Exogenous surfactant application in a rat lung ischemia reperfusion injury model: effects on edema formation and alveolar type II cells

BACKGROUND: Prophylactic exogenous surfactant therapy is a promising way to attenuate the ischemia and reperfusion (I/R) injury associated with lung transplantation and thereby to decrease the clinical occurrence of acute lung injury and acute respiratory distress syndrome. However, there is little information on the mode by which exogenous surfactant attenuates I/R injury of the lung. We hypothesized that exogenous surfactant may act by limiting pulmonary edema formation and by enhancing alveolar type II cell and lamellar body preservation. Therefore, we investigated the effect of exogenous surfactant therapy on the formation of pulmonary edema in different lung compartments and on the ultrastructure of the surfactant producing alveolar epithelial type II cells. METHODS: Rats were randomly assigned to a control, Celsior (CE) or Celsior + surfactant (CE+S) group (n = 5 each). In both Celsior groups, the lungs were flush-perfused with Celsior and subsequently exposed to 4 h of extracorporeal ischemia at 4 degrees C and 50 min of reperfusion at 37 degrees C. The CE+S group received an intratracheal bolus of a modified natural bovine surfactant at a dosage of 50 mg/kg body weight before flush perfusion. After reperfusion (Celsior groups) or immediately after sacrifice (Control), the lungs were fixed by vascular perfusion and processed for light and electron microscopy. Stereology was used to quantify edematous changes as well as alterations of the alveolar epithelial type II cells. RESULTS: Surfactant treatment decreased the intraalveolar edema formation (mean (coefficient of variation): CE: 160 mm3 (0.61) vs. CE+S: 4 mm3 (0.75); p < 0.05) and the development of atelectases (CE: 342 mm3 (0.90) vs. CE+S: 0 mm3; p < 0.05) but led to a higher degree of peribronchovascular edema (CE: 89 mm3 (0.39) vs. CE+S: 268 mm3 (0.43); p < 0.05). Alveolar type II cells were similarly swollen in CE (423 microm3(0.10)) and CE+S (481 microm3(0.10)) compared with controls (323 microm3(0.07); p < 0.05 vs. CE and CE+S). The number of lamellar bodies was increased and the mean lamellar body volume was decreased in both CE groups compared with the control group (p < 0.05). CONCLUSION: Intratracheal surfactant application before I/R significantly reduces the intraalveolar edema formation and development of atelectases but leads to an increased development of peribronchovascular edema. Morphological changes of alveolar type II cells due to I/R are not affected by surfactant treatment. The beneficial effects of exogenous surfactant therapy are related to the intraalveolar activity of the exogenous surfactant.

Discrete element methods for asphalt concrete : development and application of user-defined microstructural models and a viscoelastic micromechanical model

As an important Civil Engineering material, asphalt concrete (AC) is commonly used to build road surfaces, airports, and parking lots. With traditional laboratory tests and theoretical equations, it is a challenge to fully understand such a random composite material. Based on the discrete element method (DEM), this research seeks to develop and implement computer models as research approaches for improving understandings of AC microstructure-based mechanics. In this research, three categories of approaches were developed or employed to simulate microstructures of AC materials, namely the randomly-generated models, the idealized models, and image-based models. The image-based models were recommended for accurately predicting AC performance, while the other models were recommended as research tools to obtain deep insight into the AC microstructure-based mechanics. A viscoelastic micromechanical model was developed to capture viscoelastic interactions within the AC microstructure. Four types of constitutive models were built to address the four categories of interactions within an AC specimen. Each of the constitutive models consists of three parts which represent three different interaction behaviors: a stiffness model (force-displace relation), a bonding model (shear and tensile strengths), and a slip model (frictional property). Three techniques were developed to reduce the computational time for AC viscoelastic simulations. It was found that the computational time was significantly reduced to days or hours from years or months for typical three-dimensional models. Dynamic modulus and creep stiffness tests were simulated and methodologies were developed to determine the viscoelastic parameters. It was found that the DE models could successfully predict dynamic modulus, phase angles, and creep stiffness in a wide range of frequencies, temperatures, and time spans. Mineral aggregate morphology characteristics (sphericity, orientation, and angularity) were studied to investigate their impacts on AC creep stiffness. It was found that aggregate characteristics significantly impact creep stiffness. Pavement responses and pavement-vehicle interactions were investigated by simulating pavement sections under a rolling wheel. It was found that wheel acceleration, steadily moving, and deceleration significantly impact contact forces. Additionally, summary and recommendations were provided in the last chapter and part of computer programming codes wree provided in the appendixes.

Optimal beam forming for laser beam propagation through random media

Focusing optical beams on a target through random propagation media is very important in many applications such as free space optical communica- tions and laser weapons. Random media effects such as beam spread and scintillation can degrade the optical system's performance severely. Compensation schemes are needed in these applications to overcome these random media effcts. In this research, we investigated the optimal beams for two different optimization criteria: one is to maximize the concentrated received intensity and the other is to minimize the scintillation index at the target plane. In the study of the optimal beam to maximize the weighted integrated intensity, we derive a similarity relationship between pupil-plane phase screen and extended Huygens-Fresnel model, and demonstrate the limited utility of maximizing the average integrated intensity. In the study ofthe optimal beam to minimize the scintillation index, we derive the first- and second-order moments for the integrated intensity of multiple coherent modes. Hermite-Gaussian and Laguerre-Gaussian modes are used as the coherent modes to synthesize an optimal partially coherent beam. The optimal beams demonstrate evident reduction of scintillation index, and prove to be insensitive to the aperture averaging effect.

DEVELOPMENT OF A CONCEPTUAL MODEL AND PARAMETERIZATION OF A MATHEMATICAL MODEL FOR SEDIMENT PHOSPHORUS DIAGENESIS, SORPTION AND RELEASE FROM ONONDAGA LAKE SYRACUSE, NEW YORK

Eutrophication is a persistent problem in many fresh water lakes. Delay in lake recovery following reductions in external loading of phosphorus, the limiting nutrient in fresh water ecosystems, is often observed. Models have been created to assist with lake remediation efforts, however, the application of management tools to sediment diagenesis is often neglected due to conceptual and mathematical complexity. SED2K (Chapra et al. 2012) is proposed as a "middle way", offering engineering rigor while being accessible to users. An objective of this research is to further support the development and application SED2K for sediment phosphorus diagenesis and release to the water column of Onondaga Lake. Application of SED2K has been made to eutrophic Lake Alice in Minnesota. The more homogenous sediment characteristics of Lake Alice, compared with the industrially polluted sediment layers of Onondaga Lake, allowed for an invariant rate coefficient to be applied to describe first order decay kinetics of phosphorus. When a similar approach was attempted on Onondaga Lake an invariant rate coefficient failed to simulate the sediment phosphorus profile. Therefore, labile P was accounted for by progressive preservation after burial and a rate coefficient which gradual decreased with depth was applied. In this study, profile sediment samples were chemically extracted into five operationally-defined fractions: CaCO3-P, Fe/Al-P, Biogenic-P, Ca Mineral-P and Residual-P. Chemical fractionation data, from this study, showed that preservation is not the only mechanism by which phosphorus may be maintained in a non-reactive state in the profile. Sorption has been shown to contribute substantially to P burial within the profile. A new kinetic approach involving partitioning of P into process based fractions is applied here. Results from this approach indicate that labile P (Ca Mineral and Organic P) is contributing to internal P loading to Onondaga Lake, through diagenesis and diffusion to the water column, while the sorbed P fraction (Fe/Al-P and CaCO3-P) is remaining consistent. Sediment profile concentrations of labile and total phosphorus at time of deposition were also modeled and compared with current labile and total phosphorus, to quantify the extent to which remaining phosphorus which will continue to contribute to internal P loading and influence the trophic status of Onondaga Lake. Results presented here also allowed for estimation of the depth of the active sediment layer and the attendant response time as well as the sediment burden of labile P and associated efflux.

Adenovirus-mediated transforming growth factor-beta ameliorates ischemic necrosis of epigastric skin flaps in a rat model

BACKGROUND: Gene therapy has been recently introduced as a novel approach to treat ischemic tissues by using the angiogenic potential of certain growth factors. We investigated the effect of adenovirus-mediated gene therapy with transforming growth factor-beta (TGF-beta) delivered into the subdermal space to treat ischemically challenged epigastric skin flaps in a rat model. MATERIAL AND METHODS: A pilot study was conducted in a group of 5 animals pretreated with Ad-GFP and expression of green fluorescent protein in the skin flap sections was demonstrated under fluorescence microscopy at 2, 4, and 7 days after the treatment, indicating a successful transfection of the skin flaps following subdermal gene therapy. Next, 30 male Sprague Dawley rats were divided into 3 groups of 10 rats each. An epigastric skin flap model, based solely on the right inferior epigastric vessels, was used as the model in this study. Rats received subdermal injections of adenovirus encoding TGF-beta (Ad-TGF-beta) or green fluorescent protein (Ad-GFP) as treatment control. The third group (n = 10) received saline and served as a control group. A flap measuring 8 x 8 cm was outlined on the abdominal skin extending from the xiphoid process proximally and the pubic region distally, to the anterior axillary lines bilaterally. Just prior to flap elevation, the injections were given subdermally in the left upper corner of the flap. The flap was then sutured back to its bed. Flap viability was evaluated seven days after the initial operation. Digital images of the epigastric flaps were taken and areas of necrotic zones relative to total flap surface area were measured and expressed as percentages by using a software program. RESULTS: There was a significant increase in mean percent surviving area between the Ad-TGF-beta group and the two other control groups (P < 0.05). (Ad-TGF-beta: 90.3 +/- 4.0% versus Ad-GFP: 82.2 +/- 8.7% and saline group: 82.6 +/- 4.3%.) CONCLUSIONS: In this study, the authors were able to demonstrate that adenovirus-mediated gene therapy using TGF-beta ameliorated ischemic necrosis in an epigastric skin flap model, as confirmed by significant reduction in the necrotic zones of the flap. The results of this study raise the possibility of using adenovirus-mediated TGF-beta gene therapy to promote perfusion in random portion of skin flaps, especially in high-risk patients.

Effect of vascular targeting agent in rat tumor model: dynamic contrast-enhanced versus diffusion-weighted MR imaging

PURPOSE: To compare dynamic contrast material-enhanced magnetic resonance (MR) imaging and diffusion-weighted MR imaging for noninvasive evaluation of early and late effects of a vascular targeting agent in a rat tumor model. MATERIALS AND METHODS: The study protocol was approved by the local ethics committee for animal care and use. Thirteen rats with one rhabdomyosarcoma in each flank (26 tumors) underwent dynamic contrast-enhanced imaging and diffusion-weighted echo-planar imaging in a 1.5-T MR unit before intraperitoneal injection of combretastatin A4 phosphate and at early (1 and 6 hours) and later (2 and 9 days) follow-up examinations after the injection. Histopathologic examination was performed at each time point. The apparent diffusion coefficient (ADC) of each tumor was calculated separately on the basis of diffusion-weighted images obtained with low b gradient values (ADC(low); b = 0, 50, and 100 sec/mm(2)) and high b gradient values (ADC(high); b = 500, 750, and 1000 sec/mm(2)). The difference between ADC(low) and ADC(high) was used as a surrogate measure of tissue perfusion (ADC(low) - ADC(high) = ADC(perf)). From the dynamic contrast-enhanced MR images, the volume transfer constant k and the initial slope of the contrast enhancement-time curve were calculated. For statistical analyses, a paired two-tailed Student t test and linear regression analysis were used. RESULTS: Early after administration of combretastatin, all perfusion-related parameters (k, initial slope, and ADC(perf)) decreased significantly (P < .001); at 9 days after combretastatin administration, they increased significantly (P < .001). Changes in ADC(perf) were correlated with changes in k (R(2) = 0.46, P < .001) and the initial slope (R(2) = 0.67, P < .001). CONCLUSION: Both dynamic contrast-enhanced MR imaging and diffusion-weighted MR imaging allow monitoring of perfusion changes induced by vascular targeting agents in tumors. Diffusion-weighted imaging provides additional information about intratumoral cell viability versus necrosis after administration of combretastatin.

Dynamic contrast-enhanced and diffusion-weighted MRI for early detection of tumoral changes in single-dose and fractionated radiotherapy: evaluation in a rat rhabdomyosarcoma model

We aimed to examine different intratumoral changes after single-dose and fractionated radiotherapy, using diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) MRI in a rat rhabdomyosarcoma model. Four WAG/Rij rats with rhabdomyosarcomas in the flanks received single-dose radiotherapy of 8 Gy, and four others underwent fractionated radiotherapy (five times 3 Gy). In rats receiving single-dose radiotherapy, a significant perfusion decrease was found in the first 2 days post-treatment, with slow recuperation afterwards. No substantial diffusion changes could be seen; tumor growth delay was 12 days. The rats undergoing fractionated radiotherapy showed a similar perfusion decrease early after the treatment. However, a very strong increase in apparent diffusion coefficient occurred in the first 10 days; growth delay was 18 days. DW-MRI and DCE-MRI can be used to show early tumoral changes induced by radiotherapy. Single-dose and fractionated radiotherapy induce an immediate perfusion effect, while the latter induces more intratumoral necrosis.

Efficiency of risk-based vs . random sampling for the monitoring of tetracycline residues in slaughtered calves in Switzerland

In all European Union countries, chemical residues are required to be routinely monitored in meat. Good farming and veterinary practice can prevent the contamination of meat with pharmaceutical substances, resulting in a low detection of drug residues through random sampling. An alternative approach is to target-monitor farms suspected of treating their animals with antimicrobials. The objective of this project was to assess, using a stochastic model, the efficiency of these two sampling strategies. The model integrated data on Swiss livestock as well as expert opinion and results from studies conducted in Switzerland. Risk-based sampling showed an increase in detection efficiency of up to 100% depending on the prevalence of contaminated herds. Sensitivity analysis of this model showed the importance of the accuracy of prior assumptions for conducting risk-based sampling. The resources gained by changing from random to risk-based sampling should be transferred to improving the quality of prior information.

Robust Proximal Femur Segmentation in Conventional X-Ray Images via Random Forest Regression on Multi-resolution Gradient Features

In this paper, we propose a fully automatic, robust approach for segmenting proximal femur in conventional X-ray images. Our method is based on hierarchical landmark detection by random forest regression, where the detection results of 22 global landmarks are used to do the spatial normalization, and the detection results of the 59 local landmarks serve as the image cue for instantiation of a statistical shape model of the proximal femur. To detect landmarks in both levels, we use multi-resolution HoG (Histogram of Oriented Gradients) as features which can achieve better accuracy and robustness. The efficacy of the present method is demonstrated by experiments conducted on 150 clinical x-ray images. It was found that the present method could achieve an average point-to-curve error of 2.0 mm and that the present method was robust to low image contrast, noise and occlusions caused by implants.

Solute transport in crystalline rocks at Äspö — I: Geological basis and model calibration

Water-conducting faults and fractures were studied in the granite-hosted A¨ spo¨ Hard Rock Laboratory (SE Sweden). On a scale of decametres and larger, steeply dipping faults dominate and contain a variety of different fault rocks (mylonites, cataclasites, fault gouges). On a smaller scale, somewhat less regular fracture patterns were found. Conceptual models of the fault and fracture geometries and of the properties of rock types adjacent to fractures were derived and used as input for the modelling of in situ dipole tracer tests that were conducted in the framework of the Tracer Retention Understanding Experiment (TRUE-1) on a scale of metres. After the identification of all relevant transport and retardation processes, blind predictions of the breakthroughs of conservative to moderately sorbing tracers were calculated and then compared with the experimental data. This paper provides the geological basis and model calibration, while the predictive and inverse modelling work is the topic of the companion paper [J. Contam. Hydrol. 61 (2003) 175]. The TRUE-1 experimental volume is highly fractured and contains the same types of fault rocks and alterations as on the decametric scale. The experimental flow field was modelled on the basis of a 2D-streamtube formalism with an underlying homogeneous and isotropic transmissivity field. Tracer transport was modelled using the dual porosity medium approach, which is linked to the flow model by the flow porosity. Given the substantial pumping rates in the extraction borehole, the transport domain has a maximum width of a few centimetres only. It is concluded that both the uncertainty with regard to the length of individual fractures and the detailed geometry of the network along the flowpath between injection and extraction boreholes are not critical because flow is largely one-dimensional, whether through a single fracture or a network. Process identification and model calibration were based on a single uranine breakthrough (test PDT3), which clearly showed that matrix diffusion had to be included in the model even over the short experimental time scales, evidenced by a characteristic shape of the trailing edge of the breakthrough curve. Using the geological information and therefore considering limited matrix diffusion into a thin fault gouge horizon resulted in a good fit to the experiment. On the other hand, fresh granite was found not to interact noticeably with the tracers over the time scales of the experiments. While fracture-filling gouge materials are very efficient in retarding tracers over short periods of time (hours–days), their volume is very small and, with time progressing, retardation will be dominated by altered wall rock and, finally, by fresh granite. In such rocks, both porosity (and therefore the effective diffusion coefficient) and sorption Kds are more than one order of magnitude smaller compared to fault gouge, thus indicating that long-term retardation is expected to occur but to be less pronounced.

Identifiability of diffusion and sorption parameters from in situ diffusion experiments by using simultaneously tracer dilution and claystone data

In situ diffusion experiments are performed in geological formations at underground research laboratories to overcome the limitations of laboratory diffusion experiments and investigate scale effects. Tracer concentrations are monitored at the injection interval during the experiment (dilution data) and measured from host rock samples around the injection interval at the end of the experiment (overcoring data). Diffusion and sorption parameters are derived from the inverse numerical modeling of the measured tracer data. The identifiability and the uncertainties of tritium and Na-22(+) diffusion and sorption parameters are studied here by synthetic experiments having the same characteristics as the in situ diffusion and retention (DR) experiment performed on Opalinus Clay. Contrary to previous identifiability analyses of in situ diffusion experiments, which used either dilution or overcoring data at approximate locations, our analysis of the parameter identifiability relies simultaneously on dilution and overcoring data, accounts for the actual position of the overcoring samples in the claystone, uses realistic values of the standard deviation of the measurement errors, relies on model identification criteria to select the most appropriate hypothesis about the existence of a borehole disturbed zone and addresses the effect of errors in the location of the sampling profiles. The simultaneous use of dilution and overcoring data provides accurate parameter estimates in the presence of measurement errors, allows the identification of the right hypothesis about the borehole disturbed zone and diminishes other model uncertainties such as those caused by errors in the volume of the circulation system and the effective diffusion coefficient of the filter. The proper interpretation of the experiment requires the right hypothesis about the borehole disturbed zone. A wrong assumption leads to large estimation errors. The use of model identification criteria helps in the selection of the best model. Small errors in the depth of the overcoring samples lead to large parameter estimation errors. Therefore, attention should be paid to minimize the errors in positioning the depth of the samples. The results of the identifiability analysis do not depend on the particular realization of random numbers. (C) 2012 Elsevier B.V. All rights reserved.

Mechanisms of perceptual learning of depth discrimination in random dot stereograms.

Perceptual learning is a training induced improvement in performance. Mechanisms underlying the perceptual learning of depth discrimination in dynamic random dot stereograms were examined by assessing stereothresholds as a function of decorrelation. The inflection point of the decorrelation function was defined as the level of decorrelation corresponding to 1.4 times the threshold when decorrelation is 0%. In general, stereothresholds increased with increasing decorrelation. Following training, stereothresholds and standard errors of measurement decreased systematically for all tested decorrelation values. Post training decorrelation functions were reduced by a multiplicative constant (approximately 5), exhibiting changes in stereothresholds without changes in the inflection points. Disparity energy model simulations indicate that a post-training reduction in neuronal noise can sufficiently account for the perceptual learning effects. In two subjects, learning effects were retained over a period of six months, which may have application for training stereo deficient subjects.

Biodiversity effects on nitrate concentrations in soil solution: a Bayesian model

Ecosystems are faced with high rates of species loss which has consequences for their functions and services. To assess the effects of plant species diversity on the nitrogen (N) cycle, we developed a model for monthly mean nitrate (NO3-N) concentrations in soil solution in 0-30 cm mineral soil depth using plant species and functional group richness and functional composition as drivers and assessing the effects of conversion of arable land to grassland, spatially heterogeneous soil properties, and climate. We used monthly mean NO3-N concentrations from 62 plots of a grassland plant diversity experiment from 2003 to 2006. Plant species richness (1-60) and functional group composition (1-4 functional groups: legumes, grasses, non-leguminous tall herbs, non-leguminous small herbs) were manipulated in a factorial design. Plant community composition, time since conversion from arable land to grassland, soil texture, and climate data (precipitation, soil moisture, air and soil temperature) were used to develop one general Bayesian multiple regression model for the 62 plots to allow an in-depth evaluation using the experimental design. The model simulated NO3-N concentrations with an overall Bayesian coefficient of determination of 0.48. The temporal course of NO3-N concentrations was simulated differently well for the individual plots with a maximum plot-specific Nash-Sutcliffe Efficiency of 0.57. The model shows that NO3-N concentrations decrease with species richness, but this relation reverses if more than approx. 25 % of legume species are included in the mixture. Presence of legumes increases and presence of grasses decreases NO3-N concentrations compared to mixtures containing only small and tall herbs. Altogether, our model shows that there is a strong influence of plant community composition on NO3-N concentrations.

Use of activity monitors for assessment of pruritus in an acute model of canine atopic dermatitis

BACKGROUND: We developed a canine model of acute atopic dermatitis to evaluate the potential of compounds to treat pruritus and skin lesions induced in Dermatophagoides farinae (Df)-sensitized dogs. HYPOTHESIS/OBJECTIVES: The aim was to investigate the effectiveness of long-term recording activity monitors to assess pruritus induced by allergen challenges. ANIMALS: Thirty-two Df-sensitized laboratory dogs. METHODS: In two blinded crossover studies, 28 Df-sensitized dogs were challenged on 3 days with a Df slurry applied to clipped abdominal skin. Dogs were treated with a positive control (prednisolone 1 mg/kg once daily for 5 days, starting 1 day before challenge) or left untreated; all were fitted with activity monitors. To confirm pruritus, a parallel study with four dogs was conducted, filming the dogs before and during challenge and assessing the film for pruritic behaviour. RESULTS: The activity of dogs treated with prednisolone was significantly lower between 00.00 and 03.00 h and between 03.00 and 06.00 h compared with untreated dogs (repeated-measures ANCOVA; P < 0.0001). To determine whether the recorded night-time activity corresponded to pruritic manifestations, we compared activity monitor and video recordings of four dogs for two periods (16.30-20.30 and 24.00-03.00 h) before and during a Df challenge. The correlation between night-time activity monitor activity and observed pruritic behaviour was highly significant (test of correlation coefficient versus zero: r = 0.57, P < 0.0001). CONCLUSIONS AND CLINICAL IMPORTANCE: Determination of night-time activity with activity monitors after allergen challenge appears to be an objective and practical way to assess pruritus in this experimental model of canine atopic dermatitis.

Automatic Segmentation of the Eye in 3D Magnetic Resonance Imaging: A novel Statistical Shape Model for treatment planning of Retinoblastoma

Purpose: Proper delineation of ocular anatomy in 3D imaging is a big challenge, particularly when developing treatment plans for ocular diseases. Magnetic Resonance Imaging (MRI) is nowadays utilized in clinical practice for the diagnosis confirmation and treatment planning of retinoblastoma in infants, where it serves as a source of information, complementary to the Fundus or Ultrasound imaging. Here we present a framework to fully automatically segment the eye anatomy in the MRI based on 3D Active Shape Models (ASM), we validate the results and present a proof of concept to automatically segment pathological eyes. Material and Methods: Manual and automatic segmentation were performed on 24 images of healthy children eyes (3.29±2.15 years). Imaging was performed using a 3T MRI scanner. The ASM comprises the lens, the vitreous humor, the sclera and the cornea. The model was fitted by first automatically detecting the position of the eye center, the lens and the optic nerve, then aligning the model and fitting it to the patient. We validated our segmentation method using a leave-one-out cross validation. The segmentation results were evaluated by measuring the overlap using the Dice Similarity Coefficient (DSC) and the mean distance error. Results: We obtained a DSC of 94.90±2.12% for the sclera and the cornea, 94.72±1.89% for the vitreous humor and 85.16±4.91% for the lens. The mean distance error was 0.26±0.09mm. The entire process took 14s on average per eye. Conclusion: We provide a reliable and accurate tool that enables clinicians to automatically segment the sclera, the cornea, the vitreous humor and the lens using MRI. We additionally present a proof of concept for fully automatically segmenting pathological eyes. This tool reduces the time needed for eye shape delineation and thus can help clinicians when planning eye treatment and confirming the extent of the tumor.