Alzheimer's disease (AD) is a neurodegenerative disease with major clinical hallmarks of memory loss, dementia, and cognitive impairment. Neuroinflammation is involved in the onset of several ...neurodegenerative disorders. Astrocyte is the most abundant type of glial cells in the central nervous system (CNS) and appears to be involved in the induction of neuroinflammation. Under stress and injury, astrocytes become astrogliotic leading to an upregulation of the expression of proinflammatory cytokines and chemokines, which are associated with the pathogenesis of AD. Cytokines and related molecules play roles in both neuroprotection and neurodegeneration in the CNS. During early AD pathogenesis, amyloid beta (Aβ), S100B and IL-1β could bring about a vicious cycle of Aβ generation between astrocytes and neurons leading to chronic, sustained and progressive neuroinflammation. In advanced stages of AD, TRAIL secreted from astrocytes have been shown to bind to death receptor 5 (DR5) on neurons to trigger apoptosis in a caspase-8-dependent manner. Furthermore, astrocytes could be reactivated by TGFβ1 to generate more Aβ and to undergo the aggravating astrogliosis. TGFβ2 was also observed to cooperate with Aβ to cause neuronal demise by destroying the stability of lysosomes in neurons. Inflammatory molecules can be either potential biomarkers for diagnosis or target molecules for therapeutic intervention. Understanding their roles and their relationship with activated astrocytes is particularly important for attenuating neuroinflammation in the early stage of AD. The main purpose of this review is to provide a comprehensive insight into the role of astrocytes in the neuroinflammatory pathogenesis of AD.
Neurodevelopmental and neurodegenerative diseases (NDDs) with severe neurological/psychiatric symptoms, such as cerebrovascular pathology in AD, CAA, and chronic stroke, have brought greater ...attention with their incidence and prevalence having markedly increased over the past few years. Causes of the significant neuropathologies, especially those observed in neurological diseases in the CNS, are commonly believed to involve multiple factors such as an age, a total environment, genetics, and an immunity contributing to their progression, neuronal, and vascular injuries. We primarily focused on the studies of glial involvement/dysfunction in part with the blood-brain barrier (BBB) and the neurovascular unit (NVU) changes, and the vascular mechanisms, which have been both suggested as critical roles in chronic stroke and many other NDDs. It has been noted that glial cells including astrocytes (which outnumber other cell types in the CNS) essentially contribute more to the BBB integrity, extracellular homeostasis, neurotransmitter release, regulation of neurogenic niches in response to neuroinflammatory stimulus, and synaptic plasticity. In a recent study for NDDs utilizing cellular and molecular biology and genetic and pharmacological tools, the role of reactive astrocytes (RACs) and gliosis was demonstrated, able to trigger pathophysiological/psychopathological detrimental changes during the disease progression. We speculate, in particular, the BBB, the NVU, and changes of the astrocytes (potentially different populations from the RACs) not only interfere with neuronal development and synaptogenesis, but also generate oxidative damages, contribute to beta-amyloid clearances and disrupted vasculature, as well as lead to neuroinflammatory disorders. During the past several decades, stem cell therapy has been investigated with a research focus to target related neuro-/vascular pathologies (cell replacement and repair) and neurological/psychiatric symptoms (paracrine protection and homeostasis). Evidence shows that transplantation of neurogenic or vasculogenic cells could be achieved to pursue differentiation and maturation within the diseased brains as expected. It would be hoped that, via regulating functions of astrocytes, astrocytic involvement, and modulation of the BBB, the NVU and astrocytes should be among major targets for therapeutics against NDDs pathogenesis by drug and cell-based therapies. The non-invasive strategies in combination with stem cell transplantation such as the well-tested intranasal deliveries for drug and stem cells by our and many other groups show great translational potentials in NDDs. Neuroimaging and clinically relevant analyzing tools need to be evaluated in various NDDs brains.
Background: Gastrointestinal bleeding (GIB) is a leading cause of morbidity during continuous-flow left ventricular assist device (CF-LVAD) support. GIB risk assessment could have important ...implications for candidate selection, informed consent, and postimplant therapeutic strategies. The aim of the study is to derive and validate a predictive model of GIB in CF-LVAD patients. Methods and Results: CF-LVAD recipients at the Utah Transplantation Affiliated Hospitals program between 2004 and 2017 were included. GIB associated with a decrease in hemoglobin ≥2 g/dL was the primary end point. A weighted score comprising preimplant variables independently associated with GIB was derived and internally validated. A total of 351 patients (median age, 59 years; 82% male) were included. After a median of 196 days, GIB occurred in 120 (34%) patients. Independent predictors of GIB included age >54 years, history of previous bleeding, coronary artery disease, chronic kidney disease, severe right ventricular dysfunction, mean pulmonary artery pressure <18 mm Hg, and fasting glucose >107 mg/dL. A weighted score termed Utah bleeding risk score, effectively stratified patients based on their probability of GIB: low (0–1 points) 4.8%, intermediate (2–4) 39.8%, and high risk (5–9) 83.8%. Discrimination was good in the development sample (c-index: 0.83) and after internal bootstrap validation (c-index: 0.74). Conclusions: The novel Utah bleeding risk score is a simple tool that can provide personalized GIB risk estimates in CF-LVAD patients. This scoring system may assist clinicians and investigators in designing tailored risk-based strategies aimed at reducing the burden posed by GIB in the individual CF-LVAD patient and healthcare systems.
Abstract only
Background:
Patient outcomes after cardiac arrest (CA) complicated by cardiogenic shock (CS) not related to acute myocardial infarction (non-AMI) remain poorly understood. The aim of ...our study was to assess differences in outcomes between non-AMI CS related to in-hospital cardiac arrest (IHCA) and out-of-hospital cardiac arrest (OHCA) using a real-world, multi-institutional registry.
Methods:
The CS Working Group (CSWG) registry is a retrospective dataset of patients hospitalized with CS from 17 clinical sites. A standardized set of data elements were collected between 2016 and 2021. Patients were identified as having either AMI or non-AMI related CS, and non-AMI related CS was further classified by acuity of etiology as acute-on-chronic heart failure (ACHF) and
de novo
HF. IHCA or OHCA were defined based on location of CA. The outcomes of this analysis were in-hospital mortality, renal replace therapy (RRT) and mechanical ventilation (MV).
Results:
There were 1767 patients (age 60.3 ± 14.6 years, 72.4% male) with non-AMI CS enrolled, of whom 1371 (77.6%) had ACHF and 349 (19.7%) had
de novo
HF. There were 152 (8.6%) IHCA and 103 (5.8%) OHCA. Mortality was higher for ACHF and
de novo
HF patients with IHCA compared with patients without IHCA, and was higher for ACHF patients with OHCA compared with patients without OHCA
(Figure 1A-B).
Rates of RRT were higher for ACHF and
de novo
HF patients with IHCA compared with patients without IHCA and was similar between ACHF and
de novo
HF patients with and without OHCA
(Figure 1C-D).
Rates of MV were higher for ACHF and
de novo
HF patients with IHCA or OHCA compared with ACHF and
de novo
HF patients without IHCA or OHCA
(Figures 1E-F)
.
Conclusion:
Outcomes are worse among patients with CA, irrespective of HF etiology or whether CA occurs in or out of the hospital. Further investigation is needed to better understand mechanisms contributing to these poor outcomes and to identify therapeutic targets for improvement.
Gastrointestinal bleeding (GIB) is a leading cause of morbidity during continuous-flow left ventricular assist device (CF-LVAD) support. GIB risk assessment could have important implications for ...candidate selection, informed consent, and postimplant therapeutic strategies. The aim of the study is to derive and validate a predictive model of GIB in CF-LVAD patients.
CF-LVAD recipients at the Utah Transplantation Affiliated Hospitals program between 2004 and 2017 were included. GIB associated with a decrease in hemoglobin ≥2 g/dL was the primary end point. A weighted score comprising preimplant variables independently associated with GIB was derived and internally validated. A total of 351 patients (median age, 59 years; 82% male) were included. After a median of 196 days, GIB occurred in 120 (34%) patients. Independent predictors of GIB included age >54 years, history of previous bleeding, coronary artery disease, chronic kidney disease, severe right ventricular dysfunction, mean pulmonary artery pressure <18 mm Hg, and fasting glucose >107 mg/dL. A weighted score termed Utah bleeding risk score, effectively stratified patients based on their probability of GIB: low (0-1 points) 4.8%, intermediate (2-4) 39.8%, and high risk (5-9) 83.8%. Discrimination was good in the development sample (c-index: 0.83) and after internal bootstrap validation (c-index: 0.74).
The novel Utah bleeding risk score is a simple tool that can provide personalized GIB risk estimates in CF-LVAD patients. This scoring system may assist clinicians and investigators in designing tailored risk-based strategies aimed at reducing the burden posed by GIB in the individual CF-LVAD patient and healthcare systems.
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