Experimental validation of an innovative approach in biokinetics study for personalised dosimetry of molecular radiation therapy treatments.

One of today's main challenges in molecular radiation therapy is to assess an individual dosimetry that allows treatment to be tailored to the specific patient, in accordance with the current paradigm of 'personalized medicine'. The evaluation of the absorbed doses for tumor and organs at risk in molecular radiotherapy is typically based on MIRD schema acquiring few experimental points for the assessement of biokinetic parameters. WIDMApp, the wearable individual dose monitoring apparatus, is an innovative approach for internal dosimetry based on a wearable radiation detecting system for individual biokinetics sampling, a Monte Carlo simulation for particle interaction, and an unfolding algorithm for data analysis and integrated activity determination at organ level. A prototype of a WIDMApp detector element was used to record the photon emissions in a body phantom containing 3 spheres with liquid sources (18F,64Cu and99mTc) to simulate organs having different washout. Modelling the phantom geometry on the basis of a CT scan imaging, the Monte Carlo simulation computed the contribution of each emitting sphere to the signal detected in 3 positions on the phantoms surface. Combining the simulated results with the data acquired for 120 h, the unfolding algorithm deconvolved the detected signal and assessed the decay half-life (T1/2) and initial activity values (A(0)) that best reproduces the observed exponential decays. A 3%-18% level of agreement is found between the actualA(0) andT1/2values and those obtained by means of the minimization procedure based on the Monte Carlo simulation. That resulted in an estimation of the cumulated activity <15%. Moreover, WIDMApp data redundancy has been used to mitigate some experimental occurrences that happened during data taking. A first experimental test of the WIDMApp approach to internal radiation dosimetry is presented. Studies with patients are foreseen to validate the technique in a real environment.

Advances in targeted alpha therapy for prostate cancer.

Amongst therapeutic radiopharmaceuticals, targeted alpha therapy (TαT) can deliver potent and local radiation selectively to cancer cells as well as the tumor microenvironment and thereby control cancer while minimizing toxicity. In this review, we discuss the history, progress, and future potential of TαT in the treatment of prostate cancer, including dosimetry-individualized treatment planning, combinations with small-molecule therapies, and conjugation to molecules directed against antigens expressed by prostate cancer cells, such as prostate-specific membrane antigen (PSMA) or components of the tumor microenvironment. A clinical proof of concept that TαT is efficacious in treating bone-metastatic castration-resistant prostate cancer has been demonstrated by radium-223 via improved overall survival and long-term safety/tolerability in the phase III ALSYMPCA trial. Dosimetry calculation and pharmacokinetic measurements of TαT provide the potential for optimization and individualized treatment planning for a precision medicine-based cancer management paradigm. The ability to combine TαTs with other agents, including chemotherapy, androgen receptor-targeting agents, DNA repair inhibitors, and immuno-oncology agents, is under investigation. Currently, TαTs that specifically target prostate cancer cells expressing PSMA represents a promising therapeutic approach. Both PSMA-targeted actinium-225 and thorium-227 conjugates are under investigation. The described clinical benefit, safety and tolerability of radium-223 and the recent progress in TαT trial development suggest that TαT occupies an important new role in prostate cancer treatment. Ongoing studies with newer dosimetry methods, PSMA targeting, and novel approaches to combination therapies should expand the utility of TαT in prostate cancer treatment.

An Adaptive Thresholding Method for BTV Estimation Incorporating PET Reconstruction Parameters: A Multicenter Study of the Robustness and the Reliability.

OBJECTIVE: The aim of this work was to assess robustness and reliability of an adaptive thresholding algorithm for the biological target volume estimation incorporating reconstruction parameters. METHOD: In a multicenter study, a phantom with spheres of different diameters (6.5-57.4 mm) was filled with (18)F-FDG at different target-to-background ratios (TBR: 2.5-70) and scanned for different acquisition periods (2-5 min). Image reconstruction algorithms were used varying number of iterations and postreconstruction transaxial smoothing. Optimal thresholds (TS) for volume estimation were determined as percentage of the maximum intensity in the cross section area of the spheres. Multiple regression techniques were used to identify relevant predictors of TS. RESULTS: The goodness of the model fit was high (R(2): 0.74-0.92). TBR was the most significant predictor of TS. For all scanners, except the Gemini scanners, FWHM was an independent predictor of TS. Significant differences were observed between scanners of different models, but not between different scanners of the same model. The shrinkage on cross validation was small and indicative of excellent reliability of model estimation. CONCLUSIONS: Incorporation of postreconstruction filtering FWHM in an adaptive thresholding algorithm for the BTV estimation allows obtaining a robust and reliable method to be applied to a variety of different scanners, without scanner-specific individual calibration.

[Epidemiology of CKD in Italy and prevention strategies]. / Epidemiologia della malattia renale cronica in italia e strategie per la prevenzione.

Although chronic kidney disease (CKD) is a major health problem worldwide; it is not adequately considered in the strategies for the prevention of non-communicable diseases. To plan properly preventive strategies in our country, we need to know what is the prevalence of CKD, the risk factors, the level of awareness for the diagnosis, the referral to specialists nephrologists and the prognosis of patients followed in primary care. The prevalence of CKD, adjusted for age and gender, is 6.3% and the major independent risk factors are represented by old age, arterial hypertension, obesity, diabetes, cardiovascular disease and smoking . The awareness of the diagnosis in our country in 2003 is underestimated and nephrology referral for individuals with glomerular filtration (GF) under 60 ml / min was only 10%. The prognosis of patients, followed exclusively in primary care, worsens progressively for values of GF under 45 ml / min, both as need for substitutive treatment and mortality, compared with patients of stage I and II. To improve the management of CKD, it would be useful to set up an electronic database on our national territory by a network among laboratories, primary care, and nephrologists. An example of this organization is Great Britain that evidences encouraging results in the treatment and prevention of this debilitating disease.

Use of the FLUKA Monte Carlo code for 3D patient-specific dosimetry on PET-CT and SPECT-CT images.

Patient-specific absorbed dose calculation for nuclear medicine therapy is a topic of increasing interest. 3D dosimetry at the voxel level is one of the major improvements for the development of more accurate calculation techniques, as compared to the standard dosimetry at the organ level. This study aims to use the FLUKA Monte Carlo code to perform patient-specific 3D dosimetry through direct Monte Carlo simulation on PET-CT and SPECT-CT images. To this aim, dedicated routines were developed in the FLUKA environment. Two sets of simulations were performed on model and phantom images. Firstly, the correct handling of PET and SPECT images was tested under the assumption of homogeneous water medium by comparing FLUKA results with those obtained with the voxel kernel convolution method and with other Monte Carlo-based tools developed to the same purpose (the EGS-based 3D-RD software and the MCNP5-based MCID). Afterwards, the correct integration of the PET/SPECT and CT information was tested, performing direct simulations on PET/CT images for both homogeneous (water) and non-homogeneous (water with air, lung and bone inserts) phantoms. Comparison was performed with the other Monte Carlo tools performing direct simulation as well. The absorbed dose maps were compared at the voxel level. In the case of homogeneous water, by simulating 10(8) primary particles a 2% average difference with respect to the kernel convolution method was achieved; such difference was lower than the statistical uncertainty affecting the FLUKA results. The agreement with the other tools was within 3­4%, partially ascribable to the differences among the simulation algorithms. Including the CT-based density map, the average difference was always within 4% irrespective of the medium (water, air, bone), except for a maximum 6% value when comparing FLUKA and 3D-RD in air. The results confirmed that the routines were properly developed, opening the way for the use of FLUKA for patient-specific, image-based dosimetry in nuclear medicine.

Kidney dosimetry in ¹77Lu and 9°Y peptide receptor radionuclide therapy: influence of image timing, time-activity integration method, and risk factors.

Kidney dosimetry in (177)Lu and (90)Y PRRT requires 3 to 6 whole-body/SPECT scans to extrapolate the peptide kinetics, and it is considered time and resource consuming. We investigated the most adequate timing for imaging and time-activity interpolating curve, as well as the performance of a simplified dosimetry, by means of just 1-2 scans. Finally the influence of risk factors and of the peptide (DOTATOC versus DOTATATE) is considered. 28 patients treated at first cycle with (177)Lu DOTATATE and 30 with (177)Lu DOTATOC underwent SPECT scans at 2 and 6 hours, 1, 2, and 3 days after the radiopharmaceutical injection. Dose was calculated with our simplified method, as well as the ones most used in the clinic, that is, trapezoids, monoexponential, and biexponential functions. The same was done skipping the 6 h and the 3 d points. We found that data should be collected until 100 h for (177)Lu therapy and 70 h for (90)Y therapy, otherwise the dose calculation is strongly influenced by the curve interpolating the data and should be carefully chosen. Risk factors (hypertension, diabetes) cause a rather statistically significant 20% increase in dose (t-test, P < 0.10), with DOTATATE affecting an increase of 25% compared to DOTATOC (t-test, P < 0.05).

Radiolabelled white blood cell scintigraphy in the work-up of dermal filler complications.

PURPOSE: Scintigraphy with radiolabelled autologous white blood cells (WBC) is a widely used method for the detection of sites of infection. In this study we evaluated the role of WBC scintigraphy in the diagnosis and follow-up of patients with suspected soft tissue infection caused by dermal fillers in the face. We compared several qualitative and quantitative interpretation criteria and the results obtained with MRI and high-frequency US (HFUS). METHODS: Between 2007 and 2011, ten consecutive patients (all women) aged between 25 and 65 years showing a reaction to dermal fillers were enrolled in the study. In five of these patients WBC scintigraphy was repeated at the end of therapy. Scintigraphy with (99m)Tc-HMPAO-labelled WBC was performed in each patient acquiring planar and SPECT images at 3 h and 20 h as well as HFUS with Doppler analysis and MRI with Gd-DTPA. The final diagnosis was determined by fine-needle aspiration and microbiological analysis of lesions in eight patients (before therapy in six and after therapy in two) and by clinical data and follow-up (at least 1 year) in seven patients (before therapy in four and after therapy in three). Two patients were treated with steroids, and the others were treated with antibiotics for 3 weeks. Several qualitative and semiquantitative interpretation criteria were applied to define the best strategy for accurate diagnosis of infections, implemented by SPECT images in patients with doubtful planar scans. The WBC scintigraphy results were also compared with the MRI and HFUS results. RESULTS: Sensitivity, specificity and accuracy were respectively 90 %, 100 % and 93.3 % for WBC scintigraphy with qualitative and semiquantitative interpretation of planar images and 100 %, 100 % and 100 % with qualitative analysis of SPECT images. Sensitivity, specificity and accuracy for HFUS were 44 %, 66 % and 50 %, and for MRI were 50 %, 100 % and 67.6 %, respectively. Scans performed after therapy in five patients were negative in three and still positive in two (all true results). CONCLUSION: In conclusion, scintigraphy with radiolabelled WBC was found to be the most accurate method for diagnosing infection in patients with long-term dermal filler complications, particularly using qualitative analysis of SPECT images. No differences were observed with planar images using either qualitative or semiquantitative analysis. HFUS and MRI may provide additional important information for defining the nature of the filler and for surgery, but are not accurate enough for diagnosing infection.

A free database of radionuclide voxel S values for the dosimetry of nonuniform activity distributions.

The increasing availability of SPECT/CT devices with advanced technology offers the opportunity for the accurate assessment of the radiation dose to the biological target volume during radionuclide therapy. Voxel dosimetry can be performed employing direct Monte Carlo radiation transport simulations, based on both morphological and functional images of the patient. On the other hand, for voxel dosimetry calculations the voxel S value method can be considered an easier approach than patient-specific Monte Carlo simulations, ensuring a good dosimetric accuracy at least for anatomic regions which are characterized by uniform density tissue. However, this approach has been limited because of the lack of tabulated S values for different voxel dimensions and radionuclides. The aim of this work is to provide a free dataset of values which can be used for voxel dosimetry in targeted radionuclide studies. Seven different radionuclides (89Sr, 90Y, 131I, 153Sm, 177Lu, 186Re, 188Re), and 13 different voxel sizes (2.21, 2.33, 2.4, 3, 3.59, 3.9, 4, 4.42, 4.8, 5, 6, 6.8 and 9.28 mm) are considered. Voxel S values are calculated performing simulations of monochromatic photon and electron sources in two different homogeneous tissues (soft tissue and bone) with DOSXYZnrc code, and weighting the contributions on the basis of the radionuclide emission spectra. The outcomes are validated by comparison with Monte Carlo simulations obtained with other codes (PENELOPE and MCNP4c) performing direct simulation of the radionuclide emission spectra. The differences among the different Monte Carlo codes are of the order of a few per cent when considering the source voxel and the bremsstrahlung tail, whereas the highest differences are observed at a distance close to the maximum continuous slowing down approximation range of electrons. These discrepancies would negligibly affect dosimetric assessments. The dataset of voxel S values can be freely downloaded from the website www.medphys.it.

An innovative iterative thresholding algorithm for tumour segmentation and volumetric quantification on SPECT images: Monte Carlo-based methodology and validation.

PURPOSE: Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging play an important role in the segmentation of functioning parts of organs or tumours, but an accurate and reproducible delineation is still a challenging task. In this work, an innovative iterative thresholding method for tumour segmentation has been proposed and implemented for a SPECT system. This method, which is based on experimental threshold-volume calibrations, implements also the recovery coefficients (RC) of the imaging system, so it has been called recovering iterative thresholding method (RIThM). The possibility to employ Monte Carlo (MC) simulations for system calibration was also investigated. METHODS: The RIThM is an iterative algorithm coded using MATLAB: after an initial rough estimate of the volume of interest, the following calculations are repeated: (i) the corresponding source-to-background ratio (SBR) is measured and corrected by means of the RC curve; (ii) the threshold corresponding to the amended SBR value and the volume estimate is then found using threshold-volume data; (iii) new volume estimate is obtained by image thresholding. The process goes on until convergence. The RIThM was implemented for an Infinia Hawkeye 4 (GE Healthcare) SPECT/CT system, using a Jaszczak phantom and several test objects. Two MC codes were tested to simulate the calibration images: SIMIND and SimSet. For validation, test images consisting of hot spheres and some anatomical structures of the Zubal head phantom were simulated with SIMIND code. Additional test objects (flasks and vials) were also imaged experimentally. Finally, the RIThM was applied to evaluate three cases of brain metastases and two cases of high grade gliomas. RESULTS: Comparing experimental thresholds and those obtained by MC simulations, a maximum difference of about 4% was found, within the errors (+/- 2% and +/- 5%, for volumes > or = 5 ml or < 5 ml, respectively). Also for the RC data, the comparison showed differences (up to 8%) within the assigned error (+/- 6%). ANOVA test demonstrated that the calibration results (in terms of thresholds or RCs at various volumes) obtained by MC simulations were indistinguishable from those obtained experimentally. The accuracy in volume determination for the simulated hot spheres was between -9% and 15% in the range 4-270 ml, whereas for volumes less than 4 ml (in the range 1-3 ml) the difference increased abruptly reaching values greater than 100%. For the Zubal head phantom, errors ranged between 9% and 18%. For the experimental test images, the accuracy level was within +/- 10%, for volumes in the range 20-110 ml. The preliminary test of application on patients evidenced the suitability of the method in a clinical setting. CONCLUSIONS: The MC-guided delineation of tumor volume may reduce the acquisition time required for the experimental calibration. Analysis of images of several simulated and experimental test objects, Zubal head phantom and clinical cases demonstrated the robustness, suitability, accuracy, and speed of the proposed method. Nevertheless, studies concerning tumors of irregular shape and/or nonuniform distribution of the background activity are still in progress.

Targeting T and B lymphocytes with radiolabelled antibodies for diagnostic and therapeutic applications.

Acute and chronic forms of inflammation may occur years before the onset of specific symptoms, on which the clinical diagnosis can be settled, and may last for years after the clinical diagnosis and the onset of treatment. Therefore, to develop a sensitive and specific diagnostic tool several novel molecules/ receptors identified and new antibodies have been radiolabelled with different radionuclides, as per their need for diagnosis or therapy. Cluster of differentiation (CD) molecules are markers on the cell surface used to identify the cell type, stage of differentiation and activity of a cell. These CD markers are recognized by specific monoclonal antibodies (mAbs). These radiolabelled mAbs bind to their targets with high affinity and specificity and consequently have an excellent diagnostic and/ or therapeutic potential. In the last two decades, the radiolabelled mAbs have demonstrated its significant impact on diagnosis and radioimmunotherapy. In this review article, we will discuss different possible targets for T and B cells and their radiolabelled mAbs for molecular imaging and radioimmunotherapy.

Differences among Monte Carlo codes in the calculations of voxel S values for radionuclide targeted therapy and analysis of their impact on absorbed dose evaluations.

Several updated Monte Carlo (MC) codes are available to perform calculations of voxel S values for radionuclide targeted therapy. The aim of this work is to analyze the differences in the calculations obtained by different MC codes and their impact on absorbed dose evaluations performed by voxel dosimetry. Voxel S values for monoenergetic sources (electrons and photons) and different radionuclides (90Y, 131I, and 188Re) were calculated. Simulations were performed in soft tissue. Three general-purpose MC codes were employed for simulating radiation transport: MCNP4C, EGSnrc, and GEANT4. The data published by the MIRD Committee in Pamphlet No. 17, obtained with the EGS4 MC code, were also included in the comparisons. The impact of the differences (in terms of voxel S values) among the MC codes was also studied by convolution calculations of the absorbed dose in a volume of interest. For uniform activity distribution of a given radionuclide, dose calculations were performed on spherical and elliptical volumes, varying the mass from 1 to 500 g. For simulations with monochromatic sources, differences for self-irradiation voxel S values were mostly confined within 10% for both photons and electrons, but with electron energy less than 500 keV, the voxel S values referred to the first neighbor voxels showed large differences (up to 130%, with respect to EGSnrc) among the updated MC codes. For radionuclide simulations, noticeable differences arose in voxel S values, especially in the bremsstrahlung tails, or when a high contribution from electrons with energy of less than 500 keV is involved. In particular, for 90Y the updated codes showed a remarkable divergence in the bremsstrahlung region (up to about 90% in terms of voxel S values) with respect to the EGS4 code. Further, variations were observed up to about 30%, for small source-target voxel distances, when low-energy electrons cover an important part of the emission spectrum of the radionuclide (in our case, for 131I). For 90Y and 188Re, the differences among the various codes have a negligible impact (within few percents) on convolution calculations of the absorbed dose; thus either one of the MC programs is suitable to produce voxel S values for radionuclide targeted therapy dosimetry. However, if a low-energy beta-emitting radionuclide is considered, these differences can affect also dose depositions at small source-target voxel distances, leading to more conspicuous variations (about 9% for 1311) when calculating the absorbed dose in the volume of interest.

Feline herpesvirus-1 down-regulates MHC class I expression in an homologous cell system.

Cytotoxic T lymphocytes (CTLs) are an essential component of the immune defense against many virus infections. CTLs recognize viral peptides in the context of the major histocompatibility complex (MHC) class I molecules on the surface of infected cells. Many viruses have evolved mechanisms to interfere with MHC class I expression as a means of evading the host immune response. In the present research we have studied the effect of in vitro Feline Herpesvirus 1 (FeHV-1) infection on MHC class I expression. The results of this study demonstrate that FeHV-1 down regulates surface expression of MHC class I molecules on infected cells, presumably to evade cytotoxic T-cell recognition and, perhaps, attenuate induction of immunity. Sensitivity to UV irradiation and insensitivity to a viral DNA synthesis inhibitor, like phosphonacetic acid, revealed that immediate early or early viral gene(s) are responsible. Use of the protein translation inhibitor cycloheximide confirmed that an early gene is primarily responsible.

2,3,7,8-Tetrachlorodibenzo-p-dioxin increases Bovine Herpesvirus type-1 (BHV-1) replication in Madin-Darby Bovine Kidney (MDBK) cells in vitro.

Dioxin-2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a common environmental toxin of current interest. In the last years, higher levels of TCDD than those permitted in UE [European Commission. 2002. European Commission Recommendation 2002/201/CE. Official Gazette, L 67/69] were detected in milk samples from cow, water buffalo, goat, and sheep raised on some areas of Campania Region (South Italy). Dioxin often causes immunosuppression and might render the animal liable to viral infections. In addition, viral infections are able to alter the pattern of dioxin distribution in different organs of the exposed animals. Bovine Herpesvirus type-1 (BHV-1) is a widespread pathogen, which causes infectious rhinotracheitis and infectious pustular vulvovaginitis in cattle. Herein, we have studied the effects of TCDD and BHV-1 infection, in Madin-Darby Bovine Kidney (MDBK) cells, alone as well as in association, so as cellular proliferation, apoptosis, and virus replication. We have observed an increase in cell viability of confluent monolayers at low TCDD concentrations. TCDD treated cells demonstrated increased viability compared to controls as evaluated by MTT test. TCDD exposure increased cell proliferation but induced no changes on apoptosis. Cells exposed to TCDD along with BHV-1 showed a dose-dependent increase in cytopathy, represented by ample syncytia formation with the elimination of the cellular sheets and increased viral titer. These results suggest that TCDD increases viral replication in MDBK cells while BHV-1 further decreases viability of TCDD exposed cells. Since very low concentrations (0.01 pg/ml) are sufficient to augment BHV-1 titer, TCDD may contribute to reactivate BHV-1 from latency, leading to recurrent disease and increase virus transmission.

Monte Carlo dose calculations using MCNP4C and EGSnrc/BEAMnrc codes to study the energy dependence of the radiochromic film response to beta-emitting sources.

The energy dependence of the radiochromic film (RCF) response to beta-emitting sources was studied by dose theoretical calculations, employing the MCNP4C and EGSnrc/BEAMnrc Monte Carlo codes. Irradiations with virtual monochromatic electron sources, electron and photon clinical beams, a (32)P intravascular brachytherapy (IVB) source and other beta-emitting radioisotopes ((188)Re, (90)Y, (90)Sr/(90)Y,(32)P) were simulated. The MD-55-2 and HS radiochromic films (RCFs) were considered, in a planar or cylindrical irradiation geometry, with water or polystyrene as the surrounding medium. For virtual monochromatic sources, a monotonic decrease with energy of the dose absorbed to the film, with respect to that absorbed to the surrounding medium, was evidenced. Considering the IVB (32)P source and the MD-55-2 in a cylindrical geometry, the calibration with a 6 MeV electron beam would yield dose underestimations from 14 to 23%, increasing the source-to-film radial distance from 1 to 6 mm. For the planar beta-emitting sources in water, calibrations with photon or electron clinical beams would yield dose underestimations between 5 and 12%. Calibrating the RCF with (90)Sr/(90)Y, the MD-55-2 would yield dose underestimations between 3 and 5% for (32)P and discrepancies within +/-2% for (188)Re and (90)Y, whereas for the HS the dose underestimation would reach 4% with (188)Re and 6% with (32)P.

Ion diffusion modelling of Fricke-agarose dosemeter gels.

In Fricke-agarose gels, an accurate determination of the spatial dose distribution is hindered by the diffusion of ferric ions. In this work, a model was developed to describe the diffusion process within gel samples of finite length and, thus, permit the reconstruction of the initial spatial distribution of the ferric ions. The temporal evolution of the ion concentration as a function of the initial concentration is derived by solving Fick's second law of diffusion in two dimensions with boundary reflections. The model was applied to magnetic resonance imaging data acquired at high spatial resolution (0.3 mm) and was found to describe accurately the observed diffusion effects.

Optical imaging of dose distributions in Fricke gels.

Ferrous-sulphate infused gels, or 'Fricke gels', encounter great interest in the field of radiation dosimetry, due to their potential for 3D radiation dose mapping. Typically, magnetic resonance (MR) relaxation rates are determined in these systems in order to derive the absorbed dose. However, when large concentration gradients are present, diffusion effects before and during the MR imaging may not be negligible. In these cases, optical techniques may represent a viable alternative. This paper describes research aimed at measuring 3D dose distributions in a Fricke-xylenol orange gel by measuring optical density with a CCD camera. This method is inexpensive and fast. A series of early experiments is described, in which optical density profiles were measured with a commercial microdensitometer for film dosimetry. The light box of the device was modified to work at 567 nm, close to the maximum absorbance of the ferric ion-xylenol orange complex. Under these conditions, the gel shows linearity with dose and high sensitivity.

Effect on prolactin secretion of Echinacea purpurea, hypericum perforatum and Eleutherococcus senticosus.

It has been recently reported that prolactin (PRL) plays an important role in immune system regulation. In this study we investigated the activity of three natural drugs with immunomodulatory activity: Echinacea purpurea (EP), Hypericum perforatum (HP) and Eleutherococcus senticosus (ES) on PRL production. Male rats were orally treated with two different doses (30 and 100 mg/kg) of extract of these drugs for 3 or 15 days. A 3-day treatment was not able to modify PRL serum levels, whereas a 15-day treatment with EP and HP at the higher dose significantly inhibits PRL production. A treatment with ES was always ineffective. A possible mechanism for this effect could be that both HP and EP extracts display a direct dopaminergic activity, although an involvement of the GABA-ergic system cannot be excluded.

The involvement of oxidative stress in bovine herpesvirus type 4-mediated apoptosis.

Bovine herpesvirus type 4 (BHV-4) belongs to the gamma-2-herpesviruses of the Gammaherpesvirinae subfamily. BHV-4 has a worldwide distribution and has been isolated in a variety of clinical diseases as well as from healthy cattle. In this report we demonstrate that BHV-4 induces apoptosis in MDBK cells. In the early phases of apoptosis, cells show an increase in the intracellular level of reactive oxygen species, which is indicative of oxidative stress. This precedes DNA fragmentation, a hallmark typical of apoptosis. Cells were protected from apoptosis only by certain antioxidants (butylated hydroxyanisole and ebselen), whereas N-acetylcysteine turned out to be ineffective. Antioxidants that protected cells from apoptosis prevented oxidative stress but failed to block virus growth. These observations suggest that oxidative stress may be a crucial event in the sequence leading to apoptotic cell death but apoptosis is not required for the multiplication of BHV-4.

Dose reconstruction in irradiated Fricke-agarose gels by means of MRI and optical techniques: 2D modelling of diffusion of ferric ions.

Fricke-agarose gels have elicited much interest in the field of radiation dosimetry, as tissue-equivalent dosemeters. magnetic resonance (MR) relaxation rates are measured for dose reconstruction. A major problem of Fricke-agarose gels is the diffusion of the ferric ions formed after irradiation. Knowledge of the diffusion coefficient of ferric ions may be necessary. Xylene orange, a dye that specifically chelates ferric ions, was added to the Fricke gel system to reduce ion diffusion and, as the binding gives a coloured complex, to allow optical detection of ferric ions. Diffusion of ferric ions in two dimensions and time evolution of ion concentration were evaluated. MR images were obtained at different times after irradiation. Ferric ion distribution, the corresponding images and the doses at different times after irradiation were reconstructed taking into account the calculated diffusion coefficients. Diffusion was then estimated by means of two different optical methods. The agreement obtained supports the reliability of the MRI method and of the model.

A correction method for diamond detector signal dependence with proton energy.

Small dosimeters as solid state detectors can be useful for the dosimetric characterization and periodic quality control of radiotherapy proton beams. The calibration of solid state detectors for proton beams is not a solved problem especially for ophthalmologic proton beams, where these detectors present a LET-dependent signal. In this work a PTW diamond detector has been selected because of its good signal reproducibility (0.3%) and stable response with accumulated dose. A method that takes into account the LET dependence of the diamond detector signal, at 62 MeV proton beam, is here proposed. In particular an empirical correction factor, kDD(Eo) (Rres), has been determined as a function of the residual range quality index, to correct the diamond detector signal for a proton beam of incident effective energy E0= 62 MeV. A dedicated software allows us to use the diamond detector as an on-line reference dosimeter, where an ionization chamber may be difficult to use, or for periodic quality control procedures. The article also reports a comparison between the signal dependence on proton energy of silicon, diamond, and radiochromic film detectors.