Elucidating the functions of fibroblast growth factor 9 in multiple sclerosis

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system. In around 85% of cases, the disease progresses through two distinct stages: relapsing-remitting MS (RRMS) is driven by repeated bouts of demyelination caused by autoimmune inflammation; and progressive MS, in which inflammation gives way to neurodegenerative processes that lead to axonal loss and the steady accumulation of disability. There is no cure for MS and the majority of disease-slowing treatments target the immune response in RRMS. These interventions are ineffective in progressive MS and other treatment options are extremely limited. Understanding the mechanisms underlying neurodegeneration in MS is critically important to developing therapeutics for progressive disease. Fibroblast growth factor 9 (FGF9) has recently been implicated in the pathogenesis of MS. FGF9 inhibits myelination and promotes the production of inflammatory chemokines. This led to the hypothesis that FGF9 is involved in remyelination failure and may promote neurodegeneration via tissue remodelling and inflammatory pathways. FGF signaling is complex and the findings in MS raised many questions: what cells respond to FGF9 in MS? Why is FGF9 expression induced in the first place? Can FGF9 cause demyelination as well as inhibit myelination? This thesis has focused on the roles of FGF9 in MS and tried to answer these questions. Through in vitro models, astrocytes, oligodendrocytes, and macrophages were shown to express feedback inhibitors of FGF signaling when treated with FGF9. Astrocytes produced FGF9 in response to hypoxic stress, macrophages expressed FGF9 when polarized towards an anti-inflammatory phenotype, suggesting hypoxia, and repair processes may drive FGF9 expression in the CNS. FGF9 did not cause demyelination in vitro but over-expression in vivo induced severe demyelination over the course of several months. Oligodendrocytes exposed to FGF9 failed to differentiate properly when the factor was removed which led to aberrant myelination. Long-term treatment with FGF9 induced axonal pathology, potentially via deficits in axon-transport. Over-expression of FGF9 in rat cortex also produced an axonal pathology, which suggests chronic exposure is detrimental to neurons. Together, these findings indicate that increased levels of FGF9 are detrimental to myelination and neurons in the CNS. Demyelination, and axonal pathology are hallmarks of MS and these studies provide evidence that FGF9 can mediate these processes in in vitro and in vivo models

A State University’s Assessment of ACUE: Feasible Model for Evaluating the Impact of a Faculty Instruction Quality Program

State comprehensive universities often stress the development of teaching quality to improve the outcomes and retention of students, especially for recently matriculated students. These universities invest in teaching quality programs, but often lack a feasible method to examine the longitudinal impacts of these programs. The purpose of this paper is to provide a model for universities to evaluate outcomes related teaching quality programs. ACUE, a teaching quality program, was implemented across 30 instructors, which equated to 463 course sections. ACUE instructors were matched to non-ACUE instructors using propensity score matching (PSM) and compared on the rate of end-of-the-semester students with DFW (underperformance) standing across course sections. PSM was based on if courses were honors sections, lower level classes, size of enrollment in the sections, and if the section occurred after the completion of the program. DFW rate is a parsimonious metric that predict retention. The ACUE recipients had an average treatment effect of -.37, or 3.7% fewer students receiving a DFW. That translated to 171 fewer DFW grades. Implications include that the use of PSM and DFW rates could help universities examine longitudinal outcomes for teaching quality programs. Given the financial and personnel resources needed for program like ACUE, comprehensive regional universities could use similar methods to determine if the investment yields satisfactory returns

Performance of Foundations and Retaining Structures

The design, construction, and performance of several building foundations and temporary earth retaining structures located in the downtown area of White Plains, New York are presented in this paper. High rise structures were supported on shallow mat or spread foundations bearing on erratic saturated alluvial silt and sand deposits. Additionally, the construction of two and three level underground parking structures required the use of cantilevered and braced excavation support systems to retain the adjacent streets and utilities. Several assumptions were required to design and predict the performance of the building foundations and retaining structures. The accuracy of these assumptions was verified through the use of precise field measurements during and after construction. The results of these field measurements and comparison with predicted values are presented and discussed

Quantifying the stratigraphic completeness of delta shoreline trajectories

Understanding the incomplete nature of the stratigraphic record is fundamental for interpreting stratigraphic sequences. Methods for quantifying stratigraphic completeness for one-dimensional stratigraphic columns, defined as the proportion of time intervals of some length that contain stratigraphy, are commonplace; however, quantitative assessments of completeness in higher dimensions are lacking. Here we present a metric for defining stratigraphic completeness of two-dimensional shoreline trajectories using topset-foreset rollover positions in dip-parallel sections and describe the preservation potential of a shoreline trajectory derived from the geometry of the delta surface profile and the kinematics of the geomorphic shoreline trajectory. Two end-member forward models are required to fully constrain the preservation potential of the shoreline dependent on whether or not a topset is eroded during base level fall. A laboratory fan-delta was constructed under nonsteady boundary conditions, and one-dimensional stratigraphic column and two-dimensional shoreline completeness curves were calculated. Results are consistent with the hypothesis derived from conservation of sediment mass that completeness over all timescales should increase given increasing dimensions of analysis. Stratigraphic trajectories and completeness curves determined from forward models using experimental geomorphic trajectories compare well to values from transects when subsampled to the equivalent stratigraphic resolution as observed in the actual preserved sequence. The concept of stratigraphic completeness applied to two-dimensional trajectory analysis and the end-member forward models presented here provide novel tools for a conceptual understanding of the nature of stratigraphic preservation at basin scales

Cardiac Tamponade: Innovative Sternotomy Simulation Model for Training Pediatric Cardiac Intensive Care Team

Introduction: Cardiac tamponade occurring after cardiac surgery is rare but life threatening and requires simultaneous resuscitation and emergent sternotomy by the intensive care team. A simulated scenario using innovative mannequin with sternotomy wound has the capability of reproducing cardiac arrest associated with postoperative tamponade. We evaluated the face validity of this innovative mannequin, the confidence level and crisis resource management skills of the team during sternotomy to manage postoperative cardiac tamponade. Methods: The simulation case scenario was developed using innovative sternotomy mannequin for children’s hospital cardiac intensive care unit (CICU) teams. The case involved a 3-year old male, intubated, mechanically ventilated after surgical repair of CHD, progressing to cardiac arrest due to cardiac tamponade. We conducted a structured, video debriefing following each scenario. We conducted a formative learner assessment before and after each scenario and analyzed the data using student t-test. Results: Of the 72 CICU providers, a statistically significant proportion of providers (p \u3c 0.0001) showed improved confidence in assessing and managing cardiac arrest occurring following postoperative cardiac tamponade. All the providers scored ≥ 3 for impact of the scenario on practice, teamwork, communication, assessment skills, improvement in CPR and opening the chest and their confidence in attending similar clinical situation in future. Most (96–100%) scored ≥ 3 for perception on realism of mannequin, the scenario, re-opening the sternotomy and level of stress. Conclusions: Innovative adaptation of a high-fidelity mannequin for cardiac tamponade simulation can achieve a realistic and reproducible training model with a positive impact on multi-disciplinary team training

Space Station Engineering Design Issues

Space Station Freedom topics addressed include: general design issues; issues related to utilization and operations; issues related to systems requirements and design; and management issues relevant to design

Oxygen treatment reduces neurological deficits and demyelination in two animal models of multiple sclerosis

AIMS: To explore the importance of tissue hypoxia in causing neurological deficits and demyelination in the inflamed CNS, and the value of inspiratory oxygen treatment, using both active and passive experimental autoimmune encephalomyelitis (EAE). METHODS: Normobaric oxygen treatment was administered to Dark Agouti rats with either active or passive EAE, compared with room air-treated, and naïve, controls. RESULTS: Severe neurological deficits in active EAE were significantly improved after just 1 hour of breathing ~95% oxygen. The improvement was greater and more persistent when oxygen was applied either prophylactically (from immunization for 23 days), or therapeutically from the onset of neurological deficits for 24, 48, or 72 hours. Therapeutic oxygen for 72 hours significantly reduced demyelination and the integrated stress response in oligodendrocytes at the peak of disease, and protected from oligodendrocyte loss, without evidence of increased oxidative damage. T-cell infiltration and cytokine expression in the spinal cord remained similar to that in untreated animals. The severe neurological deficit of animals with passive EAE occurred in conjunction with spinal hypoxia and was significantly reduced by oxygen treatment initiated before their onset. CONCLUSIONS: Severe neurological deficits in both active and passive EAE can be caused by hypoxia and reduced by oxygen treatment. Oxygen treatment also reduces demyelination in active EAE, despite the autoimmune origin of the disease

Sulfatide Preserves Insulin Crystals Not by Being Integrated in the Lattice but by Stabilizing Their Surface

Background. Sulfatide is known to chaperone insulin crystallization within the pancreatic beta cell, but it is not known if this results from sulfatide being integrated inside the crystal structure or by binding the surface of the crystal. With this study, we aimed to characterize the molecular mechanisms underlying the integral role for sulfatide in stabilizing insulin crystals prior to exocytosis. Methods. We cocrystallized human insulin in the presence of sulfatide and solved the structure by molecular replacement. Results. The crystal structure of insulin crystallized in the presence of sulfatide does not reveal ordered occupancy representing sulfatide in the crystal lattice, suggesting that sulfatide does not permeate the crystal lattice but exerts its stabilizing effect by alternative interactions such as on the external surface of insulin crystals. Conclusions. Sulfatide is known to stabilize insulin crystals, and we demonstrate here that in beta cells sulfatide is likely coating insulin crystals. However, there is no evidence for sulfatide to be built into the crystal lattice

Gender differences in the association between adiposity and probable major depression: a cross-sectional study of 140,564 UK Biobank participants

<b>Background</b><p></p> Previous studies on the association between adiposity and mood disorder have produced contradictory results, and few have used measurements other than body mass index (BMI). We examined the association between probable major depression and several measurements of adiposity: BMI, waist circumference (WC), waist-hip-ratio (WHR), and body fat percentage (BF%).<p></p> <b>Methods</b><p></p> We conducted a cross-sectional study using baseline data on the sub-group of UK Biobank participants who were assessed for mood disorder. Multivariate logistic regression models were used, adjusting for potential confounders including: demographic and life-style factors, comorbidity and psychotropic medication.<p></p> <b>Results</b><p></p> Of the 140,564 eligible participants, evidence of probable major depression was reported by 30,145 (21.5%). The fully adjusted odds ratios (OR) for obese participants were 1.16 (95% confidence interval (CI) 1.12, 1.20) using BMI, 1.15 (95% CI 1.11, 1.19) using WC, 1.09 (95% CI 1.05, 1.13) using WHR and 1.18 (95% CI 1.12, 1.25) using BF% (all p <0.001). There was a significant interaction between adiposity and gender (p = 0.001). Overweight women were at increased risk of depression with a dose response relationship across the overweight (25.0-29.9 kg/m2), obese I (30.0-34.9 kg/m2), II (35.0-39.9 kg/m2) and III (≥40.0 kg/m2) categories; fully adjusted ORs 1.14, 1.20, 1.29 and 1.48, respectively (all p < 0.001). In contrast, only obese III men had significantly increased risk of depression (OR 1.29, 95% CI 1.08, 1.54, p = 0.006).<p></p> <b>Conclusion</b><p></p> Adiposity was associated with probable major depression, irrespective of the measurement used. The association was stronger in women than men. Physicians managing overweight and obese women should be alert to this increased risk