-bubble dosemeter (BD), developed by Bubble Technology Industries, has been used for space applications. Both the bubble detector-personal neutron dosemeter and bubble detector spectrometer have been studied at ground-based facilities in order to characterise their response due to neutrons, heavy ion particles and protons. This technology was first used during the Canadian-Russian collaboration aboard the Russian satellite BION-9, and subsequently on other space missions, including later BION satellites, the space transportation system, Russian MIR space station and International Space Station. This paper provides an overview of the experiments that have been performed for both ground-based and space studies in an effort to characterise the response of these detectors to various particle types in low earth orbit and presents results from the various space investigations.

Use of a dual-labelled oligonucleotide as a DNA dosemeter for radiological exposure detection.

A reporter molecule consisting of a synthetic oligonucleotide is being characterised for a novel damage detection scenario for its potential use as a field-deployable, personal deoxyribonucleic acid (DNA) dosemeter for radiation detection. This dosemeter is devoid of any biological properties other than being naked DNA and therefore has no DNA repair capabilities. It supports biodosimetry techniques, which require lengthy analysis of cells from irradiated individuals, and improves upon inorganic dosimetry, thereby providing for a more relevant means of measuring the accumulated dose from a potentially mixed-radiation field. Radiation-induced single strand breaks (SSBs) within the DNA result in a quantifiable fluorescent signal. Proof of concept has been achieved over 250 mGy-10 Gy dose range in radiation fields from 6°Co, with similar results seen using a linear accelerator X-ray source. Further refinements to both the molecule and the exposure/detection platform are expected to lead to enhanced levels of detection for mixed-field radiological events.

Modelling of radiation exposure at high altitudes during solar storms.

A transport code analysis using Monte Carlo N-Particle eXtended code, MCNPX, has been used to propagate an extrapolated particle spectrum based on satellite measurements through the atmosphere to estimate radiation exposure during solar storms at high altitudes. Neutron monitor count rate data from stations around the world were used to benchmark the model calculations during a ground-level event (GLE). A comparison was made between the model predictions and actual flight measurements taken with various types of instruments used to measure the mixed radiation field during GLE 60. A computer code has been developed to implement the model for routine analysis.

Development of a predictive code for aircrew radiation exposure.

Using the empirical data measured by the Royal Military College with a tissue equivalent proportional counter, a model was derived to allow for the interpolation of the dose rate for any global position, altitude and date. Through integration of the dose-rate function over a great circle flight path or between various waypoints, a Predictive Code for Aircrew Radiation Exposure (PCAire) was further developed to provide an estimate of the total dose equivalent on any route worldwide at any period in the solar cycle.

Modelling of aircrew radiation exposure from galactic cosmic rays and solar particle events.

Correlations have been developed for implementation into the semi-empirical Predictive Code for Aircrew Radiation Exposure (PCAIRE) to account for effects of extremum conditions of solar modulation and low altitude based on transport code calculations. An improved solar modulation model, as proposed by NASA, has been further adopted to interpolate between the bounding correlations for solar modulation. The conversion ratio of effective dose to ambient dose equivalent, as applied to the PCAIRE calculation (based on measurements) for the legal regulation of aircrew exposure, was re-evaluated in this work to take into consideration new ICRP-92 radiation-weighting factors and different possible irradiation geometries of the source cosmic-radiation field. A computational analysis with Monte Carlo N-Particle eXtended Code was further used to estimate additional aircrew exposure that may result from sporadic solar energetic particle events considering real-time monitoring by the Geosynchronous Operational Environmental Satellite. These predictions were compared with the ambient dose equivalent rates measured on-board an aircraft and to count rate data observed at various ground-level neutron monitors.

Characterisation of bubble detectors for aircrew and space radiation exposure.

The Earth's atmosphere acts as a natural radiation shield which protects terrestrial dwellers from the radiation environment encountered in space. In general, the intensity of this radiation field increases with distance from the ground owing to a decrease in the amount of atmospheric shielding. Neutrons form an important component of the radiation field to which the aircrew and spacecrew are exposed. In light of this, the neutron-sensitive bubble detector may be ideal as a portable personal dosemeter at jet altitudes and in space. This paper describes the ground-based characterisation of the bubble detector and the application of the bubble detector for the measurement of aircrew and spacecrew radiation exposure.

LET dependence of bubble detector response to heavy ions.

A series of experiments have been recently performed at the Heavy Ion Medical Accelerator in Chiba (HIMAC) laboratory to study the response of bubble detectors to high-mass high-energy (HZE) particles. The motivation for this study was to improve our ability to interpret measurements of neutron energy spectra in space. A recent analysis showed that emulsions of light halocarbons display common properties when they are characterised by a quantity called 'reduced superheat'. This quantity evolved from the examination of neutron and gamma responses of many types of detectors. In this study, we describe direct irradiations with N, Ar and Kr charged particles at HIMAC. It was observed that when the linear energy transfer (LET) corresponding to bubble formation was plotted vs. reduced superheat, different curves were obtained for a particular ion for detectors at different temperatures. Different curves were also obtained when data from different ions were plotted. These results confirm that bubble nucleation is not a simple function of particle LET and that an analysis based on track-structure appears warranted.

Determination of natural and depleted uranium in urine at the ppt level: an interlaboratory analytical exercise.

An analytical exercise was initiated in order to determine those procedures with the capability to measure total uranium and uranium (238U/235U) isotopic ratios in urine samples containing >0.02 microg U kg-1 urine. A host laboratory prepared six identical sets of twelve synthetic urine samples containing total uranium in the range of 25 to 770 ng U kg-1 urine and with 238U/235U isotopic ratios ranging from 138 (100% NU) to 215 (51% DU). Sets of samples were shipped to five testing laboratories (four based in Canada and one based in Europe). Each laboratory utilized one of the following analytical techniques: sector field inductively coupled plasma mass spectrometry (ICP-SF-MS), quadrupole inductively coupled plasma mass spectrometry (ICP-Q-MS), thermal ionization mass spectrometry (TIMS), and instrumental/delayed neutron activation analysis (I/DNAA), in their analyses.

Bubble detector characterization for space radiation.

In light of the importance of the neutron contribution to the dose equivalent received by space workers in the near-Earth radiation environment, there is an increasing need for a personal dosimeter that is passive in nature and able to respond to this neutron field in real time. Recent Canadian technology has led to the development of a bubble detector, which is sensitive to neutrons, but insensitive to low linear energy transfer (LET) radiation. By changing the composition of the bubble detector fluid (or "superheat"), the detectors can be fabricated to respond to different types of radiation. This paper describes a preliminary ground-based research effort to better characterize the bubble detectors of different compositions at various charged-particle accelerator facilities, which are capable of simulating the space radiation field.

Estimated neutron dose to embryo and foetus during commercial flight.

A study has been carried out to assess the radiation exposure from cosmic-ray neutrons to the embryo and foetus of pregnant aircrew and air travellers in consideration of the radiation exposure from cosmic-ray neutrons to the embryo and foetus. A Monte Carlo analysis was performed to determine the equivalent dose from neutrons to the brain and body of an embryo at 8 weeks and to the foetus at the 3, 6 and 9 month periods. Neutron fluence-to-absorbed dose conversion coefficients for the foetal brain and for the entire foetal body (isotropic irradiation geometry) have been determined at the four developmental stages. The equivalent dose rate to the foetus during commercial flights has been further evaluated considering the fluence-to-absorbed dose conversion coefficients, a neutron spectrum measured at an altitude of 11.3 km and an ICRP-92 radiation-weighting factor for neutrons. This study indicates that the foetus can exceed the annual dose limit of 1 mSv for the general public after, for example, 15 round trips on commercial trans-Atlantic flights.

Aircrew dosimetry using the Predictive Code for Aircrew Radiation Exposure (PCAIRE).

During 2003, a portable instrument suite was used to conduct cosmic radiation measurements on 49 jet-altitude flights, which brings the total number of in-flight measurements by this research group to over 160 flights since 1999. From previous measurements, correlations have been developed to allow for the interpolation of the dose-equivalent rate for any global position, altitude and date. The result was a Predictive Code for Aircrew Radiation Exposure (PCAIRE), which has since been improved. This version of the PCAIRE has been validated against the integral route dose measurements made at commercial aircraft altitudes during the 49 flights. On most flights, the code gave predictions that agreed to the measured data (within +/- 25%), providing confidence in the use of PCAIRE to predict aircrew exposure to galactic cosmic radiation. An empirical correlation, based on ground-level neutron monitoring data, has also been developed for the estimation of aircrew exposure from solar energetic particle (SEP) events. This model has been used to determine the significance of SEP exposure on a theoretical jet altitude flight during GLE 42.