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Background: Radiochromic silicone-based dosimeters are flexible 3D dosimeters, which at appropriate concentration of leucomalachite green (LMG) and curing agent are dose-rate independent for clinical photon beams. However, their dose response is based on chemical processes that can be influenced by temporal and thermal conditions, impacting measurement stability. Purpose: The aim of this study was to investigate the temporal stability of the dose response of radiochromic dosimeters for different curing times and post-irradiation storage temperatures. Methods: Six cylindrical dosimeters (5 cm diameter, 5 cm length) were produced in a single batch and separated into two groups that were irradiated 72 and 118 h after production. The same photon plan, consisting of two 10 × 1.6 cm 2 opposing fields, was delivered to all dosimeters. After irradiation, the dosimeters were separated into three groups, stored at 5°C, 15°C, and 20°C, and read out for five consecutive days. Results: Storage temperature influenced the measurement stability, and changes in the optical response with time differed between irradiated and non-irradiated parts of the dosimeters. The relative change between signal and background was greater than 10% for all measurements performed 24 h or more after irradiation, except for dosimeters stored at 5°C, which changed by 2%–5% after 24 h. The dosimeter temporal stability was not influenced by curing time. Conclusions: For room temperature storage (15°C and 20°C), readout should take place as soon as possible after irradiation since the background color increased rapidly for both curing times (72 and 118 h), whereas the dosimeters are stored at 5°C, readout can be performed up to 24 h after.

Radiation therapy (RT) is one of the major curative approaches for cancer. It is a complex and risky treatment approach, which requires precise planning, prior to the administration of the treatment. Visual Computing (VC) is a fundamental component of RT planning, providing solutions in all parts of the process-from imaging to delivery. Despite the significant technological advancements of RT over the last decades, there are still many challenges to address. This survey provides an overview of the compound planning process of RT, and of the ways that VC has supported RT in all its facets. The RT planning process is described to enable a basic understanding in the involved data, users and workflow steps. A systematic categorization and an extensive analysis of existing literature in the joint VC/RT research is presented, covering the entire planning process. The survey concludes with a discussion on lessons learnt, current status, open challenges, and future directions in VC/RT research.

PURPOSE: Photon counting detectors (PCDs) are being introduced in advanced x-ray computed tomography (CT) scanners. From a single PCD-CT acquisition, multiple images can be reconstructed, each based on only a part of the original x-ray spectrum. In this study, we investigated whether PCD-CT can be used to estimate stopping power ratios (SPRs) for proton therapy treatment planning, both by comparing to other SPR methods proposed for single energy CT (SECT) and dual energy CT (DECT) as well as to experimental measurements.METHODS: A previously developed DECT-based SPR estimation method was adapted to PCD-CT data, by adjusting the estimation equations to allow for more energy spectra. The method was calibrated directly on noisy data to increase the robustness toward image noise. The new PCD SPR estimation method was tested in theoretical calculations as well as in an experimental setup, using both four and two energy bin PCD-CT images, and through comparison to two other SPR methods proposed for SECT and DECT. These two methods were also evaluated on PCD-CT images, full spectrum (one-bin) or two-bin images, respectively. In a theoretical framework, we evaluated the effect of patient-specific tissue variations (density and elemental composition) and image noise on the SPR accuracy; the latter effect was assessed by applying three different noise levels (low, medium, and high noise). SPR estimates derived using real PCD-CT images were compared to experimentally measured SPRs in nine organic tissue samples, including fat, muscle, and bone tissues.RESULTS: For the theoretical calculations, the root-mean-square error (RMSE) of the SPR estimation was 0.1% for the new PCD method using both two and four energy bins, compared to 0.2% and 0.7% for the DECT- and SECT-based method, respectively. The PCD method was found to be very robust toward CT image noise, with a RMSE of 2.7% when high noise was added to the CT numbers. Introducing tissue variations, the RMSE only increased to 0.5%; even when adding high image noise to the changed tissues, the RMSE stayed within 3.1%. In the experimental measurements, the RMSE over the nine tissue samples was 0.8% when using two energy bins, and 1.0% for the four-bin images.CONCLUSIONS: In all tested cases, the new PCD method produced similar or better results than the SECT- and DECT-based methods, showing an overall improvement of the SPR accuracy. This study thus demonstrated that PCD-CT scans will be a qualified candidate for SPR estimations.

Purpose In this study the authors present a new method for estimation of proton stopping power ratios (SPRs) using dual energy CT (DECT), which is robust toward CT noise. The authors propose a parametrization for SPR based directly on the CT numbers in a DECT image set, whereby the intermediate steps of estimating the relative electron density, ρe, and mean excitation energy, I, are avoided. Methods The SPR parametrization proposed in this study is a purely empirical fit based on the theoretical SPR values for a list of 34 reference human tissues. To investigate the SPR estimation made with this new method the authors performed a calibration and an evaluation with the method. The authors initially calculated CT numbers using CT energy spectrum characterization parameters obtained from calibration based on a Gammex 467 electron density calibration phantom. These CT numbers were fitted to the theoretical SPR for the reference human tissues using the new SPR parametrization presented in this study. The method was evaluated based on theoretical CT numbers for the reference human tissues. The root-mean-square error (RMSE) of the SPR and the proton range error from the continuous slowing down approximation were calculated for the reference human tissues. To test the stability of the parametrization the authors varied the density and elemental composition of the reference human tissues and calculated their new SPR estimates. Further, clinically realistic noise values were added to the theoretical CT numbers to investigate how CT noise affected the estimated water equivalent range through 10 cm of the reference human tissues. All results for the new SPR parametrization were compared to the results obtained using two previously published DECT methods for SPR estimation. Comparisons were also made to a single energy CT (SECT) SPR estimation method, the stoichiometric method, which is commonly used in clinical practise for proton therapy treatment planning. Results The RMSE for the SPR of the 34 reference human tissues using the new SPR parametrization was 0.12%, compared to 0.19% and 0.28% for the two previously published DECT methods. The SPR parametrization was more stable toward variations of the calcium content in the reference human tissues, but less stable toward density variations and changes to the hydrogen content than the two other DECT methods. When adding noise to the theoretical CT numbers the SPR parametrization gave the lowest water equivalent range errors of all four tested SPR estimation methods (maximum error reduced to 0.4 mm). In all cases tested, the new SPR parametrization outperformed the SECT stoichiometric method. Conclusions The new SPR parametrization gave lower RMSEs than the two other published DECT methods, and was in particular more robust against added noise. The method has potential for reducing range uncertainty margins in treatment planning of proton therapy.

Purpose: Cone-beam CT (CBCT) imaging may enable image- and dose-guided proton therapy, but is challenged by image artefacts. The aim of this study was to demonstrate the general applicability of a previously developed a priori scatter correction algorithm to allow CBCT-based proton dose calculations. Methods: The a priori scatter correction algorithm used a plan CT (pCT) and raw cone-beam projections acquired with the Varian On-Board Imager. The projections were initially corrected for bow-tie filtering and beam hardening and subsequently reconstructed using the Feldkamp-Davis-Kress algorithm (rawCBCT). The rawCBCTs were intensity normalised before a rigid and deformable registration were applied on the pCTs to the rawCBCTs. The resulting images were forward projected onto the same angles as the raw CB projections. The two projections were subtracted from each other, Gaussian and median filtered, and then subtracted from the raw projections and finally reconstructed to the scatter-corrected CBCTs. For evaluation, water equivalent path length (WEPL) maps (from anterior to posterior) were calculated on different reconstructions of three data sets (CB projections and pCT) of three parts of an Alderson phantom. Finally, single beam spot scanning proton plans (0–360 deg gantry angle in steps of 5 deg; using PyTRiP) treating a 5 cm central spherical target in the pCT were re-calculated on scatter-corrected CBCTs with identical targets. Results: The scatter-corrected CBCTs resulted in sub-mm mean WEPL differences relative to the rigid registration of the pCT for all three data sets. These differences were considerably smaller than what was achieved with the regular Varian CBCT reconstruction algorithm (1–9 mm mean WEPL differences). Target coverage in the re-calculated plans was generally improved using the scatter-corrected CBCTs compared to the Varian CBCT reconstruction. Conclusion: We have demonstrated the general applicability of a priori CBCT scatter correction, potentially opening for CBCT-based image/dose-guided proton therapy, including adaptive strategies. Research agreement with Varian Medical Systems, not connected to the present project.

Purpose: The aim of this study was to investigate whether the stopping power ratio (SPR) of a deformable, silicone-based 3D dosimeter could be determined more accurately using dual energy (DE) CT compared to using conventional methods based on single energy (SE) CT. The use of SECT combined with the stoichiometric calibration method was therefore compared to DECT-based determination. Methods: The SPR of the dosimeter was estimated based on its Hounsfield units (HUs) in both a SECT image and a DECT image set. The stoichiometric calibration method was used for converting the HU in the SECT image to a SPR value for the dosimeter while two published SPR calibration methods for dual energy were applied on the DECT images. Finally, the SPR of the dosimeter was measured in a 60 MeV proton by quantifying the range difference with and without the dosimeter in the beam path. Results: The SPR determined from SECT and the stoichiometric method was 1.10, compared to 1.01 with both DECT calibration methods. The measured SPR for the dosimeter material was 0.97. Conclusions: The SPR of the dosimeter was overestimated by 13% using the stoichiometric method and by 3% when using DECT. If the stoichiometric method should be applied for the dosimeter, the HU of the dosimeter must be manually changed in the treatment planning system in order to give a correct SPR estimate. Using a wrong SPR value will cause differences between the calculated and the delivered treatment plans.

Aims and objectives The objective of this study was to investigate how patient education in a surgical department was experienced by patients who had undergone total knee arthroplasty or total hip arthroplasty. Background Total knee arthroplasty and total hip arthroplasty are two of the most common and clinically effective surgical treatments performed in the Western world. Patient education efforts related to these procedures have been studied, but usually only to evaluate clinical outcome and little in a patient perspective. Design The empirics consist of qualitative in-depth interviews with 11 patients admitted to the surgical department at a Norwegian hospital. The interviews were carried out in 2011. Methods The study has a qualitative design with a phenomenological approach. The data have been analysed through meaning condensation, in accordance with Amadeo Giorgi's four-step method. N = 11. Results The education programme made the patients feel mentally prepared for surgery and the postsurgical situation. Three themes were identified: (1) realistic information preparing for surgery, (2) involvement and sense of control and (3) trust in staff. Conclusion A relationship seems to exist between how informed patients feel and how much they trust the department in which they are undergoing treatment. There may also be a relationship between a sense of control and trust. Relevance to clinical practice To build a trustful relationship between healthcare providers and patients, patient education both in groups and individually should be implemented, and be designed in a way that supports trust. Information should be realistic and accurate.

Studies on patients with degenerative joint disease of the hip show that femoral periprosthetic bone mineral decreases following total hip arthroplasty. Scarcely any osteodensitometric data exist on femoral neck fracture (FNF) patients and periprosthetic bone remodelling. In two parallel cohorts we enrolled 87 patients (mean age, 72 ± 12 years; male:female ratio, 30:57) undergoing total hip arthroplasty for either primary osteoarthritis (OA) of the hip (n = 37) or for an acute FNF (n = 50) and followed them for a mean of 5.4 years. Outcomes were bone mineral density (BMD) changes in the periprosthetic Gruen zones 1–7, the incidence of periprosthetic fractures and clinical outcome. The bone mineral loss in the fracture group was more than twice that of the osteoarthritis group, −16.9% versus −6.8% (p = 0.004). The incidence of periprosthetic fractures was 12% (6/50) in the fracture cohort compared with none (0%) in the OA cohort (p = 0.03). Periprosthetic bone mineral loss following total hip arthroplasty is significantly greater in patients who are treated for acute FNF than in OA patients. This decrease of BMD follows a different pattern with the FNF patients losing larger proportions of bone in Gruen zones 1, 2, 6, and 7 while the OA patients tend to have larger losses only in zones 1 and 7. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:504–512, 2015.

Cell microarrays can serve as high-throughput platforms for the screening of a diverse range of biologically active factors and biomaterials that can induce desired cellular responses such as attachment, proliferation, or differentiation. Here, we demonstrate that surface-engineered microarrays can be used for the screening and identification of factors that allow the enrichment and isolation of rare cells from tissue-derived heterogeneous cell populations. In particular, we have focused on the enrichment of bovine testicular cells including type A spermatogonia and Sertoli cells. Microarray slides were coated with a copolymer synthesized from poly(ethylene glycol) methacrylate and glycidyl methacrylate to enable both the prevention of cell attachment between printed spots and the covalent anchoring of various factors such as antibodies, lectins, growth factors, extracellular matrix proteins, and synthetic macromolecules on printed spots. Microarrays were incubated with mixed cell populations from freshly isolated bovine testicular tissue. Overall, cell attachment was evaluated using CellTrackerTM staining, whereas differential attachment of testicular cells was determined by immunohistochemistry staining with Plzf and vimentin antibodies as markers for type A spermatogonia and Sertoli cells, respectively. The results indicate that various surface immobilized factors, but in particular Dolichos biflorus lectin, allowed the enrichment of Plzf positive cells. Furthermore, Pisum sativum lectin, concanavalin A, collagen type IV, and vitronectin were identified as suitable negative selection factors. To our best knowledge, this work is the first to demonstrate the utility of surface engineered cell-based microarrays for the identification of factors that allow the selective capture of rare cells from tissue isolated heterogeneous mixtures. Refereed/Peer-reviewed

Purpose: Both temporal and thermal dependencies of the dose response have been observed in radiochromic dosimeters. As these dependencies may be influenced by the dose level, the present study investigates the temperature dependence during irradiation and the temporal change of the optical response following irradiation of radiochromic dosimeters at a range of doses. Methods: Cuvette samples of the PRESAGE Trade-Mark-Sign radiochromic dosimeter were irradiated within a dose range of 0-10 Gy at irradiation temperatures within 5-35 Degree-Sign C and postirradiation storage within 6-30 Degree-Sign C. The optical response due to irradiation was measured using a standard spectrophotometer and the data were analyzed in terms of thermal and temporal change. Results: The initial dose response was linear over the applied dose range independent of irradiation temperature. However, the optical response to a specific dose increased exponentially with irradiation temperature corresponding to an activation energy of 0.114 {+-} 0.007 eV. The temporal change in dose response after irradiation consisted of an offset, an auto-oxidation rate with activation energy 0.84 {+-} 0.03 eV, and an initial exponential increase in optical response (1.6 {+-} 0.2 eV) followed by an exponential decrease in optical response (0.98 {+-} 0.08 eV). These contributions depended on both storagemore » temperature and the dose given, leading to a nonlinear dose response with time at low storage temperatures and a high auto-oxidation rate at high storage temperatures. Conclusions: Thermal equilibration is important to the radiochromic dosimeter investigated due to an exponential change in dose response with irradiation temperature and a considerable postirradiation temporal change in response. For the dosimeter version investigated in this study, a compromise in storage temperature has to be made between increasing the nonlinearity of the dose response with time and inducing a high auto-oxidation rate.« less

PURPOSE The dose response of radiochromic dosimeters is based on radiation-induced chemical reactions and is thus likely to be thermally influenced. In this study we have therefore investigated the temperature dependence of the dose response for such dosimeters, regarding both irradiation and storage conditions. METHODS Dosimeter samples in cuvettes were irradiated to 5 Gy. The temperature for the different cuvettes during irradiation and post-irradiation storage was varied in the range of 3-30 degrees C in order to quantify the temperature dependence of the dosimeter response. The optical properties of the dosimeter samples were measured using a spectrophotometer before irradiation as well as at several times after irradiation to quantify the temporal variation of dose response (expressed as the optical density change induced by irradiation) as a function of storage temperature. RESULTS The measurements show considerable temperature dependencies of dose response both during irradiation and storage. Fit to an Arrhenius equation revealed an activation energy of 1.4 +/- 0.2 eV for the variation in irradiation temperature, indicating a contribution from a thermally activated process. Variation in dose response at different storage temperatures showed an exponential increase with time followed by a decrease in optical density. Exponential Arrhenius fits to rate constants gave activation energies of 1.7 +/- 0.2 eV for the increase in dose response and 2.3 +/- 0.5 eV for the subsequent decrease, in this case dominated by thermally activated processes. CONCLUSIONS Due to the exponential dependencies, stabilization of the dosimeter during irradiation at low temperatures (e.g., 5 degrees C) is preferable in clinical use to optimize the accuracy of the dose response. In addition, a low storage temperature is recommended in order to minimize the post-irradiation temporal change in dose response and thereby increase the post-irradiation stability of the dosimeter. The measurements in this study show that if the observed temperature and temporal dependencies are not considered, this could potentially deteriorate the accuracy of the dosimeter.

Purpose: Volumetric modulated arc therapy (VMAT) includes features such as a variable dose rate and gantry speed in addition to the beam modulation achieved with multileaf collimator (MLC) motion patterns employed in intensity modulated radiotherapy. Three tests have previously been proposed for the evaluation of the performance of VMAT delivery. In order to enable a convenient and accurate routine machine quality control (QC) program, the present study proposes tolerance levels for these tests based on a department-wide implementation of an electronic portal imaging device (EPID)-based QC. Methods: Three different VMAT tests--a picket fence (PF) test, a dose rate versus gantry speed (DRGS) test, and a dose rate versus MLC leaf speed (DRMLC) test--were performed on nine accelerators using two different EPIDs (aS1000 and aS500, Varian Medical Systems). All tests were repeated six times for each accelerator. The images were analyzed using an in-house-developed software. For the PF test, the positions and widths of individual MLC leaf gaps were compared to the mean value. In the DRGS and DRMLC tests, different combinations of dose rate, gantry speed, and MLC leaf speed were used to deliver identical doses to separate parts of the EPID. The tests were evaluated by looking for deviationsmore » in the constancy of the measured dose for the preset combinations of dose rate, gantry speed, and MLC leaf speed. Results: For the PF test, a 0.3 mm tolerance level was suggested for the positioning of the MLC leaves. The tolerance level for the gap width was 0.5 mm. For the DRGS and DRMLC tests, a 3% tolerance level was proposed. Conclusions: With the adapted levels of tolerance for an EPID-based approach, the PF, the DRGS, and the DRMLC tests offer a convenient and accurate machine QC program for linear accelerators used for VMAT.« less

This paper first presents stylized evidence showing how the date of the adoption of competition policy is correlated with country size. Smaller countries tend to adopt competition policy later. We then present a theoretical model with countries of different size, trade costs, and firms competing a la Cournot. In the model we show that reduced trade costs following from increasing globalization affect countries differently depending on their size. This has implications for the incentives to introduce competition policy. The predictions of the model are consistent with the empirical regularity presented. Ce memoire presente certains resultats qui suggerent comment le moment choisi pour adopter une politique de concurrence est co-reliea la taille du pays. Les petits pays tendent a adopter des politiques de concurrence plus tard. On presente un modele theorique avec des pays de tailles differentes, qui ont aussi des couts de commerce differents, et ou les firmes se concurrencent a la Cournot. On montre que la reduction des couts de commerce qui suit une mondialisation croissante affecte les pays d'une maniere differente selon leur taille. Cela a des implications pour les incitations a mettre en place une politique de concurrence. Les predictions du modele sont consistantes avec les regularites empiriques observees.

The existence of optimism when biased decisions are costly is investigated experimentally. Subjects make an informed guess about an exogenously determined event: the outside temperature a couple of days later. Payments in the control group depend only on how close the guess was to the realized temperature, while payments in the treatment group also depend positively on realized temperature. The data show the treatment group subjects to guess higher temperatures, that is, higher payments, compared with the control group. Results thus indicate that there is optimism also when a decision bias is costly. (JEL C91, D81, D84)

The objective of the current study was to identify an optimal time period for donor cell transplantation after irradiation in sheep. The testes of recipient rams were treated with a single dose of 15 Gray (Gy) irradiation followed by germ cell transplantation either 3 or 6 weeks later. Transplantation of donor cells at 6 weeks after irradiation resulted in production of donor sperm by all five recipient rams compared with 4 of 11 rams transplanted at 3 weeks. Rams transplanted 3 weeks post-irradiation appeared to show reduced libido and fertility. Two rams produced sperm with low motility (< 20%) and two other rams were azoospermic. More than 1 year after cell transfer, there were heavy infiltrates of CD45-positive cells and more fibrous tissue in 9 of 14 recipient testes (seven rams) that received cells 3 weeks after irradiation. Taken together, these results suggest that the interval between irradiation of recipients and germ cell transplantation affects the success rate of the procedure, with a 6-week interval preferable. The elevated inflammatory/immune reaction may be responsible, at least in part, for the reduced fertility and low libido observed in the rams that received cells 3 weeks post-irradiation.

The mechanism by which leptin regulate male reproductive development during postnatal periods remain to be determined. Using immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR), we established that leptin is expressed in mouse testis with a cell-type and stage-dependent manner during the postnatal period. In testes of 5-day-old mice, leptin expression was mainly restricted to gonocytes, whereas the immunostaining of leptin was confined to spermatogonia in 10-day-old testes. From Day 20 and onwards, stage-specific expression of leptin was evident in spermatocytes at stages VII-XII of the cycle in the seminiferous epithelium. RT-PCR showed that leptin and its receptor isoforms, Ob-Ra, Ob-Rb, and Ob-Re were all expressed in testes from 5- to 60-day-old mice. The mRNA for Ob-Ra and Ob-Re, but not Ob-Rb or leptin were identified in both immature (14-day-old) and adult (60-day-old) isolated Leydig cells. These results suggest that besides its primary actions at the hypothalamic-pituitary level, leptin has direct effects in the proliferation, differentiation of germ cells and the modulation of testicular steroidogenesis, using both autocrine and paracrine mechanisms.

Pigment-dispersing factor (PDF) is a neuropeptide that has been indicated as a likely output signal from the circadian clock neurons in the brain of Drosophila. In addition to these brain neurons, there are PDF-immunoreactive (PDFI) neurons in the abdominal ganglia of Drosophila and other insects; the function of these neurons is not known. We have analyzed PDFI neurons in the abdominal ganglia of the locust Locusta migratoria. These PDFI neurons can first be detected at about 45% embryonic development and have an adult appearance at about 80%. In each of the abdominal ganglia (A3-A7) there is one pair of lateral PDFI neurons and in each of the A5-A7 ganglia there is additionally a pair of median neurons. The lateral neurons supply varicose branches to neurohemal areas of the lateral heart nerves and perisympathetic organs, whereas the median cells form processes in the terminal abdominal ganglion and supply terminals on the hindgut. Because PDF does not influence hindgut contractility, it is possible that also these median neurons release PDF into the circulation. Release from one or both the PDFI neuron types was confirmed by measurements of PDF-immunoreactivity in hemolymph by enzyme immunoassay. PDF applied to the terminal abdominal ganglion triggers firing of action potentials in motoneurons with axons in the genital nerves of males and the 8th ventral nerve of females. Because this action is blocked in calcium-free saline, it is likely that PDF acts via interneurons. Thus, PDF seems to have a modulatory role in central neuronal circuits of the terminal abdominal ganglion that control muscles of genital organs.

During the purification of tachykinin-related peptides from the brain of the cockroach Leucophaea maderae, a few other peptides were collected in adjacent high-performance liquid chromatography fractions. Edman degradation, mass spectrometry, and chemical synthesis revealed that one of these peptides had the sequence DNSQWGGFA. This nonamidated nonapeptide was designated baratin and appears not to be related to any known insect peptide. Baratin was not found to be bioactive in the L. maderae hindgut or oviduct muscle contraction assay. (Both synthetic nonamidated and amidated baratin were tested.) To screen for possible sites of action, we raised a rabbit antiserum to baratin. We found baratin-immunoreactive (BAR-IR) interneurons throughout the cockroach central nervous system. Some prominent brain neuropils were supplied by BAR-IR neuron processes: the central body, the calyx, and lobes of the mushroom bodies, parts of the optic lobe, and the tritocerebral neuropil. Additionally we found BAR-IR neurosecretory cells in the median neurosecretory cell group with processes supplying the storage lobe of the corpora cardiaca. In each of the thoracic and abdominal ganglia processes of BAR-IR projection neurons and local neurons were seen. The baratin antiserum also labeled neurons in the brain of the locust Locusta migratoria, some of which are similar to those of the cockroach. A prominent system of interganglionic BAR-IR processes was found in the locust subesophageal, thoracic, and abdominal ganglia. This was formed by four large projection neurons with cell bodies in the abdominal ganglia A1-2. The processes of these BAR-IR neurons are distributed dorsally and laterally in each of the ventral nerve cord ganglia. When baratin (10(-6)-10(-4) M) was applied to desheathed abdominal ganglia of locusts and cockroaches, we could monitor bursts of action potentials in neurons with axons in the anterior abdominal nerve (nerve 1), but not in the posterior nerve (nerve 2). In ganglia displaying spontaneous rhythmic firing in units of nerve 1, baratin strengthened the rhythmic pattern. Thus baratin appears to have a role in modulation of motor patterns in abdominal ganglia. The immunocytochemical findings suggest further modulatory actions of baratin in different circuits of the brain and ventral nerve cord.

Five isoforms of tachykinin-related peptides (TRPs), designated LemTRP-1-5, have been identified in the midgut of the cockroach Leucophaea maderae. These peptides have a conserved C-terminus hexapeptide (GFX1GX2Ramide; X1 and X2 are variable residues) and variable N-termini. Here, we address the question of whether these five isoforms are all colocalized in the two types of cells in the cockroach midgut, the endocrine cells and the neuronal processes. We also investigate whether the N-terminally extended isoforms LemTRP-2 and -3, which contain putative endoproteolytic cleavage sites, are expressed in intact form or are cleaved in the midgut cells. To this end, we used two approaches. (1) Extracts from portions of the midgut containing each of the cell types were subjected to reverse-phase high performance liquid chromatography (HPLC) and the fractions monitored in a radioimmunoassay (RIA) with an antiserum to the conserved C-terminus of insect TRPs. (2) Antisera were raised to the variable N-termini of the extended LemTRP-2 and -3 and used for immunocytochemistry. The HPLC-RIA and immunocytochemical findings indicate that LemTRP-1 and 4-5 are present in the neuronal processes and in endocrine cells of the midgut proper and of the gastric cecae. The two extended forms LemTRP-2 and -3 display a differential distribution: LemTRP-2 was found in endocrine cells of midgut and gastric cecae, but not in neuronal processes, whereas LemTRP-3 was seen in neuronal processes and endocrine cells of the midgut proper, but not in the gastric cecae. LemTRP-3 and -4 have not been identified in the brain, suggesting further cell- and tissue-specific expression of LemTRPs. The mechanisms behind the cell-specific expression of the LemTRPs are not yet understood, but the demonstration of differential distribution of the peptide isoforms provide a first indication that the isoforms may have different actions.

We have analyzed the relative distribution of tachykinin-related peptides (TRPs) in extracts of adult brains, thoracico-abdominal ganglia, and midguts and of the larval central nervous system of the blowfly Calliphora vomitoria using high performance liquid chromatography (HPLC) in combination with radioimmunoassay (RIA). The RIA employed antisera to the insect TRPs, locustatachykinin I (LomTK I) and callitachykinin II (CavTK II). For identification of the two known blowfly tachykinins we monitored the retention times of synthetic CavTK I and CAVTK II as a reference. With the CavTK II antiserum, all assayed tissues displayed two immunoreactive HPLC fractions with exactly the same retention times as synthetic CavTK I and CavTK II, respectively. An additional immunoreactive fraction eluting earlier than the reference peptides was detected in the adult midgut extract. When assaying the HPLC fractions with antiserum to LomTK I, we obtained the same patterns of immunoreactivity except that now the early eluting material was detectable in all the adult extracts. In addition, in the larval central nervous system, a third major immunoreactive component was displayed using the LomTK RIA and a fourth detected with the CavTK II RIA. We conclude that CavTK I and II are present at a ratio of about 1:1 in all assayed tissues and that two or three additional unidentified tatchykinin-immunoreactive peptides may exist. One of these was seen in the adult tissues; the others appear to be specific for the larval central nervous system (CNS). The RIA was also utilized to determine the total amount of CavTK-immunoreactive material in adult brain, thoracic-abdominal ganglia, and midgut as well as in larval CNS and intestine. The adult CNS contained about seven times more CavTK-immunoreactive material than the larval CNS, and the adult midgut contained 15 times more than the larval intestine. Correlated with these RIA results, many fewer CavTK immunoreactive endocrine cells were labeled in the larval midgut and fewer neurons in the larval CNS than in the Corresponding tissues of adults. Arch. Insect Biochem. Physiol. 34:475–491, 1997. © 1997 Wiley-Liss, Inc.

Purpose: Multi-parametric MRI (mp-MRI) is being introduced in radiotherapy (RT) of prostate cancer, including for tumour delineation in focal boosting strategies. We recently developed an image-based tumour control probability model, based on cell density distributions derived from apparent diffusion coefficient (ADC) maps. Beyond tumour volume and cell densities, tumour hypoxia is also an important determinant of RT response. Since tissue perfusion from mp-MRI has been related to hypoxia we have explored the patterns of ADC and perfusion maps, and the relations between them, inside and outside prostate index lesions. Methods: ADC and perfusion maps from 20 prostate cancer patients were used, with the prostate and index lesion delineated by a dedicated uro-radiologist. To reduce noise, the maps were averaged over a 3×3×3 voxel cube. Associations between different ADC and perfusion histogram parameters within the prostate, inside and outside the index lesion, were evaluated with the Pearson’s correlation coefficient. In the voxel-wise analysis, scatter plots of ADC vs perfusion were analysed for voxels in the prostate, inside and outside of the index lesion, again with the associations quantified with the Pearson’s correlation coefficient. Results: Overall ADC was lower inside the index lesion than in the normal prostate as opposed to ktrans that was higher inside the index lesion than outside. In the histogram analysis, the minimum ktrans was significantly correlated with the maximum ADC (Pearson=0.47; p=0.03). At the voxel level, 15 of the 20 cases had a statistically significant inverse correlation between ADC and perfusion inside the index lesion; ten of the cases had a Pearson < −0.4. Conclusion: The minimum value of ktrans across the tumour was correlated to the maximum ADC. However, on the voxel level, the ‘local’ ktrans in the index lesion is inversely (i.e. negatively) correlated to the ‘local’ ADC in most patients. Research agreement with Varian Medical Systems, not related to the work presented in this abstract.

In this study, an antiserum raised against an insect myotropic peptide, leucokinin I (DPAFNSWGamide), was used for mapping leucokinin-like immunoreactive (LK-LI) neurons in the gastropod mollusc, Helix pomatia. Immunocytochemistry performed on both whole-mounts and cryostat sections demonstrated LK-LI neurons in all ganglia of the central nervous system (CNS), except the visceral ganglion. Altogether about 700 immunolabelled neurons have been found, with nearly one-half (46%) in the cerebral ganglia. A large proportion of the LK-LI neurons have small cell bodies and are likely to be interneurons. The most prominent LK-LI cell group is represented by the entire neuron population of the mesocerebri, which is the major source of a thick fiber bundle system, encircling and innervating the whole CNS. One single LK-LI giant neuron was found, which is located in the left pedal ganglion and is termed GLPdLKC (giant left pedal leucokinin immunoreactive cell). This cell has not been identified previously. The ganglion neuropils are heavily innervated by varicose LK-LI fiber arborizations. Some integrative centers, such as the medullary neuropil of the procerebri, reveal an extreme density of LK-LI innervation. All major peripheral nerves contain a large number of LK-LI axons, and LK-LI innervation is found in the musculature of different peripheral organs (buccal mass, lip, tentacles, oviduct, intestine). Among the peripheral organs investigated, the intestine contains a rich varicose LK-LI network, composed of both intrinsic and extrinsic elements. Radioimmunoassay (RIA) demonstrates a very high content of LK-LI material in Helix ganglion extracts (about 50 pmol/CNS). This is the first report on the occurrence of a substance resembling the myotropic neuropeptide leucokinin I in a phylum outside arthropods. Based on our immunocytochemical observations, a role for leucokinin-like peptides in both central and peripheral regulatory processes in Helix is suggested. According to double-labelling experiments, only a small number of the LK-LI neurons are labelled with an antibody to the vertebrate tachykinin substance P.

Purpose: The current practice for evaluating deformable image registration (DIR) is commonly subjective as it involves input from an observer due to lack of an absolute ground truth. We have therefore developed an automated objective method to evaluate DIR in order to identify scan outliers for longitudinal datasets. Methods: The imaging dataset consisted of nine repeated CT scans (CT1–9) from four prostate patients. Six “similar” CT scans (CT1–6) from one patient (PT1) were used as ground truth meanwhile three other CT scans (CT7–9) from PT2–4 served as scan outliers. Voxel-by-voxel DIR-related uncertainties (Distance Discordance Metric, DDM) were evaluated on groups of five CT scans for the following ten scenarios: Scenario 1–5: five out of six CT scans (CT1–6) from PT1 using leave-one-out technique were used; Scenario 6–8: single scan from PT1 was replaced by another CT scan from PT2–4; and Scenario 9–10: two to three CT scans from PT1 were replaced by CT scans from PT2–4. For each scenario, the DDM map was superimposed on CT-1 and two-sample t-test was performed to compare the uncertainty distributions for all 10 scenarios. Results: The mean DDM values were 3.8–4.2 mm for the first five scenarios, 5.1–6.7 mm for scenario 6–8, and 8.3 mm and 8.9 mm for scenario 9 and scenario 10, respectively. The two-sample t-test showed that the DDM distributions for scenarios 1–5 have a similar mean while the distributions for scenarios 6–10 have statistically different means compared to scenario 1–5. Conclusion: The DIR uncertainty distributions as estimated from our method on a set of images from the same patient are of similar magnitude. When images for a patient are replaced by images from other patients, the distribution of the uncertainties changes considerably, motivating the use of DDM as a metric to automatically detect scan outliers.

Purpose: Rectum is the main dose‐limitingorgan in radiotherapy (RT) of prostate cancer (PC). This organ displays considerable motion leading to uncertainties in the rectum dose‐volume histogram (DVH), which is likely to also influence the associations between rectal DVHs and toxicity. The aim of this study was to improve the understanding of how rectum motion influences these associations by introducing and applying a rectum motion model to generate 'motion‐inclusive' DVHs. Methods: Varying amounts of random and systematic organ motion (“shifts”) were generated by altering the standard deviations (SDs) of normal distribution from 0.1 cm to 1 cm in steps of 0.1 cm. In order to simulate random shifts, we perturbed each dose fraction with a unique value of shift drawn from a normal distribution whose SD was proportional to the simulated random shift. The systematic shift was simulated similarly but with a normally distributed shift that remained constant over the entire course of trial. The delivered DVHs (dDVHs) were generated as a number of pseudo DVHs. The dDVHs were associated with prospectively registered late rectal larger than Grade 2 RTOG toxicity (dichotomized; minimum 5 year follow‐up) for a cohort of 232 PC patients treated using 35 dose fractions and compared to the planned rectum DVH (pDVH). The Spearman's rank correlation coefficient (Rs) was used as a measure of the associations. Results: Systematic errors reduced the association at rectum volumes receiving doses above 40 Gy (V40) and doses less than the dose max. The Rs (V40) was insensitive to the magnitude of systematic and random errors. Random errors smoothed out the curve describing Rs vs. Vx. Conclusions: A model for simulating rectal motion has been presented and the corresponding DVHs investigated in relation to rectal toxicity. Systematic errors reduced the association above V40 and doses less than the dose max.

Purpose: Dose accumulation following deformable image registration (DIR) is challenging. In this study, we used a statistical sampling approach, which takes into account both DIR uncertainties and patient-specific organ motion, to study the distribution of possible true dose distributions. Methods: The study included ten patients (six CT scans/patient) treated with radiotherapy for prostate cancer. For each patient, the planned dose was re-calculated on the repeated geometries, following rigid registration based on fiducial markers. The dose re-calculated on the first CT served as our snapshot dose distribution (D1) and the average of the first five repeat scans as our treatment course reference dose distribution (Dref). Patient-specific motion and DIR-uncertainties, at each voxel in CT1, were assessed using a previously developed DIR performance measure, the distance discordance metric (DDM). To sample the distribution of possible true, predicted dose distributions (Dpred), we resampled D1 by perturbing the location of each voxel with the corresponding DDM. The three dose distribution approaches are compared for the rectum and the bladder. Results: The bladder generalized equivalent uniform dose (gEUD) from the averaged Dpred was closer to the gEUDref than to the gEUD1 (difference: 0.6 vs. 1.0 Gy). For both structures, the gEUDpred was higher than themore » gEUDref, and significantly higher (p≤0.05) for the rectum (average: 50.8 Gy vs. 48.0 Gy). Conclusion: We have shown that the bladder gEUD values resulting from our DIR-uncertainty inclusive dose sampling approach, Dpred, were closer to the gEUD from Dref than the gEUD values from D1. For the rectum, gEUDpred overestimated gEUDref. Theoretically however, gEUDpred values, sampled from DDM uncertainties are more representative of dose uncertainties.« less

Purpose: The quantitative evaluation of deformable image registration (DIR) is currently challenging due to lack of a ground truth. In this study we test a new method proposed for quantifying multiple-image based DIRrelated uncertainties, for DIR of pelvic images. Methods: 19 patients were analyzed, each with 6 CT scans, who previously had radiotherapy for prostate cancer. Manually delineated structures for rectum and bladder, which served as ground truth structures, were delineated on the planning CT and each subsequent scan. For each patient, voxel-by-voxel DIR-related uncertainties were evaluated, following B-spline based DIR, by applying a previously developed metric, the distance discordance metric (DDM; Saleh et al., PMB (2014) 59:733). The DDM map was superimposed on the first acquired CT scan and DDM statistics were assessed, also relative to two metrics estimating the agreement between the propagated and the manually delineated structures. Results: The highest DDM values which correspond to greatest spatial uncertainties were observed near the body surface and in the bowel due to the presence of gas. The mean rectal and bladder DDM values ranged from 1.1–11.1 mm and 1.5–12.7 mm, respectively. There was a strong correlation in the DDMs between the rectum and bladder (Pearson R = 0.68 for the max DDM). For both structures, DDM was correlated with the ratio between the DIR-propagated and manually delineated volumes (R = 0.74 for the max rectal DDM). The maximum rectal DDM was negatively correlated with the Dice Similarity Coefficient between the propagated and the manually delineated volumes (R= −0.52). Conclusion: The multipleimage based DDM map quantified considerable DIR variability across different structures and among patients. Besides using the DDM for quantifying DIR-related uncertainties it could potentially be used to adjust for uncertainties in DIR-based accumulated dose distributions.