Tumor necrosis factor-alpha is produced by dying retinal neurons and is required for Müller glia proliferation during zebrafish retinal regeneration

Intense light exposure causes photoreceptor apoptosis in dark-adapted adult albino zebrafish (Danio rerio). Subsequently, Müller glia increase expression of the Achaete-scute complex-like 1a (Ascl1a) and Signal transducer and activator of transcription 3 (Stat3) transcription factors and re-enter the cell cycle to yield undifferentiated neuronal progenitors that continue to proliferate, migrate to the outer nuclear layer, and differentiate into photoreceptors. A proteomic analysis of light-damaged retinal homogenates, which induced Müller glia proliferation when injected into an undamaged eye, revealed increased expression of tumor necrosis factor α (TNFα) signaling proteins relative to undamaged retinal homogenates. TNFα expression initially increased in apoptotic photoreceptors and later in Müller glia. Morpholino-mediated knockdown of TNFα expression before light damage diminished the expression of both Ascl1a and Stat3 in Müller glia and significantly reduced the number of proliferating Müller glia without affecting photoreceptor cell death. Knockdown of TNFα expression in the Müller glia resulted in fewer proliferating Müller glia, suggesting that Müller glial-derived TNFα recruited additional Müller glia to re-enter the cell cycle. While TNFα is required for increased Ascl1a and Stat3 expression, Ascl1a and Stat3 are both necessary for TNFα expression in Müller glia. Apoptotic inner retinal neurons, resulting from intravitreal injection of ouabain, also exhibited increased TNFα expression that was required for Müller glia proliferation. Thus, TNFα is the first molecule identified that is produced by dying retinal neurons and is necessary to induce Müller glia to proliferate in the zebrafish retinal regeneration response. © 2013 the authors

Engineering Virtuous Health Habits Using Emotion and Neurocognition: Flexibility for Lifestyle Optimization and Weight Management (EVEN FLOW)

Interventions to preserve functional independence in older adults are critically needed to optimize \u27successful aging\u27 among the large and increasing population of older adults in the United States. For most aging adults, the management of chronic diseases is the most common and impactful risk factor for loss of functional independence. Chronic disease management inherently involves the learning and adaptation of new behaviors, such as adopting or modifying physical activity habits and managing weight. Despite the importance of chronic disease management in older adults, vanishingly few individuals optimally manage their health behavior in the service of chronic disease stabilization to preserve functional independence. Contemporary conceptual models of chronic disease management and health habit theory suggest that this lack of optimal management may result from an underappreciated distinction within the health behavior literature: the behavioral domains critical for initiation of new behaviors (Initiation Phase) are largely distinct from those that facilitate their maintenance (Maintenance Phase). Psychological factors, particularly experiential acceptance and trait levels of openness are critical to engagement with new health behaviors, willingness to make difficult lifestyle changes, and the ability to tolerate aversive affective responses in the process. Cognitive factors, particularly executive function, are critical to learning new skills, using them effectively across different areas of life and contextual demands, and updating of skills to facilitate behavioral maintenance. Emerging data therefore suggests that individuals with greater executive function are better able to sustain behavior changes, which in turn protects against cognitive decline. In addition, social and structural supports of behavior change serve a critical buffering role across phases of behavior change. The present review attempts to address these gaps by proposing a novel biobehavioral intervention framework that incorporates both individual-level and social support system-level variables for the purpose of treatment tailoring. Our intervention framework triangulates on the central importance of self-regulatory functioning, proposing that both cognitive and psychological mechanisms ultimately influence an individuals\u27 ability to engage in different aspects of self-management (individual level) in the service of maintaining independence. Importantly, the proposed linkages of cognitive and affective functioning align with emerging individual difference frameworks, suggesting that lower levels of cognitive and/or psychological flexibility represent an intermediate phenotype of risk. Individuals exhibiting self-regulatory lapses either due to the inability to regulate their emotional responses or due to the presence of executive functioning impairments are therefore the most likely to require assistance to preserve functional independence. In addition, these vulnerabilities will be more easily observable for individuals requiring greater complexity of self-management behavioral demands (e.g. complexity of medication regimen) and/or with lesser social support. Our proposed framework also intuits several distinct intervention pathways based on the profile of self-regulatory behaviors: we propose that individuals with intact affect regulation and impaired executive function will preferentially respond to \u27top-down\u27 training approaches (e.g., strategy and process work). Individuals with intact executive function and impaired affect regulation will respond to \u27bottom-up\u27 approaches (e.g., graded exposure). And individuals with impairments in both may require treatments targeting caregiving or structural supports, particularly in the context of elevated behavioral demands

Relationship Between Preexisting Cardiovascular Disease and Death and Cardiovascular Outcomes in Critically Ill Patients With COVID-19

BACKGROUND: Preexisting cardiovascular disease (CVD) is perceived as a risk factor for poor outcomes in patients with COVID-19. We sought to determine whether CVD is associated with in-hospital death and cardiovascular events in critically ill patients with COVID-19. METHODS: This study used data from a multicenter cohort of adults with laboratory-confirmed COVID-19 admitted to intensive care units at 68 centers across the United States from March 1 to July 1, 2020. The primary exposure was CVD, defined as preexisting coronary artery disease, congestive heart failure, or atrial fibrillation/flutter. Myocardial injury on intensive care unit admission defined as a troponin I or T level above the 99th percentile upper reference limit of normal was a secondary exposure. The primary outcome was 28-day in-hospital mortality. Secondary outcomes included cardiovascular events (cardiac arrest, new-onset arrhythmias, new-onset heart failure, myocarditis, pericarditis, or stroke) within 14 days. RESULTS: Among 5133 patients (3231 male [62.9%]; mean age 61 years [SD, 15]), 1174 (22.9%) had preexisting CVD. A total of 1178 (34.6%) died, and 920 (17.9%) had a cardiovascular event. After adjusting for age, sex, race, body mass index, history of smoking, and comorbidities, preexisting CVD was associated with a 1.15 (95% CI, 0.98-1.34) higher odds of death. No independent association was observed between preexisting CVD and cardiovascular events. Myocardial injury on intensive care unit admission was associated with higher odds of death (adjusted odds ratio, 1.93 [95% CI, 1.61-2.31]) and cardiovascular events (adjusted odds ratio, 1.82 [95% CI, 1.47-2.24]), regardless of the presence of CVD. CONCLUSIONS: CVD risk factors, rather than CVD itself, were the major contributors to outcomes in critically ill patients with COVID-19. The occurrence of myocardial injury, regardless of CVD, and its association with outcomes suggests it is likely due to multiorgan injury related to acute inflammation rather than exacerbation of preexisting CVD. REGISTRATION: NCT04343898; https://clinicaltrials.gov/ct2/show/NCT04343898