Abeer Rababa'h

Levosimendan Reduces Mortality in Adults with Left Ventricular Dysfunction Undergoing Cardiac Surgery: A Systematic Review and Meta-analysis.

Levosimendan is implemented in patients with low cardiac output after cardiac surgery. However, the strength of evidence is limited by randomized controlled trials enrolling a small number of patients. Hence we have conducted a systematic review to determine the role of levosimendan in adult cardiac surgery.

Off-Pump Coronary Artery Bypass Reduces Early Stroke in Octogenarians: A Meta-Analysis of 18,000 Patients

BACKGROUND Data comparing results of off-pump and conventional operations in octogenarians is very limited. Thus we chose to compare early adverse events between off-pump coronary artery bypass grafting (OPCABG) and on-pump CABG (ONCABG) in patients older than 80 years. METHODS Systematic review of multiple databases was performed to obtain original studies fulfilling search criteria. End points--early mortality, stroke, respiratory failure, atrial fibrillation, and myocardial infarction--were compared between these cohorts. A random-effects weighted analysis was performed using the trim-fill adjustment when necessary. Results are presented as risk ratios (RRs) with 95% confidence intervals (CIs); p < 0.05 is considered statistically significant. RESULTS Sixteen retrospective studies (9,744 ONCABG and 8,566 OPCABG patients) were included in the systematic review. OPCAGB patients received significantly fewer grafts (2.54 ± 0.16) compared with ONCABG patients (3.22 ± 0.41). Early mortality was comparable at 4.6% and 5.2% in the OPCABG and ONCABG cohorts, respectively (risk ratio [RR], 0.91; 95% CI, 0.64-1.28; p = 0.598). Stroke rates were higher in the ONCABG cohort (RR, 0.65; 95% CI, 0.49- 0.87; p < 0.01). Respiratory failure was higher with ONCABG (RR, 0.74; 95% CI, 0.57-0.97; p = 0.03). New-onset renal failure (p = 0.99), atrial fibrillation (p = 0.27), and myocardial infarction (p = 0.99) were comparable. CONCLUSIONS Coronary artery bypass in octogenarians can be performed safely with low early mortality. Although off-pump operations reduce the risk of early stroke, all other adverse events are comparable in on- and off-pump coronary artery bypass operations. Data regarding late mortality is at present limited; however, both on- and off-pump procedures appear to produce comparable survival.

Compartmentalization Role of A-Kinase Anchoring Proteins (AKAPs) in Mediating Protein Kinase A (PKA) Signaling and Cardiomyocyte Hypertrophy

The Beta-adrenergic receptors (β-ARs) stimulation enhances contractility through protein kinase-A (PKA) substrate phosphorylation. This PKA signaling is conferred in part by PKA binding to A-kinase anchoring proteins (AKAPs). AKAPs coordinate multi-protein signaling networks that are targeted to specific intracellular locations, resulting in the localization of enzyme activity and transmitting intracellular actions of neurotransmitters and hormones to its target substrates. In particular, mAKAP (muscle-selective AKAP) has been shown to be present on the nuclear envelope of cardiomyocytes with various proteins including: PKA-regulatory subunit (RIIα), phosphodiesterase-4D3, protein phosphatase-2A, and ryanodine receptor (RyR2). Therefore, through the coordination of spatial-temporal signaling of proteins and enzymes, mAKAP controls cyclic-adenosine monophosphate (cAMP) levels very tightly and functions as a regulator of PKA-mediated substrate phosphorylation leading to changes in calcium availability and myofilament calcium sensitivity. The goal of this review is to elucidate the critical compartmentalization role of mAKAP in mediating PKA signaling and regulating cardiomyocyte hypertrophy by acting as a scaffolding protein. Based on our literature search and studying the structure–function relationship between AKAP scaffolding protein and its binding partners, we propose possible explanations for the mechanism by which mAKAP promotes cardiac hypertrophy.

Protein Kinase A and Phosphodiesterase-4D3 Binding to Coding Polymorphisms of Cardiac Muscle Anchoring Protein (mAKAP)

Protein kinase A (PKA) substrate phosphorylation is facilitated through its co-localization with its signaling partner by A-kinase anchoring proteins (AKAPs). mAKAP (muscle-selective AKAP) localizes PKA and its substrates such as phosphodiesterase-4D3 (PDE4D3), ryanodine receptor, and protein phosphatase 2A (PP2A) to the sarcoplasmic reticulum and perinuclear space. The genetic role of mAKAP, in modulating PKA/PDE4D3 molecular signaling during cardiac diseases, remains unclear. The purpose of this study was to examine the effects of naturally occurring mutations in human mAKAP on PKA and PDE4D3 signaling. We have recently identified potentially important human mAKAP coding non-synonymous polymorphisms located within or near key protein binding sites critical to β-adrenergic receptor signaling. Three mutations (P1400S, S2195F, and L717V) were cloned and transfected into a mammalian cell line for the purpose of comparing whether those substitutions disrupt mAKAP binding to PKA or PDE4D3. Immunoprecipitation study of mAKAP-P1400S, a mutation located in the mAKAP-PDE4D3 binding site, displayed a significant reduction in binding to PDE4D3, with no significant changes in PKA binding or PKA activity. Conversely, mAKAP-S2195F, a mutation located in mAKAP-PP2A binding site, showed significant increase in both binding propensity to PKA and PKA activity. Additionally, mAKAP-L717V, a mutation flanking the mAKAP-spectrin repeat domain, exhibited a significant increase in PKA binding compared to wild type, but there was no change in PKA activity. We also demonstrate specific binding of wild-type mAKAP to PDE4D3. Binding results were demonstrated using immunoprecipitation and confirmed with surface plasmon resonance (Biacore-2000); functional results were demonstrated using activity assays, Ca(2+) measurements, and Western blot. Comparative analysis of the binding responses of mutations to mAKAP could provide important information about how these mutations modulate signaling.

Tempol prevents post-traumatic stress disorder induced memory impairment

Post-traumatic stress disorder (PTSD) is a mental health disorder that can develop after a terrifying or life threatening event. Multiple symptoms are noticed in patients with PTSD including cognitive impairment, which was shown to be is associated with oxidative stress. Tempol is a highly efficient membrane-permeable antioxidant. In this study, we investigated the possible protective effect of tempol on PTSD-induced memory impairment. To test this hypothesis, we used single prolonged stress (SPS) model (2h restrain, 20min forced swimming, 15min rest, and 1-2min diethyl ether exposure) as a model of PTSD. Rats were randomly assigned into four groups: control (provided distilled water), tempol (provided tempol; 80mg/kg/day by oral gavage for 4weeks), SPS (exposed to prolonged stress and administered distilled water) and tempol/SPS (exposed to prolonged stress and administered tempol for 4weeks). We used radial arm water maze to test spatial learning and memory functions and enzyme-linked immunosorbant assay (ELISA) to measure levels of oxidative stress biomarkers in the hippocampus. Results showed that SPS model of PTSD impaired both short and long-term memories (P<0.05), and chronic tempol administration prevented such effect. Tempol also prevented decreases in hippocampal catalase, and SOD activities, GSH/GSSG ratio and increases TBARS levels, which were all impaired by SPS model of PTSD (P<0.05). In conclusion, we suggest a protective effect of tempol administration against SPS model of PTSD-induced short- and long- term memory impairment, and we believe that this protective effect of tempol is accomplished, at least partly, through prevention of alternation in oxidative stress in the hippocampus.

Antibiotic prescribing for acute respiratory infections in children in Jordan

Background Most acute respiratory infections (ARIs) in children are due to viral etiology; however, over-prescribing of antibiotics for ARIs is common. The aim of this investigation was to identify antibiotic prescribing prevalence for children with ARIs and to identify predictors of broad-spectrum antibiotic prescribing. Methods This was a prospective cross sectional study in a sample of ambulatory care settings in Jordan. Children (<18 years) presenting with ARIs were assessed in terms of patients demographics, antibiotic prescription and clinical diagnosis. Multivariable logistic regression analysis was used to identify predictors of broad-spectrum antibiotic prescription. Results Antibiotics were prescribed for 78.4% (4575/5829) of children with ARIs. Antibiotic prescription for ARIs for which antibiotics are not indicated was 69.2% (2688/3883). Broad-spectrum antibiotic prescription occurred in 51.1% (2337/4575) of all antibiotic-prescribed participants. Some of the predictors of broad-spectrum antibiotic prescription were: otitis media (OR 4.93 [95% CI 3.44-7.14]), tonsillitis (OR 6.03 [95% CI 4.39-8.33]), age 0-5 years (OR 1.17 [95% CI 1.02-1.38]) compared to age 6-12 years, fever (OR 2.14 [95% CI 1.78-2.59]), outpatient setting (OR 73 [95% CI 2.17-3.42]) and military sector (OR 2.29 [95% CI 1.82-2.90]). Conclusions Antibiotic prescribing is high and often inappropriate. Predictors of broad-spectrum antibiotic prescribing were identified. Health policy initiatives should involve all stakeholders to minimize inappropriate antibiotic prescription and to prevent poor outcomes associated with such practice.

N-Acetyl Cysteine Therapy Does Not Prevent Renal Failure in High-Risk Patients Undergoing Open-Heart Surgery.

BACKGROUND Renal dysfunction is a common complication after cardiovascular surgery. Controversial issues have been discussed regarding the role of N-acetyl cysteine in the prevention of postoperative renal dysfunction. The purpose of this meta-analysis is to assess whether N-acetyl cysteine offers any protection against the development of acute renal dysfunction after cardiac surgery. METHODS Multiple databases were searched for randomized trials comparing the role of N-acetyl cysteine and placebo in human patients undergoing cardiac surgery. End-points studied were: the incidence of acute renal failure, hemodialysis, early mortality, duration of hospital stay, and maximal change in creatinine values. Dichotomous variables were compared using the risk difference (RD) calculated with inverse weighting; continuous data was pooled as (standardized) mean difference. Results are presented with 95% confidence interval (P < .05 is significant); results are presented within 95% confidence interval. RESULTS Thirteen randomized trials (713 and 707 patients in the N-acetyl cysteine and control groups, respectively) were included in the present analysis; nine dealing with patients at high-risk for acute renal failure. The incidence of postoperative acute renal dysfunction was 23% and 36% in the N-acetyl cysteine and control cohorts, respectively. N-acetyl cysteine therapy did not reduce acute renal dysfunction in the high-risk cohort [RD -0.03 (-0.09 to 0.02); P = .22; I2 = 24%]. Maximal change in creatinine levels after surgery was also comparable [standardized mean difference 0.07 (-0.23, 0.09); P = .39]. Early mortality was 2.9% and 3.7% in the N-acetyl cysteine and control cohorts respectively; [RD 0 (-0.03 to 0.02); P = .63; I2 = 20%]. Hospital stay (mean length of stay 10.4 and 10.1 days in the N-acetyl cysteine and control cohorts, respectively) was also similar in both cohorts [WMD 0.17 (-0.02 to 0.37) days; P = .81]. CONCLUSION Prophylactic N-acetyl cysteine therapy does not reduce the incidence of renal dysfunction in high-risk patients undergoing cardiac surgery.

Left side approach for aortic valve replacement in patient with dextrocardia and situs inversus totalis

Aortic valve replacement in patients with dextrocardia and situs inversus totalis is technically challenging due to anatomical considerations. Modifications of the cannulation strategy and operative tool sets are helpful. We report a 47-year-old man who had dextrocardia with situs inversus totalis with severe aortic regurgitation. Our approach was precisely planned depending on the clear anatomy outlined by preoperative contrast-enhanced computed tomography of the chest. We used a surgical approach in which the main surgeon was standing on the left side of the patient. Left sided approach provided excellent exposure for aortic valve replacement in this case scenario.

Tissue valves are preferable for patients with end‐stage renal disease: an aggregate meta‐analysis

Valve selection in patients with end‐stage renal disease (ESRD) is uncertain. We performed a systematic review and meta‐analysis to compare clinical outcome in ESRD patients undergoing valve replacement.

Human Signaling Scaffold Protein (mAKAP) Binding Kinetics to PKA and Phosphodiesterase (PDE4DE): Implications for a Possible Role in Heart Failure

Heart failure is a leading cause of morbidity and mortality in the USA. There are several therapeutic agents available for heart failure management. In particular, agents that block beta-adrenergic receptor improve mortality rate among heart failure patients by enhancing cardiac function. Beta-adrenergic receptor stimulation signals through protein kinase A (PKA) dependent phosphorylation, partly by binding to A-kinase anchoring proteins, influencing calcium homeostasis. In particular, mAKAP (muscle-selective A-kinase anchoring protein) is targeted to specific intracellular compartments resulting in localization of PKA with its substrates as well as to bind with ryanodine receptors and phosphodiesterase-4D3 (PDE4DE). The signal transduction complex formed by the scaffold protein mAKAP at the perinuclear envelop of striated myocytes contains cAMP specific binding protein PDE4D3 which is responsible for cAMP signaling termination. Agents that modify PKA signaling would be expected to mediate an altered inotropic response. From different genomic databases, we have recently identified fifteen human mAKAP coding non-synonymous polymorphisms located within or near key protein binding sites critical to beta-adrenergic receptors signaling. Seven of these mutants were cloned for the purpose of comparing whether those substitution disrupt mAKAP binding to either the PKA binding domain R2alpha or the phosphodiesterase PDE4DE. Using surface plasmon resonance (Biacore 2000) we demonstrate specific binding of wild type mAKAP to PDE4DE. Experiments were run in triplicate and as twofold serial dilutions to explore the kinetics of the interaction and analyzed using Scrubber2 with a 1:1 Langmuir model. Comparative analysis of the binding responses of mutations to mAKAP could provide important information about how these mutations modulate signaling.