Objective-We hypothesized that reactive oxygen species (ROS) contribute to progression of aortic valve (AV) calcification/stenosis. Methods and Results-We investigated ROS production and effects of antioxidants tempol and lipoic acid (LA) in calcification progression in rabbits given 0.5% cholesterol diet ϩ10 4 IU/d Vit.D 2 for 12 weeks. Superoxide and H 2 O 2 microfluorotopography and 3-nitrotyrosine immunoreactivity showed increased signals not only in macrophages but preferentially around calcifying foci, in cells expressing osteoblast/osteoclast, but not macrophage markers. Such cells also showed increased expression of NAD(P)H oxidase subunits Nox2, p22phox, and protein disulfide isomerase. Nox4, but not Nox1 mRNA, was increased. Tempol augmented whereas LA decreased H 2 O 2 signals. Importantly, AV calcification, assessed by echocardiography and histomorphometry, decreased 43% to 70% with LA, but increased with tempol (PՅ0.05). Tempol further enhanced apoptosis and Nox4 expression. In human sclerotic or stenotic AV, we found analogous increases in ROS production and NAD(P)H oxidase expression around calcifying foci. An in vitro vascular smooth muscle cell (VSMC) calcification model also exhibited increased, catalase-inhibitable, calcium deposit with tempol, but not with LA. Conclusions-Our data provide evidence that ROS, particularly hydrogen peroxide, potentiate AV calcification progression. However, tempol exhibited a paradoxical effect, exacerbating AV/vascular calcification, likely because of its induced increase in peroxide generation. Key Words: calcification Ⅲ atherosclerosis Ⅲ antioxidants Ⅲ valves Ⅲ free radicals D egenerative aortic valve (AV) stenosis, the third most prevalent cardiovascular disease in the elderly, 1 shares common risk factors and pathophysiological features with atherosclerosis. [2][3][4][5][6] Although the role of oxidative stress in atherosclerosis is well explored, 7,8 it is unclear whether redox processes contribute to progression of AV calcification. 2,3,9 -11,15,16 Scarce observations provide indirect support for this hypothesis. 10 In vitro studies showed that exogenous superoxide, hydrogen peroxide, or other oxidants increase the number and activity of calcifying vascular cells (CVCs), 11 referred to as a specific subpopulation of cells, derived from (de)differentiation of vascular smooth muscle cells, 12 pericytes, or mesenchymal cells 13 that can produce hydroxyapathite in the vascular wall. 14 In addition, reactive oxygen species (ROS) mediate increase in BMP2 expression and signaling, favoring osteogenesis. 2 On the other hand, calcium resorption by osteoclasts is dependent on ROS derived from its own NAD(P)H oxidase, 15 whereas nitric oxide induces osteoclast detachment and inhibits calcium resorption. 16 Recent data from an experimental mouse model of aortic stenosis suggested locally increased superoxide generation. 3 Observational clinical studies with statins indicated possible decrease in calcification progression in hypercholesterolemic patients, 4 but ...

Introduction Mechanisms underlying inotropic failure in septic shock are incompletely understood. We previously identified the presence of exosomes in the plasma of septic shock patients. These exosomes are released mainly by platelets, produce superoxide, and induce apoptosis in vascular cells by a redoxdependent pathway. We hypothesized that circulating plateletderived exosomes could contribute to inotropic dysfunction of sepsis.

There is no consensual definition of refractory shock. The use of more than 0.5 mcg/kg/min of norepinephrine or epinephrine to maintain target blood pressure is often used in clinical trials as a threshold. Nearly 6% of critically ill patients will develop refractory shock, which accounts for 18% of deaths in intensive care unit. Mortality rates are usually greater than 50%. The assessment of fluid responsiveness and cardiac function can help to guide therapy, and inotropes may be used if hypoperfusion signs persist after initial resuscitation. Arginine vasopressin is frequently used in refractory shock, although definite evidence to support this practice is still missing. Its associations with corticosteroids improved outcome in observational studies and are therefore promising alternatives. Other rescue therapies such as terlipressin, methylene blue, and high-volume isovolemic hemofiltration await more evidence before use in routine practice.

BackgroundAnemia is frequent among patients with traumatic brain injury (TBI) and is associated with an increased risk of poor outcome. The optimal hemoglobin concentration to trigger red blood cell (RBC) transfusion in patients with TBI is not clearly defined.MethodsAll eligible consecutive adult patients admitted to the intensive care unit (ICU) with moderate or severe TBI were randomized to a “restrictive” (hemoglobin transfusion threshold of 7 g/dL), or a “liberal” (threshold 9 g/dL) transfusion strategy. The transfusion strategy was continued for up to 14 days or until ICU discharge. The primary outcome was the mean difference in hemoglobin between groups. Secondary outcomes included transfusion requirements, intracranial pressure management, cerebral hemodynamics, length of stay, mortality and 6-month neurological outcome.ResultsA total of 44 patients were randomized, 21 patients to the liberal group and 23 to the restrictive group. There were no baseline differences between the groups. The mean hemoglobin concentrations during the 14-day period were 8.4 ± 1.0 and 9.3 ± 1.3 (p < 0.01) in the restrictive and liberal groups, respectively. Fewer RBC units were administered in the restrictive than in the liberal group (35 vs. 66, p = 0.02). There was negative correlation (r = − 0.265, p < 0.01) between hemoglobin concentration and middle cerebral artery flow velocity as evaluated by transcranial Doppler ultrasound and the incidence of post-traumatic vasospasm was significantly lower in the liberal strategy group (4/21, 3% vs. 15/23, 65%; p < 0.01). Hospital mortality was higher in the restrictive than in the liberal group (7/23 vs. 1/21; p = 0.048) and the liberal group tended to have a better neurological status at 6 months (p = 0.06).ConclusionsThe trial reached feasibility criteria. The restrictive group had lower hemoglobin concentrations and received fewer RBC transfusions. Hospital mortality was lower and neurological status at 6 months favored the liberal group.Trial registrationClinicalTrials.gov, NCT02203292. Registered on 29 July 2014.Electronic supplementary materialThe online version of this article (10.1186/s13054-018-2273-9) contains supplementary material, which is available to authorized users.