Interleukin-1 receptor 1 knockout has no effect on amyloid deposition in Tg2576 mice and does not alter efficacy following Aβ immunotherapy

BACKGROUND: Microglial activation has been proposed to facilitate clearance of amyloid β protein (Aβ) from the brain following Aβ immunotherapy in amyloid precursor protein (APP) transgenic mice. Interleukin-1 receptor 1 knockout (IL-1 R1-/-) mice are reported to exhibit blunted inflammatory responses to injury. To further define the role of IL-1-mediated inflammatory responses and microglial activation in this paradigm, we examined the efficacy of passive Aβ immunotherapy in Tg2576 mice crossed into the IL-1 R1-/- background. In addition, we examined if loss of IL-1 R1-/- modifies Aβ deposition in the absence of additional manipulations. METHODS: We passively immunized Tg2576 mice crossed into the IL-1 R1-/- background (APP/IL-1 R1-/- mice) with an anti-Aβ1-16 mAb (mAb9, IgG2a) that we previously showed could attenuate Aβ deposition in Tg2576 mice. We also examined whether the IL-1 R1 knockout background modifies Aβ deposition in untreated mice. Biochemical and immunohistochemical Aβ loads and microglial activation was assessed. RESULTS: Passive immunization with anti-Aβ mAb was effective in reducing plaque load in APP/IL-1 R1-/- mice when the immunization was started prior to significant plaque deposition. Similar to previous studies, immunization was not effective in older APP/IL-1 R1-/- mice or IL-1 R1 sufficient wild type Tg2576 mice. Our analysis of Aβ deposition in the untreated APP/IL-1 R1-/- mice did not show differences on biochemical Aβ loads during normal aging of these mice compared to IL-1 R1 sufficient wild type Tg2576 mice. CONCLUSION: We find no evidence that the lack of the IL-1 R1 receptor influences either Aβ deposition or the efficacy of passive immunotherapy. Such results are consistent with other studies in Tg2576 mice that suggest microglial activation may not be required for efficacy in passive immunization approaches

Cholestenoic acid, an endogenous cholesterol metabolite, is a potent γ-secretase modulator.

BackgroundAmyloid-β (Aβ) 42 has been implicated as the initiating molecule in the pathogenesis of Alzheimer's disease (AD); thus, therapeutic strategies that target Aβ42 are of great interest. γ-Secretase modulators (GSMs) are small molecules that selectively decrease Aβ42. We have previously reported that many acidic steroids are GSMs with potencies ranging in the low to mid micromolar concentration with 5β-cholanic acid being the most potent steroid identified GSM with half maximal effective concentration (EC50) of 5.7 μM.ResultsWe find that the endogenous cholesterol metabolite, 3β-hydroxy-5-cholestenoic acid (CA), is a steroid GSM with enhanced potency (EC50 of 250 nM) relative to 5β-cholanic acid. CA i) is found in human plasma at ~100-300 nM concentrations ii) has the typical acidic GSM signature of decreasing Aβ42 and increasing Aβ38 levels iii) is active in in vitro γ-secretase assay iv) is made in the brain. To test if CA acts as an endogenous GSM, we used Cyp27a1 knockout (Cyp27a1-/-) and Cyp7b1 knockout (Cyp7b1-/-) mice to investigate if manipulation of cholesterol metabolism pathways relevant to CA formation would affect brain Aβ42 levels. Our data show that Cyp27a1-/- had increased brain Aβ42, whereas Cyp7b1-/- mice had decreased brain Aβ42 levels; however, peripheral dosing of up to 100 mg/kg CA did not affect brain Aβ levels. Structure-activity relationship (SAR) studies with multiple known and novel CA analogs studies failed to reveal CA analogs with increased potency.ConclusionThese data suggest that CA may act as an endogenous GSM within the brain. Although it is conceptually attractive to try and increase the levels of CA in the brain for prevention of AD, our data suggest that this will not be easily accomplished

VCU Volunteers

VCU Volunteers follows VCU’s history of developing mutually partnerships with the community and is supported by VCU 2020 Theme 5- A model for community-university partnerships. VCU Volunteers will make VCU a better place to work by fostering a sense of belonging and pride in employees at all levels. The mission of VCU Volunteers is to build a collaborative employee community through the shared experience of volunteering. An employee-driven steering committee will guide the activities of the program. This committee will be denied by an employee and will include representative’s membership for Human Resources – Work/Life Resources, Community Engagement, the VCU Caring to Act Calendar Committee, and departments throughout the University. The steering committee will develop guidelines and a volunteer handbook. Volunteer activity opportunities will be presented to the steering committee, vetted according to the guidelines, and publicized to employees

Unifying Multi-State Efforts Through a Nationally Coordinated Extension Diabetes Program

The Cooperative Extension System translates research to practice and “brings the University to the people” throughout the U.S. However, the system suffers from program duplication and is challenged to scale-out effective programs. One program, Dining with Diabetes (DWD), stands out for its dissemination to multiple states. DWD is a community-based program aimed at improving diabetes management, nutrition, and physical activity behaviors. DWD was coordinated through a national working group and implemented by state Extension systems. A pragmatic, quasi-experimental study was conducted to determine the effectiveness of the national coordination model and the overall impact of DWD. Four states reported data representing 355 DWD participants. Significant differences were found in diabetes management behaviors and knowledge from pre to post- program. However, there were challenges with data analysis due to state differences in data management. We detail the transition from one state to a national workgroup, strengths and challenges of the national model, and implications for other Extension programs

Novel rat Alzheimer's disease models based on AAV-mediated gene transfer to selectively increase hippocampal Aβ levels

<p>Abstract</p> <p>Background</p> <p>Alzheimer's disease (AD) is characterized by a decline in cognitive function and accumulation of amyloid-β peptide (Aβ) in extracellular plaques. Mutations in amyloid precursor protein (APP) and presenilins alter APP metabolism resulting in accumulation of Aβ42, a peptide essential for the formation of amyloid deposits and proposed to initiate the cascade leading to AD. However, the role of Aβ40, the more prevalent Aβ peptide secreted by cells and a major component of cerebral Aβ deposits, is less clear. In this study, virally-mediated gene transfer was used to selectively increase hippocampal levels of human Aβ42 and Aβ40 in adult Wistar rats, allowing examination of the contribution of each to the cognitive deficits and pathology seen in AD.</p> <p>Results</p> <p>Adeno-associated viral (AAV) vectors encoding BRI-Aβ cDNAs were generated resulting in high-level hippocampal expression and secretion of the specific encoded Aβ peptide. As a comparison the effect of AAV-mediated overexpression of APPsw was also examined. Animals were tested for development of learning and memory deficits (open field, Morris water maze, passive avoidance, novel object recognition) three months after infusion of AAV. A range of impairments was found, with the most pronounced deficits observed in animals co-injected with both AAV-BRI-Aβ40 and AAV-BRI-Aβ42. Brain tissue was analyzed by ELISA and immunohistochemistry to quantify levels of detergent soluble and insoluble Aβ peptides. BRI-Aβ42 and the combination of BRI-Aβ40+42 overexpression resulted in elevated levels of detergent-insoluble Aβ. No significant increase in detergent-insoluble Aβ was seen in the rats expressing APPsw or BRI-Aβ40. No pathological features were noted in any rats, except the AAV-BRI-Aβ42 rats which showed focal, amorphous, Thioflavin-negative Aβ42 deposits.</p> <p>Conclusion</p> <p>The results show that AAV-mediated gene transfer is a valuable tool to model aspects of AD pathology <it>in vivo</it>, and demonstrate that whilst expression of Aβ42 alone is sufficient to initiate Aβ deposition, both Aβ40 and Aβ42 may contribute to cognitive deficits.</p

Children's traditional ecological knowledge of wild food resources: a case study in a rural village in Northeast Thailand

Consuming wild foods is part of the food ways of people in many societies, including farming populations throughout the world. Knowledge of non-domesticated food resources is part of traditional and tacit ecological knowledge, and is largely transmitted through socialization within cultural and household contexts. The context of this study, a small village in Northeast Thailand, is one where the community has experienced changes due to the migration of the parental generation, with the children being left behind in the village to be raised by their grandparents

Molecular and Phenotypic Characteristics of Healthcare- and Community-Associated Methicillin-Resistant Staphylococcus aureus at a Rural Hospital

BACKGROUND: While methicillin-resistant Staphylococcus aureus (MRSA) originally was associated with healthcare, distinct strains later emerged in patients with no prior hospital contact. The epidemiology of MRSA continues to evolve. METHODS: To characterize the current epidemiology of MRSA-colonized patients entering a hospital serving both rural and urban communities, we interviewed patients with MRSA-positive admission nasal swabs between August 2009 and March 2010. We applied hospitalization risk factor, antimicrobial resistance phenotype, and multi-locus sequence genotype (MLST) classification schemes to 94 case-patients. RESULTS: By MLST analysis, we identified 15 strains with two dominant clonal complexes (CCs)-CC5 (51 isolates), historically associated with hospitals, and CC8 (27 isolates), historically of community origin. Among patients with CC5 isolates, 43% reported no history of hospitalization within the past six months; for CC8, 67% reported the same. Classification by hospitalization risk factor did not correlate strongly with genotypic classification. Sensitivity of isolates to ciprofloxacin, clindamycin, or amikacin was associated with the CC8 genotype; however, among CC8 strains, 59% were resistant to ciprofloxacin, 15% to clindamycin, and 15% to amikacin. CONCLUSIONS: Hospitalization history was not a strong surrogate for the CC5 genotype. Conversely, patients with a history of hospitalization were identified with the CC8 genotype. Although ciprofloxacin, clindamycin, and amikacin susceptibility distinguished CC8 strains, the high prevalence of ciprofloxacin resistance limited its predictive value. As CC8 strains become established in healthcare settings and CC5 strains disseminate into the community, community-associated MRSA definitions based on case-patient hospitalization history may prove less valuable in tracking community MRSA strains

Economic evaluation of an Australian nurse home visiting programme : a randomised trial at 3 years

Objectives To investigate the additional programme cost and cost-effectiveness of ‘right@home’ Nurse Home Visiting (NHV) programme in relation to improving maternal and child outcomes at child age 3 years compared with usual care. Design A cost–utility analysis from a government-as-payer perspective alongside a randomised trial of NHV over 3-year period. Costs and quality-adjusted lifeyears (QALYs) were discounted at 5%. Analysis used an intention-to-treat approach with multiple imputation. Setting The right@home was implemented from 2013 in Victoria and Tasmania states of Australia, as a primary care service for pregnant women, delivered until child age 2 years. Participants 722 pregnant Australian women experiencing adversity received NHV (n=363) or usual care (clinic visits) (n=359). Primary and secondary outcome measures First, a cost–consequences analysis to compare the additional costs of NHV over usual care, accounting for any reduced costs of service use, and impacts on all maternal and child outcomes assessed at 3 years. Second, cost–utility analysis from a government-as-payer perspective compared additional costs to maternal QALYs to express cost-effectiveness in terms of additional cost per additional QALY gained. Results When compared with usual care at child age 3 years, the right@home intervention cost $A7685 extra per woman (95$A7006 to $A8364) and generated 0.01 more QALYs (95$A50 000 per QALY. Conclusions Benefits of NHV to parenting at 2 years and maternal health and well-being at 3 years translate into marginal maternal QALY gains. Like previous cost-effectiveness results for NHV programmes, right@home is not cost-effective at 3 years. Given the relatively high up-front costs of NHV, long-term follow-up is needed to assess the accrual of health and economic benefits over time

The Erotic and the Vulgar: Visual Culture and Organized Labor's Critique of U.S. Hegemony in Occupied Japan

This essay engages the colonial legacy of postwar Japan by arguing that the political cartoons produced as part of the postwar Japanese labor movement’s critique of U.S. cultural hegemony illustrate how gendered discourses underpinned, and sometimes undermined, the ideologies formally represented by visual artists and the organizations that funded them. A significant component of organized labor’s propaganda rested on a corpus of visual media that depicted women as icons of Japanese national culture. Japan’s most militant labor unions were propagating anti-imperialist discourses that invoked an engendered/endangered nation that accentuated the importance of union roles for men by subordinating, then eliminating, union roles for women