Impact of early pericardial fluid chymase activation after cardiac surgery

INTRODUCTION: Chymase is a highly destructive serine protease rapidly neutralized in the circulation by protease inhibitors. Here we test whether pericardial fluid (PCF) chymase activation and other inflammatory biomarkers determine intensive care unit length of stay, and explore mechanisms of chymase delivery by extracellular vesicles to the heart. METHODS: PCF was collected from adult patients (17 on-pump; 13 off-pump) 4 h after cardiac surgery. Extracellular vesicles (EVs) containing chymase were injected into Sprague-Dawley rats to test for their ability to deliver chymase to the heart. RESULTS: The mean intensive care unit (ICU) stay and mean total length of stay was 2.17 ± 3.8 days and 6.41 ± 1.3 days respectively. Chymase activity and 32 inflammatory markers did not differ in on-pump vs. off-pump cardiac surgery. Society of Thoracic Surgeons Predicted Risk of Morbidity and Mortality Score (STS-PROM), 4-hour post-surgery PCF chymase activity and C-X-C motif chemokine ligand 6 (CXCL6) were all independent predictors of ICU and total hospital length of stay by univariate analysis. Mass spectrometry of baseline PCF shows the presence of serine protease inhibitors that neutralize chymase activity. The compartmentalization of chymase within and on the surface of PCF EVs was visualized by immunogold labeling and transmission electron microscopy. A chymase inhibitor prevented EV chymase activity (0.28 fmol/mg/min vs. 14.14 fmol/mg/min). Intravenous injection of PCF EVs obtained 24 h after surgery into Sprague Dawley rats shows diffuse human chymase uptake in the heart with extensive cardiomyocyte damage 4 h after injection. DISCUSSION: Early postoperative PCF chymase activation underscores its potential role in cardiac damage soon after on- or off-pump cardiac surgery. In addition, chymase in extracellular vesicles provides a protected delivery mechanism from neutralization by circulating serine protease inhibitors

Potential Protective Mechanisms of S-equol, a Metabolite of Soy Isoflavone by the Gut Microbiome, on Cognitive Decline and Dementia

S-equol, a metabolite of soy isoflavone daidzein transformed by the gut microbiome, is the most biologically potent among all soy isoflavones and their metabolites. Soy isoflavones are phytoestrogens and exert their actions through estrogen receptor-β. Epidemiological studies in East Asia, where soy isoflavones are regularly consumed, show that dietary isoflavone intake is inversely associated with cognitive decline and dementia; however, randomized controlled trials of soy isoflavones in Western countries did not generally show their cognitive benefit. The discrepant results may be attributed to S-equol production capability; after consuming soy isoflavones, 40–70% of East Asians produce S-equol, whereas 20–30% of Westerners do. Recent observational and clinical studies in Japan show that S-equol but not soy isoflavones is inversely associated with multiple vascular pathologies, contributing to cognitive impairment and dementia, including arterial stiffness and white matter lesion volume. S-equol has better permeability to the blood–brain barrier than soy isoflavones, although their affinity to estrogen receptor-β is similar. S-equol is also the most potent antioxidant among all known soy isoflavones. Although S-equol is available as a dietary supplement, no long-term trials in humans have examined the effect of S-equol supplementation on arterial stiffness, cerebrovascular disease, cognitive decline, or dementia

Caregiver subjective and physiological markers of stress and patient heart failure severity in family care dyads

Greater family caregiver exposure to uncontrolled patient symptoms is predictive of greater caregiver psychological and physiological stress in dementia and other chronic illnesses, but these phenomena have not been well-studied in heart failure (HF) - a disease with high symptom burden. The purpose of this study was to test the hypothesis that worse patient functional status (as reflected by increasing HF symptoms) would be associated with elevated psychological and physiological stress for the caregiver. This was a secondary analysis of data from 125 HF caregivers in the Caregiver Opportunities for Optimizing Lifestyle (COOL) study. Psychological stress was measured on four dimensions: care-related strain/burden (Oberst Caregiving Burden Scale), depression (Center for Epidemiological Studies Depression Scale), anxiety (State-Trait Anxiety Index), and general stress (Perceived Stress Scale). Physiological stress was measured by markers of HPA axis function (elevated cortisol awakening response [CAR]), endothelial dysfunction (increased PAI-1), and inflammation (increased IL-6, hsCRP). HF patient functional status was quantified by caregiver assessment of New York Heart Association (NYHA) Class. Generalized linear models were used to test associations between patient NYHA Class and stress (one model per indicator). NYHA Class (ordinal) was backwards difference coded in each model to examine caregiver stress in relation to increasing levels of HF severity. Caregivers were mostly female and in their mid-fifties, with a slight majority of the sample being African American and the patient's spouse. Overall, patient functional status was associated with greater caregiver psychological and physiological stress. In terms of psychological stress, higher NYHA Class was significantly associated with greater caregiver anxiety and general stress, but not with caregiver burden or depression. In terms of physiological stress, higher NYHA Class was associated with elevated markers in all models (elevated CAR and higher IL-6, hsCRP, and PAI-1). Across models, most associations between NYHA Class and stress were present at relatively early stages of functional limitation (i.e. Class II), while others emerged when functional limitations became more severe. To inform timing and mechanisms for much-needed caregiver interventions, research is needed to determine which aspects of HF symptomatology are most stressful for caregivers across the HF trajectory

sPDGFRβ and neuroinflammation are associated with AD biomarkers and differ by race:The ASCEND Study

INTRODUCTION: There remains an urgent need to identify preclinical pathophysiological mechanisms of Alzheimer's disease (AD) development in high-risk, racially diverse populations. We explored the relationship between cerebrospinal fluid (CSF) markers of vascular injury and neuroinflammation with AD biomarkers in middle-aged Black/African American (B/AA) and non-Hispanic White (NHW) participants.METHODS: Adults (45-65 years) with a parental history of AD were enrolled (n = 82). CSF and blood biomarkers were collected at baseline and year 2.RESULTS: CSF total tau (t-tau), phosphorylated tau (p-tau), and amyloid beta (Aβ)40 were elevated at year 2 compared to baseline. CSF soluble platelet-derived growth factor receptor β (sPDGFRβ) levels, a marker of pericyte injury, correlated positively with t-tau, p-tau, Aβ40 markers of vascular injury, and cytokines at baseline and year 2. CSF sPDGFRβ and tau were significantly lower in B/AA than NHW.DISCUSSION: Vascular dysfunction and neuroinflammation may precede cognitive decline and disease pathology in the very early preclinical stages of AD, and there are race-related differences in these relationships.HIGHLIGHTS: Cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers changed over 2 years in high-risk middle-aged adults. Markers of vascular dysfunction were associated with the CSF biomarkers amyloid beta and tau. AD biomarkers were lower in Black compared to non-Hispanic White individuals. Markers of vascular dysfunction were lower among Black individuals.</p

Epibatidine Blocks Eye-Specific Segregation in Ferret Dorsal Lateral Geniculate Nucleus during Stage III Retinal Waves

The segregation and maintenance of eye-specific inputs in the dorsal lateral geniculate nucleus (dLGN) during early postnatal development requires the patterned spontaneous activity of retinal waves. In contrast to the development of the mouse, ferret eye-specific segregation is not complete at the start of stage III glutamatergic retinal waves, and the remaining overlap is limited to the C/C1 lamina of the dLGN. To investigate the role of patterned spontaneous activity in this late segregation, we disrupted retinal waves pharmacologically for 5 day windows from postnatal day (P) 10 to P25. Multi-electrode array recordings of the retina in vitro reveal that the cholinergic agonist epibatidine disrupts correlated retinal activity during stage III waves. Epibatidine also prevents the segregation of eye-specific inputs in vivo during that period. Our results reveal a novel role for cholinergic influence on stage III retinal waves as an instructive signal for the continued segregation of eye-specific inputs in the ferret dLGN