Phase-contrast and magnification radiography at diagnostic X-ray energies using a pseudo-microfocus X-ray source.

OBJECTIVE: To investigate the use of conventional diagnostic X-ray tubes for applications in which specialist microfocus sources are normally required. METHODS: A conventional diagnostic X-ray tube was used in conjunction with a range of apertures to investigate improvements in spatial resolution using a line-pairs test object. Phase-contrast effects were investigated by varying source-to-object and object-to-receptor distances using a 2-French catheter as a clinically realistic test object. RESULTS: For magnification radiography using a computed radiography receptor and conventional X-ray tube with a 1-mm nominal focus size, the limiting spatial resolution was improved from 3.55 line-pairs per millimetre, for a conventional contact image, to 5.6 line-pairs per millimetre, for a ×2 magnified view with a 250-µm aperture. For inline phase-contrast radiography, phase contrast enhancement of a 2-French catheter was demonstrated, and the expected trends with variations in source-to-object and object-to-receptor distances were found. Images of a neonatal phantom demonstrated a subtle improvement in visibility of a superimposed 1-French catheter simulating a percutaneously inserted central catheter for no increase in patient radiation dose. CONCLUSION: Spatial resolution improvement and visible phase contrast can be produced in clinically relevant objects using a pseudo-microfocus geometry at X-ray energies in the normal diagnostic range, using conventional diagnostic X-ray tubes and image receptors. The disadvantages of the proposal are the large distances required to produce phase contrast and limitations imposed by the resulting tube loading. ADVANCES IN KNOWLEDGE: It is possible to use conventional diagnostic X-ray equipment in applications that normally require microfocus X-ray sources. This presents some possibilities for clinical applications.

Factors influencing disease phenotype and penetrance in HFE haemochromatosis.

Haemochromatosis is predominantly associated with the HFE p.C282Y homozygous genotype, which is present in approximately 1 in 200 people of Northern European origin. However, not all p.C282Y homozygotes develop clinical features of haemochromatosis, and not all p.C282Y homozygotes even present abnormal iron parameters justifying venesection therapy. This situation was not apparent from initial genotype/phenotype correlation studies as there was a selection bias of patients. Only those patients with a significant iron burden were included in these early studies. It is now largely accepted that the p.C282Y/p.C282Y genotype is necessary for the development of HFE haemochromatosis. However, this genotype provides few clues as to why certain symptoms are associated with the disease. Expression of iron overload in people with this genotype depends on the complex interplay of environmental factors and modifier genes. In this review, we restrict our discussion to work done in humans giving examples of animal models where this has helped clarify our understanding. We discuss penetrance, explaining that this concept normally does not apply to autosomal recessive disorders, and discuss the usefulness of different biochemical markers in ascertaining iron burden. Hepcidin, a peptide synthesized primarily by the liver, has been identified as the central regulator in iron homeostasis. Consequently, understanding its regulation is the key. We conclude that the main goal now is to identify important modifiers that have a significant and unambiguous effect on iron storage.

Advances in mammographic imaging.

Breast imaging in the UK is currently undergoing a major change, with the widespread implementation of full-field digital mammography (FFDM) equipment. This article looks at some of the advanced imaging techniques that have become possible following the development of FFDM units. These techniques may prove to be useful additions to standard mammography for some groups of women.

An investigation into the effects of suboptimal viewing conditions in screen-film mammography.

The ability of an observer to detect objects on a radiograph is influenced by the conditions under which the image is viewed. Therefore, to ensure that as much diagnostically relevant information as possible can be extracted from the image, it is important that satisfactory viewing conditions for the task are established and maintained. Factors that are thought to be important are the luminance of the image, glare and ambient light. Together, these factors lead to the formation of reflection on the image, which may degrade the observer's performance. The purpose of this study was to explore, in a systematic manner, the effect of the factors outlined above on the performance of an observer conducting a threshold contrast-detail diameter test. Each factor was investigated separately with attempts made to minimize the confounding effects of other factors. When examined individually, viewing box luminance, ambient light and glare were found to have little effect on the contrast-detail performance of the observers. Reflection was found to have a significant effect, particularly non-uniform reflection, and the magnitude of the effect was related to the contrast degradation factor and reflection modulation. These quantities, which are derived from basic photometric measurements, may be used to develop a protocol to assess viewing conditions in screen-film mammography.

Iron genes, iron load and risk of Alzheimer's disease.

BACKGROUND: Compound heterozygotes of the haemochromatosis gene (HFE) variants, H63D and C282Y, have raised transferrin saturation compared with that in the wild type. In the cohort of the Oxford Project To Investigate Memory and Ageing (OPTIMA), bicarriers of the HFE C282Y and the transferrin C2 gene variants are at five times greater risk of developing Alzheimer's disease; the addition of HFE H63D may raise the risk still further. OBJECTIVE: To investigate transferrin saturation by HFE and transferrin genotype among people without dementia-that is, controls and those with mild cognitive impairment (MCI)-and also among those with Alzheimer's disease. METHODS: Serum iron status and genotype were examined of 177 patients with Alzheimer's disease, 69 patients with MCI and 197 controls from the OPTIMA cohort. RESULTS: Although each of these variants alone had relatively little effect on iron status, the combination of either HFE C282Y and HFE H63D or of HFE C282Y and transferrin C2 markedly raised transferrin saturation in those without dementia, but had little effect in those with mature Alzheimer's disease. CONCLUSIONS: These combinations may raise the risk for Alzheimer's disease, owing to higher iron loads and therefore oxidative stress in the preclinical phase. If replicated, these findings will have implications for the prevention of Alzheimer's disease.

Reverse cascade screening of newborns for hereditary haemochromatosis: a model for other late onset diseases?

BACKGROUND: Genetic testing can determine those at risk for hereditary haemochromatosis (HH) caused by HFE mutations before the onset of symptoms. However, there is no optimum screening strategy, mainly owing to the variable penetrance in those who are homozygous for the HFE Cys282Tyr (C282Y) mutation. The objective of this study was to identify the majority of individuals at serious risk of developing HFE haemochromatosis before they developed life threatening complications. METHODS: We first estimated the therapeutic penetrance of the C282Y mutation in people living in la Somme, France, using genetic, demographic, biochemical, and follow up data. We examined the benefits of neonatal screening on the basis of increased risk to relatives of newborns carrying one or two copies of the C282Y mutation. Between 1999 and 2002, we screened 7038 newborns from two maternity hospitals in the north of France for the C282Y and His63Asp (H63D) mutations in the HFE gene, using bloodspots collected on Guthrie cards. Family studies and genetic counselling were undertaken, based on the results of the baby's genotype. FINDINGS: In la Somme, we found that 24% of the adults homozygous for the C282Y mutation required at least 5 g iron to be removed to restore normal iron parameters (that is, the therapeutic penetrance). In the reverse cascade screening study, we identified 19 C282Y homozygotes (1/370), 491 heterozygotes (1/14) and 166 compound heterozygotes (1/42) in 7038 newborns tested. The reverse cascade screening strategy resulted in 80 adults being screened for both mutations. We identified 10 previously unknown C282Y homozygotes of whom six (four men and two women) required venesection. Acceptance of neonatal screening was high; parents understood the risks of having HH and the benefits of early detection, but a number of parents were reluctant to take the test themselves. Neonatal screening for HH is straightforward. Reverse cascade screening increased the efficiency of detecting affected adults with undiagnosed haemochromatosis. This strategy allows almost complete coverage for HH and could be a model for efficient screening for other late onset genetic diseases.

Pilot study into optimisation of viewing conditions for electronically displayed images.

The increased use of soft-copy reporting introduces new concerns over the effect of viewing conditions on the observer's ability to report images. Owing to their lower luminance, electronic display screens may be more susceptible to poor viewing conditions than conventional viewing boxes and there is the potential for images to be displayed in locations not optimised for viewing radiographs. In the present work, the effects of sub-optimal viewing conditions on the observer's performance for images on an electronic display device are investigated. A test object was used to produce a computed radiography image containing a wide range of grey levels. The image was scored under quasi-ideal and sub-optimal conditions and the effect of changing the viewing conditions on the observer's performance determined. Basic photometric quantities were used to characterise the viewing conditions and the degradation in observer performance related to these quantities. The presence of structured reflection had a significant effect on the observer's ability to discern low-contrast objects. The study demonstrates the need for adequate viewing conditions especially when images are displayed on low luminance devices in sub-optimal conditions.

Mammographic image restoration using maximum entropy deconvolution.

An image restoration approach based on a Bayesian maximum entropy method (MEM) has been applied to a radiological image deconvolution problem, that of reduction of geometric blurring in magnification mammography. The aim of the work is to demonstrate an improvement in image spatial resolution in realistic noisy radiological images with no associated penalty in terms of reduction in the signal-to-noise ratio perceived by the observer. Images of the TORMAM mammographic image quality phantom were recorded using the standard magnification settings of 1.8 magnification/fine focus and also at 1.8 magnification/broad focus and 3.0 magnification/fine focus; the latter two arrangements would normally give rise to unacceptable geometric blurring. Measured point-spread functions were used in conjunction with the MEM image processing to de-blur these images. The results are presented as comparative images of phantom test features and as observer scores for the raw and processed images. Visualization of high resolution features and the total image scores for the test phantom were improved by the application of the MEM processing. It is argued that this successful demonstration of image de-blurring in noisy radiological images offers the possibility of weakening the link between focal spot size and geometric blurring in radiology, thus opening up new approaches to system optimization.

Recent advances in understanding haemochromatosis: a transition state.

Mutations in the hepcidin gene HAMP and the hemojuvelin gene HJV have recently been shown to result in juvenile haemochromatosis (JH). Hepcidin is an antimicrobial peptide that plays a key role in regulating intestinal iron absorption. Hepcidin levels are reduced in patients with haemochromatosis due to mutations in the HFE and HJV genes. Digenic inheritance of mutations in HFE and HAMP can result in either JH or hereditary haemochromatosis (HH) depending upon the severity of the mutation in HAMP. Here we review these findings and discuss how understanding the different types of haemochromatosis and our increasing knowledge of iron metabolism may help to elucidate the host's response to infection.

The origin and spread of the HFE-C282Y haemochromatosis mutation.

The mutation responsible for most cases of genetic haemochromatosis in Europe (HFE C282Y) appears to have been originated as a unique event on a chromosome carrying HLA-A3 and -B7. It is often described as a "Celtic mutation"--originating in a Celtic population in central Europe and spreading west and north by population movement. It has also been suggested that Viking migrations were largely responsible for the distribution of this mutation. Two, initial estimates of the age of the mutation are compatible with either of these suggestions. Here we examine the evidence about HFE C282Y frequencies, extended haplotypes involving HLA-A and -B alleles, the validity of calculations of mutation age, selective advantage and current views on the relative importance of "demic-diffusion" (population migration) and "adoption-diffusion" (cultural change) in the neolithic transition in Europe and since then. We conclude that the HFE C282Y mutation occurred in mainland Europe before 4,000 BC.

Application of low dose rate pulsed fluoroscopy in cardiac pacing and electrophysiology: patient dose and image quality implications.

The performance of a low dose rate pulsed fluoroscopy option and its successful application to cardiac pacing and electrophysiology is reported. Low dose rate 6.25 frames per second pulsed fluoroscopy was made available in two catheter laboratories at a specialist cardiac centre in February 2003, and was adopted as the standard imaging technique for cardiac pacing procedures. The image quality was found to be considerably poorer than conventional modern units, being very similar to that which would have been accepted as adequate performance 20 years ago, but at less than one-tenth of the dose rate. No problems with the clinical acceptance of this imaging mode for cardiac pacing and electrophysiology have been reported. The already low median patient dose-area product for pacing at this cardiac centre was further reduced by 50% with the introduction of this fluoroscopy option.

Hepcidin and its role in iron absorption.

Maintaining the correct iron balance is crucial to good health. Disorders of iron homeostasis have a global distribution. As iron is not actively excreted by the body, understanding the role of proteins involved in regulating iron uptake is essential to our understanding of disease involving iron homeostasis. Over the past 10 years, major advances have been made in understanding the genetics of iron metabolism and this has led to identification of a number of new proteins, including hepcidin, involved in iron homeostasis.

Synergy between the C2 allele of transferrin and the C282Y allele of the haemochromatosis gene (HFE) as risk factors for developing Alzheimer's disease.

BACKGROUND: There is evidence that iron may play a role in the pathology of Alzheimer's disease (AD). There may be genetic factors that contribute to iron deposition resulting in tissue damage thus exacerbating AD. METHODS: We have genotyped 269 healthy elderly controls, 191 cases with definite or probable AD, and 69 with mild cognitive impairment (MCI) from the OPTIMA cohort. RESULTS: We have examined the interaction between the C2 variant of the transferrin (TF) gene and the C282Y allele of the haemochromatosis (HFE) gene as risk factors for developing AD. Our results showed that each of the two variants was associated with an increased risk of AD only in the presence of the other. Neither allele alone had any effect. Carriers of both variants were at 5 times greater risk of AD compared with all others. The interaction was significant by logistic regression (p = 0.014) and by synergy factor analysis (p = 0.015, synergy factor = 5.1). Further, carriers of these two alleles plus apolipoprotein E epsilon4 (APOE4) were at still higher risk of AD: of the 14 tri-carriers of the three variants, identified in this study, 12 had AD and two MCI. CONCLUSION: We suggest that the combination of TF C2 and HFE C282Y may lead to an excess of redox-active iron and the induction of oxidative stress in neurones, which is exacerbated in carriers of APOE4. Since 4% of Northern Europeans carry the two iron-related variants and since iron overload is a treatable condition, these results merit replication.

The 16189 variant of mitochondrial DNA occurs more frequently in C282Y homozygotes with haemochromatosis than those without iron loading.

BACKGROUND: Patients with hereditary haemochromatosis (HH) are usually homozygous for the C282Y mutation in the HFE gene. They have variable expression of iron overload and present with a variety of complications, including liver disease, diabetes, arthropathy, fatigue, and cardiomyopathy. The mitochondrial 16189 variant is associated with diabetes, dilated cardiomyopathy, and low body fat at birth, and might contribute to genetic predisposition in further multifactorial disorders. The objective of this study was to determine the frequency of the 16189 variant in a range of patients with haemochromatosis, who had mutations in the HFE gene. METHODS: Blood DNA was analysed for the presence of the 16189 variant in British, French, and Australian C282Y homozygotes and controls, with known iron status, and in birth cohorts. RESULTS: The frequency of the mitochondrial 16189 variant was found to be elevated in individuals with haemochromatosis who were homozygous for the C282Y allele, compared with population controls and with C282Y homozygotes who were asymptomatic (42/292 (14.4%); 102/1186 (8.6%) (p = 0.003); and 2/64 (3.1%) (p = 0.023), respectively). CONCLUSIONS: Iron loading in C282Y homozygotes with HH was exacerbated by the presence of the mitochondrial 16189 variant.

A targeted approach significantly increases the identification rate of patients with undiagnosed haemochromatosis.

OBJECTIVE: To determine the optimal means of identifying patients with undiagnosed haemochromatosis. DESIGN: Case-control study where cases are defined by the presence of specific clinical diagnoses or symptoms. SETTING: Primary care patients were recruited from three Oxfordshire practices and secondary care patients were recruited from those patients attending specialist clinics in Amiens University Hospital. SUBJECTS: A total of 569 patients recruited via hospital clinics and 60 primary care patients (recruited from 4022 consultations) presenting with the following haemochromatosis associated conditions, diabetes, arthralgia/chronic fatigue, osteoporosis or arthropathy were studied. The control group, a total of 991 healthy volunteers, were recruited through a Health Appraisal Centre. Patients and controls were included in the study if they or their family members had not previously been diagnosed with hereditary haemochromatosis. MAIN OUTCOME MEASURES: Serum ferritin concentration, transferrin saturation (Tsat) and presence of HFE mutations, C282Y and H63D. The check-up in controls consisted of a questionnaire, clinical examination, biochemical tests and screening for the presence of the C282Y and H63D mutations. RESULTS: Patient groups presenting with unstable diabetes or chronic fatigue and arthralgia together with a raised serum ferritin concentration showed an enrichment in the haemochromatosis-associated genotype HH/YY, odds ratio (OR) = 40.1, confidence interval (CI) = 8.0-202.1 and OR = 103, CI = 22.9-469.7, respectively. CONCLUSION: Patients presenting to hospital clinics with haemochromatosis associated conditions should be screened biochemically for iron overload. Only those with a serum ferritin >300 microg L-1 or Tsat >40% should subsequently go on to be genotyped for HFE mutations. The patients at greatest risk of having undiagnosed haemochromatosis are those presenting with unstable diabetes, or fatigue and/or arthralgia in the absence of any other explanation.

Short communication: anomalous image quality phantom scores in magnification mammography: evidence of phase contrast enhancement.

Anomalously high image quality scores were noted for images of the Leeds TORMAM phantom obtained using magnification mammography. Comparison of optical density profiles of fibre features in the images with non-magnified images and images previously obtained using an in-line phase contrast geometry showed the presence of phase contrast enhancement in the magnification images. The effect on the phantom score is particularly marked for this design of phantom owing to its use of fibres, which tend to enhance well. A large proportion of the phantom score is associated with fibrous features. It is concluded that direct comparison of TORMAM phantom scores from magnified images with those from non-magnified images is not valid due to the different balance of physical mechanisms forming the two kinds of image.

A prime-boost immunisation regimen using DNA followed by recombinant modified vaccinia virus Ankara induces strong cellular immune responses against the Plasmodium falciparum TRAP antigen in chimpanzees.

Two chimpanzees were vaccinated intramuscularly against malaria using plasmid DNA expressing the pre-erythrocytic antigens thrombospondin related adhesion protein (PfTRAP) and liver stage specific antigen-1 (PfLSA-1) of Plasmodium falciparum together with GM-CSF protein. A recombinant modified vaccinia virus Ankara (MVA) expressing PfTRAP was injected intramuscularly 6 weeks later to boost the immune response. This sequence of antigen delivery induced a specific and long-lasting T cell and antibody response to PfTRAP as detected by ELISPOT assay and ELISA. Antibody responses were detected after four DNA injections, and were boosted by injection of recombinant MVA expressing PfTRAP. Interferon-gamma secreting antigen-specific T cells were detected in both animals, but only after boosting with recombinant MVA. By screening a panel of PfTRAP-derived peptides, an epitope was identified that was recognized by cytotoxic T lymphocytes in one of the chimpanzees studied. T cells specific for this epitope were present in PBMCs and liver-infiltrating lymphocytes at a frequency of between 1 in 200 and 1 in 500. The high immunogenicity of this prime-boost regimen in chimpanzees supports further assessment of this delivery strategy for the induction of protection against P. falciparum malaria in humans.

A parametric method for determining mammographic X-ray tube output and half value layer.

In the National Health Service Breast Screening Programme, regular assessment of the mean glandular doses received by a group of women is recognized as an important part of a quality assurance programme. The use of different tube voltages, to improve the beam penetration for thick or dense breasts, and of X-ray units with programmable exposure modes, requires a large number of measurements to ensure that all the values of tube output and half value layer required for the dose calculations are available. In this work, a computer model is used to produce data that allow the calculation of tube output and half value layer for the range of clinically encountered conditions from measurements routinely obtained during quality assurance tests. The data are given as a series of equations and parameters, enabling the calculations to be easily incorporated into a dose calculation spreadsheet. The results of an experimental verification of the model are presented, showing good agreement between the measured and predicted values of half value layer and tube output for a range of combinations of target, filter and tube voltage.

Receptor dose in digital fluorography: a comparison between theory and practice.

A method of identifying the dose per image when quantum mottle no longer dominates the image statistics is presented as a first step towards quantitative optimization in native and subtracted digital fluorography. The method is based on measurements of threshold contrast over a range of receptor doses and the application of a simple model of the threshold contrast detection task to estimate the magnitude of system noise sources. The point at which system and quantum noise sources are equal in magnitude is proposed as the practical upper limit for dose per image. The method is applied to a typical digital fluorography system and the results are placed into the context of the range of dose per image values found from a regional survey of digital fluorography units. While there is broad agreement between the dose per image values in the survey with values predicted from the experimental method, the considerable spread in survey doses suggests there are instances where the use of a high dose per image is unjustified.