NOS3 Protects Against Systemic Inflammation and Myocardial Dysfunction in Murine Polymicrobial Sepsis

NO has been implicated in the pathogenesis of septic shock. However, the role of NO synthase 3 (NOS3) during sepsis remains incompletely understood. Here, we examined the impact of NOS3 deficiency on systemic inflammation and myocardial dysfunction during peritonitis-induced polymicrobial sepsis. Severe polymicrobial sepsis was induced by colon ascendens stent peritonitis (CASP) in wild-type (WT) and NOS3-deficient (NOS3KO) mice. NOS3KO mice exhibited shorter survival time than did WT mice after CASP. NOS3 deficiency worsened systemic inflammation assessed by the expression of inflammatory cytokines in the lung, liver, and heart. Colon ascendens stent peritonitis markedly increased the number of leukocyte infiltrating the liver and heart in NOS3KO but not in WT mice. The exaggerated systemic inflammation in septic NOS3KO mice was associated with more marked myocardial dysfunction than in WT mice 22 h after CASP. The detrimental effects of NOS3 deficiency on myocardial function after CASP seem to be caused by impaired Ca2+ handling of cardiomyocytes. The impaired Ca2+ handling of cardiomyocytes isolated from NOS3KO mice subjected to CASP was associated with depressed mitochondrial ATP production, a determinant of the Ca2+ cycling capacity of sarcoplasmic reticulum Ca2+-ATPase. The NOS3 deficiency-induced impairment of the ability of mitochondria to produce ATP after CASP was at least in part attributable to reduction in mitochondrial respiratory chain complex I activity. These observations suggest that NOS3 protects against systemic inflammation and myocardial dysfunction after peritonitis-induced polymicrobial sepsis in mice

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

The incidence of hypotension during general anesthesia: a single-center study at a university hospital

Abstract Background Although intraoperative hypotension (IOH) has been emerging as a serious concern during general anesthesia, the incidence of IOH has not been demonstrated clearly in the Japanese population. Methods This single-center retrospective study investigated the incidence and the characteristics of IOH in non-cardiac surgery at a university hospital. IOH was defined as at least one fall of MAP during general anesthesia, which was categorized into the following groups: mild (65 to < 75 mmHg), moderate (55 to < 65 mmHg), severe (45 to < 55 mmHg), and very severe (< 45 mmHg). The incidence of IOH was calculated as a percentage of the number of events to the total anesthesia cases. Logistic regression analysis was performed to examine factors affecting IOH. Results Eleven thousand two hundred ten cases out of 13,226 adult patients were included in the analysis. We found moderate to very severe hypotension occurred in 86.3% of the patients for at least 1 to 5 min, and 48.5% experienced severe or very severe hypotension. The results of the logistic regression analysis indicated female gender, vascular surgery, American Society of Anesthesiologists physical status classification (ASA-PS) 4 or 5 in emergency surgery, and the combination with the epidural block (EDB) were significant factors of IOH. Conclusions IOH during general anesthesia was very frequent in the Japanese population. Female gender, vascular surgery, ASA-PA 4 or 5 in emergency surgery, and the combination with EDB were independent risk factors associated with IOH. However, the association with patient outcomes were not elucidated

Reliability of radio transients detected in the nasu sky survey

The higher steam temperatures and pressures in advanced supercritical steam turbines require the use of steels with improved creep rupture strength. The tempered martensitic steel P92 is a creep resistant material used for the production of components for live steam with operating temperature 550-630°C. For the application of these steels is essentially necessary to know the impact of different test atmospheres and temperatures on the crack growth rate. In the present work, the influence of atmosphere (air, vacuum, simulated live steam), proof-temperature, hold time, thermal exposure on the crack growth has been studied at temperatures between 500 and 600°C. The influence of proof-temperature and atmosphere has been reflected on micrographs of fracture surface. SEM-micrographs of the principal crack and also optical micrographs coming from the cross sections perpendicular to the plane of a crack propagation (secondary cracks) show changes in the character of a crack propagation dependent of the loading cycle and temperature. By fatigue crack growth tests has been enhancement of crack growth due to the aggressive atmosphere (air) noted. The fatigue crack growth rates in air are at least one order of magnitude faster than those in vacuum (inert atmosphere). The effects of air, vacuum, simulated live steam on creep crack growth of P92 was also studied. A hold time leads to a higher crack growth rate compared with pure creep crack growth tests. The results from crack growth tests demonstrated, that steam oxidation plays a important role among the three factor, creep crack growth, fatigue crack growth and oxidation, in crack growth of these steel in superheated steam. In this work was also effect of side-grooves on the local stress and crack growth rate experimentally examined