Citations

Background— Renal insufficiency is associated with increased morbidity and mortality after cardiopulmonary bypass cardiac surgery. B-type natriuretic peptide is a cardiac hormone that enhances glomerular filtration rate and inhibits aldosterone. Cystatin has been shown to be a better endogenous marker of renal function than creatinine. Methods and Results— We performed a double-blinded placebo-controlled proof of concept pilot study in patients (n=40) with renal insufficiency preoperatively (defined as an estimated creatinine clearance of <60 mL/min determined by the Cockroft-Gault formula), undergoing cardiopulmonary bypass cardiac surgery. Patients were randomized to placebo (n=20) or IV low dose nesiritide (n=20; 0.005 μg/Kg/min) for 24 hours started after the induction of anesthesia and before cardiopulmonary bypass. Patients in the nesiritide group had an increase of plasma B-type natriuretic peptide and its second messenger cGMP with a decrease in plasma cystatin levels at the end of the 24-hour infusion. These changes were not observed in the placebo group. There was a significant activation of aldosterone in the placebo group at the end of the 24-hour infusion, but not in the nesiritide group. At 48 and 72 hours, there was a decrease in estimated creatinine clearance and an increase in plasma cystatin as compared with end of the 24-hour infusion in the placebo group. In contrast, renal function was preserved in the nesiritide group with no significant change in estimated creatinine clearance and a trend for plasma cystatin to increase as compared with end of the 24-hour infusion. Conclusion— This proof of concept pilot study supports the conclusion that perioperative administration of low dose nesiritide is biologically active and decreases plasma cystatin in patients with renal insufficiency undergoing cardiopulmonary bypass cardiac surgery. Further studies are warranted to determine whether these physiological observations can be translated into improved clinical outcomes.

A prospective multicenter trial was conducted to evaluate the safety and feasibility of granulocyte colony-stimulating factor (G-CSF)–primed bone marrow (G-BM) in children receiving allogeneic bone marrow transplantation (BMT). A total of 42 children with a median age of 9.8 years (range, 0.8-17 years) were enrolled. Donors with median age of 9.2 years (range, 1.1-22 years) received 5 μg/kg per day of subcutaneous G-CSF for 5 consecutive days. BM was harvested on the fifth day. No donor experienced complications related to G-CSF administration or marrow har-vest. Median nucleated (NC) and CD34 cells infused was 6.7 × 108/kg (range, 2.4-18.5 × 108/kg) and 7.4 × 106/kg (range, 2-27.6 × 106/kg), respectively. Neutrophil and platelet engraftment was at a median of 19 days (range, 13-28 days) and 20 days (range, 9-44 days), respectively. A total of 13 (32%) patients developed grade 2 graft-versus-host disease (GVHD), and 5 (13%) of 40 evaluable patients developed chronic GVHD (3 limited and 2 extensive). Higher cell dose was not associated with increased risk of acute or chronic GVHD. Overall survival and event-free survival at 2 years were 81% and 69%, respectively. Collection of G-BM from pediatric donors is safe, and can result in high NC and CD34 cell doses that facilitate engraftment after myeloablative BMT without a discernable increase in the risk of GVHD.

Smaller-scale evaluations suggest that common genetic variation in candidate genes related to immune function may predispose to the development of non-Hodgkin lymphoma (NHL). We report an analysis of variants within genes associated with immunity and inflammation and risk of NHL using a panel of 9412 single-nucleotide polymorphisms (SNPs) from 1253 genes in a study of 458 patients with NHL and 484 frequency-matched controls. We modeled haplotypes and risk of NHL, as well as the main effects for all independent SNPs from a gene in multivariate logistic regression models; we separately report results for nonsynonymous (ns) SNPs. In gene-level analyses, the strongest findings (P ≤ .001) were for CREB1, FGG, MAP3K5, RIPK3, LSP1, TRAF1, DUSP2, and ITGB3. In nsSNP analyses, the strongest findings (P ≤ .01) were for ITGB3 L59P (odds ratio [OR] = 0.66; 95% confidence interval [CI] 0.52-0.85), TLR6 V427A (OR = 5.20; CI 1.77-15.3), SELPLG M264V (OR = 3.20; CI 1.48-6.91), UNC84B G671S (OR = 1.50; CI 1.12-2.00), B3GNT3 H328R (OR = 0.74; CI 0.59-0.93), and BAT2 V1883L (OR = 0.64; CI 0.45-0.90). Our results suggest that genetic variation in genes associated with immune response (TRAF1, RIPK3, BAT2, and TLR6), mitogen-activated protein kinase (MAPK) signaling (MAP3K5, DUSP2, and CREB1), lymphocyte trafficking and migration (B3GNT3, SELPLG, and LSP1), and coagulation pathways (FGG and ITGB3) may be important in the etiology of NHL, and should be prioritized in replication studies.

The proteasome is responsible for the degradation of oxidized proteins, and proteasome inhibition has been shown to generate oxidative stress in vitro. Atherosclerosis is thought to be initiated as a consequence of increased endogenous oxidative stress. The current study was designed to assess whether chronic proteasome inhibition is associated with early coronary atherosclerosis. Female pigs, 3 months of age, were randomized to a normal (N) or high-cholesterol (HC) diet (2% cholesterol, 15% lard) without or with twice weekly subcutaneous injections of the proteasome inhibitor (PSI) MLN-273 (0.08 mg/kg, N+PSI and HC+PSI) for a period of 12 weeks (n=5 per group). Coronary vasorelaxation to bradykinin (10 −10.5 to 10− 6.5 mol/L) and sodium nitroprusside (10 −9 to 10 −5 mol/L) was assessed by in vitro organ chamber experiments, intima–media ratio by morphometric analysis of Elastica–van Gieson–stained slides, and intima superoxide production by dihydroethidium fluorescence. Vasorelaxation to 10 −6.5 mol/L bradykinin was reduced in HC compared with N (69±7 versus 90±2%, P <0.05) and further reduced in N+PSI and HC+PSI (57±6 and 48±13%, P <0.05 versus N and HC for each). Compared with N (0.03±0.01), intima–media ratio was higher in N+PSI (0.09±0.04, P <0.01) and HC+PSI (0.15±0.06, P <0.05). Compared with N (0.6±0.9% of intima area), dihydroethidium fluorescence was higher in HC, N+PSI, and HC+PSI (8.9±1.6, 6.0±3.5, and 7.2±3.9% of intima area, P <0.05 for all). Thus, chronic proteasome inhibition is associated with increased coronary artery oxidative stress and early atherosclerosis. These findings support the significance of the proteasome and related protein quality control for vascular biology and pathology.

Abstract The pool of hematopoietic stem cells that actively contributes to hematopoiesis is small, and the cells replicate slowly. Patients with paroxysmal nocturnal hemoglobinuria invariably have a mutation in the PIG-A gene, and many have more than one clone of PIG-A mutated cells. Typically there is a dominant clone and a smaller second clone. By using a combination of stochastic dynamics and models of hematopoiesis, we show that it is very unlikely that more than one PIG-A mutated clone arises at the level of the hematopoietic stem cells. More likely, the smaller clone develops in the progenitor cell pool that would be expected to contribute to hematopoiesis for a shorter period of time. We provide estimates for the duration of these contributions and testable hypotheses that can shed important insights on this acquired hematopoietic stem cell disorder. Disclosure of potential conflicts of interest is found at the end of this article.

Background— Ranolazine, a piperazine derivative, reduces ischemia via inhibition of the late phase of the inward sodium current (late I Na ) during cardiac repolarization, with a consequent reduction in intracellular sodium and calcium overload. Increased intracellular calcium leads to both mechanical dysfunction and electric instability. Ranolazine reduces proarrhythmic substrate and triggers such as early afterdepolarization in experimental models. However, the potential antiarrhythmic actions of ranolazine have yet to be demonstrated in humans. Methods and Results— The Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndrome (MERLIN)–Thrombolysis in Myocardial Infarction (TIMI) 36 (MERLIN-TIMI 36) trial randomized 6560 patients hospitalized with a non–ST-elevation acute coronary syndrome to ranolazine or placebo in addition to standard therapy. Continuous ECG (Holter) recording was performed for the first 7 days after randomization. A prespecified set of arrhythmias were evaluated by a core laboratory blinded to treatment and outcomes. Of the 6560 patients in MERLIN-TIMI 36, 6351 (97%) had continuous ECG recordings that could be evaluated for arrhythmia analysis. Treatment with ranolazine resulted in significantly lower incidences of arrhythmias. Specifically, fewer patients had an episode of ventricular tachycardia lasting ≥8 beats (166 [5.3%] versus 265 [8.3%]; P <0.001), supraventricular tachycardia (1413 [44.7%] versus 1752 [55.0%]; P <0.001), or new-onset atrial fibrillation (55 [1.7%] versus 75 [2.4%]; P =0.08). In addition, pauses ≥3 seconds were less frequent with ranolazine (97 [3.1%] versus 136 [4.3%]; P =0.01). Conclusions— Ranolazine, an inhibitor of late I Na , appears to have antiarrhythmic effects as assessed by continuous ECG monitoring of patients in the first week after admission for acute coronary syndrome. Studies specifically designed to evaluate the potential role of ranolazine as an antiarrhythmic agent are warranted.