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Glutamate and N-acetylaspartate have been investigated in the neuropathology of chronic schizophrenia, with fewer studies focusing on early phase psychosis. Additionally, there has been little review and synthesis of the literature focused on multiple brain regions. This systematic review aims to provide a clear report of the current state of research on glutamate and n-acetylaspartate concentrations in early phase psychosis (defined as the first five years following psychosis onset) in multiple brain regions. Existing literature was searched systematically to compile reports of glutamate/glutamate+glutamine (Glx) and n-acetylaspartate absolute levels and ratios in both male and female individuals with early phase psychosis. Reports on glutamate/Glx concentrations in the medial prefrontal region and thalamus were varied, but the majority of reports suggested no alterations in EPP. No studies reported glutamate alterations in the hippocampus or cerebellum. There was no evidence for n-acetylaspartate alterations in the caudate, basal ganglia, and medial prefrontal cortex, and minimal evidence for NAA reductions in the thalamus, anterior cingulate cortex, and hippocampus. Future research should focus on the regions that are less commonly reported, and should aim to explore possible confounds, such as medication status and substance use.

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The design, construction and application of a multimodality, 3D magnetic resonance/computed tomography (MR/CT) image distortion phantom and analysis system for stereotactic radiosurgery (SRS) is presented. The phantom is characterized by (1) a 1 × 1 × 1 (cm)3 MRI/CT-visible 3D-Cartesian grid; (2) 2002 grid vertices that are 3D-intersections of MR-/CT-visible 'lines' in all three orthogonal planes; (3) a 3D-grid that is MR-signal positive/CT-signal negative; (4) a vertex distribution sufficiently 'dense' to characterize geometrical parameters properly, and (5) a grid/vertex resolution consistent with SRS localization accuracy. When positioned correctly, successive 3D-vertex planes along any orthogonal axis of the phantom appear as 1 × 1 (cm)2-2D grids, whereas between vertex planes, images are defined by 1 × 1 (cm)2-2D arrays of signal points. Image distortion is evaluated using a centroid algorithm that automatically identifies the center of each 3D-intersection and then calculates the deviations dx, dy, dz and dr for each vertex point; the results are presented as a color-coded 2D or 3D distribution of deviations. The phantom components and 3D-grid are machined to sub-millimeter accuracy, making the device uniquely suited to SRS applications; as such, we present it here in a form adapted for use with a Leksell stereotactic frame. Imaging reproducibility was assessed via repeated phantom imaging across ten back-to-back scans; 80%-90% of the differences in vertex deviations dx, dy, dz and dr between successive 3 T MRI scans were found to be ⩽0.05 mm for both axial and coronal acquisitions, and over >95% of the differences were observed to be ⩽0.05 mm for repeated CT scans, clearly demonstrating excellent reproducibility. Applications of the 3D-phantom/analysis system are presented, using a 32-month time-course assessment of image distortion/gradient stability and statistical control chart for 1.5 T and 3 T GE TwinSpeed MRI systems.

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BACKGROUND: Two algorithms based on sequential measurements of liver and spleen stiffness using two-dimensional shearwave elastography (2D-SWE) have been recently proposed to estimate clinically significant portal hypertension (hepatic venous pressure gradient [HVPG] ≥10 mm Hg) in patients with cirrhosis, with excellent diagnostic accuracy. AIM: To validate externally these algorithms in a large cohort of patients with cirrhosis. METHODS: One hundred and ninety-one patients with stable cirrhosis (Child-Pugh class A 39%, B 29% and C 31%) who underwent liver and spleen stiffness measurements using 2D-SWE at the time of HVPG measurement were included. Diagnostic accuracy of the 2 algorithms was assessed by calculating sensitivity, specificity, positive and negative predictive values. RESULTS: The first algorithm, using liver stiffness <16.0 kilopascals (kPa) and then spleen stiffness <26.6 kPa, was used to rule-out HVPG ≥10 mm Hg. In our population, its sensitivity and negative predictive value were 95% and 63% respectively. The second algorithm, using liver stiffness >38.0 kPa, or liver stiffness ≤38.0 kPa but spleen stiffness >27.9 kPa, was used to rule-in HVPG ≥10 mm Hg. In our population, its specificity and positive predictive value were 52% and 83% respectively. Restricting the analyses to the 74 patients without any history of decompensation of cirrhosis or to the 65 patients with highly reliable liver stiffness measurement did not improve the results. CONCLUSION: In our population, diagnostic accuracies of non-invasive algorithms based on sequential measurements of liver and spleen stiffness using 2D-SWE were acceptable, but not good enough to replace HVPG measurement or to base clinical decisions.

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AIMS: Computed tomography (CT)-based radiotherapy dose escalation for locally advanced non-small cell lung cancer (LA-NSCLC) has had limited success. In this planning study, we investigated the potential for adaptive dose escalation using respiratory-gated 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography scans (4DPET/4DCT) acquired before and during a course of chemoradiotherapy (CRT). MATERIALS AND METHODS: We prospectively enrolled patients with LA-NSCLC receiving curative intent CRT. Radiotherapy was delivered using intensity-modulated radiotherapy (IMRT) using the week 0 4DCT scan. Three alternative, dose-escalated IMRT plans were developed offline based on the week 0, 2 and 4 4DPET/4DCT scans. The FDG-avid primary (PET-T) and nodal disease (PET-N) volumes defined by the 50% of maximum standard uptake value threshold were dose escalated to as high as possible while respecting organ at risk constraints. RESULTS: Thirty-two patients were recruited, 27 completing all scans. Twenty-five patients (93%) were boosted successfully above the clinical plan doses at week 0, 23 (85%) at week 2 and 20 (74%) at week 4. The median dose received by 95% of the planning target volume (D95) at week 0, 2 and 4 to PET-T were 74.4 Gy, 75.3 Gy and 74.1 Gy and to PET-N were 74.3 Gy, 71.0 Gy and 69.5 Gy. CONCLUSIONS: Using 18F-FDG-4DPET/4DCT, it is feasible to dose escalate both primary and nodal disease in most patients. Choosing week 0 images to plan a course with an integrated boost to PET-avid disease allows for more patients to be successfully dose escalated with the highest boost dose.

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BACKGROUND: Beta-blockers may have to be interrupted in patients with cirrhosis. The concept of a rebound after interruption of beta-blockers is based on an animal study and on isolated case reports of variceal bleeding. AIM: To determine if a rebound occurs in patients with cirrhosis following abrupt interruption of beta-blockers. METHODS: We prospectively included all consecutive patients with cirrhosis undergoing right heart and hepatic vein catheterisation. Four groups were defined: 'no beta-blockers' including patients not receiving beta-blockers; '≤1 day', '2-3 days' and '≥4 days' classified according to the time patients had interrupted beta-blockers before catheterisation. Results were expressed as median (interquartile range). RESULTS: A total of 150 patients were included. Among the 25 patients in the groups '2-3 days' and '≥4 days', median duration of beta-blockers interruption was 4 (3-6) days. No gastrointestinal bleeding occurred during that period, nor during the following month. Hepatic venous pressure gradient was not different among patients in usually treated with beta-blockers. After adjustment, beta-blockers interruption was not associated with hepatic venous pressure gradient. Cardiac index was higher in the '≥4 days' group [4.6 L/min/m(2) (3.5-5.1)] than in the '≤1 day' group [3.4 (2.6-4.0); P = 0.001] or in the '2-3 days' group [3.1 (2.7-3.7); P = 0.007], but not different from the 'no beta-blockers' group. CONCLUSIONS: Abrupt interruption of beta-blockers is associated neither with an apparent increase in the risk of variceal bleeding nor with a haemodynamic rebound. Thus, interruption of beta-blockers in patients with cirrhosis may not require particular dosing or surveillance.

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PURPOSE: Functional image guided intensity-modulated radiation therapy has the potential to improve cancer treatment quality by basing treatment parameters such as heterogeneous dose distributions information derived from imaging. However, such heterogeneous dose distributions are subject to imaging uncertainty. In this paper, the authors develop a robust optimization model to design plans that are desensitized to imaging uncertainty. METHODS: Starting from the pretreatment fluorodeoxyglucose-positron emission tomography scans, the authors use the raw voxel standard uptake values (SUVs) as input into a series of intermediate functions to transform the SUV into a desired dose. The calculated desired doses were used as an input into a robust optimization model to generate beamlet intensities. For each voxel, the authors assume that the true SUV cannot be observed but instead resides in an interval centered on the nominal (i.e., observed) SUV. Then the authors evaluated the nominal and robust solutions through a simulation study. The simulation considered the effect of the true SUV being different from the nominal SUV on the quality of the treatment plan. Treatment plans were compared on the metrics of objective function value and tumor control probability (TCP). RESULTS: Computational results demonstrate the potential for improvements in tumor control probability and deviation from the desired dose distribution compared to a nonrobust model while maintaining acceptable tissue dose. CONCLUSIONS: Robust optimization can help design treatment plans that are more stable in the presence of image value uncertainties.

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Respiratory disturbances are a primary phenotype of the neurological disorder, Rett syndrome (RTT), caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). Mouse models generated with null mutations in Mecp2 mimic respiratory abnormalities in RTT girls. Large deletions, however, are seen in only ∼10% of affected human individuals. Here we characterized respiration in heterozygous females from two mouse models that genetically mimic common RTT point mutations, a missense mutation T158A (Mecp2(T158A/)(+)) or a nonsense mutation R168X (Mecp2(R168X/+)). MeCP2 T158A shows decreased binding to methylated DNA, while MeCP2 R168X retains the capacity to bind methylated DNA but lacks the ability to recruit complexes required for transcriptional repression. We found that both Mecp2(T158A/+) and Mecp2(R168X/+) heterozygotes display augmented hypoxic ventilatory responses and depressed hypercapnic responses, compared to wild-type controls. Interestingly, the incidence of apnea was much greater in Mecp2(R168X/+) heterozygotes, 189 per hour, than Mecp2(T158A/+) heterozygotes, 41 per hour. These results demonstrate that different RTT mutations lead to distinct respiratory phenotypes, suggesting that characterization of the respiratory phenotype may reveal functional differences between MeCP2 mutations and provide insights into the pathophysiology of RTT.

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Several studies found that renal transplant recipients with chronic kidney disease have untreated complications and do not attain recommended clinical targets. Using a before/after design with propensity score-matched controls, we evaluated whether an advanced practice nurse-led interprofessional collaborative chronic care approach could improve clinical outcomes for CKD transplant patients compared with a traditional physician-led model. The intervention included strategies for disease self-management, shared decision making, and healthcare system reorganization. The primary outcome was the proportion of patients attaining at least seven of nine targets as per published guidelines. A greater proportion of intervention patients achieved the outcome (68% vs. 10%; p = 0.0001) and had discussions about end-stage treatment options (88% vs. 13%; p = 0.0001) compared with controls. The intervention patients had significantly fewer emergency room visits (incidence rate ratio [IRR] 0.53; 95% CI 0.29-0.91; p = 0.02) and hospital admissions (IRR 0.34; 95% CI 0.16-0.68; p = 0.001) compared with the control patients. There were no significant differences found between the groups in systolic/diastolic blood pressure, carbon dioxide, hemoglobin, or phosphate parameters. An advanced practice nurse-led approach, based on the chronic care model, has the potential to improve clinical outcomes for renal transplant recipients and needs to be tested in a multicenter randomized controlled trial.

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Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in the gene encoding the transcription factor methyl-CpG-binding protein 2 (MeCP2). One of its targets is the gene encoding brain-derived neurotrophic factor (bdnf). In vitro studies using cultured neurons have produced conflicting results with respect to the role of MeCP2 in BDNF expression. Acute intermittent hypoxia (AIH) induces plasticity in the respiratory system characterized by long-term facilitation of phrenic nerve amplitude. This paradigm induces an increase in BDNF protein. We hypothesized that AIH leads to augmentation of BDNF transcription in respiratory-related areas of the brainstem and that MeCP2 is necessary for this process. Wild-type and mecp2 null (mecp2(-/y)) mice were subjected to three 5-min episodes of exposure to 8% O(2)/4% CO(2)/88% N(2), delivered at 5-min intervals. Normoxia control wild-type and mecp2 null mice were exposed to room air for the total length of time, that is, 30 min. Following a recovery in room air, the pons and medulla were rapidly removed. Expression of BDNF protein and transcripts were determined by ELISA and quantitative PCR, respectively. AIH induced a significant increase in BDNF protein in the pons and medulla, and in mRNA transcript levels in the pons of wild-type animals. In contrast, there were no significant changes in either BDNF protein or transcripts in the pons or medulla of mice lacking MeCP2. The results indicate that MeCP2 is required for regulation of BDNF expression by acute intermittent hypoxia in vivo.

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INTRODUCTION: An online Magnetic Resonance guided Radiation Therapy (MRgRT) system is under development. The system is comprised of an MRI with the capability of travel between and into HDR brachytherapy and external beam radiation therapy vaults. The system will provide on-line MR images immediately prior to radiation therapy. The MR images will be registered to a planning image and used for image guidance. With the intention of system safety we have performed a failure modes and effects analysis. METHODS: A process tree of the facility function was developed. Using the process tree as well as an initial design of the facility as guidelines possible failure modes were identified, for each of these failure modes root causes were identified. For each possible failure the assignment of severity, detectability and occurrence scores was performed. Finally suggestions were developed to reduce the possibility of an event. RESULTS/DISCUSSION: The process tree consists of nine main inputs and each of these main inputs consisted of 5 - 10 sub inputs and tertiary inputs were also defined. The process tree ensures that the overall safety of the system has been considered. Several possible failure modes were identified and were relevant to the design, construction, commissioning and operating phases of the facility. The utility of the analysis can be seen in that it has spawned projects prior to installation and has lead to suggestions in the design of the facility.

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The availability of respiratory synchronized PET (4DPET) imaging has enabled more accurate analysis of metabolic response since motion blur is minimized. We present our preliminary analysis of serial FDG 4DPET images acquired at weeks 0, 2, 4, and 7 during radiotherapy of seven stage II-III NSCLC patients. The tumor and nodal PTV of the week 0 images restrained a 4DPET image thresholding algorithm to automatically contour SUV levels ranging from 20 to 80% of the maximum SUV, creating an intensity volume histogram (IVH) for each week. These contours allowed analysis of PET volumes and standard PET metrics such as SUVmax and SUVmean . We found a trend for decreasing SUVmax and SUVmean over a treatment course in both the tumor and nodal regions. On average, the SUVmax within the tumor decreased by 17±13% (1 SD) after 2 weeks, 30±13% after 4 weeks, and 39±19% after 7 weeks of radiotherapy. Decreasing volume trends were also observed in the 20 to 80% max SUV autocontours, ranging from 26±29% to 50±40% respectively, over 7 weeks of treatment. Only one patient demonstrated an increase in FDG uptake within the tumor volume between week 0 and week 2 of treatment, and was also the only patient to recur locally at 3 months following treatment. Changes in tumor metabolism over the course of advanced NSCLC radiotherapy are quantifiable with serial FDG 4DPET imaging. Preliminary analysis suggests that variations in these trends could be useful in identifying non-responding patients that may require an alternative radiotherapeutic approach.

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According to a margin recipe developed by van Herk et al. the Planning Target Volume (PTV) margin to ensure the Clinical Target Volume is covered by at least 95% of the prescribed dose can be calculated by applying the following formula: M = 2.5Σ + 1.64σ2 - 1.64σp. In the van Herk Margin formula (VHMF), Σ is the standard deviation (SD) of all systematic errors; σ is the SD of random errors and σp is the width of the penumbra. This formula is based on an idealized dose profile model that may not account for factors that vary significantly in lung radiotherapy such as tumour size and tissue density. The purpose of this study was to use accurate dose calculation algorithms and respiratory motion modeling to investigate the validity of the VHMF for lung radiotherapy. Random and systematic errors were simulated in treatment planning software using dose accumulation techniques for clinically relevant 3DCRT and IMRT treatment plans constructed on virtual phantoms. Phantom parameters such as target size, peak-to-peak motion amplitude and tissue density were varied to investigate their impact on the systematic and random error components of the margin formula. The VHMF was found to provide adequate dose coverage for all plans generated on different target sizes and motion amplitudes. Although discrepancies existed between idealized and realistic dose profiles in water and lung, the dose coverage defined by the V95 was not affected. The margin formula was found to be robust; however, further investigation of the influence of plan conformity is needed.

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The early response of lung tumours to stereotactic radiotherapy was prospectively evaluated with 18F-fluorodeoxyglucose positron emission tomography-computed tomography. Three months after treatment, the maximum standardised uptake value and the tumour diameter fell by 64 and 30%, respectively. This imaging strategy therefore remains under ongoing evaluation with the aim of identifying predictive and prognostic factors.

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OBJECTIVE: To determine the geometric accuracy of conventional and stereotactic lung radiotherapy using cone-beam CT image guidance, and assess the efficacy of these image-guided radiation therapy (IGRT) processes. MATERIALS AND METHODS: IGRT was first used for our stereotactic lung program, where high geometric accuracy is required to deliver high doses in few fractions. The initial positional accuracy for 47 patients was assessed by registering daily CBCT to the planning CT; the patient position was corrected when the CBCT indicated discrepancies > ± 3 mm in any direction. For 19 of these patients, a second CBCT was acquired to assess the residual error. IGRT was also used to assess the initial and residual errors for lung cancer patients treated conventionally with (14 pts; 584 CBCT) and without (25 pts; 1032 CBCT) a remote-controlled treatment couch. Systematic (Σ) and random (σ) positional errors were assessed for these three groups. RESULTS: For stereotactic lung patients, Σ and σ ranged between 4.1 and 6.1 mm. IGRT reduces these errors to 1.2-1.9 mm, raising the proportion of patients within ± 3 mm from 16% to 82%. For conventional lung cancer patients, Σ and σ ranged between 1.4 and 3.8 mm, and IGRT raises the proportion of patients within ± 3 mm from 27% to 67%, with the remote-controlled couch further improving this proportion to 84%. CONCLUSION: IGRT clearly confirms the high geometric accuracy required for stereotactic lung patients. This new paradigm has been transported to patients with locally-advanced lung cancer, with similar accuracy.

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C57BL/6 mice are the strain into which most null mutations for neurotransmitters or their receptors are backcrossed. A number of these transgenic mice have recently been shown to have an abnormal respiratory phenotype; however, the postnatal development of the ventilatory response to hypoxia has not been characterized in C57BL/6 mice. The effect of 8% oxygen for 5 min was examined in mice at five periods from P1 to P30 using a body plethysmograph. Neonatal and juvenile animals from P7 to P30 showed a biphasic pattern in hypoxia in which the increase in minute ventilation achieved in the first min declined towards baseline by the fifth minute and was decreased below baseline in the first minute of return to air breathing. In contrast P1-P3 C57BL/6 mice had a sustained increase in both respiratory frequency and tidal volume and their minute volume remained above baseline on return to air. The decline in oxygen consumption, measured in the fifth minute of hypoxia, was not different in P1-P3 mice compared to P8-P10. These results suggest that the earliest response to hypoxia of the respiratory system in this strain is not characterized by a time dependent depression as seen in older animals and in species whose motor systems are relatively more developed at birth.

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In excitable cells, small-conductance Ca2+-activated potassium channels (SK channels) are responsible for the slow after-hyperpolarization that often follows an action potential. Three SK channel subunits have been molecularly characterized. The SK3 gene was targeted by homologous recombination for the insertion of a gene switch that permitted experimental regulation of SK3 expression while retaining normal SK3 promoter function. An absence of SK3 did not present overt phenotypic consequences. However, SK3 overexpression induced abnormal respiratory responses to hypoxia and compromised parturition. Both conditions were corrected by silencing the gene. The results implicate SK3 channels as potential therapeutic targets for disorders such as sleep apnea or sudden infant death syndrome and for regulating uterine contractions during labor.

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Selected topics in the respiratory response to acute hypoxia in the fetus and newborn are reviewed. Peripheral chemoreceptors acting through ionotrophic glutamate receptors play an important role in affecting the initial augmentation phase. Whether fall off in peripheral chemoreceptor activity contributes to the secondary depressive phase remains controversial. A number of approaches including permanent electrolytic and reversible cooling lesions, Fos protein activation, and double-labeling immunohistochemistry has converged to show that an area in and around the locus ceruleus in the rostral pons affects the central depression. There is evidence that this is mediated by catecholamines acting at alpha(2)-adrenergic receptors. Tonic activity in early expiratory (postinspiratory) neurons may contribute to hypoxia-induced apneic episodes in the fetus and newborn. Desensitization of alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptors has been demonstrated in respiratory-related neurons both in vivo and in vitro. The role that this process might play in the depressive phase of the hypoxic ventilatory response has not been established. In vitro experiments with isolated brain stem-spinal cord preparations or transverse brain stem slices usually involve anoxia, whereas whole animal experiments use 8-15% O(2). Therefore, caution must be exercised in attempting to construct a unifying framework from these two approaches.

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Developing evidence-based nursing practice among diverse health-care settings is a particular challenge in the face of current health-care restructuring. This paper describes application of the Ottawa Model of Research Use (OMRU) to increase evidence-based practice across 3 health-care settings during a time of multiple restructuring changes. The initiative was part of a provincial demonstration project to develop centers of nursing excellence with a view to improving continuity of care across the health continuum. Three Ottawa health-care agencies formed one of 4 participating sites in the Province-Wide Nursing Project (PWNP), a 3-year initiative funded by the Ontario Ministry of Health. The goal of the Ottawa-Carleton site was to increase evidence-based decision-making with a focus on pressure ulcers. The barriers and supports encountered, and the strategies used, in striving to meet this goal in a community-care, tertiary-care, and long-term-care setting are described. Multiple research transfer approaches were used, with an emphasis on education. Implementor consensus and achievements of the project support the OMRU's utility as a guide to implementing research findings in these health-care settings.

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Radiosurgery aims to deliver a high radiation dose to a small target volume while sparing surrounding healthy tissues. However, since the target volume is often large and irregularly-shaped, a significant amount of healthy tissue is irradiated. To improve conformity of the dose volume to the target volume, we propose to optimize the field shape by trimming the field described by the radiosurgery cone with the accelerator jaws for a given arc. We have measured output factors (OF), tissue-maximum ratios (TMR), off-axis ratios (OAR) and penumbrae for 40, 32.5 and 24 mm cone fields trimmed by the lower (i.e., X jaws) and /or upper (i.e., Y jaws) collimator jaws. The smallest field was 8 mm large, and length was limited by the cone size. The average penumbra due to the cone field is 2.8 mm, and 4.1 and 6.1 mm for those due to the X and Y jaws, respectively. Moreover, the penumbrae due to the X and Y jaws are independent of jaw position within the radiosurgical field. Because of the large penumbra involved with the Y jaws, radiosurgical fields should be trimmed by the X1 and/or X2 jaws only. The measured OF's have been fitted with a hyperbolic function. All of the fitted OF's fall within +/- 0.5% of the measured OF's. The TMR values obtained with trimmed fields do not change much, except for the smallest fields (up to 10% at a depth of 20 cm). Therefore, using trimmed radiosurgical fields requires straightforward dosimetric changes and provides a level of beam shaping for large cone fields (> 20 mm in diameter) without introducing additional hardware.

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