Validation of the proton range accuracy and optimization of CT calibration curves utilizing range probing.

Proton therapy is affected by range uncertainty, which is partly caused by an ambiguous conversion from x-ray attenuation to proton stopping power. CT calibration curves, or Hounsfield look-up tables (HLUTs), are institution-specific and may be a source of systematic errors in treatment planning. A range probing method to verify, optimize and validate HLUTs for proton treatment is proposed. An initial HLUT was determined according to the stoichiometric approach. For HLUT validation, three types of animal tissue phantoms were prepared: a pig's head, 'thorax' and femur. CT scans of the phantoms were taken and a structure, simulating a water slab, was added on the scan distal to the phantoms to mimic the detector used for integral depth-dose measurements. The CT scans were imported into the TPS to calculate individual pencil beams directed through the phantoms. The phantoms were positioned at the therapy system isocenter using x-ray imaging. Shoot-through pencil beams were delivered, and depth-dose profiles were measured using a multi-layer ionization chamber. Measured depth-dose curves were compared to the calculated curves and the range error per spot was determined. Based on the water equivalent path length (WEPL) of individual spot, a range error margin was defined. Ratios between measured error and theoretical margin were calculated per spot. The HLUT optimization was performed by identifying systematic shifts of the mean range error per phantom and minimizing the ratios between range errors and uncertainty margins. After optimization, the ratios of the actual range error and the uncertainty margin over the complete data set did not exceed 0.75 (1.5 SD), indicating that the actual errors are covered by the theoretical uncertainty recipe. The feasibility of using range probing to assess range errors was demonstrated. The theoretical uncertainty margins in the institution-specific setting potentially may be reduced by ~25%.

Observation of the spin Peltier effect for magnetic insulators.

We report the observation of the spin Peltier effect (SPE) in the ferrimagnetic insulator yttrium iron garnet (YIG), i.e., a heat current generated by a spin current flowing through a platinum (Pt)|YIG interface. The effect can be explained by the spin transfer torque that transforms the spin current in the Pt into a magnon current in the YIG. Via magnon-phonon interactions the magnetic fluctuations modulate the phonon temperature that is detected by a thermopile close to the interface. By finite-element modeling we verify the reciprocity between the spin Peltier and spin Seebeck effect. The observed strong coupling between thermal magnons and phonons in YIG is attractive for nanoscale cooling techniques.

Thermoelectric detection of ferromagnetic resonance of a nanoscale ferromagnet.

We present thermoelectric measurements of the heat dissipated due to ferromagnetic resonance of a Permalloy strip. A microwave magnetic field, produced by an on-chip coplanar strip waveguide, is used to drive the magnetization precession. The generated heat is detected via Seebeck measurements on a thermocouple connected to the ferromagnet. The observed resonance peak shape is in agreement with the Landau-Lifshitz-Gilbert equation and is compared with thermoelectric finite-element modeling. Unlike other methods, this technique is not restricted to electrically conductive media and is therefore also applicable to for instance ferromagnetic insulators.

A SPECT Camera for Combined MRI and SPECT for Small Animals.

We describe an MR-compatible SPECT camera for small animals. The SPECT camera system can be inserted into the bore of a state-of-the-art MRI system and allows researchers to acquire tomographic images from a mouse in-vivo with the MRI and the SPECT acquiring simultaneously. The SPECT system provides functional information, while MRI provides anatomical information. Until today it was impossible to operate conventional SPECT inside the MRI because of mutual interference. The new SPECT technology is based on semiconductor radiation sensors (CZT, ASICs), and it fits into conventional high field MRI systems with a minimum 12-cm bore size. The SPECT camera has an MR-compatible multi-pinhole collimator for mice with a ø25-mm field-of-view. For the work reported here we assembled a prototype SPECT camera system and acquired SPECT and MRI data from radioactive sources and resolution phantoms using the camera outside and inside the MRI.

MicroCT with energy-resolved photon-counting detectors.

The goal of this paper was to investigate the benefits that could be realistically achieved on a microCT imaging system with an energy-resolved photon-counting x-ray detector. To this end, we built and evaluated a prototype microCT system based on such a detector. The detector is based on cadmium telluride (CdTe) radiation sensors and application-specific integrated circuit (ASIC) readouts. Each detector pixel can simultaneously count x-ray photons above six energy thresholds, providing the capability for energy-selective x-ray imaging. We tested the spectroscopic performance of the system using polychromatic x-ray radiation and various filtering materials with K-absorption edges. Tomographic images were then acquired of a cylindrical PMMA phantom containing holes filled with various materials. Results were also compared with those acquired using an intensity-integrating x-ray detector and single-energy (i.e. non-energy-selective) CT. This paper describes the functionality and performance of the system, and presents preliminary spectroscopic and tomographic results. The spectroscopic experiments showed that the energy-resolved photon-counting detector was capable of measuring energy spectra from polychromatic sources like a standard x-ray tube, and resolving absorption edges present in the energy range used for imaging. However, the spectral quality was degraded by spectral distortions resulting from degrading factors, including finite energy resolution and charge sharing. We developed a simple charge-sharing model to reproduce these distortions. The tomographic experiments showed that the availability of multiple energy thresholds in the photon-counting detector allowed us to simultaneously measure target-to-background contrasts in different energy ranges. Compared with single-energy CT with an integrating detector, this feature was especially useful to improve differentiation of materials with different attenuation coefficient energy dependences.

Precisely timed spatiotemporal patterns of neural activity in dissociated cortical cultures.

Recurring patterns of neural activity, a potential substrate of both information transfer and transformation in cortical networks, have been observed in the intact brain and in brain slices. Do these patterns require the inherent cortical microcircuitry of such preparations or are they a general property of self-organizing neuronal networks? In networks of dissociated cortical neurons from rats--which lack evidence of the intact brain's intrinsic cortical architecture--we have observed a robust set of spontaneously repeating spatiotemporal patterns of neural activity, using a template-matching algorithm that has been successful both in vivo and in brain slices. The observed patterns in cultured monolayer networks are stable over minutes of extracellular recording, occur throughout the culture's development, and are temporally precise within milliseconds. The identification of these patterns in dissociated cultures opens a powerful methodological avenue for the study of such patterns, and their persistence despite the topological and morphological rearrangements of cellular dissociation is further evidence that precisely timed patterns are a universal emergent feature of self-organizing neuronal networks.

Human-ovine comparative sequencing of a 250-kb imprinted domain encompassing the callipyge (clpg) locus and identification of six imprinted transcripts: DLK1, DAT, GTL2, PEG11, antiPEG11, and MEG8.

Two ovine BAC clones and a connecting long-range PCR product, jointly spanning approximately 250 kb and representing most of the MULGE5-OY3 marker interval known to contain the clpg locus, were completely sequenced. The resulting genomic sequence was aligned with its human ortholog and extensively annotated. Six transcripts, four of which were novel, were predicted to originate from within the analyzed region and their existence confirmed experimentally: DLK1, DAT, GTL2, PEG11, antiPEG11, and MEG8. RT-PCR experiments performed on a range of tissues sampled from an 8-wk-old animal demonstrated the preferential expression of all six transcripts in skeletal muscle, which suggests that they are under control of common regulatory elements. The six transcripts were also shown to be subject to parental imprinting: DLK1, DAT, and PEG11 were shown to be paternally expressed and GTL2, antiPEG11, and MEG8 to be maternally expressed.

Extensive genome-wide linkage disequilibrium in cattle.

A genome-wide linkage disequilibrium (LD) map was generated using microsatellite genotypes (284 autosomal microsatellite loci) of 581 gametes sampled from the dutch black-and-white dairy cattle population. LD was measured between all marker pairs, both syntenic and nonsyntenic. Analysis of syntenic pairs revealed surprisingly high levels of LD that, although more pronounced for closely linked marker pairs, extended over several tens of centimorgan. In addition, significant gametic associations were also shown to be very common between nonsyntenic loci. Simulations using the known genealogies of the studied sample indicate that random drift alone is likely to account for most of the observed disequilibrium. No clear evidence was obtained for a direct effect of selection ("Bulmer effect"). The observation of long range disequilibrium between syntenic loci using low-density marker maps indicates that LD mapping has the potential to be very effective in livestock populations. The frequent occurrence of gametic associations between nonsyntenic loci, however, encourages the combined use of linkage and linkage disequilibrium methods to avoid false positive results when mapping genes in livestock.

Fine-mapping of quantitative trait loci by identity by descent in outbred populations: application to milk production in dairy cattle.

We previously mapped a quantitative trait locus (QTL) affecting milk production to bovine chromosome 14. To refine the map position of this QTL, we have increased the density of the genetic map of BTA14q11-16 by addition of nine microsatellites and three single nucleotide polymorphisms. Fine-mapping of the QTL was accomplished by a two-tiered approach. In the first phase, we identified seven sires heterozygous "Qq" for the QTL by marker-assisted segregation analysis in a Holstein-Friesian pedigree comprising 1,158 individuals. In a second phase, we genotyped the seven selected sires for the newly developed high-density marker map and searched for a shared haplotype flanking an hypothetical, identical-by-descent QTL allele with large substitution effect. The seven chromosomes increasing milk fat percentage were indeed shown to carry a common chromosome segment with an estimated size of 5 cM predicted to contain the studied QTL. The same haplotype was shown to be associated with increased fat percentage in the general population as well, providing additional support in favor of the location of the QTL within the corresponding interval.

A QTL affecting milk yield and composition maps to bovine chromosome 20: a confirmation.

As part of a whole genome scan undertaken to detect quantitative trait loci (QTL) affecting milk yield and composition, we have genotyped a granddaughter design comprising 1152 sons for six microsatellite markers spanning bovine chromosome 20. An analysis performed across families provided strong evidence (experiment-wise P-values < 0.01) for the presence of a QTL affecting primarily protein percentage towards the telomeric end of the chromosome. A founder sire, shown in a previous study to segregate for a similar QTL in the corresponding chromosome region, was characterized by 29 and 57 sons and maternal grandsons, respectively, in the present design. Sorting corresponding sons and grandsons by paternal or grandpaternal allele provided significant evidence for the segregation of a QTL on chromosome 20. Altogether these results confirm the location of a QTL affecting milk production on bovine chromosome 20.

A QTL with major effect on milk yield and composition maps to bovine chromosome 14.

A whole genome scan was undertaken in a granddaughter design comprising 1158 progeny-tested bulls in order to map QTL influencing milk yield and composition. In this paper we report the identification of a locus on the centromeric end of bovine Chromosome (Chr) 14, with major effect on fat and protein percentage as well as milk yield. The genuine nature of this QTL was verified using the grand2-daughter design, that is, by tracing the segregating QTL alleles from heterozygous grandsires to their maternal grandsons and confirming the predicted QTL allele substitution effect.

Evaluation of the Faces Pain Scale for use with the elderly.

OBJECTIVE: The specific objective for this research was to determine initial psychometric properties of the Faces Pain Scale (FPS) as a measure of pain intensity for use with the elderly. DESIGN: The study was descriptive correlational in nature, with nonrandom sampling. A total sample of 168 community subjects (30-121, depending on task completed), aged 65 or older, participated in the research protocol. To determine the validity, reliability, and scaling properties of the FPS, rating and ranking procedures, placement tasks, and test-retest methods were used. RESULTS: Response to six Likert-type items indicated that subjects agreed that the FPS represents pain: however, it is clear that the perception of the meaning of the faces can be influenced by the context in which they are presented. Rank ordering tasks for the individual faces demonstrated near-perfect agreement between the actual expected ranking and the ranking produced by the subjects (Kendall's W = .97, p = .00). When subjects placed individual faces along a 1-m-long red wedge indicating the amount of pain represented by each face, statistically significant separation of the faces in the anticipated equal interval position was demonstrated by the lack of overlap of the 95% confidence intervals when all faces were viewed and positioned simultaneously. However, when subjects placed faces independent of others, the expected placement fell outside the 95% confidence limit for three of the five faces placed. In addition, the actual intervals between the five faces placed by subjects demonstrated substantial variances from the 167 mm expected in several instances. Rating a vividly remembered painful experience about the degree of pain perceived using the FPS initially and again 2 weeks later, the FPS demonstrated strong reproducibility over time with a Spearman rho correlation coefficient of .94 (p = .01). CONCLUSION: These results provide preliminary support for the construct validity, strong ordinal properties, and strong test-retest reliability of the FPS with a sample of elderly individuals. The equality of intervals in the FPS has not been fully supported in the older adult, but given the complexity of the task used, the results should not be considered to be refuted. Further evaluation of the FPS with experimental and clinical pain conditions and comparison with other standard pain assessment instruments in the elderly population are warranted.

Collaboration using Internet for the development of case-based teaching files: report of the Computer and Instrumentation Council Internet Focus Group.

UNLABELLED: The Internet and particularly the World-Wide-Web is becoming a useful tool for the nuclear medicine community. METHODS: The Computer and Instrumentation Council of the Society of Nuclear Medicine convened an Internet Focus group to discuss collaboration using the Internet. The prototype application considered was development of case-based teaching files using the World-Wide-Web. Teaching file cases (clinical history, images, description of findings and discussion) on World-Wide-Web servers at different institutions are integrated using the Internet. The user can navigate from case to case using point-and-click hypertext linking. RESULTS: The initial experience with collaboration has been encouraging. An etiquette to help foster collaboration has been proposed. Development of quality control mechanisms and introduction of peer review were identified as issues needing further work. CONCLUSION: The World-Wide-Web offers great potential for new forms of collaboration. There is, however, a need to learn how to make best use of this new resource.

Effects of induced charge in the kinestatic charge detector.

The principle of the kinestatic charge detector (KCD) for digital radiography depends on the synchronization of the scan velocity of a parallel plate drift chamber with the cation drift velocity. Compared with line-beam scanners, this motion-compensated imaging technique makes better use of the x-ray tube output. A Frisch grid traditionally has been used within the KCD to minimize unwanted signal contributions from both cations and negative charge carriers during irradiation. In this work the charge induction process in a parallel plate geometry was investigated for the special case of the KCD. In the limit of infinite plates, the cathode charge density due to both cations and negative charge carriers increases quadratically in time for a kinestatically scanned narrow slit. In the KCD the cathode is segmented into an array of narrow electrodes, each aligned with the incident x-ray beam. Our conformal mapping computation determined that the shape of the induced charge signal depends critically on delta x/w, the ratio of electrode width to drift gap. Our conclusion introduces the possibility of eliminating the Frisch grid from the KCD design because the value of delta x/w required for transverse sampling in the KCD is sufficiently low as to allow "self-gridding" to take effect.

Engineering aspects of a kinestatic charge detector.

The engineering aspects of a nine-channel digital radiographic system developed for bioimaging research, based on high gas pressure ionography and kinestatic principles, are presented. The research imaging system uses a pulsed x-ray beam which allows one to study simultaneously the ionic signal characteristics at 10 different ionization sites along the drift axis. This research imaging detector system allows one to investigate methods to improve the detection and image quality parameters as part of the development of a large scale prototype medical imaging system.

Evaluation of video gray-scale display.

Setting up and maintaining video display monitors properly will help to reduce display variation and improve overall presentation of the radiological image. Display monitor gray-scale characteristics were examined using the SMPTE test pattern. This test pattern may be used as a standard for adjusting brightness and contrast. The controls should be adjusted to display the full dynamic range so that the 5% and 95% signal levels in the pattern are visible. Measured luminance on a laboratory workstation used for radiological perceptual experiments, and on the Siemens CT gray-scale monitor was determined to range from 0.17 to 76.0 nit, and 0.17 to 24.66 nit, respectively. These were compared with the range of approximately 17 to 514 nit for a typical film-viewbox combination. Characteristic curves were determined for both monitors, and CRT gammas were 3.34 and 2.48 for the perceptual workstation and CT console, respectively. The display gamma was determined from fitting luminance data to a log-log plot of luminance versus input gray level. The usefulness of the SMPTE test pattern for visual presentation as well as photometric measurement is demonstrated.

201Tl/99mTc-HMPAO SPECT imaging of treated childhood brain tumors.

To assess whether thallium-201 thallous chloride (Tl) can detect childhood tumors and whether diagnostic effectiveness improves with combined blood flow imaging, 28 children (1.0-18.6 years) were studied using single photon emission computed tomography (SPECT): Tl (1.3-1.8 mCi intravenously), followed in 13 of the patients by technetium-99m-hexamethylpropyleneamine oxime (99mTc-HMPAO; 8-18 mCi intravenously). Tl-uptake was markedly increased with histologically confirmed recurrent brain tumors (N = 12). Tl-avid tumors comprised several histologic types, including 6 astrocytomas/gliomas as well as nonastrocytic neoplasms, such as medulloblastoma and ependymoma. A questionable false-positive study was observed with a treated medulloblastoma. Tl failed to detect 5 tumors (i.e., 2 medulloblastomas, 1 ependymoma, 1 malignant schwannoma, and initially 1 low-grade astrocytoma). The sensitivity and specificity of 201Tl-SPECT for detection of childhood brain tumors was 76.9% and 93.3%, respectively. The mean tumor-to-normal brain ratio for Tl was 2.5 +/- 0.5 (N = 7). In some of the patients, 201Tl-SPECT allowed a more precise assessment of the functional state of the tumor than was possible with computed tomography and magnetic resonance imaging. HMPAO distribution was variously normal, increased or decreased at the site of tissue abnormality, and abnormal blood flow was demonstrated in the remaining neuraxis, in 3 of the 7 patients. Changes in tissue perfusion did not correlate with Tl findings, but were evaluated in only one false-negative study.

Use of a low ionization potential dopant in a kinestatic charge detector: experimental findings.

The broadening of the line spread function (LSF) in the drift direction with increasing drift distance in the kinestatic charge detector is substantially reduced when small amounts (less than 1%) of trimethylamine [(CH3)3 N] are added to the x-ray detection medium (krypton or xenon). The LSF of a mixture of Kr and 0.01% trimethylamine (TMA) was measured as a function of distance at 15, 25, and 35 atm absolute pressure. The full width at half-maximum (FWHM) of the LSF was reduced from about 1.0 mm to less than 0.5 mm at a drift distance of 4.0 mm for the three pressures. The LSF's of mixtures of xenon and TMA at concentrations ranging from 0.0004% to 0.4% in one run and 0.06% to 4.0% in a second run were measured at a constant pressure of 20 atm. The FWHM of the LSF was reduced from 0.6 to 0.4 mm at 4.0 mm for the xenon measurements. The optimum concentration of TMA in Xe was found to be in the neighborhood of 0.1%. The use of TMA reduced the drift distance-dependent LSF broadening to the level expected from ionic diffusion, space charge repulsion, and electric field nonuniformity, and it may be possible to reduce the 0.4-mm FWHM plateau through the use of an improved Frisch grid design. Observation of negative charge carriers showed that electron attachment increases with increasing TMA concentration, although this could be caused by impurities in the TMA. The implications of these results are discussed in terms of extending the maximum drift distance attainable in a kinestatic charge detector.

Space charge effects in a kinestatic charge detector.

The effects of space charge in a kinestatic charge detector (KCD) were examined using computer solutions to Poisson's equation. The KCD is a strip-beam parallel-plate drift chamber used for digital radiography. It was assumed that there is negligible electron attachment, i.e. there are no negative ions formed. The ionization rate per mA as a function of x-ray interaction depth was calculated for a detector filled with xenon at 25.3 x 10(5) Pa. Solution of Thomson's equations gave the positive ion density at the cathode, also as a function of depth. Water filtration values ranging from 0 to 30 cm were used in order to estimate the range of ion density values expected in a clinical KCD. The case of steady-state x-ray illumination was simulated for ionization rates less than the zero field limit (above which space charge changes the polarity of the electric field). Line spread responses were found for varying ionization rates to show the effect of space charge due to electric field distortion on the spatial resolution performance in the drift direction. The effect of imaging ideal edges with a KCD was calculated and the expected output signal was plotted for densities up to the zero field limit. Space charge dependence on the selection of KCD design and operating parameters is discussed. Because of the dependence of the KCD drift-direction spatial resolution on the uniformity of the electric field, space charge effects impose an upper limit on the detector entrance exposure and define the dynamic range of the device.