Immunity and Arginine Deprivation in Alzheimer's Disease

The pathogenesis of Alzheimer’s disease (AD) is a critical unsolved question, and while recent studies have demonstrated a strong association between altered brain immune responses and disease progression, the mechanistic cause of neuronal dysfunction and death is unknown. We have previously described the unique CVN-AD mouse model of AD, in which immune-mediated nitric oxide is lowered to mimic human levels, resulting in a mouse model that demonstrates the cardinal features of AD, including amyloid deposition, hyperphosphorylated and aggregated tau, behavioral changes and age-dependent hippocampal neuronal loss. Using this mouse model, we studied longitudinal changes in brain immunity in relation to neuronal loss and, contrary to the predominant view that AD pathology is driven by pro-inflammatory factors, we find that the pathology in CVN-AD mice is driven by local immune suppression. Areas of hippocampal neuronal death are associated with the presence of immunosuppressive CD11c+ microglia and extracellular arginase, resulting in arginine catabolism and reduced levels of total brain arginine. Pharmacologic disruption of the arginine utilization pathway by an inhibitor of arginase and ornithine decarboxylase protected the mice from AD-like pathology and significantly decreased CD11c expression. Our findings strongly implicate local immune-mediated amino acid catabolism as a novel and potentially critical mechanism mediating the age-dependent and regional loss of neurons in humans with AD.

There is a large interest in identifying, lineage tracing, and determining the physiologic roles of monophagocytes in Alzheimer’s disease. While Cx3cr1 knock-in fluorescent reporting and Cre expressing mice have been critical for studying neuroimmunology, mice that are homozygous null or hemizygous for CX3CR1 have perturbed neural development and immune responses. There is, therefore, a need for similar tools in which mice are CX3CR1+/+. Here, we describe a mouse where Cre is driven by the Cx3cr1 promoter on a bacterial artificial chromosome (BAC) transgene (Cx3cr1-CreBT) and the Cx3cr1 locus is unperturbed. Similarly to Cx3cr1-Cre knock-in mice, these mice express Cre in Ly6C-, but not Ly6C+, monocytes and tissue macrophages, including microglia. These mice represent a novel tool that maintains the Cx3cr1 locus while allowing for selective gene targeting in monocytes and tissue macrophages.

The study of immunity in Alzheimer’s requires the ability to identify and quantify specific immune cell subsets by flow cytometry. While it is possible to identify lymphocyte subsets based on cell lineage-specific markers, the lack of such markers in brain myeloid cell subsets has prevented the study of monocytes, macrophages and dendritic cells. By improving on tissue homogenization, we present a comprehensive protocol for flow cytometric analysis, that allows for the identification of several cell types that have not been previously identified by flow cytometry. These cell types include F4/80hi macrophages, which may be meningeal macrophages, IA/IE+ macrophages, which may represent perivascular macrophages, and dendritic cells. The identification of these cell types now allows for their study by flow cytometry in homeostasis and disease.

A Study of How Economic Attitudes Are Shaped by Environmental Shocks and Life Experiences

Social attitudes, attitudes toward financial risk and attitudes toward deferred gratification are thought to influence many important economic decisions over the life-course. In economic theory, these attitudes are key components in diverse models of behavior, including collective action, saving and investment decisions and occupational choice. The relevance of these attitudes have been confirmed empirically. Yet, the factors that influence them are not well understood. This research evaluates how these attitudes are affected by large disruptive events, namely, a natural disaster and a civil conflict, and also by an individual-specific life event, namely, having children.

By implementing rigorous empirical strategies drawing on rich longitudinal datasets, this research project advances our understanding of how life experiences shape these attitudes. Moreover, compelling evidence is provided that the observed changes in attitudes are likely to reflect changes in preferences given that they are not driven just by changes in financial circumstances. Therefore the findings of this research project also contribute to the discussion of whether preferences are really fixed, a usual assumption in economics.

In the first chapter, I study how altruistic and trusting attitudes are affected by exposure to the 2004 Indian Ocean tsunami as long as ten years after the disaster occurred. Establishing a causal relationship between natural disasters and attitudes presents several challenges as endogenous exposure and sample selection can confound the analysis. I take on these challenges by exploiting plausibly exogenous variation in exposure to the tsunami and by relying on a longitudinal dataset representative of the pre-tsunami population in two districts of Aceh, Indonesia. The sample is drawn from the Study of the Tsunami Aftermath and Recovery (STAR), a survey with data collected both before and after the disaster and especially designed to identify the impact of the tsunami. The altruistic and trusting attitudes of the respondents are measured by their behavior in the dictator and trust games. I find that witnessing closely the damage caused by the tsunami but without suffering severe economic damage oneself increases altruistic and trusting behavior, particularly towards individuals from tsunami affected communities. Having suffered severe economic damage has no impact on altruistic behavior but may have increased trusting behavior. These effects do not seem to be caused by the consequences of the tsunami on people’s financial situation. Instead they are consistent with how experiences of loss and solidarity may have shaped social attitudes by affecting empathy and perceptions of who is deserving of aid and trust.

In the second chapter, co-authored with Ryan Brown, Duncan Thomas and Andrea Velasquez, we investigate how attitudes toward financial risk are affected by elevated levels of insecurity and uncertainty brought on by the Mexican Drug War. To conduct our analysis, we pair the Mexican Family Life Survey (MxFLS), a rich longitudinal dataset ideally suited for our purposes, with a dataset on homicide rates at the month and municipality-level. The homicide rates capture well the overall crime environment created by the drug war. The MxFLS elicits risk attitudes by asking respondents to choose between hypothetical gambles with different payoffs. Our strategy to identify a causal effect has two key components. First, we implement an individual fixed effects strategy which allows us to control for all time-invariant heterogeneity. The remaining time variant heterogeneity is unlikely to be correlated with changes in the local crime environment given the well-documented political origins of the Mexican Drug War. We also show supporting evidence in this regard. The second component of our identification strategy is to use an intent-to-treat approach to shield our estimates from endogenous migration. Our findings indicate that exposure to greater local-area violent crime results in increased risk aversion. This effect is not driven by changes in financial circumstances, but may be explained instead by heightened fear of victimization. Nonetheless, we find that having greater economic resources mitigate the impact. This may be due to individuals with greater economic resources being able to avoid crime by affording better transportation or security at work.

The third chapter, co-authored with Duncan Thomas, evaluates whether attitudes toward deferred gratification change after having children. For this study we also exploit the MxFLS, which elicits attitudes toward deferred gratification (commonly known as time discounting) by asking individuals to choose between hypothetical payments at different points in time. We implement a difference-in-difference estimator to control for all time-invariant heterogeneity and show that our results are robust to the inclusion of time varying characteristics likely correlated with child birth. We find that becoming a mother increases time discounting especially in the first two years after childbirth and in particular for those women without a spouse at home. Having additional children does not have an effect and the effect for men seems to go in the opposite direction. These heterogeneous effects suggest that child rearing may affect time discounting due to generated stress or not fully anticipated spending needs.

Interactions between nematodes, potato and soil-borne micro-organisms and their effect on the management of potato cyst nematodes

Potato cyst nematodes (PCN) cause significant damage to the potato crop worldwide and growers experience economic losses related to yield loss and the cost of control measures. Experiments were set up to further elucidate the complex tritrophic PCNpotato-soil bacteria relationship. Bacterial strains isolated from the sugar beet rhizosphere were shown to be hatch active towards Globodera pallida and to be capable of successfully colonising the sugar beet rhizosphere when applied exogenously. A trap-crop system, based on these isolates, was proposed. Ridge and bulk soil taken from a commercial potato field were incubated with sterile potato root leachate (sPRL) and subsequent in vitro hatching assays showed that PCN hatch was influenced by microorganisms present in the ridge, but not in the bulk soil. Community level physiological profiling (CLPP) of ridge and bulk soil, using BIOLOG EcoplatesTM, demonstrated differences in bacterial functional diversity between the two soil types. An investigation of the inter-species competition between G. pallida and G. rostochiensis showed that G. pallida performed significantly better, in terms of multiplication rate, in competition with G. rostochiensis compared to its multiplication rate in single-species populations. Effectively removing the early hatch of G. rostochiensis in pot trials led to the removal of this competitive advantage of G. pallida suggesting that this advantage was due, at least in part, to morphological changes to the root caused by the early hatching of G. rostochiensis.

Surgical Procedure Characteristics and Risk of Sharps-Related Blood and Body Fluid Exposure.

OBJECTIVE To use a unique multicomponent administrative data set assembled at a large academic teaching hospital to examine the risk of percutaneous blood and body fluid (BBF) exposures occurring in operating rooms. DESIGN A 10-year retrospective cohort design. SETTING A single large academic teaching hospital. PARTICIPANTS All surgical procedures (n=333,073) performed in 2001-2010 as well as 2,113 reported BBF exposures were analyzed. METHODS Crude exposure rates were calculated; Poisson regression was used to analyze risk factors and account for procedure duration. BBF exposures involving suture needles were examined separately from those involving other device types to examine possible differences in risk factors. RESULTS The overall rate of reported BBF exposures was 6.3 per 1,000 surgical procedures (2.9 per 1,000 surgical hours). BBF exposure rates increased with estimated patient blood loss (17.7 exposures per 1,000 procedures with 501-1,000 cc blood loss and 26.4 exposures per 1,000 procedures with >1,000 cc blood loss), number of personnel working in the surgical field during the procedure (34.4 exposures per 1,000 procedures having ≥15 personnel ever in the field), and procedure duration (14.3 exposures per 1,000 procedures lasting 4 to <6 hours, 27.1 exposures per 1,000 procedures lasting ≥6 hours). Regression results showed associations were generally stronger for suture needle-related exposures. CONCLUSIONS Results largely support other studies found in the literature. However, additional research should investigate differences in risk factors for BBF exposures associated with suture needles and those associated with all other device types. Infect. Control Hosp. Epidemiol. 2015;37(1):80-87.

A New Method for Modeling Free Surface Flows and Fluid-structure Interaction with Ocean Applications

The computational modeling of ocean waves and ocean-faring devices poses numerous challenges. Among these are the need to stably and accurately represent both the fluid-fluid interface between water and air as well as the fluid-structure interfaces arising between solid devices and one or more fluids. As techniques are developed to stably and accurately balance the interactions between fluid and structural solvers at these boundaries, a similarly pressing challenge is the development of algorithms that are massively scalable and capable of performing large-scale three-dimensional simulations on reasonable time scales. This dissertation introduces two separate methods for approaching this problem, with the first focusing on the development of sophisticated fluid-fluid interface representations and the second focusing primarily on scalability and extensibility to higher-order methods.

We begin by introducing the narrow-band gradient-augmented level set method (GALSM) for incompressible multiphase Navier-Stokes flow. This is the first use of the high-order GALSM for a fluid flow application, and its reliability and accuracy in modeling ocean environments is tested extensively. The method demonstrates numerous advantages over the traditional level set method, among these a heightened conservation of fluid volume and the representation of subgrid structures.

Next, we present a finite-volume algorithm for solving the incompressible Euler equations in two and three dimensions in the presence of a flow-driven free surface and a dynamic rigid body. In this development, the chief concerns are efficiency, scalability, and extensibility (to higher-order and truly conservative methods). These priorities informed a number of important choices: The air phase is substituted by a pressure boundary condition in order to greatly reduce the size of the computational domain, a cut-cell finite-volume approach is chosen in order to minimize fluid volume loss and open the door to higher-order methods, and adaptive mesh refinement (AMR) is employed to focus computational effort and make large-scale 3D simulations possible. This algorithm is shown to produce robust and accurate results that are well-suited for the study of ocean waves and the development of wave energy conversion (WEC) devices.

Element analyses of DSDP/ODP Hole 504B basalt and breccia (Table 2)

Geochemical well logs were used to measure the dry weight percent oxide abundances of Si, Al, Ca, Mg, Fe, Ti, and K and the elemental abundances of Gd, S, Th, and U at 0.15-m intervals throughout the basement section of Hole 504B. These geochemical data are used to estimate the integrated chemical exchange resulting from hydrothermal alteration of the oceanic crust that has occurred over the last 5.9 Ma. A large increase in Si in the transition zone between pillows and dikes (Layers 2B and 2C) indicates that mixing of hot, upwelling hydrothermal fluids with cold, downwelling seawater occurred in the past at a permeability discontinuity at this level in the crust, even though the low-to-high permeability boundary in Hole 504B is now 500 m shallower (at the Layer 2A/2B boundary). The observations of extensive Ca loss and Mg gain agree with chemical exchanges recorded in the laboratory in experiments on the reactions that occur between basalt and seawater at high temperatures. The K budget requires significant addition to Layer 2A from both high-temperature depletion in Layers 2B and 2C and low-temperature alteration by seawater. Integrated water/rock ratios are derived for the mass of seawater required to add enriched elements and for the mass of hydrothermal fluid required to remove depleted elements in the crust at Hole 504B.

Experimental and RANS-CFD Study of Nacelle Drag

The drag on a nacelle model was investigated experimentally and computationally to provide guidance and insight into the capabilities of RANS-based CFD. The research goal was to determine whether industry constrained CFD could participate in the aerodynamic design of nacelle bodies. Grid refinement level, turbulence model and near wall treatment settings, to predict drag to the highest accuracy, were key deliverables. Cold flow low-speed wind tunnel experiments were conducted at a Reynolds number of 6∙〖10〗^5, 293 K and a Mach number of 0.1. Total drag force was measured by a six-component force balance. Detailed wake analysis, using a seven-hole pressure probe traverse, allowed for drag decomposition via the far-field method. Drag decomposition was performed through a range of angles of attack between 0o and 45o. Both methods agreed on total drag within their respective uncertainties. Reversed flow at the measurement plane and saturation of the load cell caused discrepancies at high angles of attack. A parallel CFD study was conducted using commercial software, ICEM 15.0 and FLUENT 15.0. Simulating a similar nacelle geometry operating under inlet boundary conditions obtained through wind tunnel characterization allowed for direct comparisons with experiment. It was determined that the Realizable k-ϵ was best suited for drag prediction of this geometry. This model predicted the axial momentum loss and secondary flow in the wake, as well as the integrated surface forces, within experimental error up to 20o angle of attack. SST k-ω required additional surface grid resolution on the nacelle suction side, resulting in 15% more elements, due to separation point prediction sensitivity. It was further recommended to apply enhanced wall treatment to more accurately capture the viscous drag and separated flow structures. Overall, total drag was predicted within 5% at 0o angle of attack and 10% at 20o, each within experimental uncertainty. What is more, the form and induced drag predicted by CFD and measured by the wake traverse shared good agreement. Which indicated CFD captured the key flow features accurately despite simplification of the nacelle interior geometry.

Duelo, ansiedad y depresión en familiares de pacientes en una unidad de cuidados paliativos a los dos meses de la pérdida

Aim: This study is going to assess the prevalance of prolonged grief diagnoses and it will evaluate the severity of the symptoms of depression, anxiety and complicated grief two months after a loved one is lost. We also intend to study which variables associated with the risk of grief could be more decisive when diagnosing it, its symptoms and the consequent emotional distress.Method: A total of 66 families of patients in the Palliative Care Unit (PCU) at Hospital San Cecilio in Granada have been evaluated. Measurements were taken two months after the death. This investigation has explored the existing emotional distress using the following questionnaires: Beck Depression Inventory (BDI-II), Beck Anxiety Inventory (BAI), Inventory of Complicated Grief (ICG) and Prolongued Grief Disorder (PG-12).Results: The results show that 33.3% and 21.21% of the sufferers had high levels of depression and clinical anxiety two months after the death. The prevalence of prolongued grief diagnoses, according to the PG-12, is 10.6% and 53.03% of the participants showed symptoms of complicated grief according to the ICG. Additionally, statistically significant differences are found in the sufferers with and without a prolongued grief diagnosis and scores in the ICG and BDI-II. The family’s financial situation is linked to the presence of symptoms of anxiety and depression and complicated grief, with the most determining variable being the risk of grief. Finally, the greater the age of the deceased and the longer the time spent in the PCU is linked to fewer symptoms of grief. However, important links have been found between the sufferers who have experienced stressful critical events prior to losing their loved one, with symptoms of depression, anxiety and complicated grief.Conclusions: The high numbers of cases of symptoms of complicated grief and levels of anxiety and clinical depression two months after a death suggests that early interventions should be carried out in those individuals with greater vulnerability.

Managing Rentals with Usage-Based Loss

Motivated by new and innovative rental business models, this paper develops a novel discrete-time model of a rental operation with random loss of inventory due to customer use. The inventory level is chosen before the start of a finite rental season, and customers not immediately served are lost. Our analysis framework uses stochastic comparisons of sample paths to derive structural results that hold under good generality for demands, rental durations, and rental unit lifetimes. Considering different \recirculation" rules | i.e., which rental unit to choose to meet each demand | we prove the concavity of the expected profit function and identify the optimal recirculation rule. A numerical study clarifies when considering rental unit loss and recirculation rules matters most for the inventory decision: Accounting for rental unit loss can increase the expected profit by 7% for a single season and becomes even more important as the time horizon lengthens. We also observe that the optimal inventory level in response to increasing loss probability is non-monotonic. Finally, we show that choosing the optimal recirculation rule over another simple policy allows more rental units to be profitably added, and the profit-maximizing service level increases by up to 6 percentage points.

Assessing the Association between Receipt of Antimalarial Drugs and Adverse Pregnancy Outcomes using Pooled Data

Thesis (Ph.D.)--University of Washington, 2016-08

Mania Triggered by Sleep Loss: Implications for Postpartum Psychosis

Background and Aims To examine whether a history of mood episodes triggered by sleep loss is associated with (1) postpartum psychosis (PP) and (2) more broadly-defined postpartum mood episodes that included postnatal depression (PND), in women with bipolar disorder (BD). Methods Participants were 622 parous women with a diagnosis of bipolar-I disorder recruited in the UK to the Bipolar Disorder Research Network. Diagnosis and perinatal episodes were assessed via interview and case note data. Women were also asked during the interview whether episodes of mania and/or depression were triggered by sleep loss. We compared the rates of PP and PND within women who did and did not endorse sleep loss as a trigger of mood episodes. Results Women who reported that their episodes of mania were usually triggered by sleep loss were twice as likely to have experienced an episode of PP (OR = 2.00, 95% CI = 1.20–3.36) than women who did not report this. This effect remained significant when controlling for clinical and demographic factors. We found no significant associations between depression triggered by sleep loss and PP. Analyses in which we defined postpartum episodes at a broader level to include both PP and PND were not significant. Conclusions In pregnant women with BD, a history of mania following sleep loss could be a potential marker of vulnerability to severe postpartum episodes. Further study in prospective samples is required in order to confirm these findings, which may have important implications for understanding the aetiology of PP and of mood disorders more generally.

Mutations in SNX14 cause a distinctive autosomal-recessive cerebellar ataxia and intellectual disability syndrome

Intellectual disability and cerebellar atrophy occur together in a large number of genetic conditions and are frequently associated with microcephaly and/or epilepsy. Here we report the identification of causal mutations in Sorting Nexin 14 (SNX14) found in seven affected individuals from three unrelated consanguineous families who presented with recessively inherited moderate-severe intellectual disability, cerebellar ataxia, early-onset cerebellar atrophy, sensorineural hearing loss, and the distinctive association of progressively coarsening facial features, relative macrocephaly, and the absence of seizures. We used homozygosity mapping and whole-exome sequencing to identify a homozygous nonsense mutation and an in-frame multiexon deletion in two families. A homozygous splice site mutation was identified by Sanger sequencing of SNX14 in a third family, selected purely by phenotypic similarity. This discovery confirms that these characteristic features represent a distinct and recognizable syndrome. SNX14 encodes a cellular protein containing Phox (PX) and regulator of G protein signaling (RGS) domains. Weighted gene coexpression network analysis predicts that SNX14 is highly coexpressed with genes involved in cellular protein metabolism and vesicle-mediated transport. All three mutations either directly affected the PX domain or diminished SNX14 levels, implicating a loss of normal cellular function. This manifested as increased cytoplasmic vacuolation as observed in cultured fibroblasts. Our findings indicate an essential role for SNX14 in neural development and function, particularly in development and maturation of the cerebellum.

Exploring the Process of Meaning-making after Partner Suicide

Meaning-making is increasingly recognized as a fundamental aspect of the grief experience. This study investigated the process of meaning-making in the narratives of individuals whose partners died by suicide, exploring their meaning reconstruction in response to this form of loss. The narratives of users of a public online grief support forum (n = 50) were analyzed using the Meaning of Loss Codebook (Gillies, Neimeyer, & Milman, 2014), which consists of core categories of meaning of loss in response to the death of a loved one. The results indicated that these individuals predominantly experienced negative affect, a lack of understanding associated with the loss, and a longing for their partners. The grief experience of participants in this study was marked by substantial psychological distress and an ongoing struggle to make sense of and find meaning in this type of loss. It is clear that grieving the loss of a partner as a result of suicide presents unique challenges to meaning-making in comparison to other types of loss. Given the importance of this aspect of adjustment to loss, these findings deepen the understanding of this component of grief and inform the provision of support for those grieving a loved one who died by suicide.

GEOTECHNICAL AND ENVIRONMENTAL IMPACTS OF STEEL SLAG IN EMBANKMENTS

Steel slag is a byproduct of iron and steel production by the metallurgical industries. Annually, 21 million tons of steel slag is produced in the United States. Most of the slag is landfilled, which represents a significant economic loss and a waste of valuable land space. Steel slag has great potential for the construction of highway embankments; however, its use has been limited due to its high swelling potential and alkalinity. The swelling potential of steel slags may lead to deterioration of the structural stability of highways, and high alkalinity poses an environmental challenge as it affects the leaching behavior of trace metals. This study seeks a methodology that promotes the use of steel slag in highway embankments by minimizing these two main disadvantages. Accelerated swelling tests were conducted to evaluate the swelling behavior of pure steel slag and water treatment residual (WTR) treated steel slag, where WTR is an alum-rich by-product of drinking water treatment plants. Sequential batch tests and column leach tests, as well as two different numerical analyses, UMDSurf and WiscLEACH, were carried out to check the environmental suitability of the methods. Tests were conducted to study the effect of a common borrow fill material that encapsulated the slag in the embankment and the effects of two subgrade soils on the chemical properties of slag leachate. The results indicated that an increase in WTR content in the steel slag-WTR mixtures yields a decrease in pH and most of the leached metal concentrations, except aluminum. The change in the levels of pH, after passing through encapsulation and subgrade, depends on the natural pHs of materials.

IDEATIONAL REPRESENTATIONS OF EDENTULISM AND PROSTHETIC REHABILITATION FROM THE POINT OF VIEW OF THE ELDERLY

Objetivo: Identificar as representações ideativas de idosos edêntulos uni ou bimaxilares acerca das perdas dentárias e da reabilitação protética oral. Métodos: Estudo qualitativo, realizado entre janeiro e março de 2011 com sete idosos residentes em uma Instituição Pública de Longa Permanência do Recife-PE, com 14 idosos em atendimento na Clínica de Prótese Dentária da Universidade Federal de Pernambuco (UFPE). Coletaram-se os dados através de uma entrevista semiestruturada que passou por análise de conteúdo. Resultados: Os achados possibilitaram identificar que, para os idosos, os dentes contribuíam tanto para a saúde quanto como para facilitar interações sociais, enquanto o edentulismo foi associado a uma pluralidade de sentimentos negativos. Quanto à reabilitação protética, eles enfatizaram os prejuízos para a saúde devido a próteses mal adaptadas. Conclusão: Os idosos acreditam que o edentulismo e a reabilitação protética estão associados, principalmente, a um conceito mecanicista da profissão, amplamente difundido entre os profissionais que privilegiam mais a odontologia curativa em detrimento da prevenção. Nesse contexto, para que o envelhecimento possa ser considerado uma etapa da vida com as mesmas qualidades e dificuldades de qualquer outra, sugere-se aos gestores e aos próprios profissionais em saúde que se comprometam mais com uma prática odontológica humanizadora e preventiva, a fim de proverem os requisitos mínimos para um envelhecimento com dignidade.