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Introduction The combined modalities of optical measurement with ultrasound to

Introduction
The combined modalities of optical measurement with ultrasound to assist in revealing spatial information of optical characteristics in light-scattering media are promising methods for biomedical imaging. In particular, various photoacoustic imaging techniques are developed and applied for practical in vivo imaging [1]. These techniques achieve tomographic imaging beyond the optical diffusion limit in biological tissue by detecting ultrasonic pressure waves that are converted thermoelastically from pulsed photons bearing local nmda receptor antagonist properties in light-scattering media. By contrast, a variety of multimodal methods by which focused ultrasound serves to assist determination of spatial information of optical properties (absorption, fluorescence, or luminescence) in light-scattering media are proposed and studied [2–8]. Most of them are based on ultrasound-modulated optical phenomena, however these techniques have a challenging issue of low modulation depth. Recently, we proposed a novel tomographic imaging technique based on the sonochemical effect of ultrasonic enhancement of chemiluminescence (CL), with demonstration of imaging capabilities using a peroxyoxalate chemiluminescence (POCL) system [9]. The POCL reaction is a well-known highly efficient CL system containing fluorophore (in our case, indocyanine green; ICG) as finally excited molecules. The fluorophore molecules are excited through energy transfer from a high-energy intermediate (HEI) generated in oxidation of oxalate with hydrogen peroxide. Thereby, this system is generally used for the quantitative detection of a small amount of fluorophore or H2O2 in analytic chemistry. Results showed that POCL system is sensitive to low-power ultrasonic waves that can be applicable for in vivo bio-imaging. By combination with focused ultrasound, which has power of less than 0.14W/cm2, the spatial distribution of CL substances in optically turbid media can be resolved, leading to functional or structural CL probe imaging. The effect of ultrasonic CL enhancement is considered to originate in ultrasonic promotion of chemical reactions, known to be used in the process of sonochemistry, which is derived in the emergence of microscopic high-pressure and high-temperature regions through cavitation to accelerate oxidation, generally accompanied by free radical generation. These facts imply that this phenomenon is not specific to POCL systems, but is instead extensible nmda receptor antagonist for other CL systems leading to the development of ultrasound-sensitive CL probes. In a previous paper [9], the CL enhancement ratio of POCL, defined as the ratio of increased CL intensity to the base intensity, is constant even in varying conditions of the base CL intensity, suggesting that it is useful for the quantitative determination of fluorophore or H2O2.
This paper demonstrates the capability of the CL enhancement technique to apply it for in vivo imaging in biological materials. We report the imaging performance using an agar base phantom and a practical tissue slab of porcine muscle in which CL targets are embedded at depths of 25–30mm from the detecting surface. We also discuss the mechanism of the CL enhancement through characterization of the enhancement effect under various concentrations of the oxidizer and fluorophore.

Materials and methods
Experimental arrangement is described in a previous paper [9]. Configuration between the direction of optical detection (X axis) and that of the ultrasound beam (Y axis) was perpendicular, as shown in the schematic diagram displayed in Fig. 1. An ultrasonic transducer (V302-SU; Olympus Corp., Japan), which has a 25-mm-diameter element with 46.5mm focal length, equipped on the side wall of a water tank was placed on an X–Y translational stage for mechanical scanning of the ultrasound focus, probing the inside of phantoms set in a sample holder. The sample holder was fixed from the outside of the water tank. All of this equipment was installed in a dark box. A photomultiplier tube (PMT, R669; Hamamatsu Photonics K.K, Japan), which has a 46-mm-diameter photocathode, was attached on the side wall of the dark box to detect light through the transparent water tank. Distance between the center of the sample holder and the PMT photocathode was constant (200mm) even during X–Y scanning. We used 1MHz continuous-wave (CW) driven focused-ultrasound that has focal area measuring 2.9mm on the transverse axis (X) (beam diameter) and 35mm on the longitudinal (Y) axis (focal zone), which determines the spatial resolution of the acquired image. The transducer was driven with sinusoidal wave of 180V amplitude through a power amplifier, which was the maximum limit for CW driving of the transducer. Sound pressure at the focus, which was measured using a calibrated hydrophone (NH8144 needle-type hydrophone; Toray Engineering Co. Ltd., Japan), was 61kPa, being equivalent to 0.14W/cm2 ultrasound power. In this condition, the temperature rise at the focus measured with a thermocouple was 0.7°C/hr. Samples that we have used to demonstrate imaging performance were an agar base phantom molded with an agarose gel mixed with Intralipid solution and a practical tissue made of a slab of porcine muscle prepared from pork meat. The agar base phantom was made with mixing Intralipid solution, which is fat emulsion widely used as a standard optical scattering medium. 20mL/L concentration of Intralipid (Intralipid-10%; Fresenius Kabi AG, Germany) in water and glycerol (final concentration 20%) was mixed to adjust the optical scattering coefficient (estimated reduced scattering coefficient was ca. 1.5mm−1), and molded with agarose (2wt% Yamato agar; Ina Food Industry Co. Ltd.) with dimensions of 60mm (X)×60mm (Y)×75mm (Z). The tissue sample of porcine muscle was prepared with cuts of lean pork purchased from a supermarket to fit in the sample holder having dimensions of 50mm (X)×50mm (Y)×75mm (Z). A CL target of POCL solution filled in a small capsule was embedded in the phantom or tissue sample to simulate a localized CL probe in a deep site of light-scattering media. The embedded position of the target was the center on the X–Y plane with 45mm depth on the Z-axis. For an experiment to evaluate the spatial resolution, the second target was additionally embedded in the agar phantom, 15mm distant from the center target on the X-axis.

Ward a attempted to account

Ward (2006a) attempted to account for the consequences of parasitism on calf performance by developing an animal growth model and by considering the effects of parasitism on host feed intake and metabolism. Parasite dynamics were expressed by the same equations that formed the basis of the above model (Smith et al., 1987). This implies that parasite establishment and fecundity were considered a function of time, as opposed to being a function of the development of the immune response (Smith and Grenfell, 1994); the only description of calf state used in the model was its bodyweight. A consequence of these assumptions would be an under- or over-estimation of calf performance during parasitism, as was indeed the case in the validation of the model by Ward (2006b). This could arise, for example, by over or under nmda receptor antagonist of the immune function to parasites as a consequence of nutrition (Ploeger et al., 1995; Coop and Kyriazakis, 1999).
The previously developed models identify the challenges associated with the development of a model that predicts the interactions between O. ostertagi and calves. In our model the animal state was characterised by calf degree of maturity (current protein mass divided by mature protein mass) and level of fatness, consistent with other animal growth models (Emmans and Kyriazakis, 2001), and by the cumulative exposure to parasitic challenge (larvaldays). The former feature enables simulation of different genotypes. A further attraction of describing the calf through these traits is that it is possible to introduce variation and co-variation in them and as a consequence to convert a deterministic model into a stochastic one (Vagenas et al., 2007c; Laurenson et al., 2012b). The consideration of larvaldays enabled to relate the immune response of the animal to be linked to the duration of parasite exposure, which is hypothesised to have greater effect on immune acquisition than the level of infection per se (Hilderson et al., 1993). Hence this model was able to portray differences in rate of immune development at different levels of infection.
Protein loss, which is the main consequence of gastrointestinal parasite challenge (Taylor et al., 1989), was related to current worm mass and larval burden, as opposed to worm burden and larval intake (Ward, 2006a). It was not possible to treat the impact of larvae mass similarly to worm mass, due to the difficulties in estimating the impact of immunity on larval mortality. On entering the host the model immediately discarded any larvae that failed to establish hence potentially resulting in an underestimation of the larval burden. Although there is currently little quantitative information about parasite-induced protein loss in calves, some assumptions were made, consistent with the quantitative estimates of protein loss during abomasal parasitism in sheep (Laurenson et al., 2011) and our current estimates of the effects of O. ostertagi on calf productivity (Szyszka and Kyriazakis, 2013). Better estimates of these relationships will enhance model accuracy.
The basis of the causal reduction in feed intake during parasitism has been the subject of considerable debate (Fox et al., 1989b; Kyriazakis et al., 1998; Laurenson et al., 2011). Feed intake reduction during parasitism was related to the rate of change in each of the immune parameters: this was in order to relate parasite-induced anorexia to the development of the immune response, as has been suggested by Sandberg et al. (2006) and Kyriazakis (2011, 2014). The rapid recovery in feed intake post administration of anthelmintics in cattle (Bell et al., 1990) and other ruminants (Kyriazakis et al., 1996), suggests that anorexia is not a consequence of pathology, but is inextribaly linked to the stimulation of the immune response caused by the exposure to the parasites. Feed intake recovers when the immune reponse is fully developed (Kyriazakis et al., 1996; Sandberg et al., 2006); however it was assumed that there would be no compensatory increase in feed intake and perfomance (Kyriazakis and Houdijk, 2007). The existence of such compensatory response would affect the predictions of the model in terms of calf performance, but not its parasitological outputs.