Na+/H+ exchanger isoform 1 induced cardiomyocyte hypertrophy involves activation of p90 ribosomal S6 Kinase

Studies using pharmacological and genetic approaches have shown that increased activity/expression of the Na+/H+ exchanger isoform 1 (NHE1) play a critical role in the pathogenesis of cardiac hypertrophy. Despite the importance of NHE1 in cardiac hypertrophy, severe cerebrovascular side effects were associated with the use of NHE1 inhibitors when administered to patients with myocardial infarctions. p90 ribosomal S6 Kinase (RSK), a downstream regulator of the mitogen-activated protein kinase pathway, has also been implicated in cardiac hypertrophy. We hypothesized that RSK plays a role in the NHE1 induced cardiomyocyte hypertrophic response. Infection of H9c2 cardiomyoblasts with the active form of the NHE1 adenovirus induced hypertrophy and was associated with an increase in the phosphorylation of RSK (P<0.05). Parameters of hypertrophy such as cell area, protein content and atrial natriuretic mRNA expression were significantly reduced in H9c2 cardiomyoblasts infected with active NHE1 in the presence of dominant negative RSK (DN-RSK) (P<0.05). These results confirm that NHE1 lies upstream of RSK. Increased phosphorylation and activation of GATA4 at Ser261 was correlated with increased RSK phosphorylation. This increase was reversed upon inhibition of RSK or NHE1. These findings demonstrate for the first time that the NHE1 mediated hypertrophy is accounted for by increased activation and phosphorylation of RSK, which subsequently increased the phosphorylation of GATA4; eventually activating fetal gene transcriptional machinery.Qatar University Internal Grant (QUUG-CPH-CPH-11/12-1) and by the Undergraduate Research Experience Program (UREP11-027-3-005) provided by the Qatar National Research Fund, Doha, Qatar.Scopu

The Efficacy of Etoposide on H9c2 Cardiomyoblasts Against Doxorubicin Induced Cardiotoxicity

Background: Doxorubicin (DOX), a widely used anticancer drug, has been associated with cardiotoxicity. Recently, DOX-induced cardiotoxicity has been attributed to topoisomerase II (TOPII)-β expression and activity. In our study, we investigated the effect of inhibiting TOPII in attenuating the DOX induced cardiotoxicity. Method: H9c2 cardiomyoblasts were treated with 1 or 2 µM DOX (+/-) 1 µM ETO. Cardiotoxicity was assessed by examining cell viability using the MTT assay, hypertrophy of crystal violet stained cardiomyoblasts and ROS production. Results: DOX induced a dose dependent increase in cardiotoxicity as indicated by the significant reduction in cell viability (71.77 ± 9.25% 2 µM DOX vs. 100% control, P<0.05), ROS production and hypertrophy. Stimulation of H9c2 cardiomyoblasts with both 2 µM DOX and 1µM ETO did not show a significant difference in cell viability, ROS production or hypertrophy. Conclusion: DOX induced cardiotoxicity in H9c2 cardiomyoblasts was not exacerbated in the presence of 1 µM ETO. This provides further support to using the combinatio

Decoupled models for vehicle dynamics and estimation of coupling terms

International audienceThis paper presents different dynamic models of vehicles to compare their dynamics. The main objective is to appreciate the couplings between the different model blocks after splitting systems to five sub models. The passivity approach is used and illustrated by simulation results obtained by the proposed simulator SimK106N

International Nosocomial Infection Control Consortium (INICC) report, data summary for 2003-2008, issued June 2009

Q3Artículo original95-106We report the results of the International Infection Control Consortium (INICC) surveillance study from January 2003 throughDecember 2008 in 173 intensive care units (ICUs) in Latin America, Asia, Africa, and Europe. During the 6-year study, using Centersfor Disease Control and Prevention (CDC) US National Healthcare Safety Network (NHSN; formerly the National Nosocomial Infec-tion Surveillance system [NNIS]) definitions for device-associated health care-associated infection, we collected prospective datafrom 155,358 patients hospitalized in the consortium’s hospital ICUs for an aggregate of 923,624 days. Although device utilizationin the developing countries’ ICUs was remarkably similar to that reported from US ICUs in the CDC’s NHSN, rates of device-asso-ciated nosocomial infection were markedly higher in the ICUs of the INICC hospitals: the pooled rate of central venous catheter(CVC)-associated bloodstream infections (BSI) in the INICC ICUs, 7.6 per 1000 CVC-days, is nearly 3-fold higher than the 2.0 per1000 CVC-days reported from comparable US ICUs, and the overall rate of ventilator-associated pneumonia (VAP) was also farhigher, 13.6 versus 3.3 per 1000 ventilator-days, respectively, as was the rate of catheter-associated urinary tract infection (CAUTI),6.3 versus 3.3 per 1000 catheter-days, respectively. Most strikingly, the frequencies of resistance ofStaphylococcus aureusisolatesto methicillin (MRSA) (84.1% vs 56.8%, respectively),Klebsiella pneumoniaeto ceftazidime or ceftriaxone (76.1% vs 27.1%, respec-tively),Acinetobacter baumanniito imipenem (46.3% vs 29.2%, respectively), andPseudomonas aeruginosato piperacillin (78.0%vs 20.2%, respectively) were also far higher in the consortium’s ICUs, and the crude unadjusted excess mortalities of device-relatedinfections ranged from 23.6% (CVC-associated bloodstream infections) to 29.3% (VAP)

International Nosocomial Infection Control Consortium report, datasummary of 50 countries for 2010-2015 : Device-associated module

Q3Artículo original1495-1504Background: We report the results of International Nosocomial Infection Control Consortium (INICC) sur-veillance study from January 2010-December 2015 in 703 intensive care units (ICUs) in Latin America,Europe, Eastern Mediterranean, Southeast Asia, and Western Pacific.Methods:During the 6-year study period, using Centers for Disease Control and Prevention National Health-care Safety Network (CDC-NHSN) definitions for device-associated health care-associated infection (DA-HAI), we collected prospective data from 861,284 patients hospitalized in INICC hospital ICUs for an aggregateof 3,506,562 days.Results:Although device use in INICC ICUs was similar to that reported from CDC-NHSN ICUs, DA-HAIrates were higher in the INICC ICUs: in the INICC medical-surgical ICUs, the pooled rate of central line-associated bloodstream infection, 4.1 per 1,000 central line-days, was nearly 5-fold higher than the 0.8per 1,000 central line-days reported from comparable US ICUs, the overall rate of ventilator-associatedpneumonia was also higher, 13.1 versus 0.9 per 1,000 ventilator-days, as was the rate of catheter-associated urinary tract infection, 5.07 versus 1.7 per 1,000 catheter-days. From blood cultures samples,frequencies of resistance ofPseudomonasisolates to amikacin (29.87% vs 10%) and to imipenem (44.3%vs 26.1%), and ofKlebsiella pneumoniaeisolates to ceftazidime (73.2% vs 28.8%) and to imipenem (43.27%vs 12.8%) were also higher in the INICC ICUs compared with CDC-NHSN ICUs.Conclusions:Although DA-HAIs in INICC ICU patients continue to be higher than the rates reported inCDC-NSHN ICUs representing the developed world, we have observed a significant trend toward the re-duction of DA-HAI rates in INICC ICUs as shown in each international report. It is INICC’s main goal tocontinue facilitating education, training, and basic and cost-effective tools and resources, such as stan-dardized forms and an online platform, to tackle this problem effectively and systematically

Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012

OBJECTIVE: To provide an update to the "Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock," last published in 2008. DESIGN: A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict of interest policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. A stand-alone meeting was held for all subgroup heads, co- and vice-chairs, and selected individuals. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS: The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations as strong (1) or weak (2). The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Recommendations were classified into three groups: (1) those directly targeting severe sepsis; (2) those targeting general care of the critically ill patient and considered high priority in severe sepsis; and (3) pediatric considerations. RESULTS: Key recommendations and suggestions, listed by category, include: early quantitative resuscitation of the septic patient during the first 6 h after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm a potential source of infection (UG); administration of broad-spectrum antimicrobials therapy within 1 h of the recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B); infection source control with attention to the balance of risks and benefits of the chosen method within 12 h of diagnosis (1C); initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1B); initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients (1C); fluid challenge technique continued as long as hemodynamic improvement is based on either dynamic or static variables (UG); norepinephrine as the first-choice vasopressor to maintain mean arterial pressure ≥65 mmHg (1B); epinephrine when an additional agent is needed to maintain adequate blood pressure (2B); vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or to decrease norepinephrine dose but should not be used as the initial vasopressor (UG); dopamine is not recommended except in highly selected circumstances (2C); dobutamine infusion administered or added to vasopressor in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C); avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C); hemoglobin target of 7-9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B); low tidal volume (1A) and limitation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B); higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C); recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C); prone positioning in sepsis-induced ARDS patients with a PaO (2)/FiO (2) ratio of ≤100 mm Hg in facilities that have experience with such practices (2C); head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B); a conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C); protocols for weaning and sedation (1A); minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B); avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C); a short course of neuromuscular blocker (no longer than 48 h) for patients with early ARDS and a PaO (2)/FI O (2) 180 mg/dL, targeting an upper blood glucose ≤180 mg/dL (1A); equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1B); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B); oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 h after a diagnosis of severe sepsis/septic shock (2C); and addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 h of intensive care unit admission (2C). Recommendations specific to pediatric severe sepsis include: therapy with face mask oxygen, high flow nasal cannula oxygen, or nasopharyngeal continuous PEEP in the presence of respiratory distress and hypoxemia (2C), use of physical examination therapeutic endpoints such as capillary refill (2C); for septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 mL/kg of crystalloids (or albumin equivalent) over 5-10 min (2C); more common use of inotropes and vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or proven "absolute"' adrenal insufficiency (2C). CONCLUSIONS: Strong agreement existed among a large cohort of international experts regarding many level 1 recommendations for the best care of patients with severe sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for this important group of critically ill patients