Radiation protection and dose monitoring in medical imaging: a journey from awareness, through accountability, ability and action but where will we arrive?

Radiation awareness and protection of patients have been the fundamental responsibilities in diagnostic imaging since the discovery of x-rays late in 1895 and the first reports of radiation injury in 1896. In the ensuing years, there have been significant advancements in equipment that uses either x-rays to form images, such as fluoroscopy or computed tomography (CT), or the types of radiation emitted during nuclear imaging procedures (e.g., positron emission tomography [PET]). These advancements have allowed detailed and indispensable evaluation of a vast array of disorders. In fact, in 2001, CT and MRI were cited by physicians as the most significant medical innovations in the previous 3 decades. Rapid technological advancements in the last decade with CT, especially, have required imaging professionals to keep pace with increasingly complex technology to derive the maximum benefits of improved image acquisition and display techniques, in essence, the improved quality of the examination. It has also been challenging to fulfill the fundamental responsibilities of safety during this period of rapid growth (e.g., radiation protection, management of the risk of additional interventions driven by incidental findings, performing studies that were not indicated). The purpose of this paper is to define critical issues pertinent to ensuring patient safety through the appropriate assessment, recording, monitoring, and reporting of the radiation dose from CT.

The Image Gently pediatric digital radiography safety checklist: tools for improving pediatric radiography.

Transition from film-screen to digital radiography requires changes in radiographic technique and workflow processes to ensure that the minimum radiation exposure is used while maintaining diagnostic image quality. Checklists have been demonstrated to be useful tools for decreasing errors and improving safety in several areas, including commercial aviation and surgical procedures. The Image Gently campaign, through a competitive grant from the FDA, developed a checklist for technologists to use during the performance of digital radiography in pediatric patients. The checklist outlines the critical steps in digital radiography workflow, with an emphasis on steps that affect radiation exposure and image quality. The checklist and its accompanying implementation manual and practice quality improvement project are open source and downloadable at www.imagegently.org. The authors describe the process of developing and testing the checklist and offer suggestions for using the checklist to minimize radiation exposure to children during radiography.

FDA working to ensure the safety of medical devices used in the pediatric population.

Special initiatives exist in FDA's Center for Devices and Radiological Health (CDRH), the Center for Drug Evaluation and Research, and the Center for Biologics Evaluation and Research to ensure the safety and effectiveness of medical products used in the vulnerable pediatric population. This article focuses on the special programs, projects, and special studies implemented by CDRH to ensure this safety and effectiveness in devices used in pediatric patients throughout the devices' total product life-cycles. Pediatricians play a major role in keeping medical devices safe for use in children by reporting device problems to FDA.

Image Gently: challenges for radiologic technologists when performing digital radiography in children.

The development of digital radiography (DR) has provided numerous benefits for pediatric imaging, including the ability to post-process images and to make images immediately available for access by care providers. However, DR presents several significant challenges for the radiologic technologists who are responsible for operating the equipment and producing high-quality images in children. This paper discusses those challenges, including lack of standardization among vendors, particularly with regard to the exposure indicator; lack of pediatric-specific educational materials and pediatric techniques; the need for manual technique instead of the use of automatic exposure control in smaller children; and complications related to field size, collimation and shielding in small children. Specific actions and design modifications that might facilitate the effective management of these challenges will be also described. The implementation of measures to promote the production of optimal images while minimizing radiation exposure requires cooperation and communication among imaging professionals, manufacturers and regulatory agencies.

Effects of cholesterol and unsaturated DOPC lipid on chain packing of saturated gel-phase DPPC bilayers.

Wide angle x-ray scattering (WAXS) from oriented lipid multilayers was used to study the effect of adding cholesterol (Chol) or 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) to gel-phase 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) bilayers. Small quantities (X < 0.10 mole fraction) of both molecules disrupt the tight packing of tilted chains of pure gel-phase DPPC, forming a more disordered, untilted phase. The addition of larger quantities of DOPC causes the sample to phase-separate into a gel-phase, characterized by a narrow WAXS peak, and liquid disordered phase, characterized by wide, diffuse WAXS scattering. In contrast, two WAXS peaks indicative of two coexisting phases were not observed in Chol/DPPC mixtures (X(Chol) = 0.07 to 0.40). Instead, Chol caused a gradual increase in the width of the WAXS peak, consistent with a gradual change from a more gel-like to a more liquid-like state rather than passing through a region of two phase coexistence. Our WAXS data include a huge amount of information. A new method of analysis suggests that WAXS data may provide definitive results relating to the disagreements between previously published phase diagrams for Chol/DPPC.

Cholesterol perturbs lipid bilayers nonuniversally.

Cholesterol is well known to modulate the physical properties of biomembranes. Using modern x-ray scattering methods, we have studied the effects of cholesterol on the bending modulus K(C), the thickness D(HH), and the orientational order parameter S(xray) of lipid bilayers. We find that the effects are different for at least three classes of phospholipids characterized by different numbers of saturated hydrocarbon chains. Most strikingly, cholesterol strongly increases K(C) when both chains of the phospholipid are fully saturated but not at all when there are two monounsaturated chains.

Liquid-liquid domains in bilayers detected by wide angle X-ray scattering.

Wide angle x-ray scattering (WAXS) from oriented lipid multilayers is used to examine liquid-ordered (Lo)/liquid-disordered (Ld) phase coexistence in the system 1,2-dioleoyl-sn-glycero-3-phosphocholine/1,2-dipalmitoyl-sn-glycero-3-phosphocholine/cholesterol (DOPC/DPPC/Chol), which is a model for the outer leaflet of the animal cell plasma membrane. Using the method of analysis developed in the accompanying work, we find that two orientational distributions are necessary to fit the WAXS data at lower temperatures, whereas only one distribution is needed at temperatures higher than the miscibility transition temperature, T(mix) = 25-35 degrees C (for 1:1 DOPC/DPPC with 15%, 20%, 25%, and 30% Chol). We propose that the necessity for two distributions is a criterion for coexistence of Lo domains with a high S(x-ray) order parameter and Ld domains with a lower order parameter. This criterion is capable of detecting coexistence of small domains or rafts that the conventional x-ray criterion of two lamellar D spacings may not. Our T(mix) values tend to be slightly larger than published NMR results and microscopy results when the fluorescence probe artifact is considered. This is consistent with the sensitivity of WAXS to very short time and length scales, which makes it more capable of detecting small, short-lived domains that are likely close to T(mix).

Order parameters and areas in fluid-phase oriented lipid membranes using wide angle X-ray scattering.

We used wide angle x-ray scattering (WAXS) from stacks of oriented lipid bilayers to measure chain orientational order parameters and lipid areas in model membranes consisting of mixtures of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC)/cholesterol and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)/cholesterol in fluid phases. The addition of 40% cholesterol to either DOPC or DPPC changes the WAXS pattern due to an increase in acyl chain orientational order, which is one of the main properties distinguishing the cholesterol-rich liquid-ordered (Lo) phase from the liquid-disordered (Ld) phase. In contrast, powder x-ray data from multilamellar vesicles does not yield information about orientational order, and the scattering from the Lo and Ld phases looks similar. An analytical model to describe the relationship between the chain orientational distribution and WAXS data was used to obtain an average orientational order parameter, S(x-ray). When 40% cholesterol is added to either DOPC or DPPC, S(x-ray) more than doubles, consistent with previous NMR order parameter measurements. By combining information about the average chain orientation with the chain-chain correlation spacing, we extended a commonly used method for calculating areas for gel-phase lipids to fluid-phase lipids and obtained agreement to within 5% of literature values.

CRAC motif peptide of the HIV-1 gp41 protein thins SOPC membranes and interacts with cholesterol.

This study uses low-angle (LAXS) and wide-angle (WAXS) X-ray synchrotron scattering, volume measurements and thin layer chromatography to determine the structure and interactions of SOPC, SOPC/cholesterol mixtures, SOPC/peptide and SOPC/cholesterol/peptide mixtures. N-acetyl-LWYIK-amide (LWYIK) represents the naturally-occurring CRAC motif segment in the pretransmembrane region of the gp41 protein of HIV-1, and N-acetyl-IWYIK-amide (IWYIK), an unnatural isomer, is used as a control. Both peptides thin the SOPC bilayer by approximately 3 A, and cause the area/unit cell (peptide+SOPC) to increase by approximately 9 A2 from the area/lipid of SOPC at 30 degrees C (67.0+/-0.9 A2). Model fitting suggests that LWYIK's average position is slightly closer to the bilayer center than IWYIK's, and both peptides are just inside of the phosphate headgroup. Both peptides increase the wide-angle spacing d of SOPC without cholesterol, whereas with 50% cholesterol LWYIK increases d but IWYIK decreases d. TLC shows that LWYIK is more hydrophobic than IWYIK; this difference persists in peptide/SOPC 1:9 mole ratio mixtures. Both peptides counteract the chain ordering effect of cholesterol to roughly the same degree, and both decrease KC, the bending modulus, thus increasing the SOPC membrane fluidity. Both peptides nucleate crystals of cholesterol, but the LWYIK-induced crystals are weaker and dissolve more easily.

Phase studies of model biomembranes: complex behavior of DSPC/DOPC/cholesterol.

We have undertaken a series of experiments to examine the behavior of individual components of cell membranes. Here we report an initial stage of these experiments, in which the properties of a chemically simple lipid mixture are carefully mapped onto a phase diagram. Four different experimental methods were used to establish the phase behavior of the 3-component mixture DSPC/DOPC/chol: (1) confocal fluorescence microscopy observation of giant unilamellar vesicles, GUVs; (2) FRET from perylene to C20:0-DiI; (3) fluorescence of dilute dyes C18:2-DiO and C20:0-DiI; and (4) wide angle X-ray diffraction. This particular 3-component mixture was chosen, in part, for a high level of immiscibility of the components in order to facilitate solving the phase behavior at all compositions. At 23 degrees C, a large fraction of the possible compositions for this mixture give rise to a solid phase. A region of 3-phase coexistence of {Lalpha+Lbeta+Lo} was detected and defined based on a combination of fluorescence microscopy of GUVs, FRET, and dilute C20:0-DiI fluorescence. At very low cholesterol concentrations, the solid phase is the tilted-chain phase Lbeta'. Most of the phase boundaries have been determined to be within a few percent of the composition. Measurements of the perturbations of the boundaries of this accurate phase diagram could serve as a means to understand the behaviors of a range of added lipids and proteins.

Small-angle neutron scattering to detect rafts and lipid domains.

The detection and characterization of lateral heterogeneities or domains in lipid mixtures has attracted considerable interest, because of the roles that such domains may play in biological function. Studies on both model and cell membranes demonstrate that domains can be formed over a wide range of length scales, as small as nanometers in diameter up to microns. However, although the size and shape of micron-sized domains are readily visualized in freely suspended vesicles, by techniques such as fluorescence microscopy, imaging of nanometer-sized domains has thus far been performed only on substrate-supported membranes (through, e.g., atomic force microscopy), whereas additional evidence for nanodomains has depended on indirect detection (through, e.g., nuclear magnetic resonance or fluorescence resonance energy transfer). Small-angle neutron scattering (SANS) is a technique able to characterize structural features on nanometer length scales and can be used to probe freely suspended membranes. As such, SANS shows promise to characterize nanometer-sized domains in model membranes. The authors have recently demonstrated the efficacy of SANS to detect and characterize nanodomains in freely suspended mixed lipid vesicles.

The fastest global events in RNA folding: electrostatic relaxation and tertiary collapse of the Tetrahymena ribozyme.

Large RNAs can collapse into compact conformations well before the stable formation of the tertiary contacts that define their final folds. This study identifies likely physical mechanisms driving these early compaction events in RNA folding. We have employed time-resolved small-angle X-ray scattering to monitor the fastest global shape changes of the Tetrahymena ribozyme under different ionic conditions and with RNA mutations that remove long-range tertiary contacts. A partial collapse in each of the folding time-courses occurs within tens of milliseconds with either monovalent or divalent cations. Combined with comparison to predictions from structural models, this observation suggests a relaxation of the RNA to a more compact but denatured conformational ensemble in response to enhanced electrostatic screening at higher ionic concentrations. Further, the results provide evidence against counterion-correlation-mediated attraction between RNA double helices, a recently proposed model for early collapse. A previous study revealed a second 100 ms phase of collapse to a globular state. Surprisingly, we find that progression to this second early folding intermediate requires RNA sequence motifs that eventually mediate native long-range tertiary interactions, even though these regions of the RNA were observed to be solvent-accessible in previous footprinting studies under similar conditions. These results help delineate an analogy between the early conformational changes in RNA folding and the "burst phase" changes and molten globule formation in protein folding.