Photoacoustic tomography: principles and advances.

Photoacoustic tomography (PAT) is an emerging imaging modality that shows great potential for preclinical research and clinical practice. As a hybrid technique, PAT is based on the acoustic detection of optical absorption from either endogenous chromophores, such as oxy-hemoglobin and deoxy-hemoglobin, or exogenous contrast agents, such as organic dyes and nanoparticles. Because ultrasound scatters much less than light in tissue, PAT generates high-resolution images in both the optical ballistic and diffusive regimes. Over the past decade, the photoacoustic technique has been evolving rapidly, leading to a variety of exciting discoveries and applications. This review covers the basic principles of PAT and its different implementations. Strengths of PAT are highlighted, along with the most recent imaging results.

Multiscale photoacoustic tomography using reversibly switchable bacterial phytochrome as a near-infrared photochromic probe.

Photoacoustic tomography (PAT) of genetically encoded probes allows for imaging of targeted biological processes deep in tissues with high spatial resolution; however, high background signals from blood can limit the achievable detection sensitivity. Here we describe a reversibly switchable nonfluorescent bacterial phytochrome for use in multiscale photoacoustic imaging, BphP1, with the most red-shifted absorption among genetically encoded probes. BphP1 binds a heme-derived biliverdin chromophore and is reversibly photoconvertible between red and near-infrared light-absorption states. We combined single-wavelength PAT with efficient BphP1 photoswitching, which enabled differential imaging with substantially decreased background signals, enhanced detection sensitivity, increased penetration depth and improved spatial resolution. We monitored tumor growth and metastasis with ∼ 100-μm resolution at depths approaching 10 mm using photoacoustic computed tomography, and we imaged individual cancer cells with a suboptical-diffraction resolution of ∼ 140 nm using photoacoustic microscopy. This technology is promising for biomedical studies at several scales.

Live volumetric (4D) visualization and guidance of in vivo human ophthalmic surgery with intraoperative optical coherence tomography.

Minimally-invasive microsurgery has resulted in improved outcomes for patients. However, operating through a microscope limits depth perception and fixes the visual perspective, which result in a steep learning curve to achieve microsurgical proficiency. We introduce a surgical imaging system employing four-dimensional (live volumetric imaging through time) microscope-integrated optical coherence tomography (4D MIOCT) capable of imaging at up to 10 volumes per second to visualize human microsurgery. A custom stereoscopic heads-up display provides real-time interactive volumetric feedback to the surgeon. We report that 4D MIOCT enhanced suturing accuracy and control of instrument positioning in mock surgical trials involving 17 ophthalmic surgeons. Additionally, 4D MIOCT imaging was performed in 48 human eye surgeries and was demonstrated to successfully visualize the pathology of interest in concordance with preoperative diagnosis in 93% of retinal surgeries and the surgical site of interest in 100% of anterior segment surgeries. In vivo 4D MIOCT imaging revealed sub-surface pathologic structures and instrument-induced lesions that were invisible through the operating microscope during standard surgical maneuvers. In select cases, 4D MIOCT guidance was necessary to resolve such lesions and prevent post-operative complications. Our novel surgical visualization platform achieves surgeon-interactive 4D visualization of live surgery which could expand the surgeon's capabilities.

Coding Strategies for X-ray Tomography

This work focuses on the construction and application of coded apertures to compressive X-ray tomography. Coded apertures can be made in a number of ways, each method having an impact on system background and signal contrast. Methods of constructing coded apertures for structuring X-ray illumination and scatter are compared and analyzed. Apertures can create structured X-ray bundles that investigate specific sets of object voxels. The tailored bundles of rays form a code (or pattern) and are later estimated through computational inversion. Structured illumination can be used to subsample object voxels and make inversion feasible for low dose computed tomography (CT) systems, or it can be used to reduce background in limited angle CT systems.

On the detection side, coded apertures modulate X-ray scatter signals to determine the position and radiance of scatter points. By forming object dependent projections in measurement space, coded apertures multiplex modulated scatter signals onto a detector. The multiplexed signals can be inverted with knowledge of the code pattern and system geometry. This work shows two systems capable of determining object position and type in a 2D plane, by illuminating objects with an X-ray `fan beam,' using coded apertures and compressive measurements. Scatter tomography can help identify materials in security and medicine that may be ambiguous with transmission tomography alone.

When static meets dynamic: Comparing cone-beam computed tomography and acoustic reflection for upper airway analysis

INTRODUCTION: Upper airway measurement can be important for the diagnosis of breathing disorders. Acoustic reflection (AR) is an accepted tool for studying the airway. Our objective was to investigate the differences between cone-beam computed tomography (CBCT) and AR in calculating airway volumes and areas. METHODS: Subjects with prescribed CBCT images as part of their records were also asked to have AR performed. A total of 59 subjects (mean age, 15 ± 3.8 years) had their upper airway (5 areas) measured from CBCT images, acoustic rhinometry, and acoustic pharyngometry. Volumes and minimal cross-sectional areas were extracted and compared with software. RESULTS: Intraclass correlation on 20 randomly selected subjects, remeasured 2 weeks apart, showed high reliability (r >0.77). Means of total nasal volume were significantly different between the 2 methods (P = 0.035), but anterior nasal volume and minimal cross-sectional area showed no differences (P = 0.532 and P = 0.066, respectively). Pharyngeal volume showed significant differences (P = 0.01) with high correlation (r = 0.755), whereas pharyngeal minimal cross-sectional area showed no differences (P = 0.109). The pharyngeal volume difference may not be considered clinically significant, since it is 758 mm3 for measurements showing means of 11,000 ± 4000 mm3. CONCLUSIONS: CBCT is an accurate method for measuring anterior nasal volume, nasal minimal cross-sectional area, pharyngeal volume, and pharyngeal minimal cross-sectional area.

Iterative reconstruction as a novel method of radiation dose reduction at computed tomography in patients with Crohn's disease

Prior work of our research group, that quantified the alarming levels of radiation dose to patients with Crohn’s disease from medical imaging and the notable shift towards CT imaging making these patients an at risk group, provided context for this work. CT delivers some of the highest doses of ionising radiation in diagnostic radiology. Once a medical imaging examination is deemed justified, there is an onus on the imaging team to endeavour to produce diagnostic quality CT images at the lowest possible radiation dose to that patient. The fundamental limitation with conventional CT raw data reconstruction was the inherent coupling of administered radiation dose with observed image noise – the lower the radiation dose, the noisier the image. The renaissance, rediscovery and refinement of iterative reconstruction removes this limitation allowing either an improvement in image quality without increasing radiation dose or maintenance of image quality at a lower radiation dose compared with traditional image reconstruction. This thesis is fundamentally an exercise in optimisation in clinical CT practice with the objectives of assessment of iterative reconstruction as a method for improvement of image quality in CT, exploration of the associated potential for radiation dose reduction, and development of a new split dose CT protocol with the aim of achieving and validating diagnostic quality submillisiever t CT imaging in patients with Crohn’s disease. In this study, we investigated the interplay of user-selected parameters on radiation dose and image quality in phantoms and cadavers, comparing traditional filtered back projection (FBP) with iterative reconstruction algorithms. This resulted in the development of an optimised, refined and appropriate split dose protocol for CT of the abdomen and pelvis in clinical patients with Crohn’s disease allowing contemporaneous acquisition of both modified and conventional dose CT studies. This novel algorithm was then applied to 50 patients with a suspected acute complication of known Crohn’s disease and the raw data reconstructed with FBP, adaptive statistical iterative reconstruction (ASiR) and model based iterative reconstruction (MBIR). Conventional dose CT images with FBP reconstruction were used as the reference standard with which the modified dose CT images were compared in terms of radiation dose, diagnostic findings and image quality indices. As there are multiple possible user-selected strengths of ASiR available, these were compared in terms of image quality to determine the optimal strength for this modified dose CT protocol. Modified dose CT images with MBIR were also compared with contemporaneous abdominal radiograph, where performed, in terms of diagnostic yield and radiation dose. Finally, attenuation measurements in organs, tissues, etc. with each reconstruction algorithm were compared to assess for preservation of tissue characterisation capabilities. In the phantom and cadaveric models, both forms of iterative reconstruction examined (ASiR and MBIR) were superior to FBP across a wide variety of imaging protocols, with MBIR superior to ASiR in all areas other than reconstruction speed. We established that ASiR appears to work to a target percentage noise reduction whilst MBIR works to a target residual level of absolute noise in the image. Modified dose CT images reconstructed with both ASiR and MBIR were non-inferior to conventional dose CT with FBP in terms of diagnostic findings, despite reduced subjective and objective indices of image quality. Mean dose reductions of 72.9-73.5% were achieved with the modified dose protocol with a mean effective dose of 1.26mSv. MBIR was again demonstrated superior to ASiR in terms of image quality. The overall optimal ASiR strength for the modified dose protocol used in this work is ASiR 80%, as this provides the most favourable balance of peak subjective image quality indices with less objective image noise than the corresponding conventional dose CT images reconstructed with FBP. Despite guidelines to the contrary, abdominal radiographs are still often used in the initial imaging of patients with a suspected complication of Crohn’s disease. We confirmed the superiority of modified dose CT with MBIR over abdominal radiographs at comparable doses in detection of Crohn’s disease and non-Crohn’s disease related findings. Finally, we demonstrated (in phantoms, cadavers and in vivo) that attenuation values do not change significantly across reconstruction algorithms meaning preserved tissue characterisation capabilities with iterative reconstruction. Both adaptive statistical and model based iterative reconstruction algorithms represent feasible methods of facilitating acquisition diagnostic quality CT images of the abdomen and pelvis in patients with Crohn’s disease at markedly reduced radiation doses. Our modified dose CT protocol allows dose savings of up to 73.5% compared with conventional dose CT, meaning submillisievert imaging is possible in many of these patients.

Design and Synthesis of 4-N-Alkanoyl and 4-N-Alkyl Gemcitabine Analogues Suitable for Positron Emission Tomography

Gemcitabine is a highly potent chemotherapeutic nucleoside agent used in the treatment of several cancers and solid tumors. However, it is therapeutically limitated because of toxicity to normal cells and its rapid intracellular deamination by cytidine deaminase into the inactive uracil derivative. Modification at the 4-(N) position of gemcitabine's exocyclic amine to an -amide functionality is a well reported prodrug strategy which has been that confers a resistance to intracellular deamination while also altering pharmacokinetics of the parent drug. Coupling of gemcitabine to carboxylic acids with varying terminal moieties afforded the 4-N-alkanoylgemcitabines whereas reaction of 4-N-tosylgemcitabine with the corresponding alkyl amines gave the 4-N-alkylgemcitabines. The 4-N-alkanoyl and 4-N-alkyl gemcitabine analogues with a terminal hydroxyl group on the 4-N-alkanoyl or 4-N-alkyl chain were efficiently fluorinated either with diethylaminosulfur trifluoride or under conditions that are compatible with the synthetic protocols for 18F labeling, such as displacement of the corresponding mesylate with KF/Kryptofix 2.2.2. The 4-N-alkanoylgemcitabine analogues displayed potent cytostatic activities against murine and human tumor cell lines with 50% inhibitory concentration (IC50) values in the range of low nM, whereas cytotoxicity of the 4-N-alkylgemcitabine derivatives were in the low to modest µM range. The cytostatic activity of the 4-N-alkanoylgemcitabines was reduced by several orders of magnitude in the 2'-deoxycytidine kinase (dCK)-deficient CEM/dCK- cell line while the 4-N-alkylgemcitabines were only lowered by 2-5 times. None of the 4-N-modified gemcitabines were found to be substrates for cytosolic dCK, however all were found to inhibit DNA synthesis. As such, the 4-N-alkanoyl gemcitabine derivatives likely need to be converted to gemcitabine prior to achieving their significant cytostatic potential, whereas the 4-N-alkylgemcitabines reach their modest activity without "measurable" conversion to gemcitabine. Thus, the 4-N-alkylgemcitabines provide valuable insight on the metabolism of 4-N-modified gemcitabine prodrugs.

Radionuclide measurements in sediments and water of the Kara Sea

In this report, the results of a 2000-2001 radiogeoecological investigation are presented for the region of the Ob and Yenisei estuaries and the adjacent Kara Sea. In order to study the behaviour and migration of Cs, Sr and Pu radionuclides in a river - sea system experimental research on the distribution of these radionuclides in the water column and surface sediments has been carried out. In addition, the role of suspended and dissolved organic matter on the behaviour of radionuclides in water solutions has been studied. The 137Cs and 239,240Pu concentrations in the upper 0-2cm layer of the sediments varied between 1,4 and 50,0 Bq/kg, with a mean of 12,4 Bq/kg, and between 0,065-1,96 Bq/kg, with a mean of 0,62 Bq/kg, respectively. There is a direct relationship of a specific radioactivity of 137Cs and 239,240Pu in the sediments and the content of clay fraction. The 137Cs, 90Sr and 239,240Pu concentrations in the water samples varied between 0,4 and 7,0 Bq/m**3 (mean of 3,6 Bq/m**3), 0,4 and 9,7 Bq/m**3 (mean of 3,3 Bq/m**3), and 0,01-0,3 Bq/m**3 (mean of 0,02 Bq/m**3), respectively. In the water samples the concentration of the water-soluble species l37Cs increases with increasing salinity, whereas the concentration of the 90Sr-radionuclide decreases with increasing salinity. This may be related to the physico-chemical behaviour of these radionuclides in water solutions and the influence of several sources on radioactive pollution in this basin. In sea water the suspended matter may absorb up to 10% 137Cs, 90Sr and 239,240Pu, in river water samples these values may reach 15-30%. More than 50% 90Sr and 239,240Pu is able to form complexes with dissolved organic matter. This effect is smaller in saline water. The comparison of the data of 137Cs radioactivity in the surface sediments in 1995 and 2000-2001 showed that the level of radioactivity has decreased.

Ground penetrating radar (GPR) and electrical resistivity tomography (ERT) survey on the neotectonic activity of the Padul-Nigüelas Fault Zone (PNFZ), Southern Spain

The Padul-Nigüelas Fault Zone (PNFZ) is situated at the south-western mountain front of the Sierra Nevada (Spain) in an extensive regime and belongs to the internal zone of the Betic Cordilleras. The aim of this study is a collection of new evidence for neotectonic activity of the fault zone with classical geological field work and modern geophysical methods, such as ground penetrating radar (GPR). Among an apparently existing bed rock fault scarp with triangular facets, other evidences, such as deeply incised valleys and faults in the colluvial wedges, are present in the PNFZ. The preliminary results of our recent field work have shown that the synsedimentary faults within the colluvial sediments seem to propagate basinwards and the bed rock fault is only exhumed due to erosion for the studied segment (west of Marchena). We will use further GPR data and geomorphologic indices to gather further evidences of neotectonic activity of the PNFZ.

Application of computer-aided tomography techniques to visualize kelp holdfast structure reveals the importance of habitat complexity for supporting marine biodiversity

Ecosystem engineers that increase habitat complexity are keystone species in marine systems, increasing shelter and niche availability, and therefore biodiversity. For example, kelp holdfasts form intricate structures and host the largest number of organisms in kelp ecosystems. However, methods that quantify 3D habitat complexity have only seldom been used in marine habitats, and never in kelp holdfast communities. This study investigated the role of kelp holdfasts (Laminaria hyperborea) in supporting benthic faunal biodiversity. Computer-aided tomography (CT-) scanning was used to quantify the three-dimensional geometrical complexity of holdfasts, including volume, surface area and surface fractal dimension (FD). Additionally, the number of haptera, number of haptera per unit of volume, and age of kelps were estimated. These measurements were compared to faunal biodiversity and community structure, using partial least-squares regression and multivariate ordination. Holdfast volume explained most of the variance observed in biodiversity indices, however all other complexity measures also strongly contributed to the variance observed. Multivariate ordinations further revealed that surface area and haptera per unit of volume accounted for the patterns observed in faunal community structure. Using 3D image analysis, this study makes a strong contribution to elucidate quantitative mechanisms underlying the observed relationship between biodiversity and habitat complexity. Furthermore, the potential of CT-scanning as an ecological tool is demonstrated, and a methodology for its use in future similar studies is established. Such spatially resolved imager analysis could help identify structurally complex areas as biodiversity hotspots, and may support the prioritization of areas for conservation.

Application of computer-aided tomography techniques to visualize kelp holdfast structure reveals the importance of habitat complexity for supporting marine biodiversity

Ecosystem engineers that increase habitat complexity are keystone species in marine systems, increasing shelter and niche availability, and therefore biodiversity. For example, kelp holdfasts form intricate structures and host the largest number of organisms in kelp ecosystems. However, methods that quantify 3D habitat complexity have only seldom been used in marine habitats, and never in kelp holdfast communities. This study investigated the role of kelp holdfasts (Laminaria hyperborea) in supporting benthic faunal biodiversity. Computer-aided tomography (CT-) scanning was used to quantify the three-dimensional geometrical complexity of holdfasts, including volume, surface area and surface fractal dimension (FD). Additionally, the number of haptera, number of haptera per unit of volume, and age of kelps were estimated. These measurements were compared to faunal biodiversity and community structure, using partial least-squares regression and multivariate ordination. Holdfast volume explained most of the variance observed in biodiversity indices, however all other complexity measures also strongly contributed to the variance observed. Multivariate ordinations further revealed that surface area and haptera per unit of volume accounted for the patterns observed in faunal community structure. Using 3D image analysis, this study makes a strong contribution to elucidate quantitative mechanisms underlying the observed relationship between biodiversity and habitat complexity. Furthermore, the potential of CT-scanning as an ecological tool is demonstrated, and a methodology for its use in future similar studies is established. Such spatially resolved imager analysis could help identify structurally complex areas as biodiversity hotspots, and may support the prioritization of areas for conservation.

Roche tomography of cataclysmic variables - VII. The long-term magnetic activity of AE Aqr

We present a long-term study of the secondary star in the cataclysmic variable AE Aqr, using Roche tomography to indirectly image starspots on the stellar surface spanning 8 years of observations. The seven maps show an abundance of spot features at both high and low latitudes. We find that all maps have at least one large high-latitude spot region, and we discuss its complex evolution between maps, as well as its compatibility with current dynamo theories. Furthermore, we see the apparent growth in fractional spot coverage, fs, around 45° latitude over the duration of observations, with a persistently high fs near latitudes of 20°. These bands of spots may form as part of a magnetic activity cycle, with magnetic flux tubes emerging at different latitudes, similar to the `butterfly' diagram for the Sun. We discuss the nature of flux tube emergence in close binaries, as well as the activity of AE Aqr in the context of other stars.