When astronauts travel in space, their primary health hazards are high-energy cosmic radiations from galactic cosmic rays (GCR). Most galactic cosmic rays have energies between 100 MeV and 10 GeV. For occupants inside of a space shuttle, the structural material is efficient to absorb most of the cosmic-ray energy and reduce the interior dose rate to below 1.2 mGy per day. However, the biological effects of prolonged exposure to low-dose radiation are not well understood. The purpose of this research was to examine the feasibility of constructing a low-dose irradiation facility to simulate the uniform radiation field that exists in space. In this research, we used a pre-manufactured incubator, specifically the Thermo Scientific Forma Series II Water Jacketed CO2 Incubator, to act as shielding and simulate the exterior of the space shuttle. To achieve the desired dose rate (< 1 mGy/h) inside the incubator volume, the computer code MCNPX was used to determine required source activity and distance between the shielding and source. Once the activity and distance were calculated, an experiment was carried out to confirm the simulation results. The confirmation used survey meters and thermoluminescence dosimeters (TLDs) to map the radiation field within the incubator.

Made available in DSpace on 2014-10-09T12:32:56Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T14:06:03Z (GMT). No. of bitstreams: 1 17895.pdf: 786964 bytes, checksum: 781fa1b1bc7332a3c1c707115a8e0243 (MD5) / Dissertacao (Mestrado Profissionalizante em Lasers em Odontologia) / IPEN/D-MPLO / Instituto de Pesquisas Energeticas e Nucleares - IPEN-CNEN/SP; Faculdade de Odontologia, Universidade de São Paulo, São Paulo

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Yes / Objectives; To evaluate radiation doses for all low-dose CT scans performed during the first year of a lung screening trial. Methods; For all lung screening scans that were performed using a CT protocol that delivered image quality meeting the RSNA QIBA criteria, , radiation dose metrics, participant height, weight, gender and age were recorded. Values of CTDIvol and DLP were evaluated as a function of weight in order to assess the performance of the scan protocol across the participant cohort. Calculated effective doses were used to establish the additional lifetime attributable cancer risks arising from trial scans. Results; Median values of CTDIvol, DLP and effective dose (IQR) from the 3521 scans were 1.1mGy (0.70), 42.4mGycm (24.9) and 1.15mSv (0.67), whilst for 60-80kg participants the values were 1.0mGy (0.30), 35.8mGycm (11.4) and 0.97mSv (0.31). A statistically significant correlation between CTDIvol and weight was identified for males (r=0.9123, p<0.001) and females (r=0.9052, p<0.001), however the effect of gender on CTDIvol was not statistically significant (p=0.2328) despite notable differences existing at the extremes of the weight range. The additional lifetime attributable cancer risks from a single scan were in the range 0.001-0.006%. Conclusions; Low radiation doses can be achieved across a typical lung screening cohort using scan protocols that have been shown to deliver high levels of image quality. The observed dose levels may be considered as typical values for lung screening scans on similar types of scanner for an equivalent participant cohort. Advances in Knowledge; Presentation of typical radiation dose levels for CT lung screening examinations in a large UK trial. Effective radiation doses can be of the order of 1mSv for standard sized participants. Lifetime attributable cancer risks resulting from a single LDCT scan did not exceed 0.006%. / The Yorkshire Lung Screening Trial is funded by Yorkshire Cancer Research (award reference L403).

The aim of this project is to keep the x-ray exposure of the patient as low as reasonably achievable while improving the diagnostic image quality for the radiologist. The means to achieve these goals is to develop and evaluate an ecient adaptive ltering (denoising/image enhancement) method that fully explores true 4D image acquisition modes. The proposed prototype system uses a novel lter set having directional lter responses being monomials. The monomial lter concept is used both for estimation of local structure and for the anisotropic adaptive ltering. Initial tests on clinical 4D CT-heart data with ECG-gated exposure has resulted in a signicant reduction of the noise level and an increased detail compared to 2D and 3D methods. Another promising feature is that the reconstruction induced streak artifacts which generally occur in low dose CT are remarkably reduced in 4D.

Ionising radiation can cause damage to DNA that can result in gene mutations contributing to carcinogenesis. Radiation-protection policy currently estimates cancer risks from exposures to radiation in terms of excess risk per unit dose. At very low radiation dose-rates, where not all cells are absorbing radiation energy, this formula carries the inherent assumption that risk is limited to those cells receiving direct energy depositions. Numerous studies have now called this assumption into question. Such low dose-rates are in the relevant range that the public receives from natural background and man-made sources, and, if this fundamental assumption proves unfounded, current estimations of radiation-induced cancer risk at low doses will be incorrect. Accurate predictions of stochastic cancer risks from low-dose radiation exposures are crucial to evaluating the safety of radiation-based technologies for industry, power generation and the increasing use of radiation for medical diagnostic and screening purposes. This thesis explores phenomena known as radiation-induced bystander effects. The term bystander effects, as used here, describes biological responses to ionising radiation (hitherto observed in vitro) in cells not directly traversed by an ionising track, due to intercellular signals received from neighbouring cells that did receive energy depositions. This study aimed to determine whether radiation effects are communicated between irradiated and unirradiated cells in vivo, and if so, whether this effect alters current estimations of cancer risk following low-dose radiation exposures. In order to answer these questions, an in vivo experimental system for studying bystander effects in mice was developed. The method was based on the adoptive transfer of irradiated splenocytes into unirradiated hosts with simultaneous identification of irradiated donor cells, and biological endpoints in unirradiated bystander cells in situ using fluorescence microscopy and image analysis. Splenocytes from donor mice were radiolabelled with 3H-thymidine or received an acute X-ray dose. The irradiated donor cells, labelled with a fluorescent probe, were then adoptively transferred into unirradiated recipient mice via the tail vein, whilst control mice received sham-irradiated donor cells. A proportion of the cells lodged in the recipient mouse spleens where they remained for a period before the tissues were cryopreserved. The locations of donor cells were identified in frozen spleen sections by the fluorescent probe, and the levels of apoptosis and proliferation were simultaneously evaluated in situ in the surrounding unirradiated bystander cells using fluorescence-based assays. Transgenic pKZ1 recipient mice were also used to quantify chromosomal inversions in bystander cells. Since three-dimensional spatial relationships were preserved, responses could be measured in the local area surrounding irradiated cells as well as further afield. Following the development of the irradiated-cell adoptive transfer protocol and validation of the sensitivity and reproducibility of the biological assays in situ, a series of experiments was performed. In the initial experiments, 500,000 radiolabelled cells (0.33 mBq.cell-1) were injected into recipient mice and the spleen tissues were isolated 22 h later. No changes in apoptosis or proliferation were detected in local bystander spleen cells or throughout the spleen, compared to mice receiving sham-radiolabelled donor cells. In subsequent experiments, the effects of a number of experimental conditions were explored including the injection of tenfold more donor cells, analysis of spleen tissues after three days lodging in vivo, radiolabelling of donor cells with 100-fold higher 3H dose-rate and irradiation of donor cells ex vivo with 0.1 or 1 Gy X-rays. In each case, no changes in apoptosis or proliferation were observed. The in vivo method described here was designed to simulate the conditions of a bystander scenario from low dose-rate exposures relevant to public radiation protection. Contrary to the many reports of bystander effects in vitro, experiments using this sensitive method for examining the in vivo responses of unirradiated cells to neighbouring low-dose irradiated cells, have so far shown no changes in bystander cells in the spleen. This adoptive transfer method is the first in vivo method for examining the effects of known irradiated cells exposed to low radiation doses at low dose-rates, on neighbouring cells in situ that are truly unirradiated. Both the irradiated and bystander cells are normal, non-transformed primary spleen cells functioning in their natural environment. This in vivo experimental system allows the examination of tens of thousands of bystander cells and has shown a remarkable sensitivity, with statistical power to rule out changes in apoptosis &lt10% from the control. The relevance of in vitro bystander findings is unclear. Many reported bystander effects are more analogous to the systemic communication of abscopal effects from highly irradiated tissues. Disagreement between experimental systems and difficulty in reproducing key results between laboratories further complicate the translation of bystander data in vitro to human risk-estimation. The radiation protection community has expressed its need for in vivo validation of the bystander phenomenon before it can be included into the appraisal of carcinogenic risk. This adoptive transfer method is now available to study a range of bystander endpoints and potential signalling mechanisms in vivo, and provides a way to translate the wealth of data previously collected in vitro into findings directly relevant to human risk-estimation.

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Class of 2015 Abstract / Objectives: Guidelines from the Brain Trauma Foundation recommend that after traumatic brain injury (TBI) patients should be given seizure prophylaxis for up to seven days. Currently, phenytoin is the first line therapy for this indication. However, levetiracetam is increasingly being used as an alternative because it does not require serum concentration monitoring and has a desirable safety profile. Studies evaluating levetiracetam have used a loading dose, followed by a maintenance dose of 1000 mg every 12 hours. The primary objective of this study was to evaluate the efficacy of low-dose (500 mg every 12 hours) levetiracetam for seizure prophylaxis after TBI. Methods: This was a retrospective cohort study conducted in a tertiary care, academic institution that is designated as a level 1 trauma center. Institutional review board approval was obtained prior to data collection. Consecutive patients with TBI between 2010 and 2012, who received levetiracetam for seizure prophylaxis, were included. Patients who met at least one of the following criteria were included: cortical contusion on computerized tomography scan, subdural hematoma, epidural hematoma, intracerebral hematoma, depressed skull fracture, penetrating head injury, or Glasgow Coma Scale (GCS) of 10 or less. Patients were excluded if they were less than 16 years of age, had a previous head injury, previous neurosurgery, history of seizure, or anti-seizure medication, or were given a loading dose of levetiracetam, or given a maintenance dose greater than 500 mg every 12 hours. The primary outcome was the occurrence of a seizure within seven days of TBI. A one-sample test of proportions was used to compare the rate of seizures while being treated with levetiracetam to a hypothesized value of 3.6 percent (from previous trials), using an a priori alpha for 0.05. Results: There were a total of 146 patients included in the study, who were treated with levetiracetam 500 mg every 12 hours. The median age was 51 years (interquartile range 31 to 65 years), 110 (75 percent) were male, and the median GCS on admission was 11 (interquartile range 5 to 14). The mechanisms of injury were fall (n equals 49), motor vehicle or motorcycle collisions (n equals 42), pedestrian or bicyclist (n equals19), assault (n equals16), suicide attempt (n equals 2), and other (n equals18). The median time to first dose of levetiracetam was 4 hours after injury (interquartile range 1 to 13 hours). After initiation of levetiracetam, there were 5 (3.4 percent) patients who had a seizure within seven days. This was not significantly different than the hypothesized population value (p equals 0.910). The median length of stay was 13 days (interquartile range 9 to 21) and 7 (4.8 percent) patients died during hospitalization. Conclusions: A low-dose of levetiracetam 500 mg every 12 hours after TBI was effective for early seizure prevention. This regimen may be an appropriate alternative to phenytoin or traditional dose levetiracetam for this indication. Future, prospective studies are needed to confirm these findings.

The exposure to high doses of ionizing radiation (>5Gy) is unequivocally associated with increased cancer risk. However, there is substantial experimental evidence showing that in response to low doses of ionizing radiation (LDR: <100mGy), cells and organisms are benefitted with delayed ageing, improved immunity and reduced cancer growth. These intriguing findings have proposed the “Radiation Hormesis” hypothesis. Herein, I studied the senescence effects of LDR exposure to normal human HFL1 cells and examined transcriptional changes. I found that HFL1 cells exposed to 10 mGy of gamma radiation had delayed senescence measured at 12 weeks post-irradiation compared to unirradiated cells. Through qPCR array analysis, I found that genes involved in human cellular senescence functions are differentially regulated in 10 mGy exposed cells at 12 weeks compared to 1-week post-exposure. A nucleolar protein, SIRT7, that belongs to the family of proteins called Sirtuins with known roles in aging, was found to be upregulated transcriptionally in LDR-exposed HFL1 cells. Knocking out SIRT7 protein significantly accelerated senescence in HFL1 cells suggesting a direct role of SIRT7 in the deceleration of senescence and potentially in mediating radiation hormesis. Furthermore, overexpression of the HRAS oncogene strongly accelerated senescence in HFL1 cells through gene expression of cell cycle regulators and checkpoint proteins. Together, my studies revealed that LDR induces unique transcriptional changes resulting in a potentially radio adaptive protective cellular response. I also discuss the HRAS overexpression system as a time-efficient cellular model that could be used to more rapidly study the effect of LDR on senescence using primary cultures.