GM1 Ganglioside Modifies α-Synuclein Toxicity and is Neuroprotective in a Rat α-Synuclein Model of Parkinson\u27s Disease.

While GM1 may interact with α-synuclein in vitro to inhibit aggregation, the ability of GM1 to protect against α-synuclein toxicity in vivo has not been investigated. We used targeted adeno-associated viral vector (AAV) overexpression of human mutant α-synuclein (A53T) in the rat substantia nigra (SN) to produce degeneration of SN dopamine neurons, loss of striatal dopamine levels, and behavioral impairment. Some animals received daily GM1 ganglioside administration for 6 weeks, beginning 24 hours after AAV-A53T administration or delayed start GM1 administration for 5 weeks beginning 3 weeks after AAV-A53T administration. Both types of GM1 administration protected against loss of SN dopamine neurons and striatal dopamine levels, reduced α-synuclein aggregation, and delayed start administration of GM1 reversed early appearing behavioral deficits. These results extend prior positive results in MPTP models, are consistent with the results of a small clinical study of GM1 in PD patients that showed slowing of symptom progression with chronic use, and argue for the continued refinement and development of GM1 as a potential disease modifying therapy for PD

Life\u27s Simple 7 and Health Care Utilization among the Framingham Generation III Cohort

Abstract Objective: To evaluate associations of cardiovascular health status with utilization of healthcare services. Methods: Our study included 3,786 participants from the Framingham Third Generation Cohort (enrollment: May 2008 – February 2011). LS7 0-14 point summary scores were categorized as “suboptimal” (score of 0-7) and “optimal” (score of 8-14). Participants were stratified into two utilization groups. Those with 0-1 utilizations were compared to those with 2 or more visits ( Super Users”). Logistic regression was used to estimate associations of the two LS7 categories with the odds of Super User utilization (models adjusted for age, sex, race, and education). Results: Compared to those with “suboptimal” LS7 scores, participants with “optimal” LS7 scores had a 40.5% lower odds (95% confidence interval: 28-51%) of being a “Super User” of health care services (p\u3c0.005). Conclusions: In a younger population, higher LS7 cardiovascular health metric scores were associated with lower utilization of costly health care services. Public Health Implications: These results may have implications for primary care physicians and other health professionals to help identify patients at risk for over-utilization of higher-cost health care services

GM1 ganglioside modifies microglial and neuroinflammatory responses to α-synuclein in the rat AAV-A53T α-synuclein model of Parkinson\u27s disease

Among the pathological events associated with the dopaminergic neurodegeneration characteristic of Parkinson\u27s disease (PD) are the accumulation of toxic forms of α-synuclein and microglial activation associated with neuroinflammation. Although numerous other processes may participate in the pathogenesis of PD, the two factors mentioned above may play critical roles in the initiation and progression of dopamine neuron degeneration in PD. In this study, we employed a slowly progressing model of PD using adeno-associated virus-mediated expression of human A53T α-synuclein into the substantia nigra on one side of the brain and examined the microglial response in the striatum on the injected side compared to the non-injected (control) side. We further examined the extent to which administration of the neuroprotective ganglioside GM1 influenced α-synuclein-induced glial responses. Changes in a number of microglial morphological measures (i.e., process length, number of endpoints, fractal dimension, lacunarity, density, and cell perimeter) were indicative of the presence of activated microglial and an inflammatory response on the injected side of the brain, compared to the control side. In GM1-treated animals, no significant differences in microglial morphology were observed between the injected and control striata. Follow-up studies showed that mRNA expression for several inflammation-related genes was increased on the A53T α-synuclein injected side vs. the non-injected side in saline-treated animals and that such changes were not observed in GM1-treated animals. These data show that inhibition of microglial activation and potentially damaging neuroinflammation by GM1 ganglioside administration may be among the many factors that contribute to the neuroprotective effects of GM1 in this model and possibly in human PD

Affective response as a mediator of the association between the physical and social environment and physical activity behavior

Perceptions of the physical and social environment have been shown to be predictive of physical activity (PA) behavior. However, the mechanisms of this association have not been examined. Affective response to PA was examined as a putative mediator of the association between perceptions of the PA environment and subsequent PA behavior. As part of a PA promotion study, 59 low-active overweight or obese but otherwise healthy adults completed real-time assessments of the perceived physical and social PA environment, affective response to PA, and PA behavior over a 6-month period. As hypothesized, decreased latency to and greater duration of subsequent PA was predicted by engaging in PA with a partner (b = 17.24, SE = .45, p \u3c .01), engaging in PA outdoors versus indoors (b = 3.70, SE = 0.67, p \u3c .01), and perceived pleasantness of the physical (b = 0.59, SE = .17, p \u3c .01) and social settings (b = 0.68, SE = .16, p \u3c .01). Affective response to PA (a shift toward feeling good versus bad during PA) mediated the association between engaging in PA with a partner (a path: 0.53(.11), p \u3c .01, b path: 0.42(.12), p \u3c .01, ab path: 0.22(.08), 95% CI .09–.41) and perceived pleasantness of the physical (a path: .38(.02), p \u3c .01; b path: .65(.23), p = .01; ab path: .25(.09), 95% CI .08–.43) and social setting (apath: .35(.02), p \u3c .01; b path: .57(.23), p = .01; ab path: .20(.08), 95% CI .03–.37) and PA behavior, but not the association between engaging in PA outdoors versus indoors and PA behavior. These findings suggest that perceived environmental variables may have their effects on PA through the process of psychological hedonism

Pharyngeal Oxygen Delivery Device Sustains Manikin Lung Oxygenation Longer Than High-Flow Nasal Cannula

PURPOSE: Hypoxemia during a failed airway scenario is life threatening. A dual-lumen pharyngeal oxygen delivery device (PODD) was developed to fit inside a traditional oropharyngeal airway for undisrupted supraglottic oxygenation and gas analysis during laryngoscopy and intubation. We hypothesized that the PODD would provide oxygen as effectively as high-flow nasal cannula (HFNC) while using lower oxygen flow rates. METHODS: We compared oxygen delivery of the PODD to HFNC in a preoxygenated, apneic manikin lung that approximated an adult functional residual capacity. Four arms were studied: HFNC at 20 and 60 liters per minute (LPM) oxygen, PODD at 10 LPM oxygen, and a control arm with no oxygen flow after initial preoxygenation. Five randomized 20-minute trials were performed for each arm (20 trials total). Descriptive statistics and analysis of variance were used with statistical significance of RESULTS: Mean oxygen concentrations were statistically different and decreased from 97% as follows: 41 ± 0% for the control, 90 ± 1% for HFNC at 20 LPM, 88 ± 2% for HFNC at 60 LPM, and 97 ± 1% (no change) for the PODD at 10 LPM. CONCLUSION: Oxygen delivery with the PODD maintained oxygen concentration longer than HFNC in this manikin model at lower flow rates than HFNC

Services just for men? Insights from a national study of the well men services pilots.

Men continue to have a lower life expectancy in most countries compared to women. Explanations of this gendered health inequality tend to focus on male risk taking, unhealthy lifestyle choices and resistance to seeking help from health services. In the period 2005-2008 the Scottish Government funded a nationwide community health promotion programme aimed at improving men's health, called Well Men Service Pilots (henceforth WMS)

Chemically-induced Neurite-like Outgrowth Reveals Multicellular Network Function in Patient-derived Glioblastoma Cells

Tumor stem cells and malignant multicellular networks have been separately implicated in the therapeutic resistance of Glioblastoma Multiforme (GBM), the most aggressive type of brain cancer in adults. We show that small molecule inhibition of RHO-associated serine/threonine kinase (ROCKi) significantly promoted the outgrowth of neurite-like cell projections in cultures of heterogeneous patient-derived GBM stem-like cells. These projections formed de novo -induced cellular network (iNet) ‘webs’, which regressed after withdrawal of ROCKi. Connected cells within the iNet web exhibited long range calcium signal transmission, and significant lysosomal and mitochondrial trafficking. In contrast to their less-connected vehicle control counterparts, iNet cells remained viable and proliferative after high-dose radiation. These findings demonstrate a link between ROCKi-regulated cell projection dynamics and the formation of radiation-resistant multicellular networks. Our study identifies means to reversibly induce iNet webs ex vivo , and may thereby accelerate future studies into the biology of GBM cellular networks

Study protocol for a type III hybrid effectiveness-implementation trial of strategies to implement firearm safety promotion as a universal suicide prevention strategy in pediatric primary care

BACKGROUND: Insights from behavioral economics, or how individuals\u27 decisions and behaviors are shaped by finite cognitive resources (e.g., time, attention) and mental heuristics, have been underutilized in efforts to increase the use of evidence-based practices in implementation science. Using the example of firearm safety promotion in pediatric primary care, which addresses an evidence-to-practice gap in universal suicide prevention, we aim to determine: is a less costly and more scalable behavioral economic-informed implementation strategy (i.e., Nudge ) powerful enough to change clinician behavior or is a more intensive and expensive facilitation strategy needed to overcome implementation barriers? METHODS: The Adolescent and child Suicide Prevention in Routine clinical Encounters (ASPIRE) hybrid type III effectiveness-implementation trial uses a longitudinal cluster randomized design. We will test the comparative effectiveness of two implementation strategies to support clinicians\u27 use of an evidence-based firearm safety practice, S.A.F.E. Firearm, in 32 pediatric practices across two health systems. All pediatric practices in the two health systems will receive S.A.F.E. Firearm materials, including training and cable locks. Half of the practices (k = 16) will be randomized to receive Nudge; the other half (k = 16) will be randomized to receive Nudge plus 1 year of facilitation to target additional practice and clinician implementation barriers (Nudge+). The primary implementation outcome is parent-reported clinician fidelity to the S.A.F.E Firearm program. Secondary implementation outcomes include reach and cost. To understand how the implementation strategies work, the primary mechanism to be tested is practice adaptive reserve, a self-report practice-level measure that includes relationship infrastructure, facilitative leadership, sense-making, teamwork, work environment, and culture of learning. DISCUSSION: The ASPIRE trial will integrate implementation science and behavioral economic approaches to advance our understanding of methods for implementing evidence-based firearm safety promotion practices in pediatric primary care. The study answers a question at the heart of many practice change efforts: which strategies are sufficient to support change, and why? Results of the trial will offer valuable insights into how best to implement evidence-based practices that address sensitive health matters in pediatric primary care. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04844021 . Registered 14 April 2021