Recent studies show synthetic PPARgamma thiazolidinediones (TZDs) rosiglitazone and pioglitazone, most notably implicated in treatment for type-2 diabetes, are useful to alleviate symptoms associated with neuropathic pain. To further characterize PPARgamma agonists as treatment for neuropathic pain we first evaluated the effects of repeated systemic administration of low doses of pioglitazone, with administration starting at the time of nerve injury, on the development of neuropathic pain. In an additional set of experiments, the beginning of drug administration was varied to determine if there is a therapeutic window. In both studies pioglitazone reduced the development of allodynia and hyperalgesia. These effects were a result of PPARgamma activation; PPARgamma antagonist GW9662 significantly attenuated the therapeutic effects of pioglitazone. In established neuropathic pain, when administered at higher doses, we found that pioglitazone reversed nerve injury-induced allodynia and hyperalgesia. This was prevented with GW9662, indicating PPARa in its mechanism of action. To investigate site of action of pioglitazone, we administered the drug via direct intrathecal and intracerebroventricular (ICV) injection. Pioglitazone administered to the spinal cord produced anti-allodynic effects that were mediated via PPARgamma, while pioglitazone administered to the brain did not; these results suggest a spinal rather than supraspinal site of action. Molecular markers for microglia, astrocytes, ERK and p38 were analyzed in rats receiving either repeated daily systemic administration or a single direct intrathecal injection of pioglitazone. Activated microglia, astrocytes, ERK and p38 were all significantly reduced in rats treated with systemic pioglitazone versus vehicle controls, whereas a single direct intrathecal injection of pioglitazone only reduced microglia activation. Together these results suggest treatment with pioglitazone inhibits the development and alleviates the maintenance of neuropathic pain / acase@tulane.edu

In the framework of statistical supervised learning, posterior probability estimation is of crucial interest. The major difficulty for the learning process is that the true class membership probabilities are never known for many real world problems. Among various learning algorithms, decision tree induction is one of the most popular and effective techniques. However, decision trees have been observed to be poor posterior probability estimators and this weakness more or less impedes its utilization in real-world contexts when accurate probability estimation is needed. Although a variety of probability estimation tree (PET) algorithms have been proposed to handle this problem, there still lacks an exhaustively unbiased empirical study and analysis of the efficacies of these algorithms with respect to the characteristics of a specific domain in terms of multiple evaluation metrics. A practical guide which can help practitioners and researchers choose the most appropriate PET algorithm in light of the datasets at hand is also missing. Moreover, even if the performances of some proposed algorithms are quite satisfactory, is it possible to develop new algorithms for better estimation? In this spirit, this dissertation systematically addresses the problem of better probability estimation and ranking through decision tree induction. In addition, the effectiveness of PETS on real-world data mining problems is also demonstrated through ozone level detection / acase@tulane.edu

Mechanical ventilation inevitably exposes the delicate tissues of the airways and alveoli to a wide range of abnormal stresses that can induce pulmonary edema and initiate or exacerbate life-threatening conditions such as acute lung injury and acute respiratory distress syndrome. The goal of our research is to characterize the cellular trauma caused by the transient, abnormal mechanical stresses that arise when air is forced into a liquidoccluded airway. Using a fluid-filled parallel-plate flow chamber to model this 'airway reopening' process, our in vitro study specifically examined consequent increases in pulmonary epithelial plasma membrane rupture, paracellular permeability, and tight junction (TJ) protein disruption. Through this analysis, we observed a distinct, unexpected drop in pulmonary epithelial injury during particularly traumatic reopening events if DeltaPcell -- the reopening-induced fore-aft pressure difference exerted across the cells -- was greater than a critical value, DeltaPcrit. Namely, when DeltaP cell < DeltaPcrit, plasma membrane rupture, paracellular permeability and TJ disruption were magnified by increases in DeltaP cell. On the other hand, further enhancing DeltaPcell beyond DeltaP crit consistently and dramatically diminished cell wounding. From these results, we propose that a passive DeltaPcell-induced shift in pulmonary epithelial rheology when DeltaPcell > DeltaP crit prevents excessive cellular trauma during airway reopening which may be exploited to improve patient prognosis during mechanical ventilation / acase@tulane.edu

The pulvinar nucleus of the thalamus is the largest subcortical visual structure in primates and appears to have increased in size in primate evolution. Pulvinar divisions termed the dorsal pulvinar and inferior pulvinar (PI) complex, as well as subdivisions in the PI complex, have been shown by calbindin and acetylcholinesterase (AChE) staining techniques. These staining techniques provide a reproducible method for quantifying pulvinar volumes in primate species. The present study measures the volumes of total pulvinar, dorsal pulvinar, PI complex, and the medial subdivision of the PI complex (PI M), using primate brain sections. Squirrel monkey, macaque, chimpanzee, and human are the species thought to give the best perspective on the evolution of the pulvinar to its current structure in humans. Because of differing brain sizes, we compare volume ratios, rather than volumes of pulvinar. Our long-term goal is to establish a structural correlation between pulvinar volume ratios and visual behavior. Results show similar PI complex/total pulvinar volume ratios in squirrel monkeys, macaques, and chimpanzees. Using calbindin stains, squirrel monkeys have larger PIM/total pulvinar volume ratios than macaques (6.24% vs. 1.83%) and chimpanzees (6.24% vs. 2.69%, p < 0.05). Chimpanzees and macaques have similar PIM/total pulvinar volume ratios (2.69% vs. 1.83%). Strong connections of PIM with area MT suggest an involvement of PIM in visual motion processing. Thus, differing PIM/total pulvinar volume ratios in squirrel monkeys vs. macaques and chimpanzees correlate structure and visual abilities in different species of primates. Differing volume ratios found for calbindin and AChE-staining suggest future quantification by different staining techniques must control for such differences / acase@tulane.edu

Inherent characteristics (autogenic behavior) of sedimentary systems are often thought to generate small-scale noise in the stratigraphic records and usually ignored in the stratigraphic interpretation. However, autogenic dynamics can also occur over large temporal and spatial scales and produce sedimentary records that mimic stratigraphic signals presumed to result from changes in external boundary conditions (allogenic forcings) such as tectonics, climate, eustatic change or a combination. As the autogenic fluctuations could impose first-order controls on stratigraphic architecture, it is necessary to search for quantitative methods in order to constrain river intrinsic behaviors and decode them from the complex stratigraphic responses by the scales over which autogenic stratigraphic patterns are most prevalent. The statistical metric we developed based on numerical modeling and physical experiments offers a good prediction on the autogenic time scales and results in a compensation index which can be used as an indicator for fluviodeltaic stratigraphic patterns. The magnitude of autogenic forcings presented in the fluvial successions is associated with the strength of channel-belt clustering and can be quantitatively classified by the compensation index. We utilize this index in conjunction with a serial of 2-D object-based stratigraphic stacking models, high-resolution experimental and field data to (1) quantify how the magnitude of autogenic processes varies with scales (2) understand how autogenic behaviors interact with river discharge and how this allogenic condition affects the stacking patterns of channel bodies (3) explore the mechanism by which surface topography and river kinetics influence the degree of stratigraphic organization in a net-aggradation system / acase@tulane.edu

The fat-derived hormone leptin communicates the status of energy stores to the brain and data suggests that the leptin pathway plays an important role in body weight control. Since leptin's discovery, leptin effects in the hypothalamus have been emphasized, whereas leptin effects on other central autonomic regions like the brainstem have been understudied. Recent studies implicate a role for the dorsal vagal complex in the feeding modulation attributed to leptin. However, possible direct cellular effects of leptin within the vagal complex have never been studied. These experiments were aimed at testing the hypothesis that at least part of the distributed network of leptin responsive cells resides within the DVC and identifying the synaptic and cellular modulation of neurons within the DVC by leptin Leptin caused a membrane hyperpolarization of gastric-related DVC neurons and was accompanied by a decrease in whole-cell input resistance and responsiveness. The leptin-induced hyperpolarization exhibited a dependence of membrane potential and was blocked by a sulfonylurea and wortmannin, which in all implicates activation of an ATP-sensitive K+ channel via a P13-kinase mechanism. The data presented here support a role for leptin in both suppression of excitatory synaptic inputs and a direct cellular inhibition of the neurons in the DVC, which are critical modulators of gastric function. Due to leptin's effects in the DVC and in particular gastric-related neurons, these responses can now be associated with neurons involved in the process of feeding and ingestion. Leptin's rapid effects may report a feed-back response to changing leptin during varying energy needs. The cellular inhibition of the DVC by leptin may also describe a modulation of several homeostatic modalities within the autonomic nervous system / acase@tulane.edu

In both physiological and pathological processes, cardiac electrical and mechanical activities are inseparably connected and affect each other via excitation-contraction coupling (ECC) and mechano-electric feedback (MEF). While ECC has been extensively studied, there is only limited information on cardiac MEF. The study presented here investigates the role of MEF in cardiac arrhythmia induction and termination through computational simulations In the study, we investigated the role of mechanical impact in the induction and maintenance of arrhythmia, the mechanism of arrhythmia termination by precordial thump and effect of mechano-electrical feedback on the defibrillation efficacy. Our results showed that mechanical impact to the chest may induce a life-threatening arrhythmia, the phenomena called commotio cordis. The timing of impact was suggested to be critical; synchronization of impact with R wave of the ECG was found most vulnerable. Exploration of the underlying mechanisms showed that a class of novel stretch-activated ionic channels (SAC) play an important role in the process, especially the most commonly reported type of nonselective SAC. In the other hand, in the present thesis, we demonstrated that precordial thump is able to terminate arrhythmia if given before the development of ischemia. Otherwise the success rate will be lower. The reason for this was proposed as the sensitized KATP channels to mechanical stimulation under the myocardial ischemia. Activation of cation non-selective SAC explained the success of termination of arrhythmias by precordial thump As the first two studies were external mechanical stimulation, the third project was internal mechanical stimulation, which was conducted with two different computational models: a 2D tissue model and a 3D realistic rabbit model. Our results showed that SAC opening induced by chronic ventricular dilatation contribute partly to the experimentally observed increase of defibrillation threshold (DFT) and arrhythmogenesis. Opening of SAC could cause stretch triggered arrhythmias or lead to earlier repolarization and larger spatial heterogeneity in repolarization, depending on the reversal potential of these channels In conclusion, the findings of the research have important implications for the future study of mechanoelectric feedback and may have clinical applications in the improvement of preventing and manipulating cardiac arrhythmia / acase@tulane.edu

Glaucoma is the second leading cause of blindness worldwide and is characterized by an irreversible damage to the retinal ganglion cell axons within the optic nerve head (ONH). Once thought to only occur at elevated levels of intraocular pressure (IOP), glaucoma can develop at normal levels without distinct etiology. Since IOP alone cannot explain the development and progression of the disease, we have theorized that the biomechanics of the ONH plays a central role in driving several pathologic mechanisms that can lead to the neuropathy The ONH is embedded within the posterior scleral shell - the white outer coat of the eye. From a biomechanical perspective, the sclera directly transmits IOP-induced stress and strain to the ONH, and we therefore hypothesize that the biomechanical behavior of the sclera contributes to the development and progression of glaucoma Our objective is to use state-of-the-art experimental and computational tools to characterize scleral biomechanics in normal and glaucomatous monkey eyes. Because the prevalence of glaucoma increases exponentially with age, we additionally characterize scleral biomechanics in the aging monkey eye to investigate the underlying mechanisms for the age-related increased susceptibility to glaucoma We introduce a constitutive model for the posterior sclera that includes stretch-induced stiffening and multi-directionality of the collagen fibers. Application of this model to an idealized eye geometry shows that scleral collagen fibers have a strong impact on ONH deformations. By experimentally measuring IOP-induced 3-D scleral deformations, and regional variations in scleral topography and thickness, we characterize the mechanical properties of individual scleral shells using an inverse finite element (FE) method. We show that monkey posterior sclera (1) is a nonlinear, anisotropic, inhomogeneous tissue, (2) stiffens with age, (3) is biomechanically altered in some, but not all, glaucomatous eyes. In normal eyes, we suggest that the sclera shields the ONH from biomechanical insult by resisting large deformations (nonlinearity), and scleral canal expansion (anisotropy). We suggest that age-related scleral stiffening could dramatically impact the homeostasis of the ONH. Finally, we suggest that scleral remodeling occurs in glaucomatous eyes to prevent further increase in ONH deformations and thus inhibits progression of the disease / acase@tulane.edu

This research addresses experimental and analytical studies on the shear behavior of post-installed mechanical concrete fasteners, primarily powder-actuated fasteners and concrete screws. The use of these types of fasteners is increasing in structural applications. Behavioral models based on experimental and analytical results have been developed to guide the design of anchorage to concrete using post-installed mechanical fasteners Single fastener tests have been performed in untracked concrete, in order to determine the basic and characteristic shear behavior offasteners. Fasteners with different lengths and diameters have been tested to determine the effect of embedment length and fastener anchor diameter on the shear behavior offasteners. Concrete slabs of different strengths were used for fastener tests to explore the effect of concrete strength. Cracked concrete slabs were used to test fasteners in cracks to examine the influence of the presence of cracks on the shear behavior of fasteners. Double fastener group tests were also performed to investigate the group effect on the shear behavior of fasteners Behavioral models have been developed to investigate the unique factors affecting the properties ofpost-installed mechanical fasteners loaded in shear. Design equations have been proposed based on the experimental and analytical results Knowledge obtained from this study will be useful for the design of anchorage to concrete. The design equations and recommendations achieved from this research will be submitted to the American Concrete Institute (ACI) for possible adoption to ACI 318, A CI 440, ACI 355 and other relative codes and standards in future Results of this study indicated that current provisions for design of anchorage to concrete located in the Appendix D of ACI 318-05, which are not meant to be applied to power-actuated or concrete screws, are not applicable to the design of anchorage to concrete using power-actuated fasteners or concrete screws. Behavioral models for concrete screws were proposed in this study. Proposed behavior models can predict the shear behavior of concrete screws very well with respect different concrete strengths and conditions (presence or absence of cracking), different screws sizes, and different screw shank diameter to embedment depth ratios / acase@tulane.edu

Three 96-ft (29.3-m) long, 72-in. (1.83-m) deep, pretensioned bulb-tee girders were tested to evaluate behavior under static shear loadings. The three girders had a design concrete compressive strength of 10,000 psi (69.0 MPa) and incorporated 0.6-in. (15.2-mm) diameter, Grade 270, low relaxation prestressing strands. In order to evaluate performance for an upcoming bridge project of the Louisiana (USA) Department of Transportation and Development (LADOTD), one of the girders was designed based on the AASHTO Standard Specifications for Highway Bridges and the other two were designed based on the AASHTO LRFD Bridge Design Specifications. The shear reinforcement designs of one end of the AASHTO designed girder and one of the two LRFD designed girders incorporated the use of welded wire fabric as an alternative to conventional bars for shear reinforcement After a fatigue loading test, each girder was cut in half and both ends were tested to evaluate static shear strength performance. The objective of this dissertation is to utilize the results of tests on six full-size high performance concrete (HPC) bulb-tee bridge girder specimens, tested in static shear, in analytical studies designed to determine the applicability of U.S. guidelines and specifications to HPC bridge girders, and to examine data collected relative to the shear behavior and strength in an attempt to define parameters that could be used in the design process / acase@tulane.edu