Multimodal nerve monitoring during periacetabular osteotomy identifies surgical steps associated with risk of injury.

PURPOSE: Sciatic nerve palsy after periacetabular osteotomy (PAO) is a serious complication. The purpose of this study was to determine whether a multimodal sciatic monitoring technique allows for identification of surgical steps that place the sciatic nerve at risk. METHODS: Transcranial electrical motor evoked potentials (TcMEPs), somatosensory evoked potentials (SSEPs), and spontaneous electromyography (EMG) were monitored in a consecutive series of 34 patients (40 hips) who underwent PAO for the treatment of symptomatic hip dysplasia between January 2012 and November 2014. There were 29 females (85%) and five males (15%) with an average age of 19 years (range, 12-36 years) at the time of surgery. RESULTS: We detected eight temporary sciatic nerve monitoring alerts in six patients (incidence of 15%). The events included decrease in amplitude of the TcMEPs related to the position of the hip during incomplete ischium osteotomy and placement of a retractor in the sciatic notch during the posterior column osteotomy (N = 3), generalized bilateral decrease in TcMEPs during fragment manipulation and fixation in association with acute blood loss (N = 2), and a change in SSEPs during a superior pubic osteotomy and supra-acetabular osteotomy (N = 1). At the end of the procedure, TcMEPs and SSEPs were at baseline and there was no abnormal pattern on EMG in all patients. Post-operatively, at two, six, 12 weeks, and six and 12 months, no motor weakness or sensory deficits were noted. CONCLUSION: Multimodal neuromonitoring allowed for identification of intra-operative steps and maneuvers that potentially place the sciatic nerve at higher risk of injury.

Molecular and structural considerations of TF-DNA binding for the generation of biologically meaningful and accurate phylogenetic footprinting analysis: the LysR-type transcriptional regulator family as a study model.

BACKGROUND: The goal of most programs developed to find transcription factor binding sites (TFBSs) is the identification of discrete sequence motifs that are significantly over-represented in a given set of sequences where a transcription factor (TF) is expected to bind. These programs assume that the nucleotide conservation of a specific motif is indicative of a selective pressure required for the recognition of a TF for its corresponding TFBS. Despite their extensive use, the accuracies reached with these programs remain low. In many cases, true TFBSs are excluded from the identification process, especially when they correspond to low-affinity but important binding sites of regulatory systems. RESULTS: We developed a computational protocol based on molecular and structural criteria to perform biologically meaningful and accurate phylogenetic footprinting analyses. Our protocol considers fundamental aspects of the TF-DNA binding process, such as: i) the active homodimeric conformations of TFs that impose symmetric structures on the TFBSs, ii) the cooperative binding of TFs, iii) the effects of the presence or absence of co-inducers, iv) the proximity between two TFBSs or one TFBS and a promoter that leads to very long spurious motifs, v) the presence of AT-rich sequences not recognized by the TF but that are required for DNA flexibility, and vi) the dynamic order in which the different binding events take place to determine a regulatory response (i.e., activation or repression). In our protocol, the abovementioned criteria were used to analyze a profile of consensus motifs generated from canonical Phylogenetic Footprinting Analyses using a set of analysis windows of incremental sizes. To evaluate the performance of our protocol, we analyzed six members of the LysR-type TF family in Gammaproteobacteria. CONCLUSIONS: The identification of TFBSs based exclusively on the significance of the over-representation of motifs in a set of sequences might lead to inaccurate results. The consideration of different molecular and structural properties of the regulatory systems benefits the identification of TFBSs and enables the development of elaborate, biologically meaningful and precise regulatory models that offer a more integrated view of the dynamics of the regulatory process of transcription.

A novel non-Hodgkin lymphoma murine model closer to the standard clinical scenario.

BACKGROUND: Non-Hodgkin lymphomas (NHL) are the most frequent hemato-oncological malignancies. Despite recent major advances in treatment, a substantial proportion of patients relapses highlighting the need for new therapeutic modalities. Promissory results obtained in pre-clinical studies are usually not translated when moving into clinical trials. Pre-clinical studies are mainly conducted in animals with high tumor burden; instead patients undergo chemotherapy as first line of treatment and most likely are under remission when immunotherapies are applied. Thus, an animal model that more closely resembles patients' conditions would be a valuable tool. METHODS: BALB/c mice were injected subcutaneously with A20 lymphoma cells and after tumor development different doses of chemotherapy were assessed to find optimal conditions for minimal residual disease (MRD) establishment. Tumor growth and survival, as well as drugs side effects, were all evaluated. Complete lymphoma remission was monitored in vivo using positron emission tomography (PET), and the results were correlated with histology. Immunological status was assessed by splenocytes proliferation assays in NHL-complete remission mice and by analyzing tumor cell infiltrates and chemokines/cytokines gene expression in the tumor microenvironment of animals with residual lymphoma. RESULTS: Two cycles of CHOP chemotherapy at days 25 and 35 post-tumor implantation induced complete remission for around 20 days. PET showed to be a suitable follow-up technique for MRD condition with 85.7 and 75% of sensibility and specificity respectively. Proliferative responses upon mitogen stimulation were similar in animals that received chemotherapy and wild type mice. Tumors from animals with residual lymphoma showed higher numbers of CD4+ and CD8+ and similar numbers of NK, neutrophils and Tregs infiltrating cells as compared with non-treated animals. Gene expression of several cytokines as well as an array of chemokines associated with migration of activated T cells to tumor sites was upregulated in the tumor microenvironment of animals that received chemotherapy treatment. CONCLUSIONS: We established a NHL-B pre-clinical model using standard chemotherapy to achieve MRD in immunocompetent animals. The MRD condition is maintained for approximately 20 days providing a therapeutic window of time where new immunotherapies can be tested in conditions closer to the clinics.

Nurses' Perception of Shared Decision-Making Processes: Quantifying a Shared Governance Culture.

OBJECTIVE: The aim of this study is to describe how measuring the perceived and desired decision-making capacity of nurses in a model of shared governance (SG) can be beneficial. BACKGROUND: Shared governance (SG) increases nurse's control over professional practice. Engagement in SG can be impacted by how much decision-making power nurses desire. This concept related to decision making has been termed decisional involvement (DI). Few studies exist that examine the concept of DI. METHODS: Using the Decisional Involvement Scale, acute care nurses were sampled concerning desired and perceived decision making on 21 topics related to nursing practice. RESULTS: Analysis of the data identified different governance priorities for several areas. Of particular interest was that those nurses on SG councils for more than 5 years did not report higher satisfaction with decision involvement. CONCLUSIONS: A comprehensive evaluation of shared decision making was a valuable tool to establish a baseline of data and seek opportunities for improvement. A well-integrated model of SG requires continuous improvement and analysis to be sustained. Measuring and evaluating staff nurses desire to control varied aspects of DI can allow organizations to make focused efforts to strengthen SG.

Skin dose investigations on a 0.5 T parallel rotating biplanar linac-MR using Monte Carlo simulations and measurements.

BACKGROUND: The Alberta rotating biplanar linac-MR has a 0.5 T magnetic field parallel to the beamline. When developing a new linac-MR system, interactions of charged particles with the magnetic field necessitate careful consideration of skin dose and tissue interface effects. PURPOSE: To investigate the effect of the magnetic field on skin dose using measurements and Monte Carlo (MC) simulations. METHODS: We develop an MC model of our linac-MR, which we validate by comparison with ion chamber measurements in a water tank. Additionally, MC simulation results are compared with radiochromic film surface dose measurements on solid water. Variations in surface dose as a function of field size are measured using a parallel plate ion chamber in solid water. Using an anthropomorphic computational phantom with a 2 mm-thick skin layer, we investigate dose distributions resulting from three beam arrangements. Magnetic field on and off scenarios are considered for all measurements and simulations. RESULTS: For a 20 × 20 cm2 field size, D 0.2 c c ${D_{0.2cc}}$ (the minimum dose to the hottest contiguous 0.2 cc volume) for the top 2 mm of a simple water phantom is 72% when the magnetic field is on, compared to 34% with magnetic field off (values are normalized to the central axis dose maximum). Parallel plate ion chamber measurements demonstrate that the relative increase in surface dose due to the magnetic field decreases with increasing field size. For the anthropomorphic phantom, D ∼ 0.2 c c ${D_{ \sim 0.2cc}}$ (minimum skin dose in the hottest 1 × 1 × 1 cm3 cube) shows relative increases of 20%-28% when the magnetic field is on compared to when it is off. With magnetic field off, skin D ∼ 0.2 c c ${D_{ \sim 0.2cc}}$ is 71%, 56%, and 21% for medial-lateral tangents, anterior-posterior beams, and a five-field arrangement, respectively. For magnetic field on, the corresponding skin D ∼ 0.2 c c ${D_{ \sim 0.2cc}}$ values are 91%, 67%, and 25%. CONCLUSIONS: Using a validated MC model of our linac-MR, surface doses are calculated in various scenarios. MC-calculated skin dose varies depending on field sizes, obliquity, and the number of beams. In general, the parallel linac-MR arrangement results in skin dose enhancement due to charged particles spiraling along magnetic field lines, which impedes lateral motion away from the central axis. Nonetheless, considering the results presented herein, treatment plans can be designed to minimize skin dose by, for example, avoiding oblique beams and using a larger number of fields.

Clinical reference dosimetry for the 0.5 T inline rotating biplanar Linac-MR.

BACKGROUND: The world's first clinical 0.5 T inline rotating biplanar Linac-MR system is commissioned for clinical use. For reference dosimetry, unique features to device, including an SAD = 120 cm, bore clearance of 60 cm × 110 cm, as well as 0.5 T inline magnetic field, provide some challenges to applying a standard dosimetry protocol (i.e., TG-51). PURPOSE: In this work, we propose a simple and practical clinical reference dosimetry protocol for the 0.5T biplanar Linac-MR and validated its results. METHODS: Our dosimetry protocol for this system is as follows: tissue phantom ratios at 20 and 10 cm are first measured and converted into %dd10x beam quality specifier using equations provided and Kalach and Rogers. The converted %dd10x is used to determine the ion chamber correction factor, using the equations in the TG-51 addendum for the Exradin A12 farmer chamber used, which is cross-calibrated with one calibrated at a standards laboratory. For a 0.5 T parallel field, magnetic field effect on chamber response is assumed to have no effect and is not explicitly corrected for. Once the ion chamber correction factor for a non-standard SAD (kQ,msr) is determined, TG-51 is performed to obtain dose at a depth of 10 cm at SAD = 120 cm. The dosimetry protocol is repeated with the magnetic field ramped down. To validate our dosimetry protocol, Monte Carlo (EGSnrc) simulations are performed to confirm the determined kQ,msr values. MC Simulations and magnetic Field On versus Field Off measurements are performed to confirm that the magnetic field has no effect. To validate our overall dosimetry protocol, external dose audits, based on optical simulated luminescent dosimeters, thermal luminescent dosimeters, and alanine dosimeters are performed on the 0.5 T Linac-MR system. RESULTS: Our EGSnrc results confirm our protocol-determined kQ,msr values, as well as our assumptions about magnetic field effects (kB = 1) within statistical uncertainty for the A-12 chamber. Our external dosimetry procedures also validated our overall dosimetry protocol for the 0.5 T biplanar Linac-MR hybrid. Ramping down the magnetic field has resulted in a dosimetric difference of 0.1%, well within experimental uncertainty. CONCLUSION: With the 0.5 T parallel magnetic field having minimal effect on the ion chamber response, a TPR20,10 approach to determine beam quality provides an accurate method to perform clinical dosimetry for the 0.5 T biplanar Linac-MR.

Influence of intra- and interfraction motion on planning target volume margin in liver stereotactic body radiation therapy using breath hold.

PURPOSE: This study aimed to investigate intra- and interfraction motion during liver stereotactic body radiation therapy for the purpose of planning target volume (PTV) margin estimation, comparing deep inspiration breath hold (DIBH) and deep expiration breath hold (DEBH). METHODS AND MATERIALS: Pre- and posttreatment kV cone beam computed tomography (CT) images were acquired for patients with liver cancer who were treated using stereotactic body radiation therapy with DIBH or DEBH. A total of 188 images were analyzed from 18 patients. Positioning errors were determined based on a comparison with planning CT images and matching to the liver. Treatment did not proceed until errors were ≤3 mm. Standard deviations of random and systematic errors resulting from this image matching process were used to calculate PTV margin estimates. RESULTS: DIBH errors are generally larger than DEBH errors, especially in the anterior-posterior and superior-inferior directions. Posttreatment errors tend to be larger than pretreatment errors, especially for DIBH. Standard deviations of random errors are larger than those of systematic errors. Considering both pre- and posttreatment cone beam CT images, PTV margins for DIBH and DEBH are estimated as anterior-posterior, superior-inferior, right-left = (5.7, 6.3, 3.0) mm and (3.1, 3.4, 2.8) mm, respectively. CONCLUSIONS: This study suggests that DEBH results in more reproducible target positioning, which could in turn justify the use of smaller PTV margins.

Selective increase in corticospinal excitability in the context of tactile exploration.

In this study, we compared changes in corticomotor excitability under various task conditions engaging the index finger of each hand. Functional demands were varied, from simple execution to demanding sensory exploration. In a first experiment, we contrasted facilitation in the first dorsal interosseus (FDI) by monitoring changes in motor evoked potentials (MEPs) when participants (young adults, n = 18) performed either a simple button pressing (BP) task or a more demanding tactile exploration (TE) task (i.e., discrimination of raised letters). This experiment showed a large effect of task conditions (p < 0.01) on MEP amplitude but no effect of "Hand", while latency measurements were unchanged. In fact, MEPs were on average 40% larger during TE (2410 +/- 1358 microV) than during BP (1670 +/- 1477 microV). The two tasks produced, however, different patterns of electromyographic (EMG) activity, which could have accounted for some of the differences observed. A second experimental session involved a subset of participants (10/18) tested in third task condition: finger movement (FM). The latter task consisted of scanning a smooth surface with the tip of the index finger to reproduce the movements seen with the TE task. The addition of this third condition task confirmed that MEP facilitation seen during TE reflected task-specific influences and not differences in background EMG activity. These results, altogether, provide further insights into the effect of task conditions on corticomotor excitability. Our findings, in particular, stress the importance of behavioural context and tactile exploration in leading to selective increase in corticomotor excitability during finger movements.

Investigating energy deposition in glandular tissues for mammography using multiscale Monte Carlo simulations.

PURPOSE: To investigate energy deposition in glandular tissues of the breast on macro- and microscopic length scales in the context of mammography. METHODS: Multiscale mammography models of breasts are developed, which include segmented, voxelized macroscopic tissue structure as well as nine regions of interest (ROIs) embedded throughout the breast tissue containing explicitly-modelled cells. Using a 30 kVp Mo/Mo spectrum, Monte Carlo (MC) techniques are used to calculate dose to ∼mm voxels containing glandular and/or adipose tissues, as well as energy deposition on cellular length scales. ROIs consist of at least 1000 mammary epithelial cells and ∼200 adipocytes; specific energy (energy imparted per unit mass; stochastic analogue of the absorbed dose) is calculated within mammary epithelial cell nuclei. RESULTS: Macroscopic dose distributions within segmented breast tissue demonstrate considerable variation in energy deposition depending on depth and tissue structure. Doses to voxels containing glandular tissue vary between ∼0.1 and ∼4 times the mean glandular dose (MGD, averaged over the entire breast). Considering microscopic length scales, mean specific energies for mammary epithelial cell nuclei are ∼30% higher than the corresponding glandular voxel dose. Additionally, due to the stochastic nature of radiation, there is considerable variation in energy deposition throughout a cell population within a ROI: for a typical glandular voxel dose of 4 mGy, the standard deviation of the specific energy for mammary epithelial cell nuclei is 85% relative to the mean. Thus, for a glandular voxel dose of 4 mGy at the centre of the breast, corresponding mammary epithelial cell nuclei will receive specific energies up to ∼9 mGy (considering the upper end of the 1σ standard deviation of the specific energy), while a ROI located 2 cm closer to the radiation source will receive specific energies up to ∼40 mGy. Energy deposition within mammary epithelial cell nuclei is sensitive to cell model details including cellular elemental compositions and nucleus size, underlining the importance of realistic cellular models. CONCLUSIONS: There is considerable variation in energy deposition on both macro- and microscopic length scales for mammography, with glandular voxel doses and corresponding cell nuclei specific energies many times higher than the MGD in parts of the breast. These results should be considered for radiation-induced cancer risk evaluation in mammography which has traditionally focused on a single metric such as the MGD.

Biological Assessment of a 18F-Labeled Sulforhodamine 101 in a Mouse Model of Alzheimer's Disease as a Potential Astrocytosis Marker.

Neurodegenerative diseases have mainly been associated with neuronal death. Recent investigations have shown that astroglia may modulate neuroinflammation in the early and late stages of the disease. [11C]Deuterodeprenyl ([11C]DED) is a tracer that has been used for reactive astrocyte detection in Alzheimer's disease, Creutzfeldt-Jakob disease and amyotrophic lateral sclerosis, among others, with some limitations. To develop a new radiotracer for detecting astrocytosis and overcoming associated difficulties, we recently reported the synthesis of a sulfonamide derivative of Sulforhodamine 101 (SR101), labeled with 18F, namely SR101 N-(3-[18F]Fluoropropyl) sulfonamide ([18F]2B-SRF101). The red fluorescent dye SR101 has been used as a specific marker of astroglia in the neocortex of rodents using in vivo models. In the present work we performed a biological characterisation of the new tracer including biodistribution and micro-PET/computed tomography (CT) images. PET/CT studies with [11C]DED were also done to compare with [18F]2B-SRF101 in order to assess its potential as an astrocyte marker. Biodistribution studies with [18F]2B-SRF101 were carried out in C57BL6J black and transgenic (3xTg) mice. A hepatointestinal metabolization as well as the pharmacokinetic profile were determined, showing appropriate characteristics to become a PET diagnostic agent. Dynamic PET/CT studies were carried out with [18F]2B-SRF101 and [11C]DED to evaluate the distribution of both tracers in the brain. A significant difference in [18F]2B-SRF101 uptake was especially observed in the cortex and hippocampus, and it was higher in 3xTg mice than it was in the control group. These results suggested that [18F]2B-SRF101 is a promising candidate for more extensive evaluation as an astrocyte tracer. The difference observed for [18F]2B-SRF101 was not found in the case of [11C]DED. The comparative studies between [18F]2B-SRF101 and [11C]DED suggest that both tracers have different roles as astrocytosis markers in this animal model, and could provide different and complementary information at the same time. In this way, by means of a multitracer approach, useful information could be obtained for the staging of the disease.

Individualized Dose-Escalation of HDR Prostate Brachytherapy Implant to Decrease Required External Beam Radiation Dose: A Retrospective Feasibility Study.

PURPOSE: High-dose-rate brachytherapy (HDR-BT) is commonly combined with external beam radiation therapy (EBRT) for the treatment of localized prostate cancer. Escalating the HDR-BT dose as far as organ-at-risk (OAR) constraints allow, on a personalized basis, would allow for a reduction in EBRT dose while achieving similar total biologic equivalence. The primary objective of this study was to determine the dosimetric feasibility of escalating the HDR-BT dose from 15 Gy to 16 or 17 Gy while continuing to meet OAR constraints from the original 15 Gy plan on an individualized basis. METHODS AND MATERIALS: A total of 53 consecutive HDR-BT plans were retrospectively assessed to determine what percentage of plans could be reoptimized to deliver a dose of 16 Gy or 17 Gy, while meeting defined 15-Gy OAR constraints. Factors independently associated with dose escalation were examined. RESULTS: Thirty-nine plans (74%) and 2 plans (4%) were successfully escalated to a dose of 16 Gy and 17 Gy, respectively. Rectum V80 and urethra Dmax were independently predictive of the ability to dose escalate to 16 Gy. CONCLUSIONS: Individualized HDR-BT dose escalation beyond 15 Gy without compromising OAR constraints is dosimetrically feasible. This approach could allow for a corresponding reduction of EBRT fractions (ie, from 15 to 12 fractions) and would be beneficial in terms of resource savings for departments, convenience for patients, and potentially better tolerance of treatment with the expected reduction in biologically equivalent doses to OARs. A clinical trial is being developed to investigate the efficacy and tolerance of personalized HDR-BT/EBRT dose fractionation for localized intracapsular prostate cancer.

Microdosimetric considerations for radiation response studies using Raman spectroscopy.

PURPOSE: Recent Raman spectroscopy (RS) studies of radiation response involve subcellular (µm-scale) sampling volumes and macroscopic doses as low as 0.005 Gy. These studies ignore the stochastic nature of radiation transport and energy deposition, which can lead to considerable microdosimetric "spread" (i.e., variation in energy deposition). The goal of this work is to use Monte Carlo (MC) simulations to investigate the microdosimetric spread across populations of microscopic targets relevant for RS studies of cellular radiation response. METHODS: Simulation geometries involve populations of 1600 cells, with two sizes of sampling volumes (representative of recent RS studies) considered within each nucleus, as well as averaging over multiple sampling volumes in the same nucleus. To investigate variation in microdosimetric spread as a function of dose and target size, simple cubic voxel geometries are also considered. MC simulations are used to score energy imparted per unit mass (specific energy, z) in targets (nuclei, sampling volumes, and voxels), considering doses from a few mGy to several Gy. Three photon spectra are considered: 120 kVp x-ray, cobalt-60, and a 6 MV medical linac. RESULTS: For µm-sized targets, there can be considerable variation in energy deposition across a population of targets: the specific energy distribution is skewed, a large fraction of targets receive no energy, and the standard deviation of the specific energy relative to the mean, σ z / z ¯ , is considerable. These results vary with source energy and (macroscopic) dose: for 60 Co with cylindrical nuclei of 12.8 µm height and diameter, σ z / z ¯ is 17% at 0.02 Gy, decreasing to 2% at 2 Gy. In contrast, for cylindrical sampling volumes with 1 µm diameter and 4 µm height, σ z / z ¯ is 170% at 0.02 Gy and 18% at 2 Gy. Results of MC simulations involving cubic voxel geometries are fit to an equation relating the relative standard deviation of the specific energy to the target volume and dose; additionally, specific energy distributions are compared with normal distributions. CONCLUSIONS: Microdosimetric considerations are important for RS cellular radiation response studies, especially for low doses. The results of this work may motivate changes to current measurement and data analysis methods for RS experiments, and motivate future work comparing MC simulation results with RS measurements to advance understanding of radiation response.

Automated One-pot Radiosynthesis of [11C]S-adenosyl Methionine.

BACKGROUND: Glycine N-methyltransferase is an enzyme overexpressed in some neoplastic tissues. It catalyses the methylation of glycine using S-adenosyl methionine (SAM or AdoMet) as substrate. SAM is involved in a great variety of biochemical processes, including transmethylation reactions. Thus, [11C]SAM could be used to evaluate transmethylation activity in tumours. The only method reported for [11C]SAM synthesis is an enzymatic process with several limitations. We propose a new chemical method to obtain [11C]SAM, through a one-pot synthesis. METHOD: The optimization of [11C]SAM synthesis was carried out in the automated TRACERlab® FX C Pro module. Different labelling conditions were performed varying methylating agent, precursor amount, temperature and reaction time. The compound was purified using a semipreparative HPLC. Radiochemical stability, lipophilicity and plasma protein binding were evaluated. RESULTS: The optimum labelling conditions were [11C]CH3OTf as the methylating agent, 5 mg of precursor dissolved in formic acid at 60 °C for 1 minute. [11C]SAM was obtained as a diastereomeric mixture. Three batches were produced and quality control was performed according to specifications. [11C]SAM was stable in final formulation and in plasma. Log POCT obtained for [11C]SAM was (-2,01 ± 0,07) (n=4), and its value for plasma protein binding was low. CONCLUSION: A new chemical method to produce [11C]SAM was optimized. The radiotracer was obtained as a diastereomeric mixture with a 53:47 [(R,S)-isomer: (S,S)-isomer] ratio. The compound was within the quality control specifications. In vitro stability was verified. This compound is suitable to perform preclinical and clinical evaluations.

Synthesis of [18F]2B-SRF101: A Sulfonamide Derivative of the Fluorescent Dye Sulforhodamine 101.

BACKGROUND: The red fluorescent dye Sulforhodamine 101 (SR101) has been used in neuroscience research as a useful tool for staining of astrocytes, since it has been reported as a marker of astroglia in the neocortex of rodents in vivo. The aim of this work is to label SR101 with positron emission radionuclides, in order to provide a radiotracer to study its biological behavior. This is the first attempt to label SR101 by [18F], using a chemical derivatization via a sulfonamidelinker and a commercially available platform. METHODS: The synthesis of SR101 N-(3-Bromopropyl) sulfonamide and SR101 N-(3- Fluoropropyl) sulfonamide (2B-SRF101) was carried out. The radiosynthesis of SR101 N-(3- [18F]Fluoropropyl) sulfonamide ([18F]2B-SRF101) was performed in a TRACERlab® FX-FN. Different labeling conditions were tested. Three pilot batches were produced and quality control was performed. Lipophilicity, plasma protein binding and radiochemical stability of [18F]2BSRF101 in final formulation and in plasma were determined. RESULTS: SR101 N-(3-Bromopropyl) sulfonamide was synthetized as a precursor for radiolabeling with [18F]. 2B-SRF101 was prepared for analytical purpose. [18F]2B-SRF101 was obtained with radiochemical purity of (97.0 ± 0.6%). The yield of the whole synthesis was (11.9 ± 1.7 %), nondecay corrected. [18F]2B-SRF101 was found to be stable in final formulation and in plasma. The octanol-water partition coefficient was (Log POCT = 1.88 ± 0.14). The product showed a high percentage of plasma protein binding. CONCLUSIONS: The derivatization of SR101 via sulfonamide-linker and the first radiosynthesis of [18 F]2B-SRF101 were performed. It was obtained in accordance with quality control specifications. In vitro stability studies verified that [18F]2B-SRF101 was suitable for preclinical evaluations.

Effect of Treatment with Caspofungin on the Diagnosis of Fungal Infections by Gamma Scintigraphy.

The aim of this work was to assess the influence of treatment with U-Caspofungin, on the quality of diagnostic scintigraphic images of induced lesions in nude mice undergoing both bacterial and fungal infections and to determine the level of specificity of 99mTc-tricarbonyl-Caspofungin to discriminate between fungal or bacterial infections. In vitro studies on the behaviour of the 99mTc-tricarbonyl-Caspofungin complex binding percentage at different yeast concentrations of Candida albicans or Staphyolococcus aureus were determined. The incubation was performed with and without U-Caspofungin. In vivo evaluation was performed of 6 groups of athymic mice: sham, inflammation (LPS), fungal infection with Candida albicans (CA) and bacterial infection with Staphylocuccus aureus (SA). In vitro studies showed that the uptake of the complex by both yeasts and bacteria, depends on the concentration of colony forming units (cfu), and that this uptake is favoured by the presence of UCaspofungin that increases the membrane permeability to the 99mTc-tricarbonyl-Caspofungin complex. In vivo evaluation showed low uptake in sterile inflammation model and moderate to high uptake in infections models both treated or not with U-Caspofungin. The results of biodistributions were compatible with scintigraphic images. CONCLUSION: The uptake of the complex depends on the load of microorganisms, but it presents high sensibility, even at low concentrations of the infecting agent. The treatment with U-Caspofungin has no influence on the quality of the scintigraphic images used for diagnosis and localization of infection foci.

3-(Benzyloxy)-1-(5-[18F]fluoropentyl)-5-nitro-1H-indazole: a PET radiotracer to measure acetylcholinesterase in brain.

AIM: Noninvasive studies of the acetylcholinesterase (AChE) level in Alzheimer's disease (AD) patients can contribute to a better understanding of the disease and its therapeutic. We propose 3-(benzyloxy)-1-(5-[18F]fluoropentyl)-5-nitro-1H-indazole, [18F]-IND1, structurally related to the AChE-inhibitor CP126,998, as a new positron emission tomography-radiotracer. EXPERIMENTAL: Radiosynthesis, with 18F, stability, lipophilicity and protein binding of [18F]-IND1 were studied. In vivo behavior, in normal mice and on AD mice models, were also analyzed. RESULTS: [18F]-IND1 was obtained in good radiochemical yield, was stable for at least 2 h in different conditions, and had adequate lipophilicity for blood-brain barrier penetration. Biodistribution studies, in normal mice, showed that [18F]-IND1 was retained in the brain after 1 h. In vivo tacrine-blocking experiments indicated this uptake could be specifically due to AChE interaction. Studies in transgenic AD mice showed differential, compared with normal mice, binding in many brain regions. CONCLUSION: [18F]-IND1 can be used to detect AChE changes in AD patients.

The Problem Behaviour Checklist: short scale to assess challenging behaviours.

BACKGROUND: Challenging behaviour, especially in intellectual disability, covers a wide range that is in need of further evaluation. AIMS: To develop a short but comprehensive instrument for all aspects of challenging behaviour. METHOD: In the first part of a two-stage enquiry, a 28-item scale was constructed to examine the components of challenging behaviour. Following a simple factor analysis this was developed further to create a new short scale, the Problem Behaviour Checklist (PBCL). The scale was subsequently used in a randomised controlled trial and tested for interrater reliability. Scores were also compared with a standard scale, the Modified Overt Aggression Scale (MOAS). RESULTS: Seven identified factors - personal violence, violence against property, self-harm, sexually inappropriate, contrary, demanding and disappearing behaviour - were scored on a 5-point scale. A subsequent factor analysis with the second population showed demanding, violent and contrary behaviour to account for most of the variance. Interrater reliability using weighted kappa showed good agreement (0.91; 95% CI 0.83-0.99). Good agreement was also shown with scores on the MOAS and a score of 1 on the PBCL showed high sensitivity (97%) and specificity (85%) for a threshold MOASscore of 4. CONCLUSIONS: The PBCL appears to be a suitable and practical scale for assessing all aspects of challenging behaviour. DECLARATION OF INTEREST: None. COPYRIGHT AND USAGE: © 2016 The Royal College of Psychiatrists. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.

68Ga-NOTA-UBI-29-41 as a PET Tracer for Detection of Bacterial Infection.

UNLABELLED: The cationic peptide (68)Ga-NOTA-UBI-29-41 was synthesized and characterized. Biodistribution and PET/CT examinations were performed for evaluation of its biologic behavior. Differentiation of infection from sterile inflammation was investigated using microbiology methods at the sites of bacterial infections. METHODS: Labeling of UBI-29-41 conjugated with NOTA with (68)Ga was optimized at 20°C-100°C and pH 3.5-5.5. Radiochemical purity, stability up to 260 min, and binding to serum proteins were determined. In vitro binding to Staphylococcus aureus was evaluated from 9.14 × 10(7) to 1.17 × 10(10) cfu/mL. Of 3 groups of Mus musculus Swiss male mice, the first was inoculated intramuscularly with 1.2 × 10(8) cfu of S. aureus to provoke infection, and the second, with 1.2 × 10(8) cfu of heat shock-treated S. aureus to generate sterile inflammation. The third mouse was not treated and served as a control. After 24 h, (68)Ga-NOTA-UBI-29-41 was administrated intravenously, and biodistribution was performed at 30, 60, and 120 min. PET/CT dynamic studies (120 min) were acquired. Sinograms were reconstructed using 3D maximum-likelihood expectation maximization and analyzed with software. Infected or inflamed muscles were dissected, homogenized, and cultured in tryptic soy agar medium. Recovered S. aureus was calculated as cfu/g. RESULTS: (68)Ga-NOTA-UBI-29-41 showed high renal excretion (83.2% ± 7.3%) of injected dose and rapid blood clearance. More than 95% was bound in vitro to 5 × 10(9) cfu/mL. A significantly higher (P< 0.05) accumulation of (68)Ga-NOTA-UBI-29-41 was observed at sites of S. aureus inoculation in infected mice (ratio of target to nontarget, 5.0 at 60 min and 4.1 at 120 min) compared with animals with inflammation (ratio of target to nontarget, 1.6 at 60 min and 1.2 at 120 min). CONCLUSION: The difference in uptake of (68)Ga-NOTA-UBI-29-41 in the infected muscles compared with the inflamed muscles was clearly observed in the PET/CT images and positively correlated with the degree of infection.

Use of the Global Assessment of Function scale in learning disability.

BACKGROUND: The Global Assessment of Function (GAF) scale is widely used in adult psychiatric practice and research but it has not often been used in learning disability, which is inherently more complex. AIMS: To evaluate the reliability of GAF in the assessment of learning disability. METHOD: GAF reliability was tested by simultaneous multiple rating of unselected case vignettes (n=19-25) from health professionals of different disciplines, under controlled conditions. Analysis of reliability was made with the intraclass correlation coefficient (R(1)) with separate assessments to determine rater bias and individual performance of raters. RESULTS: The results of three data-sets showed generally poor overall levels of agreement, with R(1) levels of 0.35 and 0.28 and somewhat better levels for current GAF scores (R(1)=0.49). However, a subset of raters was identified that achieved much higher levels (R(1)=0.54 to 0.74). CONCLUSIONS: The GAF, in its current format, is not reliable enough to be used in the routine assessment of learning disability. A subgroup of raters, however, have ratings that are, by current biostatistical criteria, sufficiently reliable.

Effects of Covert Audio Coaching on Parents' Interactions with Young Children with Autism.

Children with autism spectrum disorders (ASD) frequently present intervention challenges for parents. Covert audio coaching (CAC) has not been studied with parents, nor as an intervention to teach household routines and tasks. Further, evidence of generalization with CAC is limited. We examined the effectiveness of immediate feedback via CAC on mothers' interactions with their children with ASD. Mothers learned to deliver effective prompts and praise, and generalized these interactions to novel (untrained) routines. Children increased the accuracy of training and generalization tasks after their mothers received the coaching intervention.