Citations

Objective To comprehensively examine hypertension- and heart failure–related mortality rates in the United States to develop a targeted approach to health policy development. Methods We analyzed death certificates from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database, focusing on mortality caused by hypertensive heart failure in adults aged ≥25 years from 2006 to 2020. Age-adjusted mortality rates per 1,000,000 and annual percent changes were calculated and categorized by year, sex, race, urban status, age group, and census region. Results A total of 268,545 deaths occurred due to hypertensive heart failure between 2006 and 2020. The overall age-adjusted mortality rates increased from 60.5 in 2006 to 134.9 in 2020. Males had higher age-adjusted mortality rates than women (76.6 vs. 73.8). Older-aged people exhibited significantly higher age-adjusted mortality rates than young and middle-aged adults. Age-adjusted mortality rates were highest in non-Hispanic Blacks/African Americans and lowest in non-Hispanic Asians/Pacific Islanders (126.8–43.6). Furthermore, age-adjusted mortality rates were highest in individuals from nonmetropolitan areas and the Western region. Conclusion Following a period of decline, the age-adjusted mortality rates increased until 2020. The highest age-adjusted mortality rates were observed in non-Hispanic Blacks and nonmetropolitan areas. An urgent restructuring of healthcare policy is needed to reduce heart failure-associated mortality.

Abstract Background We previously identified a novel mechanism describing how pathological tau transfers via extracellular vesicles (EVs) in Alzheimer's disease (AD). Targeting EV secretion to mitigate tau transfer is, therefore, a promising therapeutic approach for AD. P2X purinoreceptor 7 (P2RX7), an ATP‐gated cationic channel predominantly expressed in microglia, regulates the secretion and biogenesis of EVs. Here we investigated the effect of P2rx7 deficiency in PS19 tauopathy mouse model and by proteomic profiling of brain EVs. Method PS19: P2rx7 –/– mice at 9‐10 months of age were tested for fear conditioning and their brain sections were assessed for brain atrophy. Tau pathology was evaluated using ELISA and immunofluorescence against phosphorylated (AT8) and misfolded (Alz50) tau. Brain tissues were further assessed by bulk and single cell RNA‐seq (scRNA‐seq) and brain‐EVs were subjected to proteomic profiling by mass‐spectrometry. P2rx7 –/– mice were intracranially injected with viral vectors expressing P301L tau in neurons and mEmerald‐CD9 in microglia to visualize the secretion of microglial EVs in vivo . Mice conditional knockout (cKO) for P2rx7 in microglia, neurons and astrocytes were injected with a viral vector expressing P301L tau in entorhinal cortex for tau propagation assessment. Result PS19: P2rx7 –/– mice showed significant improvement in contextual and cued memory compared to age‐matched PS19 mice, which was accompanied by preserved cortical and hippocampal volume, and significant reduction of hippocampal synapse loss and tau pathology. By weighted gene co‐expression network analysis (WGCNA) we identified a microglial and EV‐related module strongly correlated with tau pathology which was remarkably downregulated in PS19: P2rx7 –/– mice hippocampus. PS19 mice showed increased secretion of EVs containing tau and mitochondrial proteins in the mouse brain parenchyma, which was significantly downregulated in PS19: P2rx7 –/– mice. scRNA‐seq analysis showed that P2rx7 is required for microglia conversion to inflammatory phenotype with increased expression of EV genes in PS19 mice. P2rx7 deficiency reduced microglial mEmerald‐CD9 + ‐EV secretion in mice expressing P301L tau. Moreover, microglia and neuron‐specific deletion of P2rx7 inhibit tau propagation from the entorhinal cortex to the mouse hippocampus. Conclusion Our study demonstrated a microglial P2RX7‐EV axis with potential implications on neuroinflammation and neurodegeneration associated with tau pathology, further indicating the therapeutic potential of targeting P2rx7 to ameliorate AD progression.

Introduction: As the global elderly population grows, so does the incidence of acute coronary syndrome (ACS) requiring urgent intervention. Emergency coronary artery bypass grafting (CABG) may offer a survival benefit, but concerns remain about its feasibility and safety in critically ill elderly patients with multiple comorbidities. Description of Case: This single-surgeon case series includes eight patients >65 years old who underwent emergency CABG for ACS between September 2023 and September 2024. Comorbidities included diabetes, hypertension, CKD, COPD, and previous stroke. All patients were critically ill, requiring combinations of inotropes, intra-aortic balloon pump (IABP), and mechanical ventilation. Ejection fractions ranged from 20–45%, and EuroSCOREs ranged from 10.86 to 30.45. Standard cardiopulmonary bypass with moderate hypothermia and a single aortic cross-clamp was used. Postoperatively, complications included transient ischemic attacks, dialysis-requiring renal dysfunction, atrial fibrillation, and infections. All patients survived; extubation times ranged from 7 to 70 hours, and hospital stays from 5 to 12 days. Discussion: This case series examines outcomes of CABG in elderly patients, emphasizing that despite multiple comorbidities, through physiological assessment, CABG can safely be performed in critically ill patients Although the LVEF was low and multiple comorbidities like diabetes and chronic kidney disease, signify the importance of a comprehensive assessment of physiology beyond standard biomarkers is necessary to determine readiness for surgery. Ventilation times variations highlighted the consequences of pulmonary and hematological challenges encountered in these patients. Recent advances in surgical techniques and perioperative care have improved outcomes, and most patients showed enhanced quality of life and physical function within a year post-surgery. Conclusion: Emergency CABG can be a lifesaving therapy in critically ill elderly ACS patients. With careful perioperative management, advanced age and comorbidity burden should not preclude surgical intervention.

Background: Gastric cancer remains one of the leading causes of death globally and a major health concern. This study aims to analyze gastric cancer-related mortality trends over 2 decades. Methods: The CDC WONDER database was used to analyze and stratify de-identified death certificates from 1999 to 2022 across the United States. Trends in age-adjusted mortality rates (AAMR) were assessed using the Joinpoint Regression Program to determine annual percentage changes. Results: Overall, AAMR decreased from 79.26 in 1999 to 44.81 in 2022. Men and older adults had the highest AAMRs. Non-Hispanic (NH) Black or African Americans had the highest AAMR, while NH Whites had the lowest. Geographically, the Northeast had the highest AAMR, and metropolitan areas had higher AAMRs than nonmetropolitan areas. Conclusion: Gastric carcinoma has a poor prognosis, and although the general trend is decreasing across all sociodemographic areas, further research is required for targeted interventions and health policies for high-risk populations.

Abstract P2x purinoreceptor 7 (P2RX7), an ATP-gated ion channel, is known to play pivotal roles in the progression of Alzheimer’s disease (AD), although its cell type-specific pathological mechanisms have yet to be elucidated. Here, we show that genetic deletion of P2rx7 mitigates brain atrophy, tau accumulation and cognitive impairment in PS19 tauopathy mice. Specific deletion of P2rx7 in microglia, but not astrocytes, significantly suppresses tau propagation from the entorhinal cortex to CA1 in the hippocampus, an early event in AD pathology. Single-cell (sc)-RNA sequencing of mouse brains revealed specific P2rx7 expression in microglia, inducing inflammatory changes accompanied by elevated extracellular vesicles (EVs) secretion in PS19 mice. Brain-derived EVs (BDEVs) proteome demonstrated that P2RX7 increases EV cargo loading of tau and mitochondrial molecules in BDEVs from PS19 mice, which was further validated by single-molecule super-resolution. Notably, following the injection of BDEVs isolated from PS19 mice with or without P2rx7 deficiency, the microglial transcriptome of recipient mice revealed enriched DNA-sensing and type II interferon signaling in response to BDEVs from PS19 mice, which was diminished in the group injected with P2rx7-deficient BDEVs. Thus, our results indicate that P2RX7 regulates EV-mediated tau and mitochondrial transfer and inflammatory activation in microglia with increased EV secretion, thereby contributing to tauopathy and neurodegeneration, highlighting the therapeutic potential of targeting the P2RX7-EV axis in AD.

AbstractBackgroundWe previously identified the novel mechanism of pathological tau transfer via extracellular vesicles (EVs) in Alzheimer’s disease (AD). Targeting EV secretion to mitigate tau transfer is therefore a promising therapeutic approach for AD. P2X purinoreceptor 7 (P2RX7), an ATP‐gated cationic channel, regulates microvesicle shedding or secretion of multivesicular body‐derived exosomes. We aim to investigate the effect of P2rx7 deficiency on disease progression in PS19 tauopathy mouse model in vivo and by proteomic profiling of brain EVs.MethodPS19:P2rx7–/– mice at 9 months of age were tested for the fear conditioning, and pathology assessment of the brain atrophy and tau using immunofluorescence against aggregated tau (Alz50) or phosphorylated tau (AT8) and ELISA. Mice were intracranially injected with viral vectors expressing mEmerald‐CD9 in microglia and P301L tau in neurons to visualize the secretion of microglial EV and extracellular tau in vivo. Brain EV samples were subjected to proteomic profiling by data independent acquisition mass‐spectrometry.ResultPS19:P2rx7–/– mice showed significant improvement in contextual and cued memory compared to age‐matched PS19 mice, which was accompanied by preserved cortical and hippocampal volume, and significant reduction of hippocampal tau pathology and pS396 tau in sarkosyl‐insoluble fraction of brain tissues. The number of GFP+ microglial EVs were significantly reduced in P2rx7–/– compared to WT mice. Gene ontology pathway analysis of EV proteome showed significant enrichment of mitochondrial pathways in PS19 group compared to WT group, which was significantly downregulated in PS19:P2rx7–/– group.ConclusionOur study demonstrated that P2rx7 deficiency ameliorates cognitive dysfunction and tau pathology development in PS19 mice by dampening microglial EV secretion and EV‐mediated mitochondria transfer, further indicating the therapeutic potential of targeting P2RX7, an EV regulatory molecule, to ameliorate AD progression.

Abstract Extracellular vesicle (EV) secretion is mediated by purinergic receptor P2X 7 (P2RX7), an ATP‐gated cation channel highly expressed in microglia. We have previously shown that administration of GSK1482160, a P2RX7 selective inhibitor, suppresses EV secretion from murine microglia and prevents tauopathy development, leading to the recovery of the hippocampal function in PS19 mice, expressing P301S tau mutant. It is yet unknown, however, whether the effect of GSK1482160 on EV secretion from glial cells is specifically regulated through P2RX7. Here we tested GSK1482160 on primary microglia and astrocytes isolated from C57BL/6 (WT) and P2rx7 –/– mice and evaluated their EV secretion and phagocytotic activity of aggregated human tau (hTau) under ATP stimulation. GSK1482160 treatment and deletion of P2rx7 significantly reduced secretion of small and large EVs in microglia and astrocytes in both ATP stimulated or unstimulated condition as determined by nanoparticle tracking analysis, CD9 ELISA and immunoblotting of Tsg101 and Flotilin 1 using isolated EVs. GSK1482160 treatment had no effect on EV secretion from P2rx7 –/– microglia while we observed significant reduction in the secretion of small EVs from P2rx7 –/– astrocytes, suggesting its specific targeting of P2RX7 in EV secretion except small EV secretion from astrocytes. Finally, deletion of P2rx7 suppressed IL‐1β secretion and phagocytosed misfolded tau from both microglia and astrocytes. Together, these findings show that GSK1482160 suppresses EV secretion from microglia and astrocytes in P2RX7‐dependment manner, and P2RX7 critically regulates secretion of IL‐1β and misfolded hTau, demonstrating as the viable target of suppressing EV‐mediated neuroinflammation and tau propagation.

AbstractBackgroundP2X purinoceptor 7 (P2RX7), an ATP‐gated cation channel present abundantly in the microglia, induces membrane depolarization and extracellular vesicle (EV) secretion. Previous study demonstrated that administration of GSK1482160, a P2RX7 selective inhibitor, suppressed EVs secretion from murine microglia resulting in accumulation of Tsg101+ intraluminal vesicles (ILVs) in the hippocampus, and restored partial behavioral deficits in P301S tau mice. However, the specificity of GSK1482160 to P2RX7 has never been investigated in P301S tau mice. It is crucial to validate whether P2RX7 is a potential target for alleviating the tauopathy phenotype in P301S tau mice. The purpose of this study is to determine if deletion of P2RX7 is sufficient to recapiturate the therapeutic effect of GSK1482160 in tauopathy mouse model.MethodFours and nine‐months‐old P2RX7‐/‐:P301S and P301S mice were generated for the evaluation of ILV accumulation and tau pathology. Primary microglia and astrocytes from WT (C57BL/6) and P2RX7‐/‐ mice, treated with GSK1482160 and ATP for EV secretion. EVs were isolated from conditioned media via the sequential centrifugation and ultracentrifugation. Finally, EVs were quantified by nanoparticle tracking analysis and exosome specific marker CD9 ELISA. Effects of GSK1482160 on EVs secretion from astrocytes/microglia were also assessed using Western blot with EV specific markers Tsg101 and CD9.ResultExosome specific marker Tsg101, CD9, and tau expression levels were reduced in the hippocampus of nine‐months‐old P2RX7‐/‐:P301S mice compared to P301S mice. No significant difference between the two groups at 4 months of age was observed. Strikingly, primary cultured microglia and astrocytes showed reduction in EV secretion in both ATP stimulated or unstimulated condition from P2RX7‐/‐ group compared to WT group. Additionally, GSK1482160 pretreatment significantly reduced EV secretion from WT astrocytes and microglia, although it had no effects in P2RX7‐/‐ cells. These findings were validated by ELISA of EV marker CD9 and immunoblotting of Tsg101 and flotillin‐1 using isolated EVs.ConclusionResults demonstrate that P2RX7 is primarily responsible for ATP‐induced EV secretion from astrocytes and microglia, and systemic disruption of P2RX7 mimics the effect of GSK1482160 in P301S tau mice, including accumulation of ILVs in microglia and suppression of tau accumulation in the hippocampal regions.

Background: Probiotic supplementation reestablishes microbiome diversity and improves brain function in Alzheimer’s disease (AD); their molecular mechanisms, however, have not yet been fully illustrated. Objective: We investigated the effects of orally supplemented Bifidobacterium breve MCC1274 on cognitive function and AD-like pathologies in App NL- G- F mice. Methods: Three-month-old App NL- G- F mice were orally supplemented with B. breve MCC1274 for four months. The short-term memory function was evaluated using a novel object recognition test. Amyloid plaques, amyloid-β (Aβ) levels, Aβ fibril, amyloid-β protein precursor and its processing enzymes, its metabolic products, glial activity, and cell proliferation in the subgranular zone of the dentate gyrus were evaluated by immunohistochemistry, Aβ ELISA, western blotting, and immunofluorescence staining. The mRNA expression levels of pro- and anti-inflammatory cytokines were determined by qRT-PCR analysis. Results: We found that the oral B. breve MCC1 274 supplementation prevented memory impairment in App NL- G- F mice and decreased hippocampal Aβ levels through the enhancement of the a-disintegrin and metalloproteinase 10 (ADAM10) level. Moreover, administration of the probiotic activated the ERK/HIF-1 α signaling pathway responsible for increasing the ADAM10 level and also attenuated microglial activation, which in turn led to reduction in the mRNA expression levels of pro-inflammatory cytokines in the brain. In addition, B. breve MCC1274 supplementation increased the level of synaptic proteins in the hippocampus. Conclusion: Our findings support the possibility that oral B. breve MCC1274 supplementation might be used as a potential preventive therapy for AD progression.