Endothelial dysfunction and arterial stiffness are major determinants of cardiovascular risk in patients with end-stage renal failure (ESRF). Microparticles are membrane fragments shed from damaged or activated cells. Because microparticles can affect endothelial cells, this study investigated the relationship between circulating microparticles and arterial dysfunction in patients with ESRF and identified the cellular origin of microparticles associated with these alterations. Flow cytometry analysis of platelet-free plasma from 44 patients with ESRF indicated that circulating levels of Annexin V؉ microparticles were increased compared with 32 healthy subjects, as were levels of microparticles derived from endothelial cells (three-fold), platelets (16.5-fold), and erythrocytes (1.6-fold). However, when arterial function was evaluated noninvasively in patients with ESRF, only endothelial microparticle levels correlated highly with loss of flow-mediated dilation (r ؍ ؊0.543; P ؍ 0.004), increased aortic pulse wave velocity (r ؍ 0.642, P < 0.0001), and increased common carotid artery augmentation index (r ؍ 0.463, P ؍ 0.0017), whereas platelet-derived, erythrocyte-derived, and Annexin V؉ microparticle levels did not. In vitro, microparticles from patients with ESRF impaired endothelium-dependent relaxations and cyclic guanosine monophosphate generation, whereas microparticles from healthy subjects did not. Moreover, in vitro endothelial dysfunction correlated with endothelial-derived (r ؍ 0.891; P ؍ 0.003) but not platelet-derived microparticle concentrations. In fact, endothelial microparticles alone decreased endothelial nitric oxide release by 59 ؎ 7% (P ؍ 0.025). This study suggests that circulating microparticles of endothelial origin are tightly associated with endothelial dysfunction and arterial dysfunction in ESRF.J (3,4), a systemic disorder and a key variable in the pathogenesis of atherosclerosis and its complications (5). Moreover, arterial wall stiffening, which is partly influenced by nitric oxide (NO) and the endothelium (6,7), occurs frequently during ESRF and has been reported as an independent predictor of cardiovascular events (7-9) Circulating microparticles (MP) are shed membrane vesicles resulting from apoptosis or activation of several cell types in response to various stimuli (10,11). We previously demonstrated that circulating MP that are isolated from patients with acute coronary syndromes directly induce endothelial dysfunction in vitro and hypothesized that this effect could be of clinical relevance (12). In this study, we sought to extend those earlier observations by investigating the possible relationships between circulating MP levels and in vivo arterial properties in patients with ESRF. In addition, we undertook to determine the cellular origin of the circulating MP associated with these vascular alterations. Materials and MethodsWe included 44 patients with ESRF from the Fleury-Mérogis hemodialysis center. Patients were eligible for inclusion when (1) they had ha...
Vascular endothelial growth factor (VEGF)-induced blood vessel growth is involved in both physiological and pathological angiogenesis and requires integrin-mediated signaling. We now show that an integrin-binding protein initially described in milk-fat globule, MFG-E8 (also known as lactadherin), is expressed in and around blood vessels and has a crucial role in VEGF-dependent neovascularization in the adult mouse. Using neutralizing antibodies and lactadherin-deficient animals, we show that lactadherin interacts with alphavbeta3 and alphavbeta5 integrins and alters both VEGF-dependent Akt phosphorylation and neovascularization. In the absence of VEGF, lactadherin administration induced alphavbeta3- and alphavbeta5-dependent Akt phosphorylation in endothelial cells in vitro and strongly improved postischemic neovascularization in vivo. These results show a crucial role for lactadherin in VEGF-dependent neovascularization and identify lactadherin as an important target for the modulation of neovascularization.
Background— Atherosclerosis is an immunoinflammatory disease; however, the key factors responsible for the maintenance of immune regulation in a proinflammatory milieu are poorly understood. Methods and Results— Here, we show that milk fat globule-EGF factor 8 (Mfge8, also known as lactadherin) is expressed in normal and atherosclerotic human arteries and is involved in phagocytic clearance of apoptotic cells by peritoneal macrophages. Disruption of bone marrow–derived Mfge8 in a murine model of atherosclerosis leads to substantial accumulation of apoptotic debris both systemically and within the developing lipid lesions. The accumulation of apoptotic material is associated with a reduction in interleukin-10 in the spleen but an increase in interferon-γ production in both the spleen and the atherosclerotic arteries. In addition, we report a dendritic cell-dependent alteration of natural regulatory T-cell function in the absence of Mfge8. These events are associated with a marked acceleration of atherosclerosis. Conclusions— Lack of Mfge8 in bone marrow–derived cells enhances the accumulation of apoptotic cell corpses in atherosclerosis and alters the protective immune response, which leads to an acceleration of plaque development.
BackgroundElderly patients with hip fracture have a 5 to 8 fold increased risk of death during the months following surgery. We tested the hypothesis that early geriatric management of these patients focused on co-morbidities and rehabilitation improved long term mortality.Methods and FindingsIn a cohort study over a 6 year period, we compared patients aged >70 years with hip fracture admitted to orthopedic versus geriatric departments in a time series analysis corresponding to the creation of a dedicated geriatric unit. Co-morbidities were assessed using the Cumulative Illness Rating Scale (CIRS). Each cohort was compared to matched cohorts extracted from a national registry (n = 51,275) to validate the observed results. Main outcome measure was 6-month mortality. We included 131 patients in the orthopedic cohort and 203 in the geriatric cohort. Co-morbidities were more frequent in the geriatric cohort (median CIRS: 8 vs 5, P<0.001). In the geriatric cohort, the proportion of patients who never walked again decreased (6% versus 22%, P<0.001). At 6 months, re-admission (14% versus 29%, P = 0.007) and mortality (15% versus 24%, P = 0.04) were decreased. When co-morbidities were taken into account, the risk ratio of death at 6 months was reduced (0·43, 95%CI 0·25 to 0·73, P = 0.002). Using matched cohorts, the average treatment effects on the treated associated to early geriatric management indicated a reduction in hospital mortality (−63%; 95% CI: −92% to −6%, P = 0.006).ConclusionsEarly admission to a dedicated geriatric unit improved 6-month mortality and morbidity in elderly patients with hip fracture.
There are only few data concerning persistence of neutralizing antibodies (NAbs) among SARS-CoV-2-infected healthcare workers (HCW). These individuals are particularly exposed to SARS-CoV-2 infection and at potential risk of reinfection. We followed 26 HCW with mild COVID-19 three weeks (D21), two months (M2) and three months (M3) after the onset of symptoms. All the HCW had anti-receptor binding domain (RBD) IgA at D21, decreasing to 38.5% at M3 (p < 0.0001). Concomitantly a significant decrease in NAb titers was observed between D21 and M2 (p = 0.03) and between D21 and M3 (p < 0.0001). Here, we report that SARS-CoV-2 can elicit a NAb response correlated with anti-RBD antibody levels. However, this neutralizing activity declines, and may even be lost, in association with a decrease in systemic IgA antibody levels, from two months after disease onset. This short-lasting humoral protection supports strong recommendations to maintain infection prevention and control measures in HCW, and suggests that periodic boosts of SARS-CoV-2 vaccination may be required.
Background— The mechanisms of thrombosis on plaque erosion are poorly understood. We examined the potential role of endothelial apoptosis in endothelial erosion and vessel thrombosis. Methods and Results— Segments of New Zealand White rabbit femoral arteries were temporarily isolated in vivo. One artery was incubated with staurosporin for 30 minutes, whereas the contralateral artery was incubated with saline and served as control. Three days later, thrombosis was evaluated angiographically and histologically. TUNEL score in the endothelial layer was significantly increased in staurosporin-treated arteries compared with controls (2.43±0.30 versus 0.93±0.44, respectively; P =0.001). Large areas of endothelial denudation were detectable in staurosporin-treated vessels, whereas endothelium integrity was almost preserved in the saline group. Vessel thrombosis occurred in 58% of staurosporin-treated arteries (7 of 12) but in only 8% of saline-treated segments ( P <0.01). Immunoreactivities for tissue factor, platelets, and fibrin were detectable within the thrombus. Addition of ZVAD-fmk (0.1 mmol/L) significantly reduced the occurrence of thrombosis (1 of 7 arteries or 14%, P =0.04). These results were confirmed in balloon-injured atheromatous arteries. Conclusions— In vivo induction of endothelial apoptosis leads to both vessel thrombosis and endothelial denudation. Endothelial apoptosis may be a critical step in the transition from a stable endothelialized plaque to plaque erosion and thrombosis.
Introduction Our objectives were to determine the causes of acute respiratory failure (ARF) in elderly patients and to assess the accuracy of the initial diagnosis by the emergency physician, and that of the prognosis.
In a large cohort of French patients, hip fracture surgery compared with elective THR was associated with a higher risk of in-hospital mortality after adjustment for age, sex, and measured comorbidities. Further studies are needed to define the causes for these differences.
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