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P Metcalfe

Publications and source records attributed to P Metcalfe.

At least 19 recordsLinked to original sources
PubMed2006

TNF-alpha neutralization ameliorates obstruction-induced renal fibrosis and dysfunction.

Upper urinary tract obstruction results in tubulointerstitial fibrosis and a progressive decline in renal function. Although several inflammatory mediators have been implicated in the pathophysiology of renal obstruction, the contribution of TNF-alpha to obstruction-induced fibrosis and renal dysfunction has not been thoroughly evaluated. To study this, male Sprague-Dawley rats were subjected to left unilateral ureteral obstruction vs. sham operation. Rats received either vehicle or a pegylated form of soluble TNF receptor type 1 (PEG-sTNFR1) every 84 h. The kidneys were harvested 1, 3, or 7 days postoperatively, and tissue samples were analyzed for TNF-alpha expression (ELISA), macrophage infiltration (ED-1 staining), transforming growth factor-beta(1) expression (ELISA, RT-PCR), collagen I and IV activity (Western Blot, immunohistochemistry), alpha-smooth muscle actin accumulation (immunohistochemistry, Western blot analysis), and angiotensinogen expression (Western blot). In a separate arm, the glomerular filtration rate (inulin clearance) of rats subjected to unilateral ureteral obstruction in the presence of either vehicle or PEG-sTNFR1 was determined. Renal obstruction induced increased tissue TNF-alpha and transforming growth factor-beta(1) levels, collagen I and IV activity, interstitial volume, alpha-smooth muscle actin accumulation, angiotensinogen expression, and renal dysfunction, whereas treatment with PEG-sTNFR1 significantly reduced each of these markers of renal fibrosis. These results demonstrate that TNF-alpha mediates obstruction-induced renal fibrosis and identify TNF-alpha neutralization as a potential therapeutic option for the amelioration of obstruction-induced renal injury.

Actins↗
PubMed2006

Verification of a rounded leaf-end MLC model used in a radiotherapy treatment planning system.

A new multileaf collimator (MLC) model has been incorporated into version 7.4 of the Pinnacle radiotherapy treatment planning system (Philips Radiation Oncology Systems, Milpitas, CA). The MLC model allows for rounded MLC leaf-ends and provides separate parameters for inter-leaf transmission, intra-leaf transmission and the tongue width of the MLC leaf. In this report we detail the method followed to commission the MLC model for a Varian 120-leaf Millennium MLC (Varian Medical Systems, Palo Alto, CA, USA) for both 6 and 10 MV photons, and test the validity of the model for an IMRT field. Dose profiles in water were measured for a range of square MLC field sizes and compared to the Pinnacle computed dose profiles; in addition, the dose distribution for a series of adjacent MLC fields was measured to observe the model's behaviour along match-lines. Based on these results intra-leaf transmissions of 1.5% for 6 MV and 1.8% for 10 MV, leaf-tip radius of 12.0 cm, an inter-leaf transmission of 0.5%, and a tongue width of 0.1 cm were chosen. Using these values to compute the planar dose distribution for a 6 MV IMRT field, the new version of Pinnacle displayed improved dosimetric agreement with the dose-to-water EPID image and ion chamber measurements when compared to the old version of Pinnacle, particularly along the MLC tongue edge and across match-lines. Discrepancies of up to 5% were observed between calculated and measured doses along match-lines for both 6 MV and 10 MV photons; however, the new MLC model did predict the presence of match-lines and was a significant improvement on the previous model.

Body Burden↗
PubMed2006

Comparison of skin dose between conventional radiotherapy and IMRT.

The purpose of this study was to measure skin dose using radiochromic film for two step-and-shoot IMRT fields and compare the results to the skin dose for a conventional open field. All exposures were made using a 6 MV photon beam produced by a Varian 21EX linear accelerator (Varian Medical Systems, CA, USA) equipped with a Millennium 120 leaf MLC. Three different field configurations were used, these were an open field, a step-and-shoot IMRT field and a clinical IMRT field. The mean ratio of the skin dose to dose at d(max) for an open 10 x 10 cm2 field at 100 cm SSD was 0.178 +/- 0.003. The step-and-shoot IMRT field consisted of 1 cm wide strips of decreasing intensity that were delivered using a step-and-shoot technique across a 10 x 10 cm2 field. The ratio of skin dose to dose at d(max) ranged from 0.180 to 0.257, with the low intensity steps having a higher relative skin dose compared to the high intensity steps. A model was derived that attributed these variations to the electron contamination from both the adjacent and more distant high intensity steps. The clinical field consisted of a 25 segment 9.8 x 10.0 cm2 beam arrangement. The ratio of skin dose to dose at d(max) for the clinical IMRT field ranged from 0.093 to 0.284. The results indicated that an IMRT field produced only minor changes in the relative skin dose, with variations potentially attributable to fluctuations in the electron contamination produced by neighbouring regions of different intensity. The use of an individual IMRT field does not significantly increase the skin dose above that of a conventional photon field.

Body Burden↗
PubMed2005

Collaborative study to establish the first international standard for quantitation of anti-HPA-1a.

BACKGROUND AND OBJECTIVES: This report describes the production of a freeze-dried preparation of pooled human plasma, containing immunoglobulin G (IgG) antibodies against the human platelet antigen 1a (HPA-1a). The material, coded 03/152, is proposed as an International Standard containing 100 arbitrary units of anti-HPA-1a for use in quantitative assays to determine the anti-HPA-1a activity in clinical samples. MATERIALS AND METHODS: Plasma samples containing potent anti-HPA-1a were pooled and freeze dried in 1-ml ampoules. In addition, three individual plasma samples were selected which had varying levels of anti-HPA-1a activity. The anti-HPA-1a activity of these three samples was determined by using a variety of quantitative assays with the proposed standard as a reference. RESULTS: An international collaborative study, which was part of the 2004 ISBT Platelet Immunology Workshop, involved 39 laboratories in 24 countries and showed that the anti-HPA-1a activity in three test samples could be reliably determined by using the proposed standard. CONCLUSIONS: Laboratories can use this standard to measure the anti-HPA-1a activity in patient's samples. Further studies are required to determine the relationship between anti-HPA-1a activity and clinical outcome in patients with neonatal alloimmune thrombocytopenia (NAIT).

Antibodies, Monoclonal↗
PubMed2005

Report on the 12th International Society of Blood Transfusion platelet immunology workshop.

BACKGROUND AND OBJECTIVES: The aims of the 12th International Society of Blood Transfusion (ISBT) Platelet Immunology Workshop were to evaluate the proficiency of molecular human platelet antigen (HPA) genotyping and detection of platelet antibodies of unusual specificity or reactivity, to assess whether quantification of anti-HPA-1a is practicable, and to determine the variability of reagents and components used in the monoclonal antibody immobilization of platelet antigens assay (MAIPA). MATERIALS AND METHODS: Forty participants from 23 countries were sent 10 samples for DNA typing, five samples for antibody detection, a freeze-dried anti-HPA-1a standard, three samples for anti-HPA-1a quantification and a MAIPA method questionnaire. RESULTS: The detection and identification of HPA antibodies varied from 2.7 to 95% of participants. The number of HPA genotyping errors per sample ranged from 0 to 3.96% per HPA loci. The majority of laboratories were able to assign an arbitrary number of units/ml of anti-HPA-1a activity to the unknown samples. The MAIPA questionnaire indicated a wide variation among participants, both in method and in reagents used. CONCLUSIONS: The results obtained from this workshop highlighted deficiencies in testing regimes and identified a need for internationally available reference materials.

Antibodies, Monoclonal↗
PubMed2004

Matchline dosimetry in step and shoot IMRT fields: a film study.

The Varian millennium 120 multileaf collimator has curved leaf ends. Transmission through the leaf ends generates a small asymmetric penumbral dose effect. This design can lead to hot spots between neighbouring beam segments during step and shoot IMRT dose delivery. We have observed some matchlines with film for clinical beams optimized using the pinnacle radiotherapy treatment planning system; hence we sought to verify the optimum leaf offset required to minimize the matchline effect. An in-house program was created to control the MLC leaf banks in 2 cm steps with a 2 cm gap. The gap was varied by the following offset values from 0.0 to 0.1 cm. Two types of radiographic films (Kodak EDR and XV films) and a radiochromic film (Gafchromic MD-55-2) were used to measure the optical density maps. The films were positioned in a solid water phantom perpendicular to the beam axis and irradiated at d(max) using a 6 MV photon beam. An ion chamber (IC4) was used to measure point doses for normalization in a beam umbral minima position. The relative mean peak to valley dose ratios measured with no leaf offset were 1.31, 1.30 and 1.31 for the XV, EDR2 and Gafchromic films, respectively. For a 0.07 cm gap per leaf and a performance of end leaf repeatability of 0.01 cm, the central matchline was reduced to about 1.0 for all dosimeters, with two mini-peaks measured as 1.05, 1.05 and 1.08 each side of the matchline, for XV, EDR2 and Gafchromic, respectively. The average relative dose across the umbra for this offset was XO-mat V = 1.01, EDR = 1.01 and radiochromic film = 1.02, respectively. While we expected the beam penumbral tails from segment neighbours to cause overprediction of the dose in the central valley regions due to the energy response of radiographic films, by normalizing all dosimeters to an ion chamber reading in the minimum we could not observe any major shape distortion between the radiographic film and radiochromic film results. In conclusion, relative doses measured by radiographic and radiochromic films agree well with IC4 within +/-2%.

Film Dosimetry↗
PubMed2004

Intensity-modulated radiation therapy: overlapping co-axial modulated fields.

The Varian multi-leaf collimator has a 14.5 cm leaf extension limit from each carriage. This means the target volumes in the head and neck region are sometimes too wide for standard width-modulated fields to provide adequate dose coverage. A solution is to set up asymmetric co-axial overlapping fields. This protects the MLC carriage while in return the MLC provides modulated dose blending in the field overlap region. Planar dose maps for coincident fields from the Pinnacle radiotherapy treatment planning system are compared with planar dose maps reconstructed from radiographic film and electronic portal images. The film and portal images show small leaf-jaw matchlines at each field overlap border. Linear profiles taken across each image show that the observed leaf-jaw matchlines from the accelerator images are not accounted for by the treatment planning system. Dose difference between film reconstructed electronic portal images and planning system are about 2.5 cGy in a modulated field at d(max). While the magnitude of the dose differences are small improved round end leaf modelling combined with a finer dose calculation grid may minimize the discrepancy between calculated and delivered dose.

Film Dosimetry↗
PubMed2003

Intensity modulated radiation therapy: film verification of planar dose maps.

A new slow response radiographic film (Kodak EDR) is compared with a more traditional faster responding dosimetry film (Kodak XV) in an intensity modulated radiation therapy x-ray field. Dose profiles derived from the two films are compared with doses obtained using a radiotherapy dose planning system (Philips-Pinnacle) which calculates planar dose using a collapsed cone convolution algorithm. Comparisons of the dose maps delivered from film with the Pinnacle dose maps are useful to ensure accurate dose delivery. The Pinnacle dose maps agreed with measurement using both film types to within +/- 3% (in the umbral region) at depths ranging from d(max) to 15 cm. Both XV and EDR films can be used to verify IMRT. EDR film is better suited for dosimetry for combined field dose maps due to its useful dose range of 1-5 Gy. We found XV to be more suitable for individual field dose maps (dose range 0-1 Gy) as no scaling of monitor units were required to achieve acceptable optical density response.

Algorithms↗
PubMed2003

Collaborative studies to establish the first WHO Reference Reagent for detection of human antibody against human platelet antigen-5b.

BACKGROUND AND OBJECTIVES: This report describes the production of a freeze-dried preparation of pooled human plasma, coded 99/666, containing immunoglobulin G (IgG) antibodies against human platelet antigen 5b (HPA-5b). MATERIALS AND METHODS: The material is intended for use as a minimum sensitivity reagent in the assays currently used for detection of antibodies to HPA-5b. Laboratories can use it to assess the sensitivity of their 'in-house' assays for antibodies to HPA-5b and to calibrate local controls for routine use in each batch of tests. RESULTS: Two collaborative studies demonstrated that the two candidate materials contained antibodies to HPA-5b and that there were no other HPA or human leucocyte antigen (HLA) antibodies which might confuse the detection of antibodies to HPA-5b. The two samples were pooled and freeze-dried in 1-ml ampoules. CONCLUSIONS: The minimum dilution of the antibody against 5b required to yield a positive result was determined, by two international collaborative studies involving a total of 49 laboratories in 26 countries, to be 1 in 2.

Antibodies, Monoclonal↗
PubMed2002

Radiobiological indices that consider volume: a review.

Understanding and predicting the impact of any radiotherapy treatment is critical if patients are to receive treatment with a high likelihood of eliminating the tumour and low likelihood of complications. One of the major contributing factors in determining these effects is the volume treated. This review assesses the current use and accuracy of a series of models which consider volume, building on a previous review which investigated the impact of fractionation particularly with respect to the linear quadratic model. Volume is particularly important in assessing the overall effect with respect to destroying the clonogenic cells and preventing damage to the normal tissues. Dose volume histograms are one of the simplest and most useful forms of representing volume information, however it is difficult to correlate plans based only on DVHs. For this reason various reduction schemes have been introduced and tumour control probability and normal tissues complication probability models adjusted to use this information. Many of these models have proved quite useful in the clinic although they are limited by the available radiobiological data.

Dose-Response Relationship, Radiation↗
PubMed2002

Verification of CT number to density conversion for a simulator-T attachment.

The calculation and verification of a CT number to density conversion table for a simulator-CT attachment known as Scanvision, which provides CT images for radiotherapy treatment planning, is presented. While the linear fit for CT-number-to-density is similar to most conventional doughnut gantry CT scanners, an offset of approximately 178 Hounsfield units was found for air using a polyethylene normalisation, and approximately 262 for air using air normalisation. The offset continues for other low-density samples. Results show that the simulator-CT reproducibly measures CT numbers. However a separate calibration line needs to be entered into the radiotherapy planning computer to ensure accurate CT-number-to-density. conversion.

Humans↗
PubMed2002

Genotyping for platelet-specific antigens: techniques for the detection of single nucleotide polymorphisms.

Accurate typing of patients for platelet-specific (human platelet) antigens (HPA) is required in several different clinical situations, and blood services need to maintain panels of HPA-typed apheresis platelet donors and whole-blood donors to support HPA alloimmunized patients. Six clinically relevant HPA alloantigen systems have been described and, in addition, a significant number of HPA alloantigens with a highly skewed allele frequency or of very low immunogenicity have been reported. Certain well-characterized biallelic systems such as Gov have not as yet been included in the HPA nomenclature but are included in this review. Biochemical studies have identified the platelet membrane proteins on which the HPA antigens are localized. Cloning of the genes encoding these proteins and the realization that there is adequate mRNA in fresh platelets has led to identification of the molecular basis of HPA antigens over the last decade. All but one of the biallelic platelet-specific alloantigen systems are based on a single nucleotide polymorphism in the DNA sequence, corresponding to a single amino acid substitution in the encoded primary protein sequence. The discovery of the genetic basis of the alloantigens has allowed the development of polymerase chain reaction-based techniques for HPA genotyping using genomic DNA. The genetic basis of the HPA alloantigens, the most commonly used genome typing techniques and their pitfalls, and future developments, are discussed in this review.

Antigens, Human Platelet↗
PubMed2001

The use of the linear quadratic model in radiotherapy: a review.

To be able to predict the impact of any radiotherapy treatment the physics of radiation interactions and the expected biological effect for any radiotherapy treatment situation (dose, fractionation, modality) must be both understood and modelled. This review considers the current use and accuracy of the linear quadratic model which can be used to consider the variation in tissue response with fraction size. Cell kill following radiation damage results from damage to the DNA which can take a variety of forms. In many cases the linear quadratic model is used to estimate the relative impact for different situations especially clinical studies relating to fraction size. This is mainly undertaken using parameters derived from the linear quadratic model such as biological effective dose and standard effective dose. The model has also been adapted to consider the effect of overall treatment time, repair during treatment (as occurs for brachytherapy treatments) and other situations. There are some concerns over its use, mainly in the small dose ranges (both total low doses and low doses per fraction) where studies have shown its inaccuracy. In other situations however it does appear to provide a reasonable estimate of relative clinical effect. As with all models, however results should never be considered out of clinical context.

Biophysical Phenomena↗
PubMed2001

The effect of human platelet alloantigen polymorphisms on the in vitro responsiveness to adrenaline and collagen.

A number of clinical studies have suggested that carriage of the low frequency allele (b) of the human platelet antigen 1 (HPA-1) system is a risk factor for coronary thrombosis. We have examined the effect of a series of HPA biallelic polymorphisms (systems -1, -2, -3 and -5) on the in vitro platelet aggregation in response to adrenaline and collagen in 30 healthy volunteers. There was a significantly higher prevalence (10 out of 18) of carriers of the HPA-1b polymorphism among subjects showing a > 50% aggregation response to adrenaline ('responders') than the prevalence (1/12) in 'non-responders' (P < 0.05). Platelets heterozygous for the HPA-1b polymorphism showed a significantly higher rate (slope) and greater extent (%) of adrenaline-induced aggregation than platelets not carrying the HPA-1b allele (P < 0.05). A greater extent of collagen-induced aggregation was also demonstrated in HPA-1ab platelets (P < 0.05). Inhibition of adrenaline-induced aggregation following incubation with aspirin was greater (P < 0.01) in HPA-1ab than in HPA-1aa platelets. Collagen-induced aggregation was slower in carriers of the HPA-5b allele than in HPA-5aa subjects (P < 0.05). Polymorphisms of the HPA-2 and HPA-3 systems were not associated with different aggregation responses to either adrenaline or collagen. These results support the clinical observation that polymorphism HPA-1b may predispose to increased platelet thrombogenicity and suggest that the presence of polymorphism HPA-5b might render the platelet less reactive to collagen.

Adult↗
PubMed2001

Directional dependence in film dosimetry: radiographic and radiochromic film.

The trend towards conformal, intensity modulated radiotherapy treatments has established the need for a true integrating dosimeter. In traditional radiotherapy, radiographic film dosimetry is commonly used. The accuracy and reproducibility of film optical density as an indicator of dose is influenced by several variables, including the chemical processing conditions. As a result radiochromic film, with all the advantages of radiographic film but without the need for chemical processing, has increased in popularity, although the low-dose sensitivity of radiochromic film does remain a disadvantage for some experiments. Several studies have investigated the reproducibility of radiochromic film results, but none have specifically addressed the well-known directional dependence seen with traditional radiographic film. In this study, the directional dependence of radiographic (Kodak X-omat V) and radiochromic (Gafchromic) films were measured. It was found that both films over responded when exposed parallel to the central axis of the beam as opposed to perpendicular exposure. An attempt is made to explain the reason for the responses of both films in terms of spectral effects and the air gap between the phantom segments. Although radiographic film exposed parallel rather than perpendicular to the central axis of the beam exhibits a measured difference in film response at depth, this over response does not occur when the extent of the film is restricted to a small region at the centre of the phantom (in this case an air gap is not introduced across the phantom). This suggests that it is the air gap rather than the orientation of the film that is the cause of the over response. Furthermore, when film occupies a slice through the entire phantom an over response occurs for both radiographic and radiochromic film, indicating that spectral effects are not the cause.

Film Dosimetry↗
PubMed2001

Calciphylaxis of the penis: a unique cause of Fournier's gangrene.

Calciphylaxis is a rare disease that is caused by calcium deposition in medium and small sized vessels of the skin causing ischemic necrosis. These lesions often become infected and cause septicemia. We report a unique case of penile and scrotal calciphylaxis that rapidly progressed to Fournier's gangrene. We review the etiology of calciphylaxis and also its management.

Aged↗