Optimization of 68Ga production at an 18 MeV medical cyclotron with solid targets by means of cross-section measurement of 66Ga, 67Ga and 68Ga.

The future development of personalized nuclear medicine relies on the availability of novel medical radionuclides. In particular, radiometals are attracting considerable interest since they can be used to label both proteins and peptides. Among them, the ß+-emitter 68Ga is widely used in nuclear medicine for positron emission tomography (PET). It is used in theranostics as the diagnostic partner of the therapeutic ß--emitters 177Lu and 90Y for the treatment of a wide range of diseases, including prostate cancer. Currently, 68Ga is usually obtained via 68Ge/68Ga generators. However, their availability, high price and limited produced radioactivity per elution are a major barrier for a wider use of the 68Ga-based diagnostic radiotracers. A promising solution is the production of 68Ga by means of proton irradiation of enriched 68Zn liquid or solid targets. Along this line, a research program is ongoing at the Bern medical cyclotron, equipped with a solid target station. In this paper, we report on the measurements of 68Ga, 67Ga and 66Ga production cross-sections using natural Zn and enriched 68Zn material, which served as the basis to perform optimized 68Ga production tests with enriched 68Zn solid targets.

Total parenteral nutrition is associated with worse hospital outcomes among elderly diabetic patients: a propensity score matched analysis on discharge records.

Background: Recent trials and reviews have raised question about the safety of total parenteral nutrition (TPN), due to the increased rate of TPN related complications. Diabetic patients are vulnerable to hyperglycaemia, and poor studies have investigated hospital out-comes of diabetic patients requiring TPN. The aim of this study was to evaluate the association of in-hospital mortality, prolonged length of stay and transfer to long-term care facilities among diabetic patients with TPN. Methods: The study considered all hospital admissions of diabetic patients over 65 years of age performed between 2006 and 2015 in Abruzzo Region, Italy. To compare the outcomes of TPN and non-TPN patients, a propensity score matching procedure was performed. Results: A total of 140,556 admissions were analyzed. After matching, 1947 patients were included into the analyses: 649 patients with TPN and 1298 controls. TPN was significantly associated to in-hospital mortality (OR=7.15; 95%CI 5.54-9.22), prolonged LOS (OR=2.78; 95%CI 2.28-3.38) and transfer to LTCF (OR=2.16; 95%CI 1.64-2.85). Discussion: TPN is associated with poor outcomes among elderly diabetic patients in the Italian setting. Being aware of the risk factors among diabetic patients with TPN can be used to anticipate the patients' needs during the admission and the immediate post-discharge period.

Predictors and Trend of Ketoacidosis Hospitalization Rate in Type 2 Diabetes Mellitus Patients from 2006 to 2015 in Abruzzo Region, Italy.

AIMS: This study aimed to assess the trend of hospitalizations for DKA in adult patients with type 2 diabetes mellitus and its associated factors. DESIGN: A retrospective cross-sectional study was performed. Data were collected from hospital discharge records (HDRs) of patients (age ≥18) with either primary or secondary discharge diagnosis for DKA and type 2 diabetes from 2006 to 2015 in Abruzzo region. Age-adjusted hospitalization rates were computed by gender and standardized on the regional population in 2006. A logistic regression model was implemented using presence of DKA as dependent variable. RESULTS: We identified 160,366 HDRs with type 2 diabetes. Out of them, 1611 (1.00%) were due to DKA. The hospitalization rates for DKA increased both for male +115.9 and female +142.8%, from 2006 to 2015. The most significant predictors of DKA were age 18-44 (aOR=4.17), uncontrolled diabetes (aOR=1.79), trauma (aOR=1.38), any infection (aOR=1.68), liver disease (aOR=1.29), fluid and electrolyte disorders (aOR=2.09), psychosis (aOR=1.69). CONCLUSIONS: Trends of DKA in adult patients with type 2 diabetes has been increasing in both male and female. Multimorbidity is an open challenge for public health, therefore better coordination is needed among different specialist consultants to reduce the occurrence of this preventable complication.

Bedrock sculpting under an active alpine glacier revealed from cosmic-ray muon radiography.

Mountain glaciers form landscapes with U-shaped valleys, roche moutonées and overdeepenings through bedrock erosion. However, little evidence for active glacial carving has been provided particularly for areas above the Equilibrium Line Altitude (ELA) where glaciers originate. This is mainly due to our lack of information about the shape of the bedrock underneath active glaciers in highly elevated areas. In the past years, the bedrock morphology underneath active glaciers has been studied by geophysical methods in order to infer the subglacial mechanisms of bedrock erosion. However, these comprise surveys on the glaciers' surface, from where it has been difficult to investigate the lateral boundary between the ice and the bedrock with sufficient resolution. Here we perform a muon-radiographic inspection of the Eiger glacier (Switzerland, European Alps) with the aid of cosmic-ray muon attenuation. We find a reach (600 × 300 m) within the accumulation area where strong lateral glacial erosion has cut nearly vertically into the underlying bedrock. This suggests that the Eiger glacier has profoundly sculpted its bedrock in its accumulation area. This also reveals that the cosmic-ray muon radiography is an ideal technology to reconstruct the shape of the bedrock underneath an active glacier.

First demonstration of antimatter wave interferometry.

Interference of matter waves is at the heart of quantum physics and has been observed for a wide range of particles from electrons to complex molecules. Here, we demonstrate matter wave interference of single positrons using a period-magnifying Talbot-Lau interferometer based on material diffraction gratings. The system produced high-contrast periodic fringes, which were detected by means of nuclear emulsions capable of determining the impact point of each individual positron with submicrometric resolution. The measured energy dependence of fringe contrast in the range of 8 to 16 keV proves the quantum-mechanical origin of the periodic pattern and excludes classical projective effects, providing the first observation to date of antimatter wave interference. Future applications of this interferometric technique include the measurement of the gravitational acceleration of neutral antimatter systems exploiting the inertial sensing capabilities of Talbot-Lau interference.

Study of the radioactivity induced in air by a 15-MeV proton beam.

Radioactivity induced by a 15-MeV proton beam extracted into air was studied at the beam transport line of the 18-MeV cyclotron at the Bern University Hospital (Inselspital). The produced radioactivity was calculated and measured by means of proportional counters located at the main exhaust of the laboratory. These devices were designed for precise assessment of air contamination for radiation protection purposes. The main produced isotopes were (11)C, (13)N and (14)O. Both measurements and calculations correspond to two different irradiation conditions. In the former, protons were allowed to travel for their full range in air. In the latter, they were stopped at the distance of 1.5 m by a beam dump. Radioactivity was measured continuously in the exhausted air starting from 2 min after the end of irradiation. For this reason, the short-lived (14)O isotope gave a negligible contribution to the measured activity. Good agreement was found between the measurements and the calculations within the estimated uncertainties. Currents in the range of 120-370 nA were extracted in air for 10-30 s producing activities of 9-22 MBq of (11)C and (13)N. The total activities for (11)C and (13)N per beam current and irradiation time for the former and the latter irradiation conditions were measured to be (3.60 ± 0.48) × 10(-3) MBq (nA s)(-1) and (2.89 ± 0.37) × 10(-3) MBq (nA s)(-1), respectively.

Effects of modulated microwave radiation at cellular telephone frequency (1.95 GHz) on X-ray-induced chromosome aberrations in human lymphocytes in vitro.

The case for a DNA-damaging action produced by radiofrequency (RF) signals remains controversial despite extensive research. With the advent of the Universal Mobile Telecommunication System (UMTS) the number of RF-radiation-exposed individuals is likely to escalate. Since the epigenetic effects of RF radiation are poorly understood and since the potential modifications of repair efficiency after exposure to known cytotoxic agents such as ionizing radiation have been investigated infrequently thus far, we studied the influence of UMTS exposure on the yield of chromosome aberrations induced by X rays. Human peripheral blood lymphocytes were exposed in vitro to a UMTS signal (frequency carrier of 1.95 GHz) for 24 h at 0.5 and 2.0 W/kg specific absorption rate (SAR) using a previously characterized waveguide system. The frequency of chromosome aberrations was measured on metaphase spreads from cells given 4 Gy of X rays immediately before RF radiation or sham exposures by fluorescence in situ hybridization. Unirradiated controls were RF-radiation- or sham-exposed. No significant variations due to the UMTS exposure were found in the fraction of aberrant cells. However, the frequency of exchanges per cell was affected by the SAR, showing a small but statistically significant increase of 0.11 exchange per cell compared to 0 W/kg SAR. We conclude that, although the 1.95 GHz signal (UMTS modulated) does not exacerbate the yield of aberrant cells caused by ionizing radiation, the overall burden of X-ray-induced chromosomal damage per cell in first-mitosis lymphocytes may be enhanced at 2.0 W/kg SAR. Hence the SAR may either influence the repair of X-ray-induced DNA breaks or alter the cell death pathways of the damage response.

Accelerator-based tests of radiation shielding properties of materials used in human space infrastructures.

Shielding is the only practical countermeasure for the exposure to cosmic radiation during space travel. It is well known that light, hydrogenated materials, such as water and polyethylene, provide the best shielding against space radiation. Kevlar and Nextel are two materials of great interest for spacecraft shielding because of their known ability to protect human space infrastructures from meteoroids and debris. We measured the response to simulated heavy-ion cosmic radiation of these shielding materials and compared it to polyethylene, Lucite (PMMA), and aluminum. As proxy to galactic nuclei we used 1 GeV n iron or titanium ions. Both physics and biology tests were performed. The results show that Kevlar, which is rich in carbon atoms (about 50% in number), is an excellent space radiation shielding material. Physics tests show that its effectiveness is close (80-90%) to that of polyethylene, and biology data suggest that it can reduce the chromosomal damage more efficiently than PMMA. Nextel is less efficient as a radiation shield, and the expected reduction on dose is roughly half that provided by the same mass of polyethylene. Both Kevlar and Nextel are more effective than aluminum in the attenuation of heavy-ion dose.

Shielding of relativistic protons.

Protons are the most abundant element in the galactic cosmic radiation, and the energy spectrum peaks around 1 GeV. Shielding of relativistic protons is therefore a key problem in the radiation protection strategy of crewmembers involved in long-term missions in deep space. Hydrogen ions were accelerated up to 1 GeV at the NASA Space Radiation Laboratory, Brookhaven National Laboratory, New York. The proton beam was also shielded with thick (about 20 g/cm2) blocks of lucite (PMMA) or aluminium (Al). We found that the dose rate was increased 40-60% by the shielding and decreased as a function of the distance along the axis. Simulations using the General-Purpose Particle and Heavy-Ion Transport code System (PHITS) show that the dose increase is mostly caused by secondary protons emitted by the target. The modified radiation field after the shield has been characterized for its biological effectiveness by measuring chromosomal aberrations in human peripheral blood lymphocytes exposed just behind the shield block, or to the direct beam, in the dose range 0.5-3 Gy. Notwithstanding the increased dose per incident proton, the fraction of aberrant cells at the same dose in the sample position was not significantly modified by the shield. The PHITS code simulations show that, albeit secondary protons are slower than incident nuclei, the LET spectrum is still contained in the low-LET range (<10 keV/microm), which explains the approximately unitary value measured for the relative biological effectiveness.

Cytogenetic effects of high-energy iron ions: dependence on shielding thickness and material.

We report results for chromosomal aberrations in human peripheral blood lymphocytes after they were exposed to high-energy iron ions with or without shielding at the HIMAC, AGS and NSRL accelerators. Isolated lymphocytes were exposed to iron ions with energies between 200 and 5000 MeV/nucleon in the 0.1-1-Gy dose range. Shielding materials consisted of polyethylene, lucite (PMMA), carbon, aluminum and lead, with mass thickness ranging from 2 to 30 g/cm2. After exposure, lymphocytes were stimulated to grow in vitro, and chromosomes were prematurely condensed using a phosphatase inhibitor (calyculin A). Aberrations were scored using FISH painting. The yield of total interchromosomal exchanges (including dicentrics, translocations and complex rearrangements) increased linearly with dose or fluence in the range studied. Shielding decreased the effectiveness per unit dose of iron ions. The highest RBE value was measured with the 1 GeV/nucleon iron-ion beam at NSRL. However, the RBE for the induction of aberrations apparently is not well correlated with the mean LET. When shielding thickness was increased, the frequency of aberrations per particle incident on the shield increased for the 500 MeV/nucleon ions and decreased for the 1 GeV/nucleon ions. Maximum variation at equal mass thickness was obtained with light materials (polyethylene, carbon or PMMA). Variations in the yield of chromosomal aberrations per iron particle incident on the shield follow variations in the dose per incident particle behind the shield but can be modified by the different RBE of the mixed radiation field produced by nuclear fragmentation. The results suggest that shielding design models should be benchmarked using both physics and biological data.

Modelled microgravity does not modify the yield of chromosome aberrations induced by high-energy protons in human lymphocytes.

The aim was to evaluate the effect of modelled microgravity on radiation-induced chromosome aberrations (CAs). G0 peripheral blood lymphocytes were exposed to 60 MeV protons or 250 kVp X-rays in the dose range 0-6 Gy, and allowed to repair DNA damage for 24 h under either normal gravity or microgravity modelled by the NASA-designed rotating-wall bioreactor. Cells were then stimulated to proliferate by phytohaemagglutinin (PHA) under normal gravity conditions and prematurely condensed chromosomes were harvested after 48 h. CAs were scored in chromosomes 1 and 2 by fluorescence in-situ hybridization. Proliferation gravisensitivity was examined by cell growth curves and by morphological evaluation of mitogen-induced activation. Cell replication rounds were monitored by bromodeoxyuridine labelling. Modelled microgravity markedly reduced PHA-mediated lymphocyte blastogenesis and cell growth. However, no significant differences between normal gravity and modelled microgravity were found in the dose-response curves for the induction of aberrant cells or total interchromosomal exchange frequency. Rotating-wall bioreactor-based microgravity reproduced space-related alterations of mitogen stimulation in human lymphocytes but did not affect the yield of CAs induced by low-linear energy transfer radiation.

Fragmentation studies of relativistic iron ions using plastic nuclear track detectors.

We measured fluence and fragmentation of high-energy (1 or 5 A GeV) 56Fe ions accelerated at the Alternating Gradient Synchrotron or at the NASA Space Radiation Laboratory (Brookhaven National Laboratory, NY, USA) using solid-state CR-39 nuclear track detectors. Different targets (polyethylene, PMMA, C, Al, Pb) were used to produce a large spectrum of charged fragments. CR-39 plastics were exposed both in front and behind the shielding block (thickness ranging from 5 to 30 g/cm2) at a normal incidence and low fluence. The radiation dose deposited by surviving Fe ions and charged fragments was measured behind the shield using an ionization chamber. The distribution of the measured track size was exploited to distinguish the primary 56Fe ions tracks from the lighter fragments. Measurements of projectile's fluence in front of the shield were used to determine the dose per incident particle behind the block. Simultaneous measurements of primary 56Fe ion tracks in front and behind the shield were used to evaluate the fraction of surviving iron projectiles and the total charge-changing fragmentation cross-section. These physical measurements will be used to characterize the beam used in parallel biological experiments.

Chromosomal aberrations induced by high-energy iron ions with shielding.

Biophysical models are commonly used to evaluate the effectiveness of shielding in reducing the biological damage caused by cosmic radiation in space flights. To improve and validate these codes biophysical experiments are needed. We have measured the induction of chromosomal aberrations in human peripheral blood lymphocytes exposed in vitro to 500 MeV/n iron ion beams (dose range 0.1-1 Gy) after traversing shields of different material (lucite, aluminium, or lead) and thickness (0-11.3 g/cm2). For comparison, cells were exposed to 200 MeV/n iron ions and to X-rays. Chromosomes were prematurely condensed by a phosphatase inhibitor (calyculin A) to avoid cell-cycle selection produced by the exposure to high-LET heavy-ion beams. Aberrations were scored in chromosomes 1, 2, and 4 following fluorescence in situ hybridization. The fraction of aberrant lymphocytes has been evaluated as a function of the dose at the sample position, and of the fluence of primary 56Fe ions hitting the shield. The influence of shield thickness on the action cross-section for the induction of exchange-type aberrations has been analyzed, and the dose average-LET measured as a function of the shield thickness. These preliminary results prove that the effectiveness of heavy ions is modified by shielding, and the biological damage is dependent upon shield thickness and material.

Biological dosimetry in Russian and Italian astronauts.

Large uncertainties are associated with estimates of equivalent dose and cancer risk for crews of long-term space missions. Biological dosimetry in astronauts is emerging as a useful technique to compare predictions based on quality factors and risk coefficients with actual measurements of biological damage in-flight. In the present study, chromosomal aberrations were analyzed in one Italian and eight Russian cosmonauts following missions of different duration on the MIR and the international space station (ISS). We used the technique of fluorescence in situ hybridization (FISH) to visualize translocations in chromosomes 1 and 2. In some cases, an increase in chromosome damage was observed after flight, but no correlation could be found between chromosome damage and flight history, in terms of number of flights at the time of sampling, duration in space and extra-vehicular activity. Blood samples from one of the cosmonauts were exposed in vitro to 6 MeV X-rays both before and after the flight. An enhancement in radiosensitivity induced by the spaceflight was observed.

On the radiosensitivity of man in space.

Astronauts' radiation exposure limits are based on experimental and epidemiological data obtained on Earth. It is assumed that radiation sensitivity remains the same in the extraterrestrial space. However, human radiosensitivity is dependent upon the response of the hematopoietic tissue to the radiation insult. It is well known that the immune system is affected by microgravity. We have developed a mathematical model of radiation-induced myelopoiesis which includes the effect of microgravity on bone marrow kinetics. It is assumed that cellular radiosensitivity is not modified by the space environment, but repopulation rates of stem and stromal cells are reduced as a function of time in weightlessness. A realistic model of the space radiation environment, including the HZE component, is used to simulate the radiation damage. A dedicated computer code was written and applied to solar particle events and to the mission to Mars. The results suggest that altered myelopoiesis and lymphopoiesis in microgravity might increase human radiosensitivity in space.

Calibration curves for biological dosimetry by fluorescence in situ hybridisation.

Dose-response curves were measured for the induction of chromosomal aberrations in peripheral blood lymphocytes after acute exposure in vitro to 60Co gamma rays. Blood was obtained from four different healthy donors, and chromosomes were either observed at metaphase, following colcemid accumulation, or prematurely condensed by calyculin A. Cells were analysed in three different Italian laboratories. Chromosomes 1, 2, and 4 were painted, and simple-type interchanges between painted and non-painted chromosomes were scored in cells exposed in the dose range 0.1-3.0 Gy. The chemical-induced premature chromosome condensation method was also used combined with chromosome painting (chromosome 4 only) to determine calibration curves for high dose exposures (up to 20 Gy X rays). Calibration curves described in this paper will be used in our laboratories for biological dosimetry by fluorescence in situ hybridisation.

Inactivation of human cells exposed to fractionated doses of low energy protons: relationship between cell sensitivity and recovery efficiency.

Within the framework of radiation biophysics research in the hadrontherapy field, split-dose studies have been performed on four human cell lines with different radiation sensitivity (SCC25, HF19, H184B5 F5-1 M10, and SQ20B). Low energy protons of about 8 and 20 keV/micron LET and gamma-rays were used to study the relationship between the recovery ratio and the radiation quality. Each cell line was irradiated with two dose values corresponding to survival levels of about 5% and 1%. The same total dose was also delivered in two equal fractions separated by 1.5, 3, and 4.5 hours. A higher maximum recovery ratio was observed for radiosensitive cell lines as compared to radioresistant cells. The recovery potential after split doses was small for slow protons, compared to low-LET radiation. These data show that radiosensitivity may not be related to a deficient recovery, and suggest a possible involvement of inducible repair mechanisms.

Cell inactivation by beryllium, boron and carbon ions at the low-energy irradiation facility of the Naples University.

The 3MV HVEC TTT-3 Tandem accelerator at the University of Naples, already used for radiobiological studies with protons and alpha particles, was set up for irradiation of biological samples with low energy carbon, boron, and beryllium beams. Radiobiological characterisation and study of these ion beams is essential in hadrontherapy (correction of hadrotherapy) to understand, for example, the possible biological effect of the target fragmentation products. Furthermore in space radiation biology we need to know the biological effects of heavy ions, a component of cosmic radiation that can contribute to the radiobiological risk when long sojourns in space are concerned. V79 Chinese hamster cells were irradiated with the different ions and the resulting cell inactivation data are reported.

A model of radiation-induced myelopoiesis in space.

Astronauts' radiation exposure limits are based on experimental and epidemiological data obtained on Earth. It is assumed that radiation sensitivity remains the same in the extraterrestrial space. However, human radiosensitivity is dependent upon the response of the hematopoietic tissue to the radiation insult. It is well known that the immune system is affected by microgravity. We have developed a mathematical model of radiation-induced myelopoiesis which includes the effect of microgravity on bone marrow kinetics. It is assumed that cellular radiosensitivity is not modified by the space environment, but repopulation rates of stem and stromal cells are reduced as a function of time in weightlessness. A realistic model of the space radiation environment, including the HZE component, is used to simulate the radiation damage. A dedicated computer code was written and applied to solar particle events and to the mission to Mars. The results suggest that altered myelopoiesis and lymphopoiesis in microgravity might increase human radiosensitivity in space.

Effect of space radiation on expression of apoptosis-related genes in endometrial cells: a preliminary study.

In this paper we present some preliminary results on alteration of gene expression caused by radiation on human endometrial cells. To this purpose, we have studied the modulation of the expression of the bcl-2 gene family in two cell lines following irradiations with low energy protons and gamma-rays from a 60Co. The two epithelial cell strains, namely AN3Ca and HEC1B cells, both obtained from human neoplastic endometrial tissues, grow in culture and continue to maintain some differentiated functions typical of the original tissue. Indeed, these cells, that can be considered as representative of different stages of cellular transformation of endometrium. Because their epithelial nature and rapid growth, the expression of genes related to the maintenance of the cellular homeostasis (correction of omeostasis), as the pro and anti-apoptotic ones, is expected to be susceptible to changes in environment, including radiation. The effects have been evaluated in terms of both cell survival and changes in the expression of pro- and anti apoptotic proteins. Even though the data reported above can not be considered complete and/or definitive, nevertheless, in whole, they confirm that these cells may constitute a suitable model system to study, at molecular level, the effects of cosmic radiation on endometrium. Further observation, ensuing from these preliminary data, is that endometrial cells present different sensitivity to radiation in regard to its 'quality' and 'dosage', in accord to the original stage of differentiation.