Latrophilin receptors: novel bronchodilator targets in asthma.

BACKGROUND: Asthma affects 300 million people worldwide. In asthma, the major cause of morbidity and mortality is acute airway narrowing, due to airway smooth muscle (ASM) hypercontraction, associated with airway remodelling. However, little is known about the transcriptional differences between healthy and asthmatic ASM cells. OBJECTIVES: To investigate the transcriptional differences between asthmatic and healthy airway smooth muscle cells (ASMC) in culture and investigate the identified targets using in vitro and ex vivo techniques. METHODS: Human asthmatic and healthy ASMC grown in culture were run on Affymetrix_Hugene_1.0_ST microarrays. Identified candidates were confirmed by PCR, and immunohistochemistry. Functional analysis was conducted using in vitro ASMC proliferation, attachment and contraction assays and ex vivo contraction of mouse airways. RESULTS: We suggest a novel role for latrophilin (LPHN) receptors, finding increased expression on ASMC from asthmatics, compared with non-asthmatics in vivo and in vitro, suggesting a role in mediating airway function. A single nucleotide polymorphism in LPHN1 was associated with asthma and with increased LPHN1 expression in lung tissue. When activated, LPHNs regulated ASMC adhesion and proliferation in vitro, and promoted contraction of mouse airways and ASMC. CONCLUSIONS: Given the need for novel inhibitors of airway remodelling and bronchodilators in asthma, the LPHN family may represent promising novel targets for future dual therapeutic intervention.

Model-based versus specific dosimetry in diagnostic context: comparison of three dosimetric approaches.

PURPOSE: The dosimetric assessment of novel radiotracers represents a legal requirement in most countries. While the techniques for the computation of internal absorbed dose in a therapeutic context have made huge progresses in recent years, in a diagnostic scenario the absorbed dose is usually extracted from model-based lookup tables, most often derived from International Commission on Radiological Protection (ICRP) or Medical Internal Radiation Dose (MIRD) Committee models. The level of approximation introduced by these models may impact the resulting dosimetry. The aim of this work is to establish whether a more refined approach to dosimetry can be implemented in nuclear medicine diagnostics, by analyzing a specific case. METHODS: The authors calculated absorbed doses to various organs in six healthy volunteers administered with flutemetamol ((18)F) injection. Each patient underwent from 8 to 10 whole body 3D PET/CT scans. This dataset was analyzed using a Monte Carlo (MC) application developed in-house using the toolkit gate that is capable to take into account patient-specific anatomy and radiotracer distribution at the voxel level. They compared the absorbed doses obtained with GATE to those calculated with two commercially available software: OLINDA/EXM and STRATOS implementing a dose voxel kernel convolution approach. RESULTS: Absorbed doses calculated with gate were higher than those calculated with OLINDA. The average ratio between gate absorbed doses and OLINDA's was 1.38 ± 0.34 σ (from 0.93 to 2.23). The discrepancy was particularly high for the thyroid, with an average GATE/OLINDA ratio of 1.97 ± 0.83 σ for the six patients. Differences between STRATOS and GATE were found to be higher. The average ratio between GATE and STRATOS absorbed doses was 2.51 ± 1.21 σ (from 1.09 to 6.06). CONCLUSIONS: This study demonstrates how the choice of the absorbed dose calculation algorithm may introduce a bias when gamma radiations are of importance, as is the case in nuclear medicine diagnostics.

Human urinary excretion of NC100692, an RGD-peptide for imaging angiogenesis.

The (99m)Tc complex of NC100692 is being evaluated as a diagnostic agent for the detection of angiogenesis. In the present study, human urine samples from a clinical Phase I study were analysed using reversed-phase liquid chromatography coupled with an ion-trap mass spectrometer (LC-MS) in order to estimate the amount of intact NC100692 and any metabolites excreted in urine following intravenous injection of 150microg (99m)Tc-NC100692. Only intact NC100692 was observed in these urine samples, no metabolites were detected, in contrast to data earlier reported for rat urine where two metabolites and no NC100692 were observed. Within 4-8h after injection, 30+/-6% of the injected NC100692 was excreted in the urine, with the majority (23+/-5%) recovered within the first hour post-injection. There was good agreement between the calculated urinary recoveries of NC100692 and total radioactivity in urine samples voided approximately 1h post-injection. NC100692 constituting 98+/-24% of the total urinary (99m)Tc recovery indicating that the (99m)Tc excreted during this period was most likely excreted as (99m)Tc-NC100692. The ratio of NC100692 to (99m)Tc decreased in the urine samples as a function of time following injection for all subjects; this change is most likely due to reduced accuracy in the results at low levels of NC100692.

Airway mechanics and methods used to visualize smooth muscle dynamics in vitro.

Contraction of airway smooth muscle (ASM) is regulated by the physiological, structural and mechanical environment in the lung. We review two in vitro techniques, lung slices and airway segment preparations, that enable in situ ASM contraction and airway narrowing to be visualized. Lung slices and airway segment approaches bridge a gap between cell culture and isolated ASM, and whole animal studies. Imaging techniques enable key upstream events involved in airway narrowing, such as ASM cell signalling and structural and mechanical events impinging on ASM, to be investigated.

Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma.

Excessive airway obstruction is the cause of symptoms and abnormal lung function in asthma. As airway smooth muscle (ASM) is the effecter controlling airway calibre, it is suspected that dysfunction of ASM contributes to the pathophysiology of asthma. However, the precise role of ASM in the series of events leading to asthmatic symptoms is not clear. It is not certain whether, in asthma, there is a change in the intrinsic properties of ASM, a change in the structure and mechanical properties of the noncontractile components of the airway wall, or a change in the interdependence of the airway wall with the surrounding lung parenchyma. All these potential changes could result from acute or chronic airway inflammation and associated tissue repair and remodelling. Anti-inflammatory therapy, however, does not "cure" asthma, and airway hyperresponsiveness can persist in asthmatics, even in the absence of airway inflammation. This is perhaps because the therapy does not directly address a fundamental abnormality of asthma, that of exaggerated airway narrowing due to excessive shortening of ASM. In the present study, a central role for airway smooth muscle in the pathogenesis of airway hyperresponsiveness in asthma is explored.

X-ray image intensifier performance and patient doses for combinations of supplemental beam filters and vascular contrast agents.

We present an investigation of the fluoroscopic imaging and dosimetric performances of iodine- and gadolinium-based vascular contrast agents in combination with K-absorption edge filters of atomic numbers between 50 (tin) and 82 (lead). These combinations were studied using a theoretical model for a range of diagnostic x-ray spectra (55 to 100 kVp) and for water phantoms representative of thin and thick anatomies. Performance was characterized by radiographic contrast, a derived image quality index, the patient integral and entrance skin doses, and the x-ray tube load. For a given thickness of anatomy, an optimum combination of spectrum kVp, contrast agent and supplemental filter was defined by maximum imaging performance for a minimum or tolerable x-ray tube load and patient dose. It was possible to both improve imaging performance and reduce dose by the use of an appropriate combination of spectrum kVp and filter. For gadolinium-based contrast, performance was optimized with tungsten filtration at 90 kVp for both thin and thick anatomies. It was not possible, however, to optimize the iodinated contrast performance with a single combination of supplemental filter and spectrum kVp. The optimal performance for iodinated contrast was achieved with gadolinium filtration at 60 kVp for thin anatomy and with ytterbium filtration at 80 kVp for thick anatomy. The best performance for thin anatomy was that of the combination of iodinated contrast/gadolinium filter at 60 kVp and the best performance for thick anatomy was that of the combination of gadolinium-based contrast/tungsten filter at 90 kVp.

An epithelial-derived factor inhibits contraction in canine perfused bronchial segments.

We have previously reported, using a novel preparation of canine airway segments, that the sensitivity of acetylcholine was greater when applied to the adventitial (outside) surface than the epithelial (inside) surface. The present study investigated if this "barrier-effect" was partly the result of pharmacological modulation by the epithelium. As previously demonstrated, canine airway segments were less sensitive to inside than outside application of acetylcholine (pD(2) 3.0+/-0.4 and 4.5+/-0.4, respectively, P<0.001, n=5). The addition of donor bronchi significantly decreased the sensitivity of the airway segment to outside application of acetylcholine (pD(2) 4.3+/-0.2 and 3.6+/-0.2, respectively, P<0.002, n=4). Indomethacin (2.5 microM) treatment of both the donor bronchi and the airway segment and removal of donor epithelium abolished the rightward shift in the acetylcholine-response curves. In addition, inhibition of cyclooxygenase within the airway segments themselves, but not the donor bronchi, also inhibited the rightward shift in the curves. These results indicate that the donor epithelium is capable of pharmacologically modulating responses of the airway segment to outside applied acetylcholine by producing an epithelial-derived factor, which in turn causes the release of a downstream cyclooxygenase product from within the airway segment.

A comparison of fixed and variable kVp technique protocols for film-screen mammography.

Mammographic image quality, contrast and dose for a variable tube potential (kVp) technique protocol for film-screen mammography have been investigated. In this protocol, the tube potential is increased for larger breast thicknesses. Comparisons were made with fixed kVp protocols, in which the tube potential is kept constant and the breast thickness compensated for by prolonging the exposure ("fixed kVp" protocol). All measurements were performed on a mammography unit with a molybdenum target and filter. Image quality was quantified by image contrast, image detail detection and the minimum detectable dimension of low contrast objects. It was demonstrated that for a compressed breast thickness of less than about 40 mm, varying the tube potential had a negligible effect upon dose but a significant effect upon image quality. For a compressed breast thickness greater than about 60 mm, the effect of the tube potential upon image quality was much reduced; however, the effect upon dose was significantly greater. The variable kVp protocol takes advantage of this feature to yield a significantly lower dose for thicker breasts with a small reduction in image quality, often only within experimental uncertainty. For an exposure under automatic exposure control, increasing the tube potential from 26 kVp to 30 kVp for a breast of a reference tissue composition (50% adipose and 50% glandular) with a compressed thickness of 60 mm reduced the mean glandular dose from 6 mGy to 3.9 mGy (-35%), but increased the minimum detectable dimension of a low contrast mass from 0.8 (+/- 0.1) mm to 1.1 (+/- 0.1) mm. Adopting a variable kVp protocol led to a median patient mean glandular dose per film of 2.7 mGy, nearly independent of compressed breast thickness. In our survey, the mean age of women presenting for mammography is younger and the mean compressed breast thickness is less than reported from screening centres. This suggests that there will be a higher proportion of denser, glandular tissue in the breasts incorporated within this survey than for surveys from screening centres. The clinical use of the variable kVp protocol allows the extraction from patient data of separate changes in breast composition which are due to patient age and breast thickness. It is concluded that the reference breast tissue composition is not an accurate representation of the women presenting at this centre.

Image quality and dose in film-screen magnification mammography.

Extended exposure times in magnification mammography are a result of the reduced X-ray tube currents required for a small focal spot. The consequences of this are the potential for reduced image quality through motion blur during exposure as well as the onset of film reciprocity law failure. Previous investigators have suggested increasing the X-ray tube potential as a practical mechanism for reducing exposure times in magnification mammography and have demonstrated negligible image quality degradation at least up to 32 kVp. This paper describes a film-screen magnification mammography study that expands upon this previous work to investigate the magnitude of the reduction of breast mean glandular dose and exposure time and the changes in subjective image quality (visibility of low contrast details in an RMI 152 phantom) with increases in tube potential between 28 kVp and 35 kVp. Measures of changes in the radiographic contrast and in the scatter-to-primary ratio (SPR) in magnification geometry as a function of tube potential were also obtained. Evidence for reciprocity law failure was also assessed. For a constant film optical density, increasing the X-ray tube potential from 28 kVp to 35 kVp reduced the mean glandular dose from 3.9 mGy to 2.7 mGy and reduced the exposure time from 3.2 s to 1.0 s. Over this range, the detection rate of fibrils and microcalcification-mimicking specks did not vary with tube potential at the 0.05 level of significance. It was found that only the low contrast mass detail detection rate at 35 kVp was significantly less than that at 28 kVp. The measured radiographic contrast decreased with tube potential and the SPR increased with tube potential. However, both changes were weak, and linear regressions determined that the 95% confidence intervals of the slopes relating both contrast and SPR with tube potential encompassed zero. It is concluded that magnification mammography performed at 34 kVp yields significant reductions in exposure time and mean glandular dose, with a detail detection capability similar to that at 28 kVp.

A comparison of two mammography film-screen combinations designed for standard-cycle processing.

This paper presents comparisons of the Kodak Min-R 2000 mammography film-screen combination designed for standard-cycle processing with that of the older Min-RM/Min-R combination. Comparisons were performed in terms of characteristic curves and relative image quality. The Min-R 2000 combination had a speed of 1.7 relative to the Min-RM/Min-R combination to yield an optical density of 1.25; the maximum gradients of the characteristic curves for the two combinations were 4.6 and 2.7, respectively. Image quality was evaluated in a breast detail phantom study. It was demonstrated that image qualities of the film-screen combinations were comparable.

A study of patient radiation doses in interventional radiological procedures.

Patient radiation doses received during interventional radiological procedures can be significant. To aid in the establishment of reference dose levels, a patient dose survey has been conducted of such procedures. A total of 288 non-coronary procedures (177 classified as diagnostic and 111 as therapeutic) were accrued into the study. For each procedure, the fluoroscopy screening time and the fluoroscopic and digital radiographic dose-area products were recorded in a computer database. For example, median dose-area product values (due to fluoroscopy and digital radiography combined) of 24.2, 27.9, 69.6 and 74.7 Gy cm2 were obtained for nephrostomy, biliary stent removal/insertion, cerebral angiography and percutaneous transhepatic cholangiography procedures. While the effective dose is not an accurate measure of patient risk, it is convenient for comparing the radiological risks associated with various procedures. Effective doses were estimated from the total dose-area products. The respective median estimated effective dose values for the four procedures noted above were 3.9, 4.5, 7.0 and 12.0 mSv. While an infrequently performed procedure at this institution (n = 4 during this survey), the transjugular intrahepatic portosystemic shunt (TIPS) procedure had the greatest median dose-area product and effective dose values: 347 Gy cm2 and 55.5 mSv, respectively. Excluding the extreme case of TIPS, it was found that among commonly-performed procedures, those that are categorized as therapeutic do not necessarily present a statistically significant greater radiation risk than those which are diagnostic. Comparisons between dose-area product values obtained from this study are made with data from other interventional radiology patient dose surveys and reasons for some differences noted are discussed.

Optimizing optical density of a Kodak mammography film-screen combination with standard-cycle processing.

The optimization of optical density in film-screen mammography is crucial in attaining good image quality. While a target range for film optical density of 1.4-1.8 has been recommended for centres participating in the National Health Service Breast Screening Programme (NHSBSP), past investigations have shown that combinations of mammography film and screen and processor conditions can have various optimum densities, some of which are outside this recommended range. The optimum optical density of the film/screen/processor conditions combination used at our institution (the Kodak MIN-RM/MIN-R combination designed for standard-cycle processing) was evaluated using a breast detail phantom study. It was found that the optimum optical density was 1.25 OD. We recommend that an individual institution determines the optimum optical density for the film-screen combination it uses and the processing conditions specific to it.

Entrance skin dose estimates derived from dose-area product measurements in interventional radiological procedures.

Patient skin doses resulting from interventional radiological procedures have the potential to exceed threshold doses for deterministic effects such as erythema and epilation. If the irradiation geometry is known, the entrance skin dose can be estimated from the measured dose-area product. For each of 10 non-coronary interventional procedures, a nominal geometry was identified. From a previous survey of patient dose-area products, the entrance skin doses were estimated under the assumption that all procedures were performed with the nominal geometry specific to it. An analysis of the uncertainties in these doses caused by realistic deviations from the nominal geometry was also performed and it was shown that the estimated entrance skin dose values are at least to within 40%, and generally to within about 30%, of those actually received. For example, the median estimated entrance skin doses for the posteroanterior and lateral projections of cerebral angiography were 100 and 110 mGy. respectively, and for hepatic angiography 425 mGy. The largest entrance skin dose estimate for a single projection was for the angiography component of a CT arterial portography procedure at 670 mGy. Comparisons between entrance skin dose estimates obtained from this study are made with data from other interventional radiology patient dose surveys.

Radiology in the neonatal intensive care unit: dose reduction and image quality.

This paper describes a prospective study of the diagnostic radiation doses received in a neonatal intensive care unit (NICU) for a representative radiological technique used at our institution for a number of years and a "low dose" technique similar to that recommended by the Commission of the European Communities (CEC). A 400 speed film-screen combination was used in both techniques. A total of 363 anteroposterior (AP) chest and abdominal films of 77 neonates were accrued. For each radiograph, the entrance skin dose (FSD), energy imparted (EI) and mean whole body dose were determined. For a neonatal AP chest, there was an 18% reduction in the mean ESD per radiograph from 20.0 muGy for the representative technique to 16.4 muGy for the low dose technique (p < 0.0005). The reduction in the mean EI per radiograph values for the two techniques from 7.9 muJ to 7.1 muJ (10%) was statistically significant at the p < 0.017 level, after compensating for the difference in mean field dimensions between the two patient cohorts. The mean whole body dose per radiograph reduction from 4.4 to 3.5 muGy (20%) was statistically significant at the p < 0.0028 level. It was determined that the ESD and EI could be fitted by an exponential function in the equivalent patient diameter, a single parameter indicative of neonate size. Absolute excess childhood cancer mortality risk per film was estimated using risk factors derived for fetal exposures. A "worst case" absolute excess mortality risk per chest radiograph was estimated to be 1.40 x 10(-7) for the conventional technique and was further reduced to 1.11 x 10(-7) for the low dose technique. A blind comparison of patient-matched film pairs for each technique was performed by three radiologists using criteria similar to those specified by the CEC. No statistically significant difference in clinical image quality was found between the two techniques.

Diagnostic value of Doppler ultrasound in the assessment of liver cirrhosis in children: histopathological correlation.

We have correlated flow abnormalities in the hepatic vasculature with histological findings in the liver to determine the accuracy of Doppler ultrasound in the diagnosis of liver cirrhosis in children. Eighteen children admitted for evaluation of unknown liver disease were examined prospectively and blindly with Doppler ultrasound prior to liver biopsy. Biopsy specimens showed established cirrhosis in 9 of 18, early cirrhosis in 5 of 18, and no cirrhosis in 4 of 18 children. Doppler studies were also performed on 20 control subjects. The portal vein velocity was decreased (p < 0.0005) and the arterio-portal velocity ratio was increased (p < 0.0005) in the established cirrhosis cohort relative to the controls. For the criteria of the established cirrhosis cohort, the sensitivities of the loss of the reverse flow component in the hepatic veins, the arterio-portal velocity ratio being greater than 3.0, the portal vein velocity being less than 20 cm/s, and the existence of focal flow acceleration in the hepatic veins were 100%, 78%, 67%, and 44%, respectively. The specificity of all these criteria was 100%. The indicators were not useful in the diagnosis of early cirrhosis.

Digital portal image registration by sequential anatomical matchpoint and image correlations for real-time continuous field alignment verification.

Detection of radiotherapy field misalignments with electronic portal imaging devices requires the precise initial registration of the digital portal image with a reference image indicating the prescribed field alignment. Moreover, for real-time continuous detection this registration must be performed rapidly--arguably within 250 ms. The quality of this registration is sensitive to the ability of the user to accurately identify corresponding anatomical landmarks in the image pair. To improve the accuracy of the registration and, ultimately, that of the field misalignment measurement, we have developed a sequential digital portal image registration method using both user-identified anatomical matchpoints and image information. A first pass generates registration parameters from user-provided matchpoint coordinates and explicitly accounts for the uncertainty in matchpoint identification. The second pass uses both the initial registration parameters and image information to further improve the registration quality by maximizing cross correlations between segments of the image pair. As this registration method does not use massive matrix/vector computations common to other algorithms, it is inherently faster and well-suited for real-time field placement error detection. On a platform representative of those controlling many commercial electronic portal imaging devices (486 CPU), this algorithm registers portal images in times of less than 6 ms per matchpoint with errors of less than 2% in magnification, 0.5 degree in in-plane rotation, and less than 1 pixel dimension in in-plane translation. As the algorithm assumes a rigid-body geometry, it is sensitive to out-of-plane rotations. A quantitative analysis of this algorithm is presented, indicates its accuracy, and describes its sensitivity to out-of-plane rotations.

A fluoroscopy credentialling programme for orthopaedic surgeons.

We have developed a teaching programme for non-radiologists who use fluoroscopy, which includes techniques for reducing the radiation received by the patient and the surgeon during orthopaedic procedures. The techniques resolve around the radiation protection concepts of time, distance and shielding. The programme has been very successful in reducing the total fluoroscopy times of orthopaedic surgeons; in our institute, durations have been reduced to about 10% of those before the training started. We review the aims and content of our programme.