Dosimetry of ultra-high dose rate electron beams using thermoluminescence and optically stimulated luminescence detectors.

Objective.The aim of this work is to investigate the dose rate dependence of thermoluminescence and optically stimulated luminescence detectors (TLDs and OSLDs) in a wide uniform ultra-high dose rate electron beam and demonstrate the potential use of TLDs and OSLDs to correct the ion recombination in air-filled ionization chambers. This study avoids previously reported complications related to the field size and homogeneity.Approach.Two types of OSLDs (BeO and Al2O3:C) and three types of TLDs (LiF:Mg,Ti, LiF:Mg,Cu,P, CaF2:Tm) were irradiated simultaneously in a uniform 16 MeV electron beam generated by a clinically decommissioned C-Arm LINAC, modified to deliver doses per pulse between 8.3 × 10-4Gy and 1.255 Gy, corresponding to instantaneous dose rates between 2 × 102Gy s-1and 3 × 105Gy s-1. A prototype ultra-thin parallel plate ionization chamber was employed as reference detector.Main results.Reproducible results were achieved both at conventional (standard deviation of the data <2%) and at the highest dose per pulse (standard deviation of the data <4%). No trend in the dose rate response of the TLDs and OSLDs was observed in the investigated dose per pulse range. The Al2O3:C OSLD was found to be the most precise detector, with a standard deviation of the data <2% at all investigated dose rates and dose levels.Significance.The dose rate independence of the investigated TLDs and OSLDs make them good candidates for dosimetry at ultra-high dose rates, at least up to 3 × 105Gy s-1. A dose rate independent method to measure the dose per pulse is proposed, which can be applied to characterize ultra-high dose rate electron beams and correct for ion recombination in ionization chambers.

Investigation of TL and OSL detectors in ultra-high dose rate electron beams.

Objective.This work aims at investigating the response of various thermally stimulated luminescence detectors (TLDs) and optically stimulated luminescence detectors (OSLDs) for dosimetry of ultra-high dose rate electron beams. The study was driven by the challenges of dosimetry at ultra-high dose rates and the importance of dosimetry for FLASH radiotherapy and radiobiology experiments.Approach.Three types of TLDs (LiF:Mg,Ti; LiF:Mg,Cu,P; CaF2:Tm) and one type of OSLD (Al2O3:C) were irradiated in a 15 MeV electron beam with instantaneous dose rates in the (1-324) kGy s-1range. Reference dosimetry was carried out with an integrating current transformer, which was calibrated in absorbed dose to water against a reference ionization chamber. Additionally, dose rate independent BeO OSLDs were employed as a reference. Beam non-uniformity was addressed using a matrix of TLDs/OSLDs.Main results.The investigated TLDs were shown to be dose rate independent within the experimental uncertainties, which take into account the uncertainty of the dosimetry protocol and the irradiation uncertainty. The relative deviation between the TLDs and the reference dose was lower than 4 % for all dose rates. A decreasing response with the dose rate was observed for Al2O3:C OSLDs, but still within 10 % from the reference dose.Significance.The precision of the investigated luminescence detectors make them suitable for dosimetry of ultra-high dose rate electron beams. Specifically, the dose rate independence of the TLDs can support the investigation of the beam uniformity as a function of the dose rate, which is one of the challenges of the employed beam. Al2O3:C OSLDs provided high precision measurements, but the decreasing response with the dose rate needs to be confirmed by additional experiments.

Characterization of LiF:Mg,Ti thermoluminescence detectors in low-LET proton beams at ultra-high dose rates.

Objective.This work aims at characterizing LiF:Mg,Ti thermoluminescence detectors (TLDs) for dosimetry of a 250 MeV proton beam delivered at ultra-high dose rates (UHDR). Possible dose rate effects in LiF:Mg,Ti, as well as its usability for dosimetry of narrow proton beams are investigated.Approach.LiF:Mg,Ti (TLD-100TMMicrocubes, 1 mm × 1 mm × 1 mm) was packaged in matrices of 5 × 5 detectors. The center of each matrix was irradiated with single-spot low-LET (energy >244 MeV) proton beam in the (1-4500) Gy s-1average dose rates range. A beam reconstruction procedure was applied to the detectors irradiated at the highest dose rate (Gaussian beam sigma <2 mm) to correct for volumetric averaging effects. Reference dosimetry was carried out with a diamond detector and radiochromic films. The delivered number of protons was measured by a Faraday cup, which was employed to normalize the detector responses.Main results.The lateral beam spread obtained from the beam reconstruction agreed with the one derived from the radiochromic film measurements. No dose rates effects were observed in LiF:Mg,Ti for the investigated dose rates within 3% (k= 1). On average, the dose response of the TLDs agreed with the reference detectors within their uncertainties. The largest deviation (-5%) was measured at 4500 Gy s-1.Significance.The dose rate independence of LiF:Mg,Ti TLDs makes them suitable for dosimetry of UHDR proton beams. Additionally, the combination of a matrix of TLDs and the beam reconstruction can be applied to determine the beam profile of narrow proton beams.

Ultra-high dose rate dosimetry for pre-clinical experiments with mm-small proton fields.

PURPOSE: To characterize an experimental setup for ultra-high dose rate (UHDR) proton irradiations, and to address the challenges of dosimetry in millimetre-small pencil proton beams. METHODS: At the PSI Gantry 1, high-energy transmission pencil beams can be delivered to biological samples and detectors up to a maximum local dose rate of âˆ¼9000 Gy/s. In the presented setup, a Faraday cup is used to measure the delivered number of protons up to ultra-high dose rates. The response of transmission ion-chambers, as well as of different field detectors, was characterized over a wide range of dose rates using the Faraday cup as reference. RESULTS: The reproducibility of the delivered proton charge was better than 1 % in the proposed experimental setup. EBT3 films, Al2O3:C optically stimulated luminescence detectors and a PTW microDiamond were used to validate the predicted dose. Transmission ionization chambers showed significant volume ion-recombination (>30 % in the tested conditions) which can be parametrized as a function of the maximum proton current density. Over the considered range, EBT3 films, inorganic scintillator-based screens and the PTW microDiamond were demonstrated to be dose rate independent within ±3 %, ±1.8 % and ±1 %, respectively. CONCLUSIONS: Faraday cups are versatile dosimetry instruments that can be used for dose estimation, field detector characterization and on-line dose verification for pre-clinical experiments in UHDR proton pencil beams. Among the tested detectors, the commercial PTW microDiamond was found to be a suitable option to measure real time the dosimetric properties of narrow pencil proton beams for dose rates up to 2.2 kGy/s.

Mapping initial and general recombination in scanning proton pencil beams.

The ion recombination is examined in parallel-plate ionization chambers in scanning proton beams at the Danish Centre for Particle Therapy and the Skandion Clinic. The recombination correction factor k s is investigated for clinically relevant energies between 70 MeV and 244 MeV for dose rates below 400 Gy min-1 in air. The Boutillon formalism is used to separate the initial and general recombination. The general recombination is compared to predictions from the numerical recombination code IonTracks and the initial recombination to the Jaffé theory. k s is furthermore calculated with the two-voltage method (TVM) and extrapolation approaches, in particular the recently proposed three-voltage (3VL) method. The TVM is in agreement with the Boutillon method and IonTracks for dose rates above 100 Gy min-1. However, the TVM calculated k s is closer related to the Jaffé theory for initial recombination for lower dose rate, indicating a limited application in scanning light ion beams. The 3VL is in turn found to generally be in agreement with Boutillon's method. The recombination is mapped as a function of the dose rate and proton energy at the two centres using the Boutillon formalism: the initial recombination parameter was found to be A = (0.10 ± 0.01) V at DCPT and A = (0.22 ± 0.13) V at Skandion, which is in better agreement with the Jaffé theory for initial recombination than previously reported values. The general recombination parameter was estimated to [Formula: see text] and [Formula: see text]. Furthermore, the numerical algorithm IonTracks is demonstrated to correctly predict the initial recombination at low dose rates and the general recombination at high dose rates.

Shape-preserving and unidirectional frequency conversion by four-wave mixing.

In this work, we investigate the properties of four-wave mixing Bragg scattering driven by orthogonally polarized pumps in a birefringent waveguide. This configuration enables a large signal conversion bandwidth, and allows strongly unidirectional frequency conversion as undesired Bragg-scattering processes are suppressed by waveguide birefringence. Moreover, we show that this form of Bragg scattering preserves the (arbitrary) signal pulse shape, even when driven by pulsed pumps.

Engineering spectrally unentangled photon pairs from nonlinear microring resonators by pump manipulation.

The future of integrated quantum photonics relies heavily on the ability to engineer refined methods for preparing the quantum states needed to implement various quantum protocols. An important example of such states is quantum-correlated photon pairs, which can be efficiently generated using spontaneous nonlinear processes in integrated microring-resonator structures. In this work, we propose a method for generating spectrally unentangled photon pairs from a standard microring resonator. The method utilizes interference between a primary and a delayed secondary pump pulse to effectively increase the pump spectral width inside the cavity. This enables on-chip generation of heralded single photons with state purities in excess of 99% without spectral filtering.

Generation of two-temporal-mode photon states by vector four-wave mixing.

Photon pair states and multiple-photon squeezed states have many applications in quantum information science. In this paper, Green functions are derived for spontaneous four-wave mixing in the low- and high-gain regimes. Nondegenerate four-wave mixing in a strongly-birefringent medium generates signal and idler photons that are associated with only one pair of temporal (Schmidt) modes, for a wide range of pump powers and arbitrary pump shapes. The Schmidt coefficients (expected photon numbers) depend sensitively on the pump powers, and the Schmidt functions (shapes of the photon wavepackets) depend sensitively on the pump powers and shapes, which can be controlled.

Superconducting state of the organic conductor (TMTSF)2ClO4.

(TMTSF)2ClO4 is a quasi-one-dimensional organic conductor and superconductor with Tc=1.4 K, and one of at least two Bechgaard salts observed to have upper critical fields far exceeding the paramagnetic limit. Nevertheless, the 77Se NMR Knight shift at low fields reveals a decrease in spin susceptibility chi(s) consistent with singlet spin pairing. The field dependence of the spin-lattice relaxation rate at 100 mK exhibits a sharp crossover (or phase transition) at a field Hs approximately 15 kOe, to a regime where chi(s) is close to the normal state value, even though Hc2>> Hs.

Role for the adenovirus IVa2 protein in packaging of viral DNA.

Although it has been demonstrated that the adenovirus IVa2 protein binds to the packaging domains on the viral chromosome and interacts with the viral L1 52/55-kDa protein, which is required for viral DNA packaging, there has been no direct evidence demonstrating that the IVa2 protein is involved in DNA packaging. To understand in greater detail the DNA packaging mechanisms of adenovirus, we have asked whether DNA packaging is serotype or subgroup specific. We found that Ad7 (subgroup B), Ad12 (subgroup A), and Ad17 (subgroup D) cannot complement the defect of an Ad5 (subgroup C) mutant, pm8001, which does not package its DNA due to a mutation in the L1 52/55-kDa gene. This indicates that the DNA packaging systems of different serotypes cannot interact productively with Ad5 DNA. Based on this, a chimeric virus containing the Ad7 genome except for the inverted terminal repeats and packaging sequence from Ad5 was constructed. This chimeric virus replicates its DNA and synthesizes Ad7 proteins, but it cannot package its DNA in 293 cells or 293 cells expressing the Ad5 L1 52/55-kDa protein. However, this chimeric virus packages its DNA in 293 cells expressing the Ad5 IVa2 protein. These results indicate that the IVa2 protein plays a role in viral DNA packaging and that its function is serotype specific. Since this chimeric virus cannot package its own DNA, but produces all the components for packaging Ad7 DNA, it may be a more suitable helper virus for the growth of Ad7 gutted vectors for gene transfer.

Engineering and characterization of functional human microvessels in immunodeficient mice.

SUMMARY: Current model systems used to investigate angiogenesis in vivo rely on the interpretation of results obtained with nonhuman endothelial cells. Recent advances in tissue engineering and molecular biology suggest the possibility of engineering human microvessels in vivo. Here we show that human dermal microvascular endothelial cells (HDMEC) transplanted into severe combined immunodeficient (SCID) mice on biodegradable polymer matrices differentiate into functional human microvessels that anastomose with the mouse vasculature. HDMEC were stably transduced with Flag epitope or alkaline phosphatase to confirm the human origin of the microvessels. Endothelial cells appeared dispersed throughout the sponge 1 day after transplantation, became organized into empty tubular structures by Day 5, and differentiated into functional microvessels within 7 to 10 days. Human microvessels in SCID mice expressed the physiological markers of angiogenesis: CD31, CD34, vascular cellular adhesion molecule 1 (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1). Human endothelial cells became invested by perivascular smooth muscle alpha-actin-expressing mouse cells 21 days after implantation. This model was used previously to demonstrate that overexpression of the antiapoptotic protein Bcl-2 in HDMEC enhances neovascularization, and that apoptotic disruption of tumor microvessels is associated with apoptosis of surrounding tumor cells. The proposed SCID mouse model of human angiogenesis is ideally suited for the study of the physiology of microvessel development, pathologic neovascular responses such as tumor angiogenesis, and for the development and investigation of strategies designed to enhance the neovascularization of engineered human tissues and organs.

BK virus as a potential co-factor in human cancer.

BK virus (BKV) is a member of the polyomavirus family that persistently infects 75-80% of the human population. BKV encodes a large T antigen which is responsible for the transforming functions of the virus. Recent studies have shown an association of BKV DNA with a variety of human tumours including pancreatic islet, brain, urinary tract and Kaposi's sarcoma. Despite the detection of BKV DNA in several human tumours, there is no clear evidence for a causative role in tumour formation. We have sought to characterize the interactions of BKV TAg with cellular tumour suppressor proteins including p53, pRb, p107, and p130 in an attempt to further understand the molecular mechanisms of transformation by BKV. We have shown that BKV TAg can bind to and functionally inhibit p53 and the p53-mediated response to DNA damage. Additionally, we have shown that low levels of BKV TAg are sufficient to induce free E2F and a serum-independent phenotype despite the absence of detectable interactions with pRb family members. Taken together, these results suggest that BKV TAg can both inhibit the cellular response to DNA damage and induce proliferation, allowing for potential accumulation of mutations in cellular growth control genes. These results suggest a possible role for BKV TAg in cellular transformation and tumour formation in the human host.

Novel mechanisms of E2F induction by BK virus large-T antigen: requirement of both the pRb-binding and the J domains.

E2F activity is regulated in part by the retinoblastoma family of tumor suppressor proteins. Viral oncoproteins, such as simian virus 40 (SV40) large-T antigen (TAg), adenovirus E1A, and human papillomavirus E7, can disrupt the regulation of cellular proliferation by binding to pRb family members and dissociating E2F-pRb family protein complexes. BK virus (BKV), which infects a large percentage of the human population and has been associated with a variety of human tumors, encodes a TAg homologous to SV40 TAg. It has been shown that BKV TAg, when expressed at low levels, does not detectably bind to pRb family members, yet it induces a serum-independent phenotype and causes a decrease in the overall levels of pRb family proteins. The experiments presented in this report show that, despite the lack of TAg-pRb interactions, BKV TAg can induce transcriptionally active E2F and that this induction does in fact require an intact pRb-binding domain as well as an intact J domain. In addition, E2F-pRb family member complexes can be detected in both BKV and SV40 TAg-expressing cells. These results suggest the presence of alternate cellular mechanisms for the release of E2F in addition to the well-established model for TAg-pRb interactions. These results also emphasize a role for BKV TAg in the deregulation of cellular proliferation, which may ultimately contribute to neoplasia.

BK virus large T antigen: interactions with the retinoblastoma family of tumor suppressor proteins and effects on cellular growth control.

BK virus (BKV) is a polyomavirus which infects a large percentage of the human population. It is a potent transforming agent and is tumorigenic in rodents. BKV DNA has also been found in human brain, pancreatic islet, and urinary tract tumors, implicating this virus in neoplastic processes. BKV T antigen (TAg) is highly homologous to simian virus 40 TAg, particularly in regions required for mitogenic stimulation and binding to tumor suppressor proteins, The experiments presented in this report show that BKV TAg can bind the tumor suppressor protein p53. BKV TAg also has the ability to bind to members of the retinoblastoma (pRb) family of tumor suppressor proteins both in vivo and in vitro. However, these interactions are detected only when large amounts of total protein are used, because the levels of BKV TAg normally produced from viral promoter-enhancer elements are too low to bind a significant amount of the pRb family proteins in the cell. The low levels of BKV TAg produced by the viral promoter elements are sufficient to affect the levels and the phosphorylation patterns of these proteins and to induce serum-independent growth in these cells. Additional events, however, are required for full transformation. These data further support the notion that BKV TAg can affect cellular growth control mechanisms and may in fact be involved in neoplastic processes.

[Perioperative risk in heart surgery. An original material and review of difficulties in correct comparisons with other materials]. / Perioperativ risiko ved hjerteoperationer. Et originalmateriale og en gennemgang af vanskelighederne ved korrekt sammenligning med andre materialer.

The purpose of this study was to present data concerning morbidity and mortality after cardiac surgery and to establish a method to make the presentation comparable to other reports. The main difficulty in comparing results of surgery of one institution with those of another is the lack of a simple and widely acceptable quantification of risk. A preoperative risk classification of patients requires readily available and objective data. The shortage of standardized criteria for comparing outcome was obvious as only a few comprehensive reports regarding preoperative predictors were found in the literature. The method of Tuman et al is based on 12 preoperative risk factors that are reasonably free of observer bias and practically obtainable. This method was used to report the results of 628 consecutive patients undergoing coronary revascularization or valvular surgery. Total in-hospital morbidity was 3.5% and mortality 1.0%. The most important predictors for postoperative morbidity were valvular surgery, advanced age, renal dysfunction, recent myocardial infarction and pulmonary hypertension. The system is most useful in predicting good outcome in low-risk patients. The identification of high-risk patients is valuable in spite of the limited predictive ability, by allowing special attention to be directed to the patient at risk.

The effects of 'in-use' surgical handwashing on the pre- and postoperative fingertip flora during cardiothoracic and orthopaedic surgery.

Two operating teams (25 persons) were followed for two months with fingerprint samples taken preoperatively; before and after 'in-use' surgical handwashing; and immediately postoperatively, with and without surgical gloves. The mean time for handwashing for the cardiothoracic team (CT) was 2 min and for the orthopaedic team (OT) was 3.5 min. A closer observation of 10 persons revealed a great individual variation in washing techniques, in spite of standard guidelines. The CT team performed eight, and the OT team nine sterile operations with an average duration of 3 h and 20 min and 2 h and 40 min, respectively. Surgical handwashing resulted in fingertip sterility in 111/118 (94.1%) cases; in 61/66 (92.4%) samples from the surgeons and in 50/52 (96.2%) samples from the assistants. Postoperative fingerprinting with gloves on showed sterile conditions in 85/91 (93.4%) samples; 57/59 (96.6%) from the surgeons and 28/32 (87.5%) from the assistants. Immediately after removal of the gloves, 43/67 (64.2%) of fingerprint samples from the surgeons and 13/48 (27.1%) from the assistants were still sterile. Coagulase-negative staphylococci (CNS) and Bacillus species predominated in fingerprint samples. Of the 105 CNS strains tested, 11.4% were methicillin resistant. Only five strains of Staphylococcus aureus were isolated; in 4/5 cases from the OT. This study illustrates that in spite of standard guidelines, there is great individual variation in surgical handwashing. However, in most instances, the bacteria are eradicated from the fingertips. Even after surgery for 2-3 h, there may still be a residual effect of the hand disinfecting agent in half of the cases.

Inactivation of the retinoblastoma susceptibility protein is not sufficient for the transforming function of the conserved region 2-like domain of simian virus 40 large T antigen.

Simian virus 40 large T antigen interacts with three cellular proteins, pRb, p107, and p130, through a common binding site on the T antigen protein called the E1A conserved region 2-like (CR2-like) domain. Mutations in this domain inactivate the transforming activity of large T antigen. Since these mutations have been demonstrated to abolish binding to pRb and p107, and presumably therefore affect binding to p130, assessment of the relative roles of these three proteins in transformation of rodent fibroblasts by T antigen has been difficult. We have examined the role of T antigen-pRb interactions in transformation. We have introduced a mutant T antigen, which is unable to bind any of these three proteins, into primary mouse fibroblasts derived from the embryos of mice in which the Rb gene encoding the retinoblastoma protein had been disrupted. This mutant is unable to transform the Rb-negative fibroblasts, indicating that inactivation of pRb is not the sole function of the CR2-like domain in the induction of transformation of mouse fibroblasts by simian virus 40.

Kinetics of glucose oxidase catalyzed electron transfer mediated by sulfur and selenium compounds.

Unusually high electron transfer rates in Aspergillus niger glucose oxidase catalyzed oxidation of glucose using 5,6:11,12-Bis(dithio)tetracene (TTT), 1,2-dimethyltetraselenafulvalene (DMTSF) and tetrathiafulvalene (TTF) were observed. At pH 7.0 oxidation rate constants (TN/Km) in the range from 1.0.10(7) to 8.7.10(7) M.s-1 were deduced from experimental data. One of the investigated mediators, DMTSF, has been used for electrocatalytical glucose oxidation on graphite at a potential of 0.3 V vs. a standard calomel electrode (SCE). The prepared bioelectrodes have a sensitivity of 1.3 microA/(cm2.mM), a pH optimum at 6.5-7.0, and a linear range which covers the relevant range for monitoring physiological levels of glucose. The bioelectrodes are stable for more than one month.