Measurement of gut permeability using fluorescent tracer agent technology

Abstract The healthy gut restricts macromolecular and bacterial movement across tight junctions, while increased intestinal permeability accompanies many intestinal disorders. Dual sugar absorption tests, which measure intestinal permeability in humans, present challenges. Therefore, we asked if enterally administered fluorescent tracers could ascertain mucosal integrity, because transcutaneous measurement of differentially absorbed molecules could enable specimen-free evaluation of permeability. We induced small bowel injury in rats using high- (15 mg/kg), intermediate- (10 mg/kg), and low- (5 mg/kg) dose indomethacin. Then, we compared urinary ratios of enterally administered fluorescent tracers MB-402 and MB-301 to urinary ratios of sugar tracers lactulose and rhamnose. We also tested the ability of transcutaneous sensors to measure the ratios of absorbed fluorophores. Urinary fluorophore and sugar ratios reflect gut injury in an indomethacin dose dependent manner. The fluorophores generated smooth curvilinear ratio trajectories with wide dynamic ranges. The more chaotic sugar ratios had narrower dynamic ranges. Fluorophore ratios measured through the skin distinguished indomethacin-challenged from same day control rats. Enterally administered fluorophores can identify intestinal injury in a rat model. Fluorophore ratios are measureable through the skin, obviating drawbacks of dual sugar absorption tests. Pending validation, this technology should be considered for human use

Cone-beam CT reconstruction with gravity-induced motion.

Fixed-gantry cone-beam computed tomography (CBCT), where the imaging hardware is fixed while the subject is continuously rotated 360° in the horizontal position, has implications for building compact and affordable fixed-gantry linear accelerators (linacs). Fixed-gantry imaging with a rotating subject presents a challenging image reconstruction problem where the gravity-induced motion is coupled to the subject's rotation angle. This study is the first to investigate the feasibility of fixed-gantry CBCT using imaging data of three live rabbits in an ethics-approved study. A novel data-driven motion correction method that combines partial-view reconstruction and motion compensation was developed to overcome this challenge. Fixed-gantry CBCT scans of three live rabbits were acquired on a standard radiotherapy system with the imaging beam fixed and the rabbits continuously rotated using an in-house programmable rotation cradle. The reconstructed images of the thoracic region were validated against conventional CBCT scans acquired at different cradle rotation angles. Results showed that gravity-induced motion caused severe motion blur in all of the cases if unaccounted for. The proposed motion correction method yielded clinically usable image quality with  <1 mm gravity-induced motion blur for rabbits that were securely immobilized on the rotation cradle. Shapes of the anatomic structures were correctly reconstructed with  <0.5 mm accuracy. Translational motion accounted for the majority of gravity-induced motion. The motion-corrected reconstruction represented the time-averaged location of the thoracic region over a 360° rotation. The feasibility of fixed-gantry CBCT has been demonstrated. Future work involves the validation of imaging accuracy for human subjects, which will be useful for emerging compact fixed-gantry radiotherapy systems

Coherent Pair Production by Photons in the 20-170 GeV Energy Range Incident on Crystals and Birefringence

The cross section for coherent pair production by linearly polarised photons in the 20-170 GeV energy range was measured for photon aligned incidence on ultra-high quality diamond and germanium crystals. The theoretical description of coherent bremsstrahlung and coherent pair production phenomena is an area of active theoretical debate and development. However, under our experimental conditions, the theory predicted the combined cross section and polarisation experimental observables very well indeed. In macroscopic terms, our experiment measured a birefringence effect in pair production in a crystal. This study of this effect also constituted a measurement of the energy dependent linear polarisation of photons produced by coherent bremsstrahlung in aligned crystals. New technologies for manipulating high energy photon beams can be realised based on an improved understanding of QED phenomena at these energies. In particular, this experiment demonstrates an efficient new polarimetry technique. The pair production measurements were done using two independent methods simultaneously. The more complex method using a magnet spectrometer showed that the simpler method using a multiplicity detector was also viable.Comment: 10 pages, 13 figures, 1 table, REVTeX4 two column, Version for publicatio

Linear to Circular Polarisation Conversion using Birefringent Properties of Aligned Crystals for Multi-GeV Photons

We present the first experimental results on the use of a thick aligned Si crystal acting as a quarter wave plate to induce a degree of circular polarisation in a high energy linearly polarised photon beam. The linearly polarised photon beam is produced from coherent bremsstrahlung radiation by 178 GeV unpolarised electrons incident on an aligned Si crystal, acting as a radiator. The linear polarisation of the photon beam is characterised by measuring the asymmetry in electron-positron pair production in a Ge crystal, for different crystal orientations. The Ge crystal therefore acts as an analyser. The birefringence phenomenon, which converts the linear polarisation to circular polarisation, is observed by letting the linearly polarised photons beam pass through a thick Si quarter wave plate crystal, and then measuring the asymmetry in electron-positron pair production again for a selection of relative angles between the crystallographic planes of the radiator, analyser and quarter wave plate. The systematics of the difference between the measured asymmetries with and without the quarter wave plate are predicted by theory to reveal an evolution in the Stokes parameters from which the appearance of a circularly polarised component in the photon beam can be demonstrated. The measured magnitude of the circularly polarised component was consistent with the theoretical predictions, and therefore is in indication of the existence of the birefringence effect.Comment: 12 pages, 12 figures, 1 table, REVTeX4 two column, Version for publicatio

Results on the Coherent Interaction of High Energy Electrons and Photons in Oriented Single Crystals

The CERN-NA-59 experiment examined a wide range of electromagnetic processes for multi-GeV electrons and photons interacting with oriented single crystals. The various types of crystals and their orientations were used for producing photon beams and for converting and measuring their polarisation. The radiation emitted by 178 GeV unpolarised electrons incident on a 1.5 cm thick Si crystal oriented in the Coherent Bremsstrahlung (CB) and the String-of-Strings (SOS) modes was used to obtain multi-GeV linearly polarised photon beams. A new crystal polarimetry technique was established for measuring the linear polarisation of the photon beam. The polarimeter is based on the dependence of the Coherent Pair Production (CPP) cross section in oriented single crystals on the direction of the photon polarisation with respect to the crystal plane. Both a 1 mm thick single crystal of Germanium and a 4 mm thick multi-tile set of synthetic Diamond crystals were used as analyzers of the linear polarisation. A birefringence phenomenon, the conversion of the linear polarisation of the photon beam into circular polarisation, was observed. This was achieved by letting the linearly polarised photon beam pass through a 10 cm thick Silicon single crystal that acted as a "quarter wave plate" (QWP) as suggested by N. Cabibbo et al.Comment: Presented at International workshop "Relativistic Channeling and Related Coherent Phenomena", Frascati (Rome) 23-26 March 200

Coherent bremsstrahlung, boherent pair production, birefringence and polarimetry in the 20-170 GeV energy range using aligned crystals

The processes of coherent bremsstrahlung (CB) and coherent pair production (CPP) based on aligned crystal targets have been studied in the energy range 20-170 GeV. The experimental arrangement allowed for measurements of single photon properties of these phenomena including their polarization dependences. This is significant as the theoretical description of CB and CPP is an area of active theoretical debate and development. With the theoretical approach used in this paper both the measured cross sections and polarization observables are predicted very well. This indicates a proper understanding of CB and CPP up to energies of 170 GeV. Birefringence in CPP on aligned crystals is applied to determine the polarization parameters in our measurements. New technologies for high energy photon beam optics including phase plates and polarimeters for linear and circular polarization are demonstrated in this experiment. Coherent bremsstrahlung for the strings-on-strings (SOS) orientation yields a larger enhancement for hard photons than CB for the channeling orientations of the crystal. Our measurements and our calculations indicate low photon polarizations for the high energy SOS photons.Comment: 23 pages, 27 figures, 2 tables, REVTeX4 two column

Transdermal fluorescence detection of a dual fluorophore system for noninvasive point-of-care gastrointestinal permeability measurement

The intestinal mucosal barrier prevents macromolecules and pathogens from entering the circulatory stream. Tight junctions in this barrier are compromised in inflammatory bowel diseases, environmental enteropathy, and enteric dysfunction. Dual sugar absorption tests are a standard method for measuring gastrointestinal integrity, however, these are not clinically amenable. Herein, we report on a dual fluorophore system and fluorescence detection instrumentation for which gastrointestinal permeability is determined in a rat small bowel disease model from the longitudinal measured transdermal fluorescence of each fluorophore. This fluorophore technology enables a specimen-free, noninvasive, point-of-care gastrointestinal permeability measurement which should be translatable to human clinical studies

Pressure-induced valence anomaly in TmTe probed by resonant inelastic x-ray scattering

The pressure-induced valence transition in TmTe was investigated by resonant inelastic x-ray scattering at the Tm L(3) edge, a powerful probe of the rare-earth valent state. The data are analyzed within the Anderson impurity model which yields key parameters such as the Tm 4f-5d hybridization. In addition to the general tendency of the f electrons towards delocalization, we find a plateau in both the Tm valence and hybridization pressure dependences between 4.3 and 6.5 GPa which is interpreted in terms of an n-channel Kondo (NCK) screening process. This behavior is at odds with the usually continuous, single-channel Kondo-like f delocalization while being supported by the seminal calculations of the NCK temperature in Tm ion by Saso et al. Our study raises the interesting possibility that an NCK effect realized in a compressed mixed-valent f system could impede the concomitant electron delocalization

Black Holes as Effective Geometries

Gravitational entropy arises in string theory via coarse graining over an underlying space of microstates. In this review we would like to address the question of how the classical black hole geometry itself arises as an effective or approximate description of a pure state, in a closed string theory, which semiclassical observers are unable to distinguish from the "naive" geometry. In cases with enough supersymmetry it has been possible to explicitly construct these microstates in spacetime, and understand how coarse-graining of non-singular, horizon-free objects can lead to an effective description as an extremal black hole. We discuss how these results arise for examples in Type II string theory on AdS_5 x S^5 and on AdS_3 x S^3 x T^4 that preserve 16 and 8 supercharges respectively. For such a picture of black holes as effective geometries to extend to cases with finite horizon area the scale of quantum effects in gravity would have to extend well beyond the vicinity of the singularities in the effective theory. By studying examples in M-theory on AdS_3 x S^2 x CY that preserve 4 supersymmetries we show how this can happen.Comment: Review based on lectures of JdB at CERN RTN Winter School and of VB at PIMS Summer School. 68 pages. Added reference

Cardiac Potassium Channels: Physiological Insights for Targeted Therapy.

The development of novel drugs specifically directed at the ion channels underlying particular features of cardiac action potential (AP) initiation, recovery, and refractoriness would contribute to an optimized approach to antiarrhythmic therapy that minimizes potential cardiac and extracardiac toxicity. Of these, K(+) channels contribute numerous and diverse currents with specific actions on different phases in the time course of AP repolarization. These features and their site-specific distribution make particular K(+) channel types attractive therapeutic targets for the development of pharmacological agents attempting antiarrhythmic therapy in conditions such as atrial fibrillation. However, progress in the development of such temporally and spatially selective antiarrhythmic drugs against particular ion channels has been relatively limited, particularly in view of our incomplete understanding of the complex physiological roles and interactions of the various ionic currents. This review summarizes the physiological properties of the main cardiac potassium channels and the way in which they modulate cardiac electrical activity and then critiques a number of available potential antiarrhythmic drugs directed at them