Glucagon-like peptide-1 receptor expression on human eosinophils and its regulation of eosinophil activation.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) and its receptor are part of the incretin family of hormones that regulate glucose metabolism. GLP-1 also has immune modulatory roles. OBJECTIVES: To measure the expression of the GLP-1 receptor (GLP-1R) on eosinophils and neutrophils in normal and asthmatic subjects and evaluate effects of a GLP-1 analog on eosinophil function. METHODS: Peripheral blood samples were taken from 10 normal and 10 allergic asthmatic subjects. GLP-1R expression was measured on eosinophils and neutrophils. Subsequently, the asthmatic subjects underwent allergen and diluent inhalation challenges, and GLP-1R expression was measured. Purified eosinophils, collected from mild asthmatic subjects, were stimulated with lipopolysaccharide (LPS) and a GLP-1 analog to evaluate eosinophil cell activation markers CD11b and CD69 and cytokine (IL-4, IL-5, IL-8 and IL-13) production. RESULTS: Glucagon-like peptide-1 receptor is expressed on human eosinophils and neutrophils. Eosinophil, but not neutrophil, expression of GLP-1R is significantly higher in normal controls compared to allergic asthmatics. The expression of GLP-1R did not change on either eosinophils or neutrophils following allergen challenge. A GLP-1 analog significantly decreased the expression of eosinophil-surface activation markers following LPS stimulation and decreased eosinophil production of IL-4, IL-8 and IL-13, but not IL-5. CONCLUSION AND CLINICAL RELEVANCE: Glucagon-like peptide-1 receptor is expressed on human eosinophils and neutrophils. A GLP-1 analog attenuates LPS-stimulated eosinophil activation. GLP-1 agonists may have additional adjunctive indications in treating persons with concomitant type 2 diabetes mellitus and asthma.

Genetically modified animals from life-science, socio-economic and ethical perspectives: examining issues in an EU policy context.

The interdisciplinary EC consortium (the PEGASUS project) aimed to examine the issues raised by the development, implementation and commercialisation of genetically modified (GM) animals, and derivative foods and pharmaceutical products. The results integrated existing social (including existing public perception) environmental and economic knowledge regarding GM animals to formulate policy recommendations relevant to new developments and applications. The use of GM in farmed animals (aquatic, terrestrial and pharmaceutical) was mapped and reviewed. A foresight exercise was conducted to identity future developments. Three case studies (aquatic, terrestrial and pharmaceutical) were applied to identify the issues raised, including the potential risks and benefits of GM animals from the perspectives of the production chain (economics and agri-food sector) and the life sciences (human and animal health, environmental impact, animal welfare and sustainable production). Ethical and policy concerns were examined through application of combined ethical matrix method and policy workshops. The case studies were also used to demonstrate the utility of public engagement in the policy process. The results suggest that public perceptions, ethical issues, the competitiveness of EU animal production and risk-benefit assessments that consider human and animal health, environmental impact and sustainable production need to be considered in EU policy development. Few issues were raised with application in the pharmaceutical sector, assuming ethical and economic issues were addressed in policy, but the introduction of agricultural GM animal applications should be considered on a case-by-case basis.

Tissue characterization using a phantom to validate four-dimensional tissue deformation.

PURPOSE: This project proposes using a real tissue phantom for 4D tissue deformation reconstruction (4DTDR) and 4D deformable image registration (DIR) validation, which allows for the complete verification of the motion path rather than limited end-point to end-point of motion. METHODS: Three electro-magnetic-tracking (EMT) fiducials were implanted into fresh porcine liver that was subsequently animated in a clinically realistic phantom. The animation was previously shown to be similar to organ motion, including hysteresis, when driven using a real patient's breathing pattern. For this experiment, 4DCTs and EMT traces were acquired when the phantom was animated using both sinusoidal and recorded patient-breathing traces. Fiducial were masked prior to 4DTDR for reconstruction. The original 4DCT data (with fiducials) were sampled into 20 CT phase sets and fiducials' coordinates were recorded, resulting in time-resolved fiducial motion paths. Measured values of fiducial location were compared to EMT measured traces and the result calculated by 4DTDR. RESULTS: For the sinusoidal breathing trace, 95% of EMT measured locations were within 1.2 mm of the measured 4DCT motion path, allowing for repeatable accurate motion characterization. The 4DTDR traces matched 95% of the EMT trace within 1.6 mm. Using the more irregular (in amplitude and frequency) patient trace, 95% of the EMT trace points fitted both 4DCT and 4DTDR motion path within 4.5 mm. The average match of the 4DTDR estimation of the tissue hysteresis over all CT phases was 0.9 mm using a sinusoidal signal for animation and 1.0 mm using the patient trace. CONCLUSIONS: The real tissue phantom is a tool which can be used to accurately characterize tissue deformation, helping to validate or evaluate a DIR or 4DTDR algorithm over a complete motion path. The phantom is capable of validating, evaluating, and quantifying tissue hysteresis, thereby allowing for full motion path validation.

SU-E-T-404: A Prototype Program for Analyzing 4D Image Guidance Shifts for Lung SBRT.

PURPOSE: A prototype in-house program was developed to assist deriving image guidance shifts clinically using our 4DCT method for lung SBRT. METHODS: Our in-house prototype program was implemented in MATLAB. The 4D DICOM CT dataset of interest is imported by the program from AW and subsequently accepts input from the user regarding the desired relative IGRT shifts. The DICOM header information defining the relative 4D dataset origin is then read in and the desired relative IGRT shifts are applied to re-define the origin for the dataset that is to be shifted. Lastly, the redefined (shifted) origin coordinates are written to the header of the 4D dataset and the dataset is then exported to AW as DICOM files. We used this program to process 4DCT datasets for four patients with 3-5 fractions each. The clinical shifts that were derived previously, without this program, were applied to the images and the acceptability of these shifts were evaluated. RESULTS: All slices and planes of the shifted 4D dataset were reviewed and, in general, demonstrated acceptable re-centering of the target within the ITV. However, it is noted that some small adjustments to the shift coordinates would likely have been made had we had the opportunity to visualize the shifted 4D dataset as facilitated by the new in-house software. The additional adjustments for the four patient cases studied here had an average of lmm and maximum of 2mm in three principle directions. We look forward to exploring the potential for implementing this software into our clinical workflow, and we believe that such a workflow is worthy of consideration by vendors for implementation as an available feature in future versions of their software. CONCLUSIONS: We presented a prototype program to shift 4DCT image set for lung SBRT applications and demonstrated four clinical cases.

SU-E-J-60: Comparison of CT-On-Rails and a 3D Surface Imaging System for Image Guided Pelvic Radiation Therapy for Both Supine and Prone Patient Positions.

PURPOSE: We investigate the feasibility of using AlignRT for pelvic radiation image guidance. The uniqueness of our study is that all patients have multiple CT-on-rails (CTOR) scans to compare corresponding AlignRT images to. METHODS: Ten patients receiving pelvic radiation were enrolled in this study. Two simulation CT scans were performed in supine and prone positions for each patient. Body surface contours were generated in treatment planning system and exported to AlignRT to serve as reference images. The patient was aligned to treatment isocenter with room lasers, and then scanned with both CTOR and AlignRT in both supine and prone positions. Image guidance shifts were calculated for both modalities by comparison to the simulation CT and the differences between them were analyzed. These procedures were performed for each patient once per week for five weeks. The average and maximum difference of displacement between AlignRT and CTOR were calculated for each patient. RESULTS: For supine position, there are 4 patients who had the average difference of displacement between AlignRT and CTOR along any direction (vertical, longitudinal, and lateral) greater than 0.5cm, and 1 patient greater than 1cm. For prone position, there are 7 patients who had the average difference greater than 0.5cm, and 3 patients greater than 1cm. For supine position, there are 4 patients who had the maximum difference great than 1cm. For prone position, there are 9 patients who had the maximum difference greater than 1 cm. The difference of displacement between AlignRT and CTOR is greater for prone position than for supine position. CONCLUSIONS: AlignRT does not appear to be an advisable image guidance approach for pelvic radiation therapy for patients with either supine or prone position. There appears to be a potential for large alignment discrepancies (up to 2.25 cm) between AlignRT and CTOR.

Perioperative management of patients with cardiac implantable electronic devices.

Many anaesthesia practitioners caring for patients with a cardiac implantable electronic device (CIED) lack the knowledge, experience, and requisite programming devices to independently manage these patients perioperatively. A recently updated ASA task force Practice Advisory presents expert opinion regarding the perioperative management of patients with CIEDs, and the Heart Rhythm Society (HRS) recently published a consensus statement on this subject in collaboration with the ASA, American Heart Association (AHA), and Society of Thoracic Surgeons (STS). The main intent of these documents is to provide recommendations that promote safe management of patients with CIEDs throughout the perioperative period and reduce the likelihood of adverse outcomes. Reviews of this topic focusing on the actions of the anaesthesiologist have been published, but a multidisciplinary approach to the perioperative management is now advocated. In emergent situations, however, or when there is no time for the requisite consultations, and in practice settings where the suggested multidisciplinary approach is simply not feasible, the anaesthesia team must still provide effective, safe perioperative management. Thus, all anaesthesiologists should become familiar with the basics of the current CIED technology and the essential tenets of perioperative CIED management. This review discusses relevant advances in CIED technology and practical perioperative management as outlined in the 2011 ASA Practice Advisory and HRS consensus statement.

Quantifying variability in radiation dose due to respiratory-induced tumor motion.

State of the art radiation treatment methods such as hypo-fractionated stereotactic body radiation therapy (SBRT) can successfully destroy tumor cells and avoid damaging healthy tissue by delivering high-level radiation dose that precisely conforms to the tumor shape. Though these methods work well for stationary tumors, SBRT dose delivery is particularly susceptible to organ motion, and few techniques capable of resolving and compensating for respiratory-induced organ motion have reached clinical practice. The current treatment pipeline cannot accurately predict nor account for respiratory-induced motion in the abdomen that may result in significant displacement of target lesions during the breathing cycle. Sensitivity of dose deposition to respiratory-induced organ motion represents a significant challenge and may account for observed discrepancies between predictive treatment plan indicators and clinical patient outcomes. Improved treatment-planning and delivery of SBRT requires an accurate prediction of dose deposition uncertainties resulting from respiratory motion. To accomplish this goal, we developed a framework that models both organ displacement in response to respiration and the underlying random variations in patient-specific breathing patterns. Our organ deformation model is a four-dimensional maximum a posteriori (MAP) estimation of tissue deformation as a function of chest wall amplitudes computed from clinically obtained respiratory-correlated computed tomography (RCCT) images. We characterize patient-specific respiration as the probability density function (PDF) of chest wall amplitudes and model patient breathing patterns as a random process. We then combine the patient-specific organ motion and stochastic breathing models to calculate the resulting variability in radiation dose accumulation. This process allows us to predict uncertainties in dose delivery in the presence of organ motion and identify tissues at risk of receiving insufficient or harmful levels of radiation.

A proto-type design of a real-tissue phantom for the validation of deformation algorithms and 4D dose calculations.

The purpose of this study is to design a real-tissue phantom for use in the validation of deformation algorithms. A phantom motion controller that runs sinusoidal and non-regular patient-based breathing pattern, via a piston, was applied to porcine liver tissue. It was regulated to simulate movement ranges similar to recorded implanted liver markers from patients. 4D CT was applied to analyze deformation. The suitability of various markers in the liver and the position reproducibility of markers and of reference points were studied. The similarity of marker motion pattern in the liver phantom and in real patients was evaluated. The viability of the phantom over time and its use with electro-magnetic tracking devices were also assessed. High contrast markers, such as carbon markers, implanted in the porcine liver produced less image artifacts on CT and were well visualized compared to metallic ones. The repositionability of markers was within a measurement accuracy of +/-2 mm. Similar anatomical patient motions were reproducible up to elongations of 3 cm for a time period of at least 90 min. The phantom is compatible with electro-magnetic tracking devices and 4D CT. The phantom motion is reproducible and simulates realistic patient motion and deformation. The ability to carry out voxel-based tracking allows for the evaluation of deformation algorithms in a controlled environment with recorded patient traces. The phantom is compatible with all therapy devices clinically encountered in our department.

Dosimetric evaluation of a Monte Carlo IMRT treatment planning system incorporating the MIMiC.

The high dose per fraction delivered to lung lesions in stereotactic body radiation therapy (SBRT) demands high dose calculation and delivery accuracy. The inhomogeneous density in the thoracic region along with the small fields used typically in intensity-modulated radiation therapy (IMRT) treatments poses a challenge in the accuracy of dose calculation. In this study we dosimetrically evaluated a pre-release version of a Monte Carlo planning system (PEREGRINE 1.6b, NOMOS Corp., Cranberry Township, PA), which incorporates the modeling of serial tomotherapy IMRT treatments with the binary multileaf intensity modulating collimator (MIMiC). The aim of this study is to show the validation process of PEREGRINE 1.6b since it was used as a benchmark to investigate the accuracy of doses calculated by a finite size pencil beam (FSPB) algorithm for lung lesions treated on the SBRT dose regime via serial tomotherapy in our previous study. Doses calculated by PEREGRINE were compared against measurements in homogeneous and inhomogeneous materials carried out on a Varian 600C with a 6 MV photon beam. Phantom studies simulating various sized lesions were also carried out to explain some of the large dose discrepancies seen in the dose calculations with small lesions. Doses calculated by PEREGRINE agreed to within 2% in water and up to 3% for measurements in an inhomogeneous phantom containing lung, bone and unit density tissue.

Intensity-modulated radiosurgery for childhood arteriovenous malformations.

PURPOSE: Presentation of intensity-modulated radiosurgery (IMRS) for the treatment of inoperable, complex shaped pediatric arterio-venous malformations AVM. METHOD: Between 03/99 and 11/04, IMRS was delivered to seven children aged six to 18 years. Prescribed minimum doses ranged from 17.5 to 20 Gy (median 18 Gy). Radiosurgery planning and delivery used a serial tomotherapeutic IMRT technique (Peacock IMRT, North American Scientific/Nomos, Cranberry Township, PA) over two to four couch angles. A linear accelerator attached binary multi-leaf collimator was used to generate pencil beams of 10 mm by either 8.5 or 4.0 mm. Treatment planning employed an inverse treatment planning optimization algorithm. Parameters submitted to the treatment planning system were: prescription dose (PD), volume of target allowed to receive less dose (standard 3%), minimum dose (0.5 Gy less than PD), and maximum dose (200% of PD). Planning system specific IMRS target and tissue types were selected to prioritize dose conformality over dose homogeneity. The prescription isodose encompassed at least 95% of the target volume. We calculated conformality (CI) and homogeneity indices (HI) to characterize the quality of IMRS plans, and summarized preliminary clinical outcomes. FINDINGS: Target volumes ranged from 0.71 to 63.02 cm(3) (median 13.8 cm(3), 6/7 AVM larger than 10 cm(3)). Median CI was 1.07 (range 1.05 to 1.7) according to RTOG criteria. Median HI was 1.12 (range 1.09 to 1.23). During limited follow-up (median 32 months, range 5 to 53 months), two AVM completely obliterated at 19 and 22 months, and partial obliteration (>75%) was observed in three cases. No treatment-related side effects, other than acute nausea and temporary headaches interpreted as being associated with changes in cerebral blood distribution, were observed. CONCLUSIONS: IMRS can allow for highly conformal planning and delivery of radiosurgery radiation doses even if pediatric AVM target volumes are large and/or highly complex in shape. This technique has been seen to result in favorable preliminary outcomes, thus supporting future exploration of this technique in pediatric and adult patients.

Understanding patients' preferences for treatment: the need for innovative methodologies.

Treatment selection is now much more consumer driven than in the past. However, there is a need to develop investigative methodological approaches that are sensitive to differences in patient preferences if full account is to be taken of what the patient sees as the best option in terms of different possible treatments available for a particular condition. Previous attitude research has been criticised because it does not provide insight into reasons why people hold different preferences or beliefs. A methodology is described which allows people to describe their concerns and values associated with different treatment options in their own words. This is the repertory grid method of eliciting personal constructs used in conjunction with generalised Procrustes analysis (GPA). An example of the use of this methodology is provided, drawn from research directed towards understanding people's beliefs about genetic technologies. A possible application of the method to understanding treatment preferences related to type 2 diabetes is also discussed. It is concluded that the use of innovative methodologies is essential if our understanding of patient preferences regarding treatment options is to have a significant impact on patient quality of life.

The TALON removable head frame system for stereotactic radiosurgery/radiotherapy: measurement of the repositioning accuracy.

PURPOSE: To present the TALON removable head frame system as an immobilization device for single-fraction intensity-modulated stereotactic radiosurgery (IMRS) and fractionated stereotactic intensity-modulated radiotherapy (FS-IMRT); and to evaluate the repositioning accuracy by measurement of anatomic landmark coordinates in repeated computed tomography (CT) examinations. METHODS AND MATERIALS: Nine patients treated by fractionated stereotactic intensity-modulated radiotherapy underwent repeated CTs during their treatment courses. We evaluated anatomic landmark coordinates in a total of 26 repeat CT data sets and respective x, y, and z shifts relative to their positions in the nine treatment-planning reference CTs. An iterative optimization algorithm was employed using a root mean square scoring function to determine the best-fit orientation of subsequent sets of anatomic landmark measurements relative to the original image set. This allowed for the calculation of the x, y, and z components of translation of the target isocenter for each repeat CT. In addition to absolute target isocenter translation, the magnitude (sum vector) of isocenter motion and the patient/target rotation about the three principal axes were calculated. RESULTS: Anatomic landmark analysis over a treatment course of 6 weeks revealed a mean target isocenter translation of 0.95 +/- 0.55, 0.58 +/- 0.46, and 0.51 +/- 0.38 mm in x, y, and z directions, respectively. The mean magnitude of isocenter translation was 1.38 +/- 0.48 mm. The 95% confidence interval ([CI], mean translation plus two standard deviations) for repeated isocenter setup accuracy over the 6-week period was 2.34 mm. Average rotations about the x, y, and z axes were 0.41 +/- 0.36, 0.29 +/- 0.25, and 0.18 +/- 0.15 degrees, respectively. Analysis of the accuracy of the first repeated setup control, representative of single-fraction stereotactic radiosurgery situations, resulted in a mean target isocenter translation in the x, y, and z directions of 0.52 +/- 0.38, 0.56 +/- 0.30, and 0.46 +/- 0.25 mm, respectively. The mean magnitude of isocenter translation was 0.99 +/- 0.28 mm. The 95% confidence interval for these radiosurgery situations was 1.55 mm. Average rotations at first repeated setup control about the x, y, and z axes were 0.24 +/- 0.19, 0.19 +/- 0.17, and 0.19 +/- 0.12 degrees, respectively. CONCLUSION: The TALON relocatable head frame was seen to be well suited for immobilization and repositioning of single-fraction stereotactic radiosurgery treatments. Because of its unique removable design, the system was also seen to provide excellent repeat immobilization and alignment for fractionated stereotactic applications. The exceptional accuracy for the single-fraction stereotactic radiosurgical application of the system was seen to deteriorate only slightly over a 6-week fractionated stereotactic treatment course.

NOMOS Peacock IMRT utilizing the Beak post collimation device.

Intensity-modulated radiation therapy (IMRT), an exciting recent development in the field of radiation therapy, is widely anticipated by many to make possible significant improvements in the quality of radiation treatments delivered to patients. The NOMOS Peacock method of delivery, often referred to as serial tomotherapy because of its "slice-wise" treatment of a tumor, has been used since 1994 to treat some 8000+ patients worldwide. This slice-wise method of treatment is known to produce extremely conformal dose distributions due to its ability to specifically match the dose distribution on each slice to the shape of the target volume on that same slice. Based on the belief of this institution, and the NOMOS Corporation, that an increase in the number of treatment slices into which the target is segmented would lead directly to an improvement in three-dimensional (3D) dose conformality, a joint effort was undertaken to develop a new MIMIC collimator treatment mode. Inherent to the original design of the NOMOS MIMIC binary multileaf collimator were 2 treatment modes: a 2-cm mode with a slice thickness of approximately 1.7 cm and a 1-cm mode with a slice thickness of approximately 0.85 cm. As a result of this collaborative effort, a new MIMIC treatment mode has been developed. The method employs a slit collimator, post-collimation device known as the BEAK, enabling the treatment mode referred to as Beak Mode. The device imposes a distal redefinition of the slice thickness, or length, by effectively blocking the full retraction of the MIMIC vanes. The end result is a newly available slice thickness of approximately 4 mm, which is shown in this work to yield significant improvements in dose conformality for 2 representative patients. The comparative analysis of these 2 patient plans includes, in addition to a comparison of isodose distributions, an evaluation of dose-volume histogram (DVH) information, and a comparison of indices of conformality (CI) and homogeneity (HI).

Who rules? The new politics of medical regulation.

The recent politicization of medical regulation in the United Kingdom has destabilized the historic relationship between medicine, society and the state. The purpose of this article is to present a political analysis of that relationship and its likely future by identifying the essential elements of power which determine its composition and its capacity to change. That analysis is in three parts. First, it identifies the underlying political tensions in the relationship between medicine, society and the state and the implications of those tensions for any proposed settlement on the future of medical regulation. What are the political criteria by which such a settlement must be judged if the tensions are to be resolved? Secondly, it explores the ideological conflict concerning the nature of medical regulation between the major players, the expression of that conflict in their use of quite different discourses, and the incompatibility of the power assumptions contained therein. Thirdly, it examines the medical profession's particular response to the pressures for change. Finally, the article reflects on the necessary dialogue which must take place between medicine, society and the state before a lasting resolution of the present tensions can be achieved.

An oblique arc capable patient positioning system for sequential tomotherapy.

A new patient positioning system has been designed and manufactured, allowing for the accurate delivery of obliquely oriented intensity modulated treatment arcs via a commercially available IMRT system. The ability to deliver such obliquely oriented intensity modulated arcs allows the commercial system to more closely approach a 4pi pencil beam delivery geometry which, in turn, allows for significant improvements in conformality for many tumor geometries. While the IMRT system delivered to this institution in the fall of 1996 was capable of planning for nonparallel plane delivery schemes, it proved incapable of delivering such treatments with acceptable accuracy. Because our early clinical experience revealed that certain patients could benefit significantly from such a delivery scheme we endeavored to design and manufacture an alternative treatment couch/patient positioning system (Xlator) which could overcome the limitations of the vendor supplied system. We present our initial evidence for the benefits of obliquely oriented intensity modulated treatment arcs, along with data demonstrating the inability of the original vendor supplied system to deliver such treatments with acceptable accuracy. The design of our new system is presented, as well as data demonstrating its ability to accurately deliver obliquely oriented intensity-modulated arcs. A detailed comparison of the performance of the Xlator and the vendor-supplied system is presented with regard to match line repeatability and hysteresis. Finally, the ability of the Xlator to deliver multiple couch angle sequential tomotherapy with spatial accuracy necessary to radiosurgical applications is demonstrated via a AAPM Report 54,TG-42 hidden target test. Readers note: The Xlator patient positioning system designed and patented here has recently come to be commercially available, and is currently marketed by the vendor under the name Crane II.

Primary care. Running on empty.

There has been a management vacuum in primary care since the beginning of the NHS, but it has been disguised by the stability of the area and the dominance of the acute sector in the public's mind. Health authorities are now responsible for implementing a highly ambitious policy in a field where they have little power few skills and no extra resources. To be successful, a primary care policy requires greater management capacity on the part of health authorities support from GPs and merged general medical services and hospital and community health services budgets.