Background-Myocardial ischemia provides a potent stimulus to angiogenesis, and the mobilization and differentiation of endothelial progenitor cells (EPCs) has been shown to be important in this process. An elevated level of C-reactive protein (CRP) has emerged as one of the most powerful predictors of cardiovascular disease. However, the impact of CRP on EPC biology is unknown. Methods and Results-EPCs were isolated from the peripheral venous blood of healthy male volunteers. Cells were cultured in endothelial cell basal medium-2 in the absence and presence of CRP (5 to 20 g/mL), rosiglitazone (1 mol/L), and/or vascular endothelial growth factor. EPC differentiation, survival, and function were assayed. CRP at concentrations Ն15 g/mL significantly reduced EPC cell number, inhibited the expression of the endothelial cell-specific markers Tie-2, EC-lectin, and VE-cadherin, significantly increased EPC apoptosis, and impaired EPC-induced angiogenesis. EPC-induced angiogenesis was dependent on the presence of nitric oxide, and CRP treatment caused a decrease in endothelial nitric oxide synthase mRNA expression by EPCs. However, all of these detrimental CRP-mediated effects on EPCs were attenuated by pretreatment with rosiglitazone, a peroxisome proliferator-activated receptor-␥ (PPAR␥) agonist. Conclusions-Human recombinant CRP, at concentrations known to predict adverse vascular outcomes, directly inhibits EPC differentiation, survival, and function, key components of angiogenesis and the response to chronic ischemia. This occurs in part via an effect of CRP to reduce EPC eNOS expression. The PPAR␥ agonist rosiglitazone inhibits the negative effects of CRP on EPC biology. The ability of CRP to inhibit EPC differentiation and survival may represent an important mechanism that further links inflammation to cardiovascular disease.
Abstract-Mutations in the bone morphogenetic protein (BMP) receptor-2 (BMPR2) have been found in patients with idiopathic pulmonary arterial hypertension (IPAH); however, the mechanistic link between loss of BMPR2 signaling and the development of pulmonary arterial hypertension is unclear. We hypothesized that, contrary to smooth muscle cells, this pathway promotes survival in pulmonary artery endothelial cells (ECs) and loss of BMPR2 signaling will predispose to EC apoptosis. ECs were treated with BMP-2 or BMP-7 (200 ng/mL) for 24 hours in regular or serum-free (SF) medium, with and without addition of tumor necrosis factor ␣, and apoptosis was assessed by flow cytometry (Annexin V), TUNEL, or caspase-3 activity. Treatment for 24 hours in SF medium increased apoptosis, and both BMP-2 and BMP-7 significantly reduced apoptosis in response to serum deprivation to levels not different from serum controls. Transfection with 5 g of small interfering RNAs for BMPR2 produced specific gene silencing assessed by RT-PCR and Western blot analysis. BMPR2 gene silencing increased apoptosis almost 3-fold (Pϭ0.0027), even in the presence of serum. Circulating endothelial progenitor cells (EPCs) isolated from normal subjects or patients with IPAH were differentiated in culture for 7 days and apoptosis was determined in the presence and absence of BMPs. BMP-2 reduced apoptosis induced by serum withdrawal in EPCs from normal subjects but not in EPCs isolated from patients with IPAH. These results support the hypothesis that loss-of-function mutations in BMPR2 could lead to increased pulmonary EC apoptosis, representing a possible initiating mechanism in the pathogenesis of pulmonary arterial hypertension.
y The SNAP-2: EPICCS collaborators are listed in Supplementary material. AbstractBackground: Decisions to admit high-risk postoperative patients to critical care may be affected by resource availability. We aimed to quantify adult ICU/high-dependency unit (ICU/HDU) capacity in hospitals from the UK, Australia, and New Zealand (NZ), and to identify and describe additional 'high-acuity' beds capable of managing high-risk patients outside the ICU/HDU environment. Methods: We used a modified Delphi consensus method to design a survey that was disseminated via investigator networks in the UK, Australia, and NZ. Hospital-and ward-level data were collected, including bed numbers, tertiary services offered, presence of an emergency department, ward staffing levels, and the availability of critical care facilities. Results: We received responses from 257 UK (response rate: 97.7%), 35 Australian (response rate: 32.7%), and 17 NZ (response rate: 94.4%) hospitals (total 309). Of these hospitals, 91.6% reported on-site ICU or HDU facilities. UK hospitals
Endothelial progenitor cells (EPCs) participate in angiogenesis and the response to chronic ischemia. Risk factors and cardiovascular disease attenuate EPC number, function, and survival.
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder. Circulating angiogenic cells (CACs) play an important role in vascular repair and regeneration. This study was designed to examine the function of CACs derived from patients with HHT. Peripheral blood mononuclear cells (PBMNCs) isolated from patients with HHT and age- and gender-matched healthy volunteers were assessed for expression of CD34, CD133 and VEGF receptor 2 by flow cytometry. PBMNCs were cultured to procure early outgrowth CACs. Development of endothelial cell (EC) phenotype in CACs was analyzed by fluorescence microscopy. CAC apoptosis was assayed with Annexin V staining, and CAC migration assessed by a modified Boyden chamber assay. mRNA expression of endoglin (ENG), activin receptor-like kinase-1 (ACVLR1 or ALK1) and endothelial nitric oxide synthase (eNOS) in CACs was measured by real time RT-PCR. The percentage of CD34+ cells in PBMNCs from HHT patients was significantly higher than in PBMNCs of healthy controls. CACs derived from patients with HHT not only showed a significant reduction in EC-selective surface markers following 7-day culture, but also a significant increase in the rate of basal apoptosis and blunted migration in response to vascular endothelial growth factor and stromal cell-derived factor-1. CACs from HHT patients expressed significantly lower levels of ENG, ALK1 and eNOS mRNAs. In conclusion, CACs from patients with HHT exhibited various functional impairments, suggesting a reduced regenerative capacity of CACs to repair the vascular lesions seen in HHT patients.
Preparedness measures for the anticipated surge of coronavirus disease 2019 (COVID-19) cases within eastern Massachusetts included the establishment of alternate care sites (field hospitals). Boston Hope hospital was set up within the Boston Convention and Exhibition Center to provide low-acuity care for COVID-19 patients and to support local healthcare systems. However, early recognition of the need to provide higher levels of care, or critical care for the potential deterioration of patients recovering from COVID-19, prompted the development of a hybrid acute care–intensive care unit. We describe our experience of implementing rapid response capabilities of this innovative ad hoc unit. Combining quality improvement tools for hazards detection and testing through in situ simulation successfully identified several operational hurdles. Through rapid continuous analysis and iterative change, we implemented appropriate mitigation strategies and established rapid response and rescue capabilities. This study provides a framework for future planning of high-acuity services within a unique field hospital setting.
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General anaesthesia for obstetric surgery has distinct characteristics that may contribute towards a higher risk of accidental awareness during general anaesthesia. The primary aim of this study was to investigate the incidence, experience and psychological implications of unintended conscious awareness during general anaesthesia in obstetric patients. From May 2017 to August 2018, 3115 consenting patients receiving general anaesthesia for obstetric surgery in 72 hospitals in England were recruited to the study. Patients received three repetitions of standardised questioning over 30 days, with responses indicating memories during general anaesthesia that were verified using interviews and record interrogation. A total of 12 patients had certain/ probable or possible awareness, an incidence of 1 in 256 (95%CI 149-500) for all obstetric surgery. The incidence was 1 in 212 (95%CI 122-417) for caesarean section surgery. Distressing experiences were reported by seven (58.3%) patients, paralysis by five (41.7%) and paralysis with pain by two (16.7%). Accidental awareness occurred during induction and emergence in nine (75%) of the patients who reported awareness. Factors associated with accidental awareness during general anaesthesia were: high BMI (25-30 kg.m -2 ); low BMI (<18.5 kg.m -2 ); out-of-hours surgery; and use of ketamine or thiopental for induction. Standardised psychological impact scores at 30 days were significantly higher in awareness patients (median (IQR [range]) 15 (2.7-52.0 [2-56]) than in patients without awareness 3 (1-9 [0-64]), p = 0.010. Four patients had a provisional diagnosis of post-traumatic stress disorder. We conclude that direct postoperative questioning reveals high rates of accidental awareness during general anaesthesia for obstetric surgery, which has implications for anaesthetic practice, consent and follow-up.
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