Making it count : novel behavioural tasks to quantify symptoms of dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is a neurodegenerative disease and a common cause of dementia in the elderly. The primary pathology of DLB is the mis-folding of the α-synuclein protein, classifying DLB as a synucleinopathy. However, concomitant pathologies are commonly found in post-mortem examination of DLB patients that may complicate diagnosis. Furthermore, DLB is a relatively new disease, first discovered in 1976, while the first official diagnostic criteria released in 1996. Consequently, the diagnostic criteria for DLB have evolved as more is learnt about the clinical and neuropathological profile. Synucleinopathies are also known to be heterogeneous, with no single symptom or biomarker present in all DLB cases. Instead, combinations of common symptoms lead to a diagnosis of probable DLB. Two of the most prominent and debilitating symptoms of DLB are visual hallucinations and cognitive fluctuations. Visual hallucinations (VH) in DLB patients are typically vivid, well-formed percepts and are a major cause of patient and caregiver stress as well as a risk factor for the patient being placed into professional care. Cognitive fluctuations (CF) involve a cycling change in attention and alertness and may occur on a daily or monthly basis, while drops in awareness may last seconds or hours. Currently, the only tools to measure cognitive fluctuations or visual hallucinations are scales or questionnaires that rely on responses from the patient or informant. Furthermore, severity of the symptom is then ranked on an arbitrary ranking system. While this method has advantages in a clinical setting, the subjective nature of the scales combined with the ranking of scores results in a loss of sensitivity. In a research setting, especially imaging or clinical trials, objective measures that are sensitive to changes in symptom severity are highly valued. This allows researchers to assess the relationship between behavioural and fMRI data and clinicians to observe subtle changes in severity. Furthermore, the measures need to be easy to conduct as patients are often severely impaired. The aim of this thesis is to test cognitive function using three paradigms that are novel to DLB patients: Sustained Attention Response Task (SART), the Mental Rotation (MR) task and the Bistable Percept Paradigm (BPP). Overall, this thesis provided the groundwork needed before these three tasks can be utilised in a clinical or research setting. Moreover, as each task was accessible to DLB patients and provided a measure associated with VH or CF, they may prove useful for future neuroimaging/neuropsychological studies

AN EXPERIMENTAL ECONOMICS APPROACH TO ANALYZING PRICE DISCOVERY IN FORWARD AND SPOT MARKETS

Laboratory experiments are used to generate data that facilitate investigation of pricing behavior in forward and spot markets. Results suggest a tendency for prices in a spot market to converge to levels higher than those in a forward market. The difference in these market environments is the supply schedule. Buyers in a spot market are aware that supply is inelastic and become relatively aggressive bidders. Forward markets have a relatively elastic supply schedule and buyers fare better. This may motivate firms to promote forward markets and/or vertically integrate in the procurement of inputs.Experimental economics, Forward market, Price discovery, Spot market, Marketing,

Test Analysis Correlation of the Single Stringer Bending Tests for the Space Shuttle ET-137 Intertank Stringer Crack Investigation

On November 5, 2010, Space Shuttle mission STS-133 was scrubbed due to a hydrogen leak at the Ground Umbilical Carrier Plate (GUCP). After the scrub, a crack in the foam thermal protection system (TPS) was observed on the External Tank (ET) near the interface between the liquid oxygen (LOX) tank and the Intertank. When the damaged foam was removed, two 9-in. long cracks were found on the feet of Intertank stringer S7-2, and the stringer failure was the cause of the TPS crack. An investigation was conducted to determine the root cause of the cracks, establish a remedy/repair for the stringers, and provide flight rationale for the damaged tank, ET-137. The Space Transportation System (STS) Super Lightweight ET (SLWT) is comprised of two propellant tanks (an aft liquid hydrogen (LH2) tank and a forward LOX tank) and an Intertank. The Intertank serves as the structural connection between the two propellant tanks and also functions to receive and distribute all thrust loads from the solid rocket boosters . The Intertank is a stiffened cylinder structure consisting of eight mechanically joined panels (two integrally-stiffened, machined thrust panels to react the booster loads and six stringer-stiffened skin panels). There are one main ring frame, four intermediate ring frames, and forward and aft flange chords that mate to the respective propellant tanks.. The skin/stringer panels utilize external hat-section stringers that are mechanically attached with rivets along most of their length and with specialty fasteners, such as GP Lockbolts and Hi-Loks, at the forward and aft ends where the stringers attach to the flange chords. During the STS-133 Intertank stringer crack investigation, cracks were found on a total of five stringers. All of the cracks were at the LOX end, in the feet of the stringers, and near the forward fasteners (GP Lockbolts). Video of tanking for the November 5 launch attempt was used to determine that the TPS failure, and thus the stringer failure, occurred as the LOX liquid level crossed the LOX tank / Intertank interface ring frame. Hence, cryogenically-induced displacements were suspected as a contributing cause of the stringer cracks. To study the behavior of Intertank stringers subjected to similar displacements, static load tests of individual stringers, colloquially known as "single stringer bending tests" were performed. Approximately thirty stringers were tested, many of which were cut from the partially completed Intertank for what would have been ET-139. In addition to the tests, finite element (FE) analyses of the test configuration were also performed. In this paper, the FE analyses and test-analysis correlation for stringer test S6-8 are presented. Stringer S6-8 is a "short chord" configuration with no doubler panels

Star formation in the merging Galaxy NGC3256

The central 5 kpc of the ultra-luminous merging galaxy NGC 3256 was mapped at J, H, K, L, and 10 micrometer, and a 2 micrometer spectra of the nuclear region was obtained. This data was used to identify and characterize the super starburst which has apparently been triggered and fuelled by the merger of two gas rich galaxies. It is also shown that the old stellar population has relaxed into a single spheroidal system, and that a supernova driven wind might eventually drive any remaining gas from the system to leave a relic which will be indistinguishable from an elliptical galaxy

Changes in structural network topology correlate with severity of hallucinatory behavior in Parkinson's disease

Inefficient integration between bottom-up visual input and higher order visual processing regions is implicated in visual hallucinations in Parkinson's disease (PD). Here, we investigated white matter contributions to this perceptual imbalance hypothesis. Twenty-nine PD patients were assessed for hallucinatory behavior. Hallucination severity was correlated to connectivity strength of the network using the network-based statistic approach. The results showed that hallucination severity was associated with reduced connectivity within a subnetwork that included the majority of the diverse club. This network showed overall greater between-module scores compared with nodes not associated with hallucination severity. Reduced between-module connectivity in the lateral occipital cortex, insula, and pars orbitalis and decreased within-module connectivity in the prefrontal, somatosensory, and primary visual cortices were associated with hallucination severity. Conversely, hallucination severity was associated with increased between- and within-module connectivity in the orbitofrontal and temporal cortex, as well as regions comprising the dorsal attentional and default mode network. These results suggest that hallucination severity is associated with marked alterations in structural network topology with changes in participation along the perceptual hierarchy. This may result in the inefficient transfer of information that gives rise to hallucinations in PD. Author SummaryInefficient integration of information between external stimuli and internal perceptual predictions may lead to misperceptions or visual hallucinations in Parkinson's disease (PD). In this study, we show that hallucinatory behavior in PD patients is associated with marked alterations in structural network topology. Severity of hallucinatory behavior was associated with decreased connectivity in a large subnetwork that included the majority of the diverse club, nodes with a high number of between-module connections. Furthermore, changes in between-module connectivity were found across brain regions involved in visual processing, top-down prediction centers, and endogenous attention, including the occipital, orbitofrontal, and posterior cingulate cortex. Together, these findings suggest that impaired integration across different sides across different perceptual processing regions may result in inefficient transfer of information

GBM heterogeneity as a function of variable epidermal growth factor receptor variant III activity.

Abnormal activation of the epidermal growth factor receptor (EGFR) due to a deletion of exons 2-7 of EGFR (EGFRvIII) is a common alteration in glioblastoma (GBM). While this alteration can drive gliomagenesis, tumors harboring EGFRvIII are heterogeneous. To investigate the role for EGFRvIII activation in tumor phenotype we used a neural progenitor cell-based murine model of GBM driven by EGFR signaling and generated tumor progenitor cells with high and low EGFRvIII activation, pEGFRHi and pEGFRLo. In vivo, ex vivo, and in vitro studies suggested a direct association between EGFRvIII activity and increased tumor cell proliferation, decreased tumor cell adhesion to the extracellular matrix, and altered progenitor cell phenotype. Time-lapse confocal imaging of tumor cells in brain slice cultures demonstrated blood vessel co-option by tumor cells and highlighted differences in invasive pattern. Inhibition of EGFR signaling in pEGFRHi promoted cell differentiation and increased cell-matrix adhesion. Conversely, increased EGFRvIII activation in pEGFRLo reduced cell-matrix adhesion. Our study using a murine model for GBM driven by a single genetic driver, suggests differences in EGFR activation contribute to tumor heterogeneity and aggressiveness

Evaluating quality of life tools in North American patients with erythropoietic protoporphyria and X-linked protoporphyria.

BackgroundErythropoietic protoporphyria (EPP) and X-linked Protoporphyria (XLP) are rare photodermatoses presenting with severe phototoxicity. Although anecdotally, providers who treat EPP patients acknowledge their life-altering effects, tools that fully capture their impact on quality of life (QoL) are lacking.MethodsAdult patients with EPP/XLP were given four validated QoL tools: the Patient Reported Outcomes Measurement Information System 57 (PROMIS-57), the Hospital Anxiety and Depression Scale (HADS), the Illness Perception Questionnaire Revised (IPQR), and an EPP-Specific tool. All patients received the PROMIS-57 while the HADS, IPQR, and EPP-Specific tools were introduced at a later date. Associations between responses and clinical phenotypes were explored.ResultsTwo hundred and two patients were included; 193 completed PROMIS-57, 104 completed IPQR, 103 completed HADS, and 107 completed the EPP-Specific tool. The IPQR showed that patients strongly believed EPP/XLP had a negative impact on their lives. Mean scores in anxiety and depression domains of both HADS and PROMIS-57 were normal; however, anxiety scores from HADS were borderline/abnormal in 20% of patients. The EPP-Specific tool revealed a decreased QoL in most patients. The PROMIS-57 showed that 21.8% of patients have clinically significant pain interference. Several tool domains correlated with measures of disease severity, most being from the PROMIS-57.ConclusionsImpaired QoL is an important consequence of EPP/XLP. PROMIS-57 was most sensitive in evaluating impaired QoL in EPP/XLP. Further research is needed to compare the effectiveness of it for assessing response to treatment

Interdisciplinary Graduate Training in Teaching Labs

Modern research and training in the life sciences require cross-disciplinary programs, integrating concepts and methods from biology, physics, chemistry, and mathematics. We describe the structure and outcomes from an example of one such approach, the Physiology Course at the Marine Biological Laboratory (MBL) in Woods Hole, Massachusetts, and discuss how similar intensive, team-building research courses are also being applied to improve graduate education in universities. These courses are based on teaching laboratories that have students address contemporary research questions by combining ideas and approaches from biology, computation, and physics

The Relationships Among Social Capital, HIV Self-Management, and Substance Use in Women.

Women living with HIV (WLHIV) face unique challenges to successfully self-manage HIV including substance use and limited social capital. We conducted a 6-month mixed-methods study to describe how social capital influences HIV self-management and substance use among WLHIV. Participants completed a self-report survey and in-depth interview at baseline, and 3 and 6 months. Descriptive statistics, t-tests, and generalized estimating equations (GEEs) were used to examine quantitative relationships. Qualitative data were analyzed using qualitative description. Current substance users reported lower social capital compared with past substance users (2.63 vs. 2.80; p = .34). Over time, substance use and social capital were associated with HIV self-management (Wald χ2 = 28.43; p < .001). Qualitative data suggest that HIV self-management is influenced by overlapping experiences with social capital, including influential trust, community, and value of self can be complicated by ongoing substance use. Social capital can facilitate improved HIV self-management; however, substance use and trauma can weaken this relationship