Visible proton Bragg curve imaging by colour centre photoluminescence in radiation detectors based on lithium fluoride films on silica.

Passive solid-state radiation detectors, based on the visible photoluminescence (PL) of radiation-induced colour centres in optically transparent lithium fluoride (LiF), polycrystalline thin films are under investigation for proton beam advanced diagnostics. After proton exposure, the latent images stored in LiF as local formations of stable F2and F3+aggregate defects, are directly read with a fluorescence microscope under illumination in the blue spectral range. Adopting a suitable irradiation geometry, the energy density that protons deposit in the material can be recorded as a spatial distribution of these light-emitting defects, from which a luminous replica of the proton Bragg curve can be thereafter extracted and analysed to reconstruct the proton beam energy spectrum. Their peculiar properties, such as wide dynamic range and linearity of the spectrally-integrated PL response vs. dose, make the investigation of two-dimensional LiF film radiation detectors grown on several types of substrate highly attractive. Here, the case of a LiF thin film thermally evaporated on a silica substrate, irradiated at grazing incidence with a 35 MeV proton beam, is investigated and reported for the first time. A comparison of the measured photoluminescent Bragg curve with Monte Carlo simulations demonstrates that the Bragg peak in the film is located at the very same position that would be expected in the underlying silica substrate rather than in LiF. The film packing density is shown not to have a significant effect on the peak depth, while even small nonzero grazing angle of the impinging proton beam is able to significantly modify the shape of the Bragg curve. These findings are ascribed to the effects of multiple Coulomb scattering in both the film and the substrate and are interesting for proton beam diagnostics and dosimetry.

Advanced spectroscopic investigation of colour centres in LiF crystals irradiated with monochromatic hard x-rays.

Nominally-pure lithium fluoride (LiF) crystals were irradiated with monochromatic hard x-rays of energy 5, 7, 9 and 12 keV at the METROLOGIE beamline of the SOLEIL synchrotron facility, in order to understand the role of the selected x-ray energy on their visible photoluminescence (PL) response, which is used for high spatial resolution 2D x-ray imaging detectors characterized by a wide dynamic range. At the energies of 7 and 12 keV the irradiations were performed at five different doses corresponding to five uniformly irradiated areas, while at 5 and 9 keV only two irradiations at two different doses were carried out. The doses were planned in a range between 4 and 1.4 × 103Gy (10.5 mJ cm-3to 3.7 J cm-3), depending on the x-ray energy. After irradiation at the energies of 7 and 12 keV, the spectrally-integrated visible PL intensity of the F2and F3+colour centres (CCs) generated in the LiF crystals, carefully measured by fluorescence microscopy under blue excitation, exhibits a linear dependence on the irradiation dose in the investigated dose range. This linear behaviour was confirmed by the optical absorption spectra of the irradiated spots, which shows a similar linear behaviour for both the F2and F3+CCs, as derived from their overlapping absorption band at around 450 nm. At the highest x-ray energy, the average concentrations of the radiation-induced F, F2and F3+CCs were also estimated. The volume distributions of F2defects in the crystals irradiated with 5 and 9 keV x-rays were reconstructed in 3D by measuring their PL signal using a confocal laser scanning microscope operating in fluorescence mode. On-going investigations are focusing on the results obtained through thisz-scanning technique to explore the potential impact of absorption effects at the excitation laser wavelength.

THE TOP-IMPLART PROTON LINEAR ACCELERATOR: INTERIM CHARACTERISTICS OF THE 35 MEV BEAM.

In the framework of the Italian TOP-IMPLART project (Regione Lazio), ENEA-Frascati, ISS and IFO are developing and constructing the first proton linear accelerator based on an actively scanned beam for tumor radiotherapy with final energy of 150 MeV. An important feature of this accelerator is modularity: an exploitable beam can be delivered at any stage of its construction, which allows for immediate characterization and virtually continuous improvement of its performance. Currently, a sequence of 3 GHz accelerating modules combined with a commercial injector operating at 425 MHz delivers protons up to 35 MeV. Several dosimetry systems were used to obtain preliminary characteristics of the 35-MeV beam in terms of stability and homogeneity. Short-term stability and homogeneity better than 3% and 2.6%, respectively, were demonstrated; for stability an improvement with respect to the respective value obtained for the previous 27 MeV beam.

CHARACTERIZATION OF 27 MEV PROTON BEAM GENERATED BY TOP-IMPLART LINEAR ACCELERATOR.

The first proton linear accelerator for tumor therapy based on an actively scanned beam up to the energy of 150 MeV, is under development and construction by ENEA-Frascati, ISS and IFO, under the Italian TOP-IMPLART project. Protons up to the energy of 7 MeV are generated by a customized commercial injector operating at 425 MHz; currently three accelerating modules allow proton delivery with energy up to 27 MeV. Beam homogeneity and reproducibility were studied using a 2D ionizing chamber, EBT3 films, a silicon diode, MOSFETs, LiF crystals and alanine dosimetry systems. Measurements were taken in air with the detectors at ~1 m from the beam line exit window. The maximum energy impinging on the detectors surface was 24.1 MeV, an energy suitable for radiobiological studies. Results showed beam reproducibility within 5% and homogeneity within 4%, on a circular surface of 16 mm in diameter.

Calibration of GafChromic EBT3 for absorbed dose measurements in 5 MeV proton beam and (60)Co γ-rays.

PURPOSE: To study EBT3 GafChromic film in low-energy protons, and for comparison purposes, in a reference (60)Co beam in order to use it as a calibrated dosimetry system in the proton irradiation facility under construction within the framework of the Oncological Therapy with Protons (TOP)-Intensity Modulated Proton Linear Accelerator for RadioTherapy (IMPLART) Project at ENEA-Frascati, Italy. METHODS: EBT3 film samples were irradiated at the Istituto Nazionale di Fisica Nucleare-Laboratori Nazionali di Legnaro, Italy, with a 5 MeV proton beam generated by a 7 MV Van de Graaff CN accelerator. The nominal dose rates used were 2.1 Gy/min and 40 Gy/min. The delivered dose was determined by measuring the particle fluence and the energy spectrum in air with silicon surface barrier detector monitors. A preliminary study of the EBT3 film beam quality dependence in low-energy protons was conducted by passively degrading the beam energy. EBT3 films were also irradiated at ENEA-National Institute of Ionizing Radiation Metrology with gamma radiation produced by a (60)Co source characterized by an absorbed dose to water rate of 0.26 Gy/min as measured by a calibrated Farmer type ionization chamber. EBT3 film calibration curves were determined by means of a set of 40 film pieces irradiated to various doses ranging from 0.5 Gy to 30 Gy absorbed dose to water. An EPSON Expression 11000XL color scanner in transmission mode was used for film analysis. Scanner response stability, intrafilm uniformity, and interfilm reproducibility were verified. Optical absorption spectra measurements were performed on unirradiated and irradiated EBT3 films to choose the most sensitive color channel to the dose range used. RESULTS: EBT3 GafChromic films show an under response up to about 33% for low-energy protons with respect to (60)Co gamma radiation, which is consistent with the linear energy transfer dependence already observed with higher energy protons, and a negligible dose-rate dependence in the 2-40 Gy/min range. Short- and long-term scanner stabilities were 0.5% and 1.5%, respectively; film uniformity and reproducibility were better than 0.5%. CONCLUSIONS: The main purpose of this study was to implement EBT3 dosimetry in the proton low-energy radiobiology line of the TOP-IMPLART accelerator, having a maximum energy of 7 MeV. Low-energy proton and (60)Co calibrated sources were used to investigate the behavior of film response vs to be written in italicum dose. The calibration in 5 MeV protons is currently used for dose assessment in the radiobiological experiments at the TOP-IMPLART accelerator carried out at that energy value.

A crystallinity study of dental tissues and tartar by infrared spectroscopy.

In this paper we report a study of an important property of biomineralized phases, crystallinity, on the basis of previous results for synthetic apatite. Crystallinity is not only important for understanding biomineralization, it is also related to the maturation and mechanisms of growth of calcium phosphates in biological surroundings. We studied two kinds of sample, teeth as an example of biomineralized tissues and dental calculi (adhering) as an example of mineralization without participation of biological agents, except possibly bacteria. The investigation focused on study of ν(1)-ν(3) infrared absorption bands of PO(4)(3-) phosphates. We used ATR (attenuated total reflection) analysis to examine human dental tissues and tartar on several samples. The results confirm for the first time previous assumptions about the growth and maturation of dental calculi, i.e., crystallinity progresses from regions of high crystallinity to regions of lower crystallinity, and, in addition, its quantification with spatial resolution in the sample. A gradual pattern was observed in dental calculus. Another result from this study was that cementum and dentine had similar crystallinity, despite their different biological and mechanical functions.

Synchrotron radiation FTIR imaging in minutes: a first step towards real-time cell imaging.

FTIR microscopy with a focal plane array (FPA) of detectors enables routine chemical imaging on individual cells in only a few minutes. The brilliance of synchrotron radiation (SR) IR sources may enhance the signal obtained from such small biosamples containing small amounts of organic matter. We investigated individual cells obtained from a cell culture specifically developed for transmission FTIR imaging using either a Globar or an SR source coupled to the same instrumentation. SR-IR source focussing was optimized to control the energy distribution on the FPA of detectors. Here we show that accessing the IR absorption distribution from all the organic contents of cells at 1 x 1 microm pixel resolution was possible only with high circulating current (> or = 1.2 A) illuminating a limited number of the FPA's detectors to increase the signal-to-noise ratio of IR images. Finally, a high-current SR ring is mandatory for collecting FTIR images of biosamples with a high contrast in minutes.

Application of micro-FTIR imaging in the Earth sciences.

In this paper we describe recent applications of micro-infrared imaging in the Earth sciences. We address, in particular, the use of Fourier-transform infrared (FTIR) spectroscopy in characterizing the zoning and speciation of H and C in a variety of geological materials, including microporous minerals, nominally anhydrous volcanic minerals (NAMs), and crystal inclusions. These investigations show that use of the modern techniques of FTIR imaging enables detection of the zoning of volatile species across the studied samples, and possible configuration changes of structurally-bound carbon molecular species (e.g., CO(2) vs CO(3)) during crystal growth. Such features, which are not accessible with other micro-analytical techniques, may provide information about the physicochemical properties which act as constraints in the genesis of the samples, and important information about the evolution of the geological system. Tests performed with focal-plane-array detectors (FPA) show that resolution close to the diffraction limit can be achieved if the amounts of the target molecules in the sample are substantially different. We also point out the possibility of using FTIR imaging for investigations under non-ambient conditions.

Pregnancy induces molecular alterations reflecting impaired insulin control over glucose oxidative pathways that only in women with a family history of Type 2 diabetes last beyond pregnancy.

In circulating lymphomonocytes (CLM) of patients with Type 2 diabetes (DM2) pyruvate dehydrogenase (PDH), the major determinant of glucose oxidative breakdown, is affected by a cohort of alterations reflecting impaired insulin stimulated glucose utilization. The cohort is also expressed, although incompletely, in 40% of healthy young subjects with a DM2-family history (FH). Pregnancy restrains glucose utilization in maternal peripheral tissues to satisfy fetal requirements. Here we explore whether pregnant women develop the PDH alterations and, if so, whether there are differences between women with and without FH (FH+, FH-). Ten FH+ and 10 FH- were evaluated during pregnancy (12-14, 24-26, and 37-39 weeks) and 1 yr after (follow-up) for fasting plasma glucose and insulin as well as body mass index (BMI), and for the PDH alterations. Twenty FH- and 20 FH+ non-pregnant women served as controls. All FH+ and FH- controls exhibited normal clinical parameters and 8 FH+ had an incomplete cohort of PDH alterations. In FH- and FH+ pregnant women at 12-14 weeks clinical parameters were normal; from 24-26 weeks, with unvaried glucose, insulin and BMI rose more in FH- and only in the latter recovered the 12-14 weeks values at follow-up. In all FH-, the cohort of PDH alterations was incomplete at 24-26 weeks, complete at 37-39 weeks, and absent at follow-up but complete from 12-14 weeks including follow-up in all FH+. In FH-, the cohort is an acquired trait restricted to pregnancy signaling transiently reduced insulin-stimulated glucose utilization; in FH+, instead, it unveils the existence of an inherited DM2-related background these women all have, that is awakened by pregnancy and as such lastingly impairs insulin-stimulated glucose utilization.

Temperature dependence discontinuity of the phonon mode frequencies caused by a zero-gap state in HgCdTe alloys.

In the HgCdTe (MCT) alloys, a zero-gap state E(g)=Gamma(6)-Gamma(8)=0 may occur as the composition varies from HgTe to CdTe. This singular mechanism of the E(g) variation may be triggered by an external pressure or by a temperature. In this Letter, we present experimental data of the optical reflectivity in the far-infrared (FIR) domain in a wide interval of temperature (from 10 to 290 K) of the Hg1-xCdxTe (x=0.115) samples. Since the intensity of classical IR sources drops abruptly in this spectral region, a brilliant synchrotron radiation FIR source has been used. The results clearly show that frequencies of the optical phonon modes exhibit discontinuity in their temperature dependence when a zero-gap state occurs.

Far-infrared absorption of La1-xCaxMnO3-y at high pressure.

The first far-infrared absorption spectra of manganite samples at pressures P up to 10 GPa were obtained on La1-xCaxMnO3-y by use of synchrotron radiation. For x=0.25 and 0.20 (y=0), P promotes partial metallization at room temperature through a strong reduction of the insulating gap. An x=0.20 sample with y=0.08 does not show any charge delocalization effect up to 10 GPa. An Urbach-like model of disordered Jahn-Teller wells is shown to well fit the far-infrared band edge and allows one to obtain a reliable pressure dependence of the energy gap.

Estudo comparativo de parâmetros fisiológicos de gatos submetidos à anestesia de longa duração pelo sevofluorano e halotano

O artigo não apresenta resumo.

[Biomechanical risk for the upper limbs: experience at a factory of feeding electric cables]. / Rischio biomeccanico per gli arti superiori: esperienza in un'azienda produttrice di cavi elettrici per alimentazione.

Cumulative trauma disorders are found more and more frequently in working environments. Our examination concerns a factory of feeding electric cables, whose workers were subjected to a sanitary checking in 2001, 2002, 2003. The valuation of the risk due to a biomechanical overload of the upper limbs, carried out according to the OCRA method, pointed out, with reference to the specific task of pressing, a middle-high grade of exposure, while the clinical-instrumental results showed symptoms and objective signs of suffering on the median nerve of the wrist with regard to a significant percentage of workers. The following interventions on the production cycle and on the exposure times obtained a reduction of the risk with a subsequent decrease of the noticed troubles.

Barkas effect for antiproton stopping in H2.

We report the stopping power of molecular hydrogen for antiprotons of kinetic energy above the maximum (approximately 100 keV) with the purpose of comparing with the proton one. Our result is consistent with a positive difference in antiproton-proton stopping powers above approximately 250 keV and with a maximum difference between the stopping powers of 21%+/-3% at around 600 keV.

Enhanced blood insulin overcomes pyruvate dehydrogenase derangements that reflect systemic insulin resistance in obese adolescents.

Pyruvate dehydrogenase (PDH) has low activity in the circulating lymphocytes (CL) of obese adolescents and adults. In vitro, it is unresponsive to insulin at 5 micro-units/ml and is activated at 50 micro-units/ml, in contrast with activation and inhibition respectively at these concentrations in CL from controls. These changes are seen as being indicative of a molecular disorder underlying insulin resistance. The aims of the present study were to determine whether a substantial enhancement of blood insulin levels restores the PDH activity in CL from obese adolescents and abolishes the in vitro alterations, and whether PDH activity and indices of insulin resistance are correlated. Six obese adolescents and six normal-weight controls underwent a 4 h frequently sampled intravenous glucose test with minimal model analysis, to bring about a sharp rise in blood insulin and provide a reliable index of insulin sensitivity (S(I)). PDH activity was evaluated in CL obtained from blood samples at set times before and after their exposure to insulin in vitro. Insulin levels rose in all subjects in the first 10 min, although to a much greater extent in the obese group, and then decreased until the end of the test (240 min; t(240)). PDH activity in CL paralleled the insulin pattern in the control subjects, whereas in the obese subjects it was below normal 3 min before the start of the test (t(-3)), but rose significantly throughout the test. PDH responses in vitro to insulin in CL taken from the control subjects at t(-3) and t(240) and in CL taken from the obese subjects at t(-3) were as reported above, but were normal (i.e. the same as in control CL) in CL taken from the obese subjects at t(240). Baseline PDH activity was inversely correlated with body mass index and with fasting insulin, and directly correlated with S(I). These results show that a brief and sharp enhancement of blood insulin overcomes derangements in PDH that reflect systemic insulin resistance in obese adolescents.

Combined 5-fluorouracil infusion with fractionated epirubicin and cyclophosphamide in advanced breast cancer.

5-Fluorouracil (5-FU) given by continuous infusion (c.i.) allows higher dose delivery, causes less myelosuppression, and may interfere with repair of DNA damage caused by epirubicin and cyclophosphamide. With this rationale, we conducted a phase II study to test the activity and toxicity of 5-FU c.i., epirubicin, and cyclophosphamide in patients with metastatic breast cancer (MBC). Twenty-eight patients with MBC were entered in the trial. 5-FU (200 mg/m(2)) was administered by c.i. from day 1 to day 20. Epirubicin (35 mg/m(2)) and cyclophosphamide (400 mg/m(2)) were administered from day 2 to day 4, every 4 weeks. All patients were evaluable for response and toxicity. A total of 125 courses of chemotherapy were administered, with a median of 4 per patient (range: 2--6). Toxicity, assessed using World Health Organization criteria, was as follows: nausea and vomiting grade III--IV occurred in 36%, alopecia (grade III) in 86%, neutropenia (grade III--IV) in 50%, and cardiac toxicity grade I--II in 11% of patients. Five patients (17.9%) had a complete response to therapy, and 16 (57.1%) had a partial response (response rate 75%, 95% CI 55--89%). Disease stability and progression occurred in 4 (14.3%) and 3 (10.7%) patients, respectively. Median time to progression was 13.1 months (range: 3.4--66.9+), and median survival time was 27.7 months (range: 5.4--67.1+). Outpatient treatment with combined 5-FU c.i., epirubicin, and cyclophosphamide shows high activity in advanced breast cancer and gives prolonged remission with acceptable toxicity.

Proteasomes are a target of the anti-tumour drug vinblastine.

Proteasomes, the proteolytic machinery of the ubiquitin/ATP-dependent pathway, have a relevant role in many processes crucial for cell physiology and cell cycle progression. Proteasome inhibitors are used to block cell cycle progression and to induce apoptosis in certain cell lines. Here we examine whether proteasomal function is affected by the anti-tumour drug vinblastine, whose cytostatic action relies mainly on the disruption of mitotic spindle dynamics. The effects of vinblastine on the peptidase activities of human 20 S and 26 S proteasomes and on the proteolytic activity of 26 S proteasome were assessed in the presence of specific fluorogenic peptides and (125)I-lysozyme-ubiquitin conjugates respectively. The assays of ubiquitin-protein conjugates and of inhibitory kappa B alpha (I kappa B alpha), which are characteristic intracellular proteasome substrates, by Western blotting on lysates from HL60 cells incubated with or without vinblastine, illustrated the effects of vinblastine on proteasomes in vivo. We also evaluated the effects of vinblastine on the signal-induced degradation of I kappa B alpha. Vinblastine at 3--110 microM reversibly inhibited the chymotrypsin-like activity of the 20 S proteasome and the trypsin-like and peptidyl-glutamyl-peptide hydrolysing activities of both proteasomes, but only at 110 microM vinblastine was the chymotrypsin-like activity of the 26 S proteasome inhibited; furthermore, at 25--200 microM the drug inhibited the degradation of ubiquitinated lysozyme. In HL60 cells exposed for 6 h to 0.5--10 microM vinblastine, the drug-dose-related accumulation of polyubiquitinated proteins, as well as that of a high-molecular-mass form of I kappa B alpha, occurred. Moreover, vinblastine impaired the signal-induced degradation of I kappa B alpha. Cell viability throughout the test was approx. 95%. Proteasomes can be considered to be a new and additional vinblastine target.

Fluorescence imaging of submicrometric lattices of colour centres in LiF by an apertureless scanning near-field optical microscope.

We report fluorescence imaging of colour centres in Lithium Fluoride (LiF) using an apertureless Scanning Near Field Optical Microscope (SNOM). The sample consists of periodically spaced submicrometric coloured areas F2 laser-active colour centres produced by low-energy electron beam lithography on the surface of a LiF thin film. A silicon Atomic Force Microscope (AFM) tip is used as an apertureless optical probe. AFM images show a uniform surface roughness with a RMS of 7.2 nm. The SNOM images of the red fluorescence of colour centres excited at lambda = 458 nm with an argon ion laser show that the local photon emission is unambiguously related to the coloured areas and that topographic artefacts can be excluded.

5-fluorouracil-carboplatin continuous infusion as salvage chemotherapy in advanced cancer.

AIMS AND BACKGROUND: 5-fluorouracil given by continuous infusion allows higher dose delivery, causes less myelosuppression and may interfere with repair of DNA damage caused by carboplatin. With this rationale, we conducted a phase II study to test the activity and toxicity of 5-fluorouracil and carboplatin given in continuous infusion to patients with advanced cancer and pretreated with at least two chemotherapy regimens. METHODS: Forty patients with advanced tumors (21 colon, 4 stomach, 3 breast, 3 bladder, 3 ovary, and 6 at other sites) were entered in the trial. 5-fluorouracil (200 mg/m2) and carboplatin (20 mg/m2) were administered by continuous infusion from days 1 to 20, every 4 weeks. RESULTS: All patients were assessable for response and toxicity. A total of 138 courses of chemotherapy were administered, with a mean of 3.5 per patient (range, 2-9). Toxicity, assessed using WHO criteria, was as follows: nausea and vomiting grade 2-3 in 34% of patients, alopecia grade 2-3 in 96%, and neutropenia grade 3-4 in 26%. One patient (2.5%) had a complete response to therapy and 7 (17.5%) had a partial response (response rate 20%; 95% Cl, 9.06-35.68%). Disease stability and progression occurred in 12 (30%) and 20 (50%) patients, respectively. Median time to progression was 5.6 months (range, 2.8-45.9+), with a median survival time of 7.7 months (range, 1.5-45.9+). CONCLUSIONS: Outpatient treatment with a combination of 5-fluorouracil and carboplatin in continuous infusion was active as salvage treatment for advanced tumors and may give prolonged palliation of symptoms with manageable toxicity.

In obese individuals dexfenfluramine corrects molecular derangements reflecting insulin resistance.

BACKGROUND: Circulating lymphocytes of obese individuals with and without type 2 diabetes have derangements of pyruvate dehydrogenase (PDH) that are described as reflecting a disorder underlying systemic insulin resistance, namely basal activity below normal and, in vitro, unresponsiveness to insulin at 33 pmol/l and activation at 330 pmol/l instead of activation and inhibition as in controls. OBJECTIVE: To explore whether the above enzyme derangements are overcome in obese individuals on dexfenfluramine treatment, known to improve poor peripheral insulin sensitivity. METHODS: Fifteen obese diabetic patients and 15 age-matched euglycaemic obese subjects with normal glucose tolerance were enrolled for a trial composed of two 21-day periods; in the first (D-21-D0), participants received a placebo, and in the second (D0-D21), dexfenfluramine (30 mg/day). At D-21, D0 and D21 participants were evaluated for weight, BMI, fasting glycaemia (FG), fasting insulinaemia (FI), fasting insulin resistance index (FIRI), area under the glycaemic (G-AUC) and insulinaemic (I-AUC) curves from an OGT test, and for PDH activity assayed in their circulating lymphocytes before (basal activity) and after incubation with 33 or 330 pmol/l insulin. At D2, basal PDH activity and clinical parameters were assayed. RESULTS: In both groups of participants at D0 all parameters tested were constant with respect to D-21; at D2, only basal PDH activity rose significantly; at D21, basal and insulin stimulated PDH activities were normalized and weight decreased significantly, as did FG, FI, FIRI and G-AUC in the diabetic, and FI, FIRI, G-AUC and I-AUC in the non-diabetic participants. CONCLUSION: In obese, non-diabetic and diabetic individuals on dexfenfluramine treatment, amelioration of clinical parameters and indexes of poor insulin sensitivity of blood glucose homeostasis are preceded by correction, in their circulating lymphocytes, of PDH derangements described as reflecting a disorder underlying insulin resistance.