Assessment of White Matter Hyperintensity, Cerebral Blood Flow, and Cerebral Oxygenation in Older Subjects Stratified by Cerebrovascular Risk

Objective: Cerebrovascular disease (CVD) is the fifth most common cause of mortality in the United States. Diagnosis of CVD at an early stage is critical for optimal intervention designed to prevent ongoing and future brain injury. CVD is commonly associated with abnormalities of the cerebral microvasculature leading to tissue dysfunction, neuronal injury and death, and resultant clinical symptoms, which in turn, further impacts cerebral autoregulation (CA). This series of studies aims to test the hypothesis that white matter hyperintensities (WMH) and cerebral hemodynamics (quantified by magnetic resonance imaging (MRI) and an by innovative hybrid near-infrared diffuse optical instrument) can be used as biomarkers to distinguish cognitively healthy older subjects with high or low risk for developing CVD. Methods: Using functional MRI, WMH and cerebral blood flow (CBF) were quantified in 26 cognitively healthy older subjects (age: 77.8 ± 6.8 years). In a follow-up study, significant variability in WMH quantification methodology was addressed, with sources of variability identified in selecting image center of gravity, software compatibility, thresholding techniques, and manual editing procedures. Accordingly, post-acquisition processing methods were optimized to develop a standardized protocol with less than 0.5% inter-rater variance. Using a novel laboratory-made hybrid near-infrared spectroscopy/diffuse correlation spectroscopy (NIRS/DCS) and a finger plethysmograph, low-frequency oscillations (LFOs) of CBF, cerebral oxygenation, and main arterial pressure (MAP) were simultaneously measured before, during, and after 70° head-up-tilting (HUT). Gains (associated with CAs) to magnify LFOs were determined by transfer function analyses with MAP as the input and cerebral hemodynamic parameters as the outputs. In a follow-up study, a fast software correlator for DCS and a parallel detection technique for NIRS/DCS were adapted to improve the sampling rate of hybrid optical measurements. In addition, a new DCS probe was developed to measure CBF at the occipital lobe, which represents a novel application of the NIRS/DCS technique. Results: MRI measurements demonstrate that deep WMH (dWMH) and periventricular WMH (pWMH) volumetric measures are associated with reduced regional cortical CBF in patients at high-risk of CVD. Moreover, CBF in white matter (WM) was reduced in regions demonstrating both pWMH and dWMHs. NIRS/DCS optical measurements demonstrate that at resting baseline, LFO gains in the high-risk group were relatively lower compared to the low-risk group. The lower baseline gains in the high-risk group may be attributed to compensatory mechanisms that allow the maintenance of a stronger steady-state CA. However, HUT resulted in smaller gain reductions in the high-risk group compared to the low-risk group, suggesting weaker dynamic CA in association with increased CVD risks. A noteworthy finding in these experiments was that CVD risk more strongly influenced CBF than cerebral oxygenation. Conclusions: Regional WMH volumes, cortical and WM CBF values, and LFO gains of cerebral hemodynamics demonstrate specific associations with CA and may serve as important potential biomarkers for early diagnosis of CVD. The high spatial resolution, large penetration depth, and variety of imaging-sequences afforded by MRI make it an appealing imaging modality for evaluation of CVD, although MRI is costly, time-limited, and requires transfer of subjects from bed to imaging facility. In contrast, low-cost, portable, mobile diffuse optical technologies provide a complementary alternative for early screening of CVD, that can further allow continuous monitoring of disease attenuation or progression at the subject’s bedside. Thus, development of both methodologies is essential for progress in our future understanding of CVD as a major contributor to the morbidity and mortality associated with CVD today

MARKET STRUCTURE AND MORTGAGE PRICING: THE ROLE OF INFORMATION IN FIRM AND CONSUMER BEHAVIOR

This dissertation analyzes information, market structure, and firm pricing strate-gies. I begin the dissertation with an analysis of the market structure of the mortgage in-dustry. I find that the configuration of the mortgage market at its present state is vastly different than its historical structure. The reduction in the cost of transmitting informa-tion has increased the collaborative environment and facilitated the dis-integration of the supply chain. Generally, the mortgage industry has been successful at reducing principal-agent problems and minimizing asymmetric information concerns that arise in segmented markets. In the first essay I provide a theoretical explanation of the effect of the internet on market outcomes. Search models assume that the reduction in search frictions would lead to competitive markets. However, I argue that gatekeepers operating in online markets may create an anticompetitive effect, in addition to reducing the consumers’ search cost. Therefore, the conduct of the gatekeeper can cause prices in online markets to be higher than in retail markets and provide online firms with larger profits. In the second essay “I empirically examine the role of the internet and Internet Comparison Search sites in reducing consumer search costs and their effects on the prices consumers pay for mortgages. Additionally, I expand the study to test for the effects of the internet on firm profits. Using a unique data set, I examine a mortgage firm’s pricing strategies and profits in online and retail markets, and find evidence of market power in online markets that do not exist in retail markets. The presumed benefits to the consumer from the reduction of search cost are offset by the anticompetitive environment in online markets. In the final essay, I examine a mortgage firm’s portfolio choice. I investigate the loan characteristics that affect the firm’s decision to retain mortgages as part of its own portfolio. I find that the decision to retain loans as a lender is driven by unobservable qualities. The firm does sort loans by quality, but it also prices non-brokered loans lower based on unobservable qualities. The sorting behavior suggests that asymmetric information exists between the lender and the secondary market

Nitrogen remobilization in wheat as influenced by nitrogen application and post-anthesis water deficit during grain filling

Pre-anthesis stored nitrogen in wheat (Triticum aestivum L.) is important because grain filling greatly depends on the remobilization of pre-anthesis nitrogen under Mediterranean growth conditions. This field study was conducted to assess the effect of post-anthesis water deficit and three N fertilizer levels on N remobilization and N losses in three wheat cultivars (‘Shiraz’, ‘Marvdasht’ and ‘Chamran’). Nitrogen remobilization in plant parts decreased to 29 to 58% under water deficit compared with the well watered (WW) treatment. Grain N was 40% higher under post-anthesis water deficit than the WW treatment and with the addition of 160 kg N ha-1. The application of nitrogen fertilizer increased N remobilization to 78%. ‘Shiraz’ remobilized 13 and 25% more nitrogen than ‘Marvdasht’ and ‘Chamran’, respectively. Under water deficit, N remobilization efficiency increased by 13%. Leaves were more efficient than stem and spike in N remobilization efficiency either in the WW or the WD treatment. The application of fertilizer N generally lowered whole plant remobilization efficiency. The N remobilization efficiency of ‘Chamran’ increased when the soil moisture and/or N were limited during the grain filling period. Grain N concentration was correlated positively with N concentration or N content of vegetative parts at anthesis. In addition to nitrogen fertilizer, WD during grain filling reduced nitrogen use efficiency by 30 and 25%, respectively. In the WW treatment, 25% of the N at anthesis was lost at maturity. In contrast, under WD only 6% of the N was lost. High amount of N led to N losses at maturity. Significant negative correlations were found between grain yield and grain protein concentration in the three wheat cultivars. Results indicate that the greater the amount of N accumulated before anthesis, the higher the translocation rates of nitrogen to grain and the greater the risk of net N losses at maturity.Key words: Nitrogen harvest index, nitrogen loss, grain protein, nitrogen use efficiency

Investigation of the constancy of the MWCNTs on the fibres surface for manufactured self-sensing composites

This the author accepted manuscript. The fial version is available from Elsevier via the DOI in this recordDifferent methods have been used to deposit the multi-walled carbon nanotubes (MWCNTs) onto the fibre surface to fabricate self-sensing composites. However, the constancy of the MWCNTs onto the fibre surfaces during infusion processing still unclear. In this study, we have deposited MWCNTs onto the glass fibre surface by two methods to investigate the state of MWCNTs during and after epoxy infusion processing. In the first method, the glass fibres were directly coated with the MWCNTs and in the second method, an adhesive was applied to coat the glass fibre surface before depositing the MWCNTs over it. Rectangular specimens for both types of self-sensing composites were cut from different specified zones and then tested. The results showed that the self-sensing composites with adhesively bonded MWCNTs exhibited more consistent in their properties than the composites where no adhesive was used. In addition, the electrical resistance of both types of self-sensing composites was monitored during the epoxy infusion process. The results showed that the electrical resistance was not obviously affected for composite with non-adhesive bonded MWCNTs and was high for the specimens where the MWCNTs were not adhesively bonded. Moreover, the numerical study was also conducted and the results indicated that the relationship between the volume fraction of the MWCNTs and their tunnelling distance was an inverse. The current study proves evidence that the properties of the self-sensing composites are strongly dependent on the method that used to deposit the MWCNTs on the surface of glass fibres layers.Iraqi Ministry of Oi

A novel simultaneous quantification method for fat-soluble vitamins using liquid chromatography-tandem mass spectrometry for clinical applications

The accurate and precise quantification of fat-soluble vitamins (FSVs), specifically vitamins A, D and E, has proved to be a challenge for clinical laboratories. This challenge is partially the result of the nature of FSV molecules and the limitations in techniques commonly used in their analysis. Consequently, there is a variation in the results obtained through different techniques or by different clinical laboratories. As a result, it has been difficult to reach agreement on the recommended levels or reference intervals of these vitamins. The current project encompassed the development of a state-of-the-art analytical method for the analysis of vitamins A (retinol), D (25-hydroxyvitamin D [25-OHD]) and E (α-tocopherol) in blood using liquid chromatography-tandem mass spectrometry (LC-MS/MS), which is a highly sensitive and specific quantification technique. Four studies were then performed to explore several scientific knowledge gaps related to vitamin measurement using the developed FSV quantification methods. The Current translational clinical research introduced novel and precise simultaneous measurement methods for blood FSV analytes, which were applicability to clinical sampling trials. This thesis also provides the first study exploring the stability FSVs simultaneously in routine sample spectrum utilising a precise LC-MS/MS method. In addition, stability of each analytes is justified based on calculation of the acceptable clinical limits, which reflect biological variation as well as method imprecision. This project also highlighted problematic issue related to trueness and reliable traceability of commercial calibrators to high order references and that interrupts effort of method harmonisation and patient result comparability. Furthermore, the current thesis provides with first study validated the measurement of 25-OHD3 and retinol in UCB diluted plasma. Lastly, this thesis reports the first study exploring status of five FSV analytes in two Australian populations at different latitudes using simultaneous measurement LC-MS/MS method. Furthermore, this is the first work examined the correlation between the blood FSV levels in two Australian populations

Transmorphic phage-guided systemic delivery of TNFα gene for the treatment of human pediatric medulloblastoma

Medulloblastoma is the most common childhood brain tumor with an unfavorable prognosis and limited options of harmful treatments that are associated with devastating long-term side effects. Therefore, the development of safe, noninvasive, and effective therapeutic approaches is required to save the quality of life of young medulloblastoma survivors. We postulated that therapeutic targeting is a solution. Thus, we used a recently designed tumor-targeted bacteriophage (phage)-derived particle, named transmorphic phage/AAV, TPA, to deliver a transgene expressing the tumor necrosis factor-alpha (TNFα) for targeted systemic therapy of medulloblastoma. This vector was engineered to display the double-cyclic RGD4C ligand to selectively target tumors after intravenous administration. Furthermore, the lack of native phage tropism in mammalian cells warrants safe and selective systemic delivery to the tumor microenvironment. In vitro RGD4C.TPA.TNFα treatment of human medulloblastoma cells generated efficient and selective TNFα expression, subsequently triggering cell death. Combination with the chemotherapeutic drug cisplatin used clinically against medulloblastoma resulted in augmented effect through the enhancement of TNFα gene expression. Systemic administration of RGD4C.TPA.TNFα to mice-bearing subcutaneous medulloblastoma xenografts resulted in selective tumor homing of these particles and consequently, targeted tumor expression of TNFα, apoptosis, and destruction of the tumor vasculature. Thus, our RGD4C.TPA.TNFα particle provides selective and efficient systemic delivery of TNFα to medulloblastoma, yielding a potential TNFα anti-medulloblastoma therapy while sparing healthy tissues from the systemic toxicity of this cytokine

Cardiorespiratory Fitness Diminishes the Effects of Age on White Matter Hyperintensity Volume

White matter hyperintensities (WMHs) are among the most commonly observed marker of cerebrovascular disease. Age is a key risk factor for WMH development. Cardiorespiratory fitness (CRF) is associated with increased vessel compliance, but it remains unknown if high CRF affects WMH volume. This study explored the effects of CRF on WMH volume in community-dwelling older adults. We further tested the possibility of an interaction between CRF and age on WMH volume. Participants were 76 adults between the ages of 59 and 77 (mean age = 65.36 years, SD = 3.92) who underwent a maximal graded exercise test and structural brain imaging. Results indicated that age was a predictor of WMH volume (beta = .32, p = .015). However, an age-by-CRF interaction was observed such that higher CRF was associated with lower WMH volume in older participants (beta = -.25, p = .040). Our findings suggest that higher levels of aerobic fitness may protect cerebrovascular health in older adults