ApoE Receptor 2 Regulates Synapse and Dendritic Spine Formation

Apolipoprotein E receptor 2 (ApoEr2) is a postsynaptic protein involved in long-term potentiation (LTP), learning, and memory through unknown mechanisms. We examined the biological effects of ApoEr2 on synapse and dendritic spine formation-processes critical for learning and memory.In a heterologous co-culture synapse assay, overexpression of ApoEr2 in COS7 cells significantly increased colocalization with synaptophysin in primary hippocampal neurons, suggesting that ApoEr2 promotes interaction with presynaptic structures. In primary neuronal cultures, overexpression of ApoEr2 increased dendritic spine density. Consistent with our in vitro findings, ApoEr2 knockout mice had decreased dendritic spine density in cortical layers II/III at 1 month of age. We also tested whether the interaction between ApoEr2 and its cytoplasmic adaptor proteins, specifically X11α and PSD-95, affected synapse and dendritic spine formation. X11α decreased cell surface levels of ApoEr2 along with synapse and dendritic spine density. In contrast, PSD-95 increased cell surface levels of ApoEr2 as well as synapse and dendritic spine density.These results suggest that ApoEr2 plays important roles in structure and function of CNS synapses and dendritic spines, and that these roles are modulated by cytoplasmic adaptor proteins X11α and PSD-95

Population Structure of a Hybrid Clonal Group of Methicillin-Resistant Staphylococcus aureus, ST239-MRSA-III

The methicillin-resistant Staphylococcus aureus (MRSA) clonal group known as ST239-MRSA-III is notable for its hybrid origin and for causing sustained hospital epidemics worldwide since the late 1970s. We studied the population structure of this MRSA clonal group using a sample of 111 isolates that were collected over 34 years from 29 countries. Genetic variation was assessed using typing methods and novel ascertainment methods, resulting in approximately 15 kb of sequence from 32 loci for all isolates. A single most parsimonious tree, free of homoplasy, partitioned 28 haplotypes into geographically-associated clades, including prominent European, Asian, and South American clades. The rate of evolution was estimated to be approximately 100× faster than standard estimates for bacteria, and dated the most recent common ancestor of these isolates to the mid-20th century. Associations were discovered between the ST239 phylogeny and the ccrB and dru loci of the methicillin resistance genetic element, SCCmec type III, but not with the accessory components of the element that are targeted by multiplex PCR subtyping tools. In summary, the evolutionary history of ST239 can be characterized by rapid clonal diversification that has left strong evidence of geographic and temporal population structure. SCCmec type III has remained linked to the ST239 chromosome during clonal diversification, but it has undergone homoplasious losses of accessory components. These results provide a population genetics framework for the precise identification of emerging ST239 variants, and invite a re-evaluation of the markers used for subtyping SCCmec

Evolutionary principles and their practical application

Evolutionary principles are now routinely incorporated into medicine and agriculture. Examples include the design of treatments that slow the evolution of resistance by weeds, pests, and pathogens, and the design of breeding programs that maximize crop yield or quality. Evolutionary principles are also increasingly incorporated into conservation biology, natural resource management, and environmental science. Examples include the protection of small and isolated populations from inbreeding depression, the identification of key traits involved in adaptation to climate change, the design of harvesting regimes that minimize unwanted life-history evolution, and the setting of conservation priorities based on populations, species, or communities that harbor the greatest evolutionary diversity and potential. The adoption of evolutionary principles has proceeded somewhat independently in these different fields, even though the underlying fundamental concepts are the same. We explore these fundamental concepts under four main themes: variation, selection, connectivity, and eco-evolutionary dynamics. Within each theme, we present several key evolutionary principles and illustrate their use in addressing applied problems. We hope that the resulting primer of evolutionary concepts and their practical utility helps to advance a unified multidisciplinary field of applied evolutionary biology

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Annual Out-of-Pocket Costs and Productivity Loss Among Patients with Diabetic Kidney Disease Compared to Type 2 Diabetes Mellitus

Thesis (Master's)--University of Washington, 2020Background Type II diabetes mellitus (T2DM) is a chronic disease of impaired glucose homeostasis characterized by both insulin resistance and a decrease in insulin production. Disease progression may lead to multisystem complications including the development of diabetic kidney disease (DKD). Though the association of T2DM and DKD with poor health outcomes and increased health care costs has been studied, there remains a paucity of literature assessing the incremental impact of DKD versus T2DM on outcomes and costs. Objective The objective of this study was to compare total annual out-of-pocket costs and workplace productivity loss measured by absenteeism and short-term disability between patients with T2DM compared to patients with DKD. Methods Data from the IBM/Watson MarketScan Commercial Claims and Encounters (CCAE) and Health and Productivity Management (HPM) Databases were used to conduct this retrospective cohort study (2013-2018). Adult patients ≥18 years with ≥2 unique service claims with a principal or secondary diagnosis for T2DM within 6-months during the enrollment period were assigned to the T2DM cohort. Among the T2DM cohort, a subset of patients with an additional ≥2 unique service claims for CKD during the enrollment period were selected and assigned to the DKD cohort. All patients were continuously enrolled for 12-months prior to the index date, beginning at the date of first T2DM claim. Inclusion in either cohort was mutually exclusive. Patients with incident DKD after the index date were followed in the T2DM cohort until the second CKD claim and were then followed in the DKD cohort thereafter. Individuals also present in the HPM databases were included in the sub-populations for the workplace absence or short-term disability outcomes. We used the Kaplan-Meier Sample Average approach to estimate outcomes using 1-month intervals during the follow-up period. To evaluate uncertainty, we performed a nonparametric bootstrap with 1000 replicates to generate 95% credible intervals (CIs). Results In the primary population (N=411,887), the mean annual out-of-pocket cost was significantly higher among patients with DKD ($151 [95$147, $153]) compared to those with T2DM ($118 [95% CI: $114,$124]), with a mean difference of $327.5 (95$326.8, $328.2). The mean annual productivity loss due to workplace absenteeism was found to be similar between those with DKD (227 hours [219 hours, 236 hours]) and T2DM (217 hours [187 hours, 226 hours]), with a mean difference of 21.7 hours (95% CI: 21.0 hours, 22.3 hours). Significantly higher mean annual short-term disability was observed among those with DKD (4.6 days [4.4 days, 4.8 days]) compared to those with T2DM (2.8 days [2.3 days, 3.4 days]), with a mean difference of 1.78 days (95% CI: 1.76 days, 1.80 days). Conclusions Patients with DKD were found to have higher mean annual OOP costs and experience more days with short-term disability claims compared to patients with T2DM. These results quantify the economic burden of T2DM and DKD from a patient and employer perspective and may be useful in economic evaluations to inform health care decision-making

Otophyma: a rare benign clinical entity mimicking leprosy

Otophyma is a rare condition characterized by edematous deformation of the ear that is considered to be the end-stage of an inflammatory process such as rosacea and eczema. This report illustrates a case in an elderly male, originally thought to have leprosy. Biopsy revealed a nodular infiltration of inflammatory cells around adnexal structures and an intraepidermal cyst. No acid-fast organisms were identified. We present a patient who is of a different ethnic group than usually seen with this disease and provide a review of the clinical presentation, histopathological features, and management of this rare condition

Otophyma: a rare benign clinical entity mimicking leprosy

Otophyma is a rare condition characterized by edematous deformation of the ear that is considered to be the end-stage of an inflammatory process such as rosacea and eczema. This report illustrates a case in an elderly male, originally thought to have leprosy. Biopsy revealed a nodular infiltration of inflammatory cells around adnexal structures and an intraepidermal cyst. No acid-fast organisms were identified. We present a patient who is of a different ethnic group than usually seen with this disease and provide a review of the clinical presentation, histopathological features, and management of this rare condition

Menthol cigarette smoking is associated with greater subjective reward, satisfaction, and throat hit , but not greater behavioral economic demand.

Aims: The cooling and minty flavor of menthol in cigarettes has been hypothesized to mask the harshness of inhaled cigarette smoke, contributing to menthol\u27s appeal and subjective reinforcement and linking menthol use to smoking initiation, progression, nicotine dependence, and difficulty quitting. This study examined differences between menthol and non-menthol smokers on behavioral economic indices of reinforcing efficacy (i.e., demand) and subjective response to smoking (i.e., satisfaction, reward, “throat hit,” aversion) and the association between measurements of reinforcement and subjective response. Design: 600 current adult smokers were recruited from an online smoking cessation program. Following website enrollment, individuals completed a self-report measurement of subjective response to smoking (reward, satisfaction, aversion, “throat hit”), and a modified cigarette purchase task (CPT) to assess behavioral economic cigarette demand. Findings: In bivariate and adjusted ANOVA models, menthol smokers reported greater subjective reward, satisfaction, and positive sensations in the throat (“throat hit”) from smoking compared to non-menthol smokers; and those outcomes were also correlated with greater nicotine dependence and lower likelihood of a past-year quit attempt. Although cigarette demand was associated with smoking level, subjective smoking reward, and nicotine dependence, there were no differences in smoking demand between menthol vs. non-menthol smokers. Conclusions: The pleasurable aspects of menthol vs non-menthol smoking may be a mechanism linking it to greater nicotine dependence and difficulty quitting. A menthol ban could decrease population-level cigarette consumption by restricting smokers\u27 access to a highly rewarding cigarette flavoring

Delivering Personalized Recommendations to Support Caregivers of People Living With Dementia: Mixed Methods Study

BackgroundEstimates suggest that 6.2 million Americans aged ≥65 years are living with Alzheimer dementia in 2021, and by 2060, this number could more than double to 13.8 million. As a result, public health officials anticipate a greater need for caregivers of persons with Alzheimer disease or related dementia and support resources for both people living with dementia and their caregivers. Despite the growing need for dementia caregiver support services, there is a lack of consensus regarding how to tailor these services to best meet the heterogeneous needs of individual caregivers. To fill this gap, Care to Plan (CtP), a web-based tool for caregivers of people living with dementia, was developed to provide tailored support recommendations to dementia caregivers. ObjectiveThe aim of this study is to formally explore the feasibility, acceptability, and utility of CtP for 20 family members of people living with dementia within a health system over a 1-month time period using a mixed methods parallel convergent design. MethodsA moderately sized health system in the mid-Atlantic region was selected as the site for CtP implementation, where 20 caregivers who were family members of people living with dementia were enrolled. The web-based CtP tool was used by caregivers and facilitated by a health care professional (ie, a senior care navigator [SCN]). Caregivers were given a 21-item review checklist to assess barriers and facilitators associated with reviewing CtP with an SCN. Following the 21-item review checklist, semistructured telephone interviews, which included 18 open-ended questions, focused on the facilitators of and barriers to CtP implementation and recommendations for future implementation. ResultsQuantitative results suggested that 85% (17/20) of caregivers indicated that CtP was helpful and 90% (18/20) would recommend CtP to someone in a similar situation. The qualitative analysis identified 4 themes regarding facilitators of and barriers to implementation: caregiver factors, SCN factors, CtP tool system factors, and recommendations and resources factors. ConclusionsCtP was found to be not only feasible but also a valuable tool for caregivers seeking resources for themselves and their people living with dementia. Long-term evaluation findings aim to generate results on how CtP can be integrated into care plans for caregivers and how SCNs can provide additional support for caregivers of people living with dementia over an extended period