MACACO II test-beam with high energy photons.

The IRIS group at IFIC Valencia is developing a three-layer Compton camera for treatment monitoring in proton therapy. The system is composed of three detector planes, each made of a [Formula: see text] monolithic crystal coupled to a SiPM array. Having obtained successful results with the first prototype (MACACO) that demonstrated the feasibility of the proposed technology, a second prototype (MACACO II) with improved performance has been developed, and is the subject of this work. The new system has an enhanced detector energy resolution which translates into a higher spatial resolution of the telescope. The image reconstruction method has also been improved with an accurate model of the sensitivity matrix. The device has been tested with high energy photons at the National Accelerator Centre (CNA, Seville). The tests involved a proton beam of 18 MeV impinging on a graphite target, to produce 4.4 MeV photons. Data were taken at different system positions of the telescope with the first detector at 65 and 160 mm from the target, and at different beam intensities. The measurements allowed successful reconstruction of the photon emission distribution at two target positions separated by 5 mm in different telescope configurations. This result was obtained both with data recorded in the first and second telescope planes (two interaction events) and, for the first time in beam experiments, with data recorded in the three planes (three interaction events).

Image reconstruction for a multi-layer Compton telescope: an analytical model for three interaction events.

Compton Cameras are electronically collimated photon imagers suitable for sub-MeV to few MeV gamma-ray detection. Such features are desirable to enable in vivo range verification in hadron therapy, through the detection of secondary Prompt Gammas. A major concern with this technique is the poor image quality obtained when the incoming gamma-ray energy is unknown. Compton Cameras with more than two detector planes (multi-layer Compton Cameras) have been proposed as a solution, given that these devices incorporate more signal sequences of interactions to the conventional two interaction events. In particular, three interaction events convey more spectral information as they allow inferring directly the incident gamma-ray energy. A three-layer Compton Telescope based on continuous Lanthanum (III) Bromide crystals coupled to Silicon Photomultipliers is being developed at the IRIS group of IFIC-Valencia. In a previous work we proposed a spectral reconstruction algorithm for two interaction events based on an analytical model for the formation of the signal. To fully exploit the capabilities of our prototype, we present here an extension of the model for three interaction events. Analytical expressions of the sensitivity and the System Matrix are derived and validated against Monte Carlo simulations. Implemented in a List Mode Maximum Likelihood Expectation Maximization algorithm, the proposed model allows us to obtain four-dimensional (energy and position) images by using exclusively three interaction events. We are able to recover the correct spectrum and spatial distribution of gamma-ray sources when ideal data are employed. However, the uncertainties associated to experimental measurements result in a degradation when real data from complex structures are employed. Incorrect estimation of the incident gamma-ray interaction positions, and missing deposited energy associated with escaping secondaries, have been identified as the causes of such degradation by means of a detailed Monte Carlo study. As expected, our current experimental resolution and efficiency to three interaction events prevents us from correctly recovering complex structures of radioactive sources. However, given the better spectral information conveyed by three interaction events, we expect an improvement of the image quality of conventional Compton imaging when including such events. In this regard, future development includes the incorporation of the model assessed in this work to the two interaction events model in order to allow using simultaneously two and three interaction events in the image reconstruction.

CCMod: a GATE module for Compton camera imaging simulation.

Compton cameras are gamma-ray imaging systems which have been proposed for a wide variety of applications such as medical imaging, nuclear decommissioning or homeland security. In the design and optimization of such a system Monte Carlo simulations play an essential role. In this work, we propose a generic module to perform Monte Carlo simulations and analyses of Compton Camera imaging which is included in the open-source GATE/Geant4 platform. Several digitization stages have been implemented within the module to mimic the performance of the most commonly employed detectors (e.g. monolithic blocks, pixelated scintillator crystals, strip detectors...). Time coincidence sorter and sequence coincidence reconstruction are also available in order to aim at providing modules to facilitate the comparison and reproduction of the data taken with different prototypes. All processing steps may be performed during the simulation (on-the-fly mode) or as a post-process of the output files (offline mode). The predictions of the module have been compared with experimental data in terms of energy spectra, angular resolution, efficiency and back-projection image reconstruction. Consistent results within a 3-sigma interval were obtained for the energy spectra except for low energies where small differences arise. The angular resolution measure for incident photons of 1275 keV was also in good agreement between both data sets with a value close to 13°. Moreover, with the aim of demonstrating the versatility of such a tool the performance of two different Compton camera designs was evaluated and compared.

Optical second harmonic generation from nanostructured graphene: a full wave approach.

Optical second harmonic generation (SHG) from nanostructured graphene has been studied in the framework of classical electromagnetism using a surface integral equation method. Single disks and dimers are considered, demonstrating that the nonlinear conversion is enhanced when a localized surface plasmon resonance is excited at either the fundamental or second harmonic frequency. The proposed approach, beyond the electric dipole approximation used in the quantum description, reveals that SHG from graphene nanostructures with centrosymmetric shapes is possible when retardation effects and the excitation of high plasmonic modes at the second harmonic frequency are taken into account. Several SHG effects similar to those arising in metallic nanostructures, such as the silencing of the nonlinear emission and the design of double resonant nanostructures, are also reported. Finally, it is shown that the SHG from graphene disk dimers is very sensitive to a relative vertical displacement of the disks, opening new possibilities for the design of nonlinear plasmonic nanorulers.

Experimental evaluation of the resolution improvement provided by a silicon PET probe.

A high-resolution PET system, which incorporates a silicon detector probe into a conventional PET scanner, has been proposed to obtain increased image quality in a limited region of interest. Detailed simulation studies have previously shown that the additional probe information improves the spatial resolution of the reconstructed image and increases lesion detectability, with no cost to other image quality measures. The current study expands on the previous work by using a laboratory prototype of the silicon PET-probe system to examine the resolution improvement in an experimental setting. Two different versions of the probe prototype were assessed, both consisting of a back-to-back pair of 1-mm thick silicon pad detectors, one arranged in 32 × 16 arrays of 1.4 mm × 1.4 mm pixels and the other in 40 × 26 arrays of 1.0 mm × 1.0 mm pixels. Each detector was read out by a set of VATAGP7 ASICs and a custom-designed data acquisition board which allowed trigger and data interfacing with the PET scanner, itself consisting of BGO block detectors segmented into 8 × 6 arrays of 6 mm × 12 mm × 30 mm crystals. Limited-angle probe data was acquired from a group of Na-22 point-like sources in order to observe the maximum resolution achievable using the probe system. Data from a Derenzo-like resolution phantom was acquired, then scaled to obtain similar statistical quality as that of previous simulation studies. In this case, images were reconstructed using measurements of the PET ring alone and with the inclusion of the probe data. Images of the Na-22 source demonstrated a resolution of 1.5 mm FWHM in the probe data, the PET ring resolution being approximately 6 mm. Profiles taken through the image of the Derenzo-like phantom showed a clear increase in spatial resolution. Improvements in peak-to-valley ratios of 50% and 38%, in the 4.8 mm and 4.0 mm phantom features respectively, were observed, while previously unresolvable 3.2 mm features were brought to light by the addition of the probe. These results support the possibility of improving the image resolution of a clinical PET scanner using the silicon PET-probe.

Noise evaluation of Compton camera imaging for proton therapy.

Compton Cameras emerged as an alternative for real-time dose monitoring techniques for Particle Therapy (PT), based on the detection of prompt-gammas. As a consequence of the Compton scattering process, the gamma origin point can be restricted onto the surface of a cone (Compton cone). Through image reconstruction techniques, the distribution of the gamma emitters can be estimated, using cone-surfaces backprojections of the Compton cones through the image space, along with more sophisticated statistical methods to improve the image quality. To calculate the Compton cone required for image reconstruction, either two interactions, the last being photoelectric absorption, or three scatter interactions are needed. Because of the high energy of the photons in PT the first option might not be adequate, as the photon is not absorbed in general. However, the second option is less efficient. That is the reason to resort to spectral reconstructions, where the incoming γ energy is considered as a variable in the reconstruction inverse problem. Jointly with prompt gamma, secondary neutrons and scattered photons, not strongly correlated with the dose map, can also reach the imaging detector and produce false events. These events deteriorate the image quality. Also, high intensity beams can produce particle accumulation in the camera, which lead to an increase of random coincidences, meaning events which gather measurements from different incoming particles. The noise scenario is expected to be different if double or triple events are used, and consequently, the reconstructed images can be affected differently by spurious data. The aim of the present work is to study the effect of false events in the reconstructed image, evaluating their impact in the determination of the beam particle ranges. A simulation study that includes misidentified events (neutrons and random coincidences) in the final image of a Compton Telescope for PT monitoring is presented. The complete chain of detection, from the beam particle entering a phantom to the event classification, is simulated using FLUKA. The range determination is later estimated from the reconstructed image obtained from a two and three-event algorithm based on Maximum Likelihood Expectation Maximization. The neutron background and random coincidences due to a therapeutic-like time structure are analyzed for mono-energetic proton beams. The time structure of the beam is included in the simulations, which will affect the rate of particles entering the detector.

Study of a high-resolution PET system using a silicon detector probe.

A high-resolution silicon detector probe, in coincidence with a conventional PET scanner, is expected to provide images of higher quality than those achievable using the scanner alone. Spatial resolution should improve due to the finer pixelization of the probe detector, while increased sensitivity in the probe vicinity is expected to decrease noise. A PET-probe prototype is being developed utilizing this principle. The system includes a probe consisting of ten layers of silicon detectors, each a 80 × 52 array of 1 × 1 × 1 mm(3) pixels, to be operated in coincidence with a modern clinical PET scanner. Detailed simulation studies of this system have been performed to assess the effect of the additional probe information on the quality of the reconstructed images. A grid of point sources was simulated to study the contribution of the probe to the system resolution at different locations over the field of view (FOV). A resolution phantom was used to demonstrate the effect on image resolution for two probe positions. A homogeneous source distribution with hot and cold regions was used to demonstrate that the localized improvement in resolution does not come at the expense of the overall quality of the image. Since the improvement is constrained to an area close to the probe, breast imaging is proposed as a potential application for the novel geometry. In this sense, a simplified breast phantom, adjacent to heart and torso compartments, was simulated and the effect of the probe on lesion detectability, through measurements of the local contrast recovery coefficient-to-noise ratio (CNR), was observed. The list-mode ML-EM algorithm was used for image reconstruction in all cases. As expected, the point spread function of the PET-probe system was found to be non-isotropic and vary with position, offering improvement in specific regions. Increase in resolution, of factors of up to 2, was observed in the region close to the probe. Images of the resolution phantom showed visible improvement in resolution when including the probe in the simulations. The image quality study demonstrated that contrast and spill-over ratio in other areas of the FOV were not sacrificed for this enhancement. The CNR study performed on the breast phantom indicates increased lesion detectability provided by the probe.

A Monte-Carlo based model of the AX-PET demonstrator and its experimental validation.

AX-PET is a novel PET detector based on axially oriented crystals and orthogonal wavelength shifter (WLS) strips, both individually read out by silicon photo-multipliers. Its design decouples sensitivity and spatial resolution, by reducing the parallax error due to the layered arrangement of the crystals. Additionally the granularity of AX-PET enhances the capability to track photons within the detector yielding a large fraction of inter-crystal scatter events. These events, if properly processed, can be included in the reconstruction stage further increasing the sensitivity. Its unique features require dedicated Monte-Carlo simulations, enabling the development of the device, interpreting data and allowing the development of reconstruction codes. At the same time the non-conventional design of AX-PET poses several challenges to the simulation and modeling tasks, mostly related to the light transport and distribution within the crystals and WLS strips, as well as the electronics readout. In this work we present a hybrid simulation tool based on an analytical model and a Monte-Carlo based description of the AX-PET demonstrator. It was extensively validated against experimental data, providing excellent agreement.

Simulated one-pass list-mode: an approach to on-the-fly system matrix calculation.

In the development of prototype systems for positron emission tomography a valid and robust image reconstruction algorithm is required. However, prototypes often employ novel detector and system geometries which may change rapidly under optimization. In addition, developing systems generally produce highly granular, or possibly continuous detection domains which require some level of on-the-fly calculation for retention of measurement precision. In this investigation a new method of on-the-fly system matrix calculation is proposed that provides advantages in application to such list-mode systems in terms of flexibility in system modeling. The new method is easily adaptable to complicated system geometries and available computational resources. Detection uncertainty models are used as random number generators to produce ensembles of possible photon trajectories at image reconstruction time for each datum in the measurement list. However, the result of this approach is that the system matrix elements change at each iteration in a non-repetitive manner. The resulting algorithm is considered the simulation of a one-pass list (SOPL) which is generated and the list traversed during image reconstruction. SOPL alters the system matrix in use at each iteration and so behavior within the maximum likelihood-expectation maximization algorithm was investigated. A two-pixel system and a small two dimensional imaging model are used to illustrate the process and quantify aspects of the algorithm. The two-dimensional imaging system showed that, while incurring a penalty in image resolution, in comparison to a non-random equal-computation counterpart, SOPL provides much enhanced noise properties. In addition, enhancement in system matrix quality is straightforward (by increasing the number of samples in the ensemble) so that the resolution penalty can be recovered when desired while retaining improvement in noise properties. Finally the approach is tested and validated against a standard (highly accurate) system matrix using experimental data from a prototype system--the AX-PET.

Alteration in alpha-synuclein mRNA expression in Parkinson's disease.

The presynaptic protein alpha-synuclein is considered to play an important role in the pathophysiology of Parkinson's disease (PD). Point mutations in the alpha-synuclein gene have been demonstrated in familial PD and alpha-synuclein is a major component of Lewy bodies, the pathological hallmark of the sporadic disease. It is not clear whether abnormal accumulation of alpha-synuclein is the result of abnormal levels of expression of the gene in neurodegenerative conditions. Expression of alpha-synuclein mRNA was therefore studied in control and PD brain using semiquantitative in situ hybridization. alpha-synuclein was expressed widely and hybridization signal was seen in most cortical regions, hippocampus, cerebellum, and brain stem. There was little mRNA in the striatum and no hybridization signal was detected in glia. High levels of alpha-synuclein mRNA expression in neurons did not seem to be a marker for Lewy body formation. Abundant signal was seen both in regions in which Lewy body deposition occurs commonly in idiopathic PD (PD), such as substantia nigra and frontal and temporal cortex, as well as in less susceptible regions, e.g. visual cortex. Quantitative comparison of mRNA expression in regions of predilection for Lewy body formation showed that mRNA expression was reduced significantly in melanized substantia nigra neurons and frontal cortex neurons in Parkinson's disease. In substantia nigra neurons there seemed to be a negative correlation between cellular mRNA expression and disease duration. These findings are in broad agreement with other studies of the expression of alpha-synuclein mRNA in human brain and suggest that Lewy body formation is unlikely to be the result of overexpression of alpha-synuclein.

[Prevalence and depression degree in patients with rheumatoid arthritis]. / Prevalencia y grado de depresión en los pacientes con artritis reumatoide.

BACKGROUND: Study goals were: a) to know the existence and depressive level among a series of rheumatoid arthritis (RA) patients; b) to assess differences in depression levels of individuals with and without RA, and c) to identify the association of depression level with socioepidemiological, clinical, and prognostic characteristics in these patients. MATERIAL AND METHODS: Cross-sectional study that undertakes a 3 years period (July 1992-March 1995) and includes 221 patients diagnosed of RA according to the 1988 criteria of the American College of Rheumatology (ACR). Association of depression levels, assessed with the Self-Rating Depression Scale of Zung-Conde, with each one of the variables was evaluated using chi 2 tests (p < 0.05). A multivariate analysis type Automatic Interaction Detection (AID), based on the statistic r2, was applied to determine patient's profile with RA and depression. RESULTS: Depressive level was identified in 33.48% of patients. Odds ratio (OR) between "not depressive" and "depressive" levels was from 20.35 with 95% CI: 8.87-47.88 (p < 0.00001). Association was found with the variables sex (p < 0.0001), profession (p = 0.02), weight and height (p < 0.0001 in both variables), Ritchie index (p < 0.004), number of painful joints (p = 0.002), morning stiffness (p = 0.049) and secondary effects of the treatment (p = 0.034). Sex was the variable that most influenced in depressive level (p < 0.00001). In females group, the factor mainly related with depression was the number of painful joints (p < 0.0002) while in males, it was the self-rating pain valuation with a Likert scale (p < 0.0001). CONCLUSIONS: RA could causes depression in the patients. The factor with highest influence in the depression of these patients was the sex. The most influential factor in the females was the number of painful joints, while in the males was the self-rating of pain.

Bartter's syndrome: physiological and pharmacological studies.

Six siblings with Bartter's syndrome were studied. Increased urinary immunoreactive prostaglandin E (iPgE) was corrected by administration of the prostaglandin synthetase inhibitors, indomethacin, ibuprofen and meclofenamate. In addition, plasma potassium rose, plasma renin activity and angiotensin resistance decreased, and the exaggerated natriuresis following saline loading was abolished. Increased urinary iPgE also became normal following the phospholipase inhibitor, mepacrine, but the other abnormalities remained unaltered. The kallikrein inhibitor, aprotinin, did not alter urinary iPgE, plasma potassium or electrolyte balance. During hypotonic saline infusion, proximal tubular potassium or electrolyte balance. During hypotonic saline infusion, proximal tubular sodium reabsorption was normal or increased. Free water clearance and the percentage of distally delivered sodium which was reabsorbed were, however, significantly decreased. The results suggest that neither the increased renal PgE production nor the hyperbradykininemia seen in Bartter's syndrome play a major role in its pathogenesis, or manifestations, and that the effects of the prostaglandin synthetase inhibitors on the syndrome are non-specific. The results and relevant literature are analysed in an attempt to identify the initial defect in the interrelated sequence of events. The data are compatible with an intrarenal defect in sodium transport, leading to increased sodium delivery to the distal tubule, with secondary hyperreninemia, hypokalemia and elevated iPgE excretion.