Critical role of the endogenous interferon ligand–receptors in type I and type II interferons response

Separate ligand–receptor paradigms are commonly used for each type of interferon (IFN). However, accumulating evidence suggests that type I and type II IFNs may not be restricted to independent pathways. Using different cell types deficient in IFNAR1, IFNAR2, IFNGR1, IFNGR2 and IFN‐γ, we evaluated the contribution of each element of the IFN system to the activity of type I and type II IFNs. We show that deficiency in IFNAR1 or IFNAR2 is associated with impairment of type II IFN activity. This impairment, presumably resulting from the disruption of the ligand–receptor complex, is obtained in all cell types tested. However, deficiency of IFNGR1, IFNGR2 or IFN‐γ was associated with an impairment of type I IFN activity in spleen cells only, correlating with the constitutive expression of type II IFN (IFN‐γ) observed on those cells. Therefore, in vitro the constitutive expression of both the receptors and the ligands of type I or type II IFN is critical for the enhancement of the IFN activity. Any IFN deficiency can totally or partially impair IFN activity, suggesting the importance of type I and type II IFN interactions. Taken together, our results suggest that type I and type II IFNs may regulate biological activities through distinct as well as common IFN receptor complexes.     

Electrocardiographic Abnormalities in Centenarians and Octogenarians: A Case‐Matched Study

Backround: Centenarians have been proposed as a model of successful aging but recent studies suggest a high prevalence of cardiovascular diseases. Some findings on their electrocardiograms (ECGs) are simply age‐related and others mirror underlying diseases. We aimed to identify ECG features truly associated with extreme age. Methods: Retrospective analysis of 55 centenarians hospitalized between January 2000 and June 2010. Each centenarian was matched with three octogenarians according to gender, presence of hypertension, aortic stenosis, heart failure, and ischemic heart disease. Results: A history of hypertension was present in 32 (58%) centenarians, aortic stenosis in 6 (11%), heart failure in 8 (15%), and ischemic heart disease in 6 (11%). Centenarians had a higher heart rate than octogenarians (81 ± 15 bpm vs. 72 ± 15 bpm, respectively, P < 0.001) but were less frequently on beta‐blockers (7% vs. 36%, respectively, P < 0.001). Centenarians displayed more frequently atrial premature beats than octogenarians (18% vs. 3%, respectively, P < 0.001) but tended to have less atrial fibrillation (15% vs. 22% respectively, P = 0.21). Centenarians had more frequently left QRS axis deviation (48% vs. 28%, P = 0.009) and Q waves (14% vs. 1%, P = 0.02). QT interval was more prolonged in centenarians (446 ± 42 ms vs. 429 ± 39 ms, P = 0.008). Two centenarians (4%) and 24 (15%) octogenarians had a strictly normal ECG (P = 0.02). Conclusions: Abnormal ECG is a common finding in centenarians, with different characteristics than in younger elderly individuals. These differences are unrelated to the presence of cardiac diseases.     

Treating Cardiac Arrhythmias Detected With an Implantable Cardiac Monitor in Patients After an Acute Myocardial Infarction

Using an implantable cardiac monitor (ICM) in patients with acute myocardial infarction (MI) allows continuous electrocardiogram monitoring and provides a much more detailed picture of the incidence of brady- and tachyarrhythmias than conventional follow-up. The CARISMA study was the first to use the ICM in post-MI patients with moderate to severe left ventricular systolic dysfunction. Atrial fibrillation (AF) events lasting longer than 30 s were associated with an almost threefold increase in the risk of major cardiac events. This confirms the current definition of clinically significant AF episodes, as patients with episodes of shorter duration were not at increased risk. The association of AF to progressive heart failure, reinfarction, and cardiovascular death underlines the need for an intensive follow-up of post-MI patients with new-onset AF in order to reveal underlying causes of AF such as progressive left ventricular dysfunction or myocardial ischemia. Asymptomatic, especially nightly, bradycardia episodes including high-degree 2°–3° atrioventricular (AV) block, sinus bradycardia, and sinus arrest were frequently documented by ICM in the CARISMA study. Ten percent of patients experienced high-degree 2°–3° AV block, of which the main part was nightly and asymptomatic, and 50% of all cardiovascular deaths occurred in this group, most from severe heart failure. Therefore, in post-MI patients with paroxysmal high-degree AV block, pacemaker implantation should be done, and in the case of left ventricular dysfunction (LVEF ≤ 35%), an implantable cardioverter defibrillator/cardiac resynchronization therapy defibrillator (ICD/CRT-D) may be indicated. Nonsustained ventricular tachycardia (VT) is very frequent in post-MI patients, and in the CARISMA study, high-risk patients with nonsustained VT were implanted with an ICD. Furthermore, in 10% of the patients, the ICM recorded nonsustained VT episodes of ≥ 16 beats per minute, resulting in a twofold increase in the risk for cardiac death. Thus, patients with nonsustained VT should undergo careful investigation, and we recommend a repeat echocardiography and electrophysiological stimulation in these patients. Patients with sustained VT or VF should receive an ICD.     

Pneumocyte Apoptosis Induction during Cardiopulmonary Bypass: Effective Prevention by Radical Scavenging Using N-Acetylcysteine

Cardiopulmonary bypass (CPB) and cardioplegic arrest are associated with pulmonary dysfunction. We sought to investigate whether pulmonary ischemia/reperfusion during standard CPB and cardioplegic arrest is associated with reactive oxygen species (ROS)-mediated pulmonary tissue injury and pneumocyte apoptosis induction, and whether ROS scavenging using N-acetylcysteine (NAC) attenuates these alterations. Twelve pigs (41 ± 8 kg) were randomized to receive either NAC (100 mg/kg prior to CPB; n = 7) or placebo (n = 5) and subjected to CPB and 60 min of cold (4°C) crystalloid cardioplegic arrest. We collected lung biopsies prior to CPB, at 60 min CPB, as well as at 30, 60, and 120 min post CPB. Lung specimens were immunocytochemically stained against nitrotyrosine, 8-isoprostaglandin-F₂α, and 8-hydroxy-2′-deoxyguanosine (8-OH-dG) as indicators for ROS-mediated tissue injury and active caspase-3, an apoptosis signal pathway key enzyme. Oxidative stress markers were judged using a scale from 1 to 4 (low to intensive staining), and caspase-3-positive pneumocytes were counted per view field. In placebo, the number of caspase-3-positive pneumocytes significantly increased over time to reach a maximum at 120 min post CPB (p =. 03 vs baseline). NAC significantly prevented caspase-3 activation in pneumocytes (p =. 001 vs Placebo). Pneumocyte nitrotyrosine and 8-OH-dG staining significantly increased over time (p =. 003) in the placebo group, but decreased in the NAC group (p =. 004). In both groups staining for 8-isoprostaglandin-F₂α showed no significant changes. This yields the conclusion that standard CPB and cardioplegic arrest initiate ROS-mediated tissue injury and apoptosis in pneumocytes that can be reduced by NAC. Thus, ROS scavenging using NAC may represent a novel approach to minimize lung injury associated with CPB.     

Peritoneal dialysis versus hemodialysis in patients with delayed graft function

Delayed graft function (DGF) in kidney transplantation affects adverse outcomes. It remains unclear whether the post‐transplant dialysis modality alters perioperative or long‐term graft outcomes. We performed a retrospective observational quality initiative at two Canadian renal transplant centers, in which DGF occurred in the recipient, necessitating one of peritoneal dialysis (PD) or hemodialysis (HD). There was no difference in baseline factors between patients with post‐transplant PD (n = 14) or HD (n = 63). The use of PD was associated with an increased risk of wound infection/leakage (PD 5/14 vs. HD 6/63, p = 0.024), shorter length of hospitalization (13.7 vs. 18.7 d, p = 0.009) and time requiring dialysis post‐operatively (6.5 vs 11.0 d, p = 0.043). There were no differences in readmission to hospital within 6 months (4/14 vs. 23/63, p = 0.759), graft loss (0/14 vs. 2/63, p = 1.000) or acute rejection episodes (1/14 vs. 4/63, p = 1.000) at one yr, and GFR did not differ between the PD or HD groups at 30 d (35.7 vs. 33.8 mL/min/m², p = 0.731), six months (46.9 vs. 45.5 mL/min/m², p = 0.835) or one yr (46.6 vs. 44.5 mL/min/m², p = 0.746). Further research is needed to determine which transplant patients are most appropriate to undergo PD catheter removal at the time of transplantation.     

Systematic Review and Meta-analysis of Pharmacological Treatment of the Symptoms of Attention-Deficit/Hyperactivity Disorder in Children with Pervasive Developmental Disorders

Many children with pervasive developmental disorders (PDD) exhibit behaviors and symptoms of attention-deficit/hyperactivity disorder (ADHD). We sought to determine the relative efficacy of medications for treating ADHD symptoms in children with PDD by identifying all double-blind, randomized, placebo-controlled trials examining the efficacy of medications for treating ADHD symptoms in children with PDD. We located seven trials involving 225 children. A random effects meta-analysis of four methylphenidate trials showed methylphenidate to be effective for treating ADHD symptoms in children with PDD (ES = .67). Several adverse events were greater for children were taking methylphenidate compared to placebo. An individual trial of clonidine and two trials of atomoxetine suggest these agents may also be effective in treating ADHD symptoms in children with PDD.