Atrial Support Pacing in Heart Failure: Results from the Multicenter PEGASUS CRT Trial

Atrial Pacing in Heart Failure. Introduction: Cardiac resynchronization therapy (CRT) efficacy trials to date used atrial‐synchronous biventricular pacing wherein there is no or minimal atrial pacing. However, bradycardia and chronotropic incompetence are common in this patient population. This trial was designed to evaluate the effect of atrial support pacing among heart failure patients receiving a CRT defibrillator. Methods and Results: PEGASUS CRT was a multicenter, 3‐arm, randomized study. At 6 weeks, patients were randomized to DDD mode at a lower rate of 40 bpm (DDD‐40; control arm), or one of the following 2 treatment arms: DDD‐70, or DDDR‐40. The primary endpoint was a clinical composite endpoint that included all‐cause mortality, heart failure events, NYHA functional class, and patient global self‐assessment. Subjects were classified as improved, unchanged, or worsened at 12 months. There were 1,433 patients randomized, of whom 66% were male, mean age was 67 ± 11 years, and mean left ventricular ejection fraction was 23 ± 7%. The average follow‐up time was 10.5 ± 3.5 months and 1,309 patients contributed to the primary endpoint. No significant differences were observed in the composite endpoint between either of the 2 treatment arms compared to the control arm (P>0.05 for both comparisons). Additionally, there were no differences among the groups in mortality or heart failure events. Conclusion: In advanced heart failure patients treated with CRT, atrial support pacing did not improve clinical outcomes compared to atrial tracking. However, atrial pacing did not adversely affect mortality or heart failure events. (J Cardiovasc Electrophysiol, Vol. 23, pp. 1317‐1325, December 2012)     

The schistosomulicidal activity and the production of IL-1 and TNF-α by peritoneal macrophages from infected mice and their potentiation by muramyl tripeptide-phosphatidyl ethanolamine (MTP-PE) treatment

Production of TNF-α and IL-1 by adherent peritoneal exudate macrophages (APEM) was monitored for 20 weeks in Schistosoma mansoni infected mice in comparison to their schistosomulicidal activity. LPS-triggered IL-1 and TNF-α production by APEM peaked 10 weeks post infection (p.i.) and declined thereafter. The schistosomulicidal activity of APEM also peaked after 10 weeks but remained elevated thereafter. Infected mice were also treated with the immunostimulator liposomal muramyl tripeptide-phosphatidyl ethanolamine (MTP-PE) 6 or 10 weeks p.i., and their APEM were tested 4 weeks later. APEM from such treated animals showed elevated IL-1 and TNF-α production when treatment commenced 6 weeks p.i., while their schistosomulicidal activity increased when treatment commenced either 6 or 10 weeks p.i. The L-arginine inhibitor, N^G monomethyl arginine, markedly inhibited the schistosomulicidal activity but not the IL-1 and TNF-α production of APEM. Our results show that monokine production increases during the acute phase of infection and declines during its chronic phase, while macrophage schistosomulicidal activity remains constant throughout. Furthermore, TNF-α or IL-1 may play a minor role in APEM mediated killing of schistosomula.     

Hematologic and immunomodulatory effects of an interleukin-1 receptor antagonist coinfusion during low-dose endotoxemia in healthy humans

Endotoxin is a component of gram-negative bacteria that causes hematologic and immunologic changes through its induction of cytokines. Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring inhibitor of IL-1 that competes with IL-1 for occupancy of cell-surface receptors but possesses no agonist activity. We investigated the ability of human recombinant IL-1Ra to block the effects of low-dose endotoxin. Fourteen healthy male volunteers between 18 and 30 years old were injected intravenously with 3 ng/kg Escherichia coli endotoxin. Concurrent with the injections, nine volunteers received a 3-hour continuous intravenous infusion of IL-1Ra. The other five subjects were given a 3-hour infusion of saline. Volunteers injected with endotoxin experienced a threefold increase in circulating neutrophils over baseline. This neutrophilia was significantly reduced by 48% in subjects administered endotoxin plus IL-1Ra (P = .0253). Ex vivo mitogen-induced peripheral blood mononuclear cell proliferation decreased by greater than 60% at 3 and 6 hours after endotoxin injection (P = .0053). This endotoxin-induced reduction in mitogen response was reversed in subjects coinjected with IL-1Ra (P = .0253). Endotoxin-induced symptoms, fever, and tachycardia were unaffected by IL-1Ra. IL-1 appears to be an important mediator in endotoxemia because some of its hematologic and immunomodulatory effects can be blocked by IL-1Ra.     

A novel 37-Kd adhesive membrane protein from cloned murine bone marrow stromal cells and cloned murine hematopoietic progenitor cells

The adhesion of hematopoietic progenitor cells to bone marrow stromal cells is critical to hematopoiesis and involves multiple effector molecules. Stromal cell molecules that participate in this interaction were sought by analyzing the detergent-soluble membrane proteins of GBI/6 stromal cells that could be adsorbed by intact FDCP-1 progenitor cells. A single-chain protein from GBI/6 cells having an apparent molecular weight of 37 Kd was selectively adsorbed by FDCP-1 cells. This protein, designated p37, could be surface-radiolabeled and thus appeared to be exposed on the cell membrane. An apparently identical 37- Kd protein was expressed by three stromal cell lines, by Swiss 3T3 fibroblastic cells, and by FDCP-1 and FDCP-2 progenitor cells. p37 was selectively adsorbed from membrane lysates by a variety of murine hematopoietic cells, including erythrocytes, but not by human erythrocytes. Binding of p37 to cells was calcium-dependent, and was not affected by inhibitors of the hematopoietic homing receptor or the cell-binding or heparin-binding functions of fibronectin. It is proposed that p37 may be a novel adhesive molecule expressed on the surface of a variety of hematopoietic cells that could participate in both homotypic and heterotypic interactions of stromal and progenitor cells.     

Nosocomial and community acquired uropathogenic isolates of Proteus mirabilis and antimicrobial susceptibility profiles at a university hospital in Sub–Saharan Africa

ObjectiveTo ascertain antimicrobial susceptibility profile of Proteus mirabilis (P. mirabilis) from clinical urine specimens at a university hospital in the spate of its recorded increasing resistance patterns.MethodsThe study was retrospective in nature. Data generated from urine cultures of patients at University of Calabar Teaching Hospital for a period of five years (2004–2009) were compiled. Relevant information obtained were age and gender of patients, organisms recovered and their antibiotic susceptibility patterns. P. mirabilis was identified using standard laboratory procedures.ResultsP. mirabilis showed the highest resistance against ampicillin, cloxacillin, amoxicillin, tetracycline, co-trimoxazole, erythromycin and chloramphenicol (100%–37.2%) while colistin, ofloxacin, ciprofloxacin, ceftriaxone, nalidixic acid and nitrofurantoin recorded the highest activity (59.1%–96.9%) with no drug recording 100% activity. The resistance of the nosocomial isolates of the organism were significantly higher than the community acquired isolates against that of the common antibiotics in use (P<0.05).ConclusionsExtreme caution should be exercised in antibiotic administration in hospital setting and the potential benefits adequately assessed while control of nosocomial infections be given a priority so as to limit the spread of resistant bacteria.     

Oxidative degradation of cholesteryl esters in low-density lipoproteins: analysis by liquid chromatography-light scattering and protection by a new synthetic antioxidant, S20478

Summary— Cholesteryl esters in the hydrophobic core of low-density lipoprotein (LDL) particles constitute a major molecular target during copper-mediated oxidation. To facilitate the rapid analysis and quantitation of the oxidative degradation of LDL cholesteryl esters, we describe a new approach based on light scattering detection following separation by HPLC. We have applied this approach to the evaluation of the protective capacity of a new synthetic antioxidant, S20478, during oxidation of LDL in the presence of copper ions. HPLC separation of cholesterol and the four major molecular species of cholesteryl esters (C16:0, C18:1, C18:2 and C20:4) of LDL was achieved in a single run of 20 min with high sensitivity (50 ng) and low background. Time course studies of the oxidative modification of LDL (ratio LDL protein: copper, 100 μg/mL: 1μM) revealed that the content of unsaturated cholesteryl esters (C20:4 and C18:2) decreased (–30% and –15%, respectively) within 90 min of copper-mediated oxidation, while only minor degradation (up to 15%) of monounsaturated (C18:1) and saturated (C16:0) esters occurred. At 24 hours of oxidation, only traces (< 5%) of the C20:4 and C18:2 esters were detectable; whereas 52% of the C18:1 ester remained (P < 0.01). Of the saturated esters, only minor proportions (35% or less) underwent oxidative modification. In addition, some 81% of free cholesterol was conserved as the native sterol. The synthetic antioxidant, S20478 (50 μM) was capable of inhibiting the initiation and the propagation of copper-mediated LDL oxidation as determined by the time- and dose-dependant inhibition of the formation of conjugated dienes and thiobarbituric acid-reactive substances, as well as the conservation of the net electrical charge of LDL; indeed S20478 conserved cholesteryl esters in their native form up to 24 hours. However, after prolonged exposure to copper ions (48 hours), only 47% of the unsaturated esters remained (C18:2, P < 0.05). Nonetheless, S20478 (10 μM) was more efficient in inhibiting copper-mediated LDL oxidation as compared to probucol at the same concentration. These findings suggest that S20478 may be of potential interest in a new antioxidant approach to therapeutic stabilisation and regression of atherosclerotic plaques. Moreover, this method should prove useful in the assessment of the integrity of native LDL, and provides a new chemical marker of the degree of LDL oxidation.     

INTERACTION OF EXOGENOUS OUABAIN AND CHRONIC MINERALOCORTICOID TREATMENT IN THE KIDNEY OF THE CONSCIOUS SHEEP

1. Ouabain is known to have natriuretic effects only at high doses, and therefore if endogenously produced ouabain has a role in the regulation of sodium excretion, the renal response to ouabain must be increased substantially in certain physiological situations. The aim of this study is to determine whether treatment with the mineralocorticoid, aldosterone, potentiates that natriuretic response to ouabain. 2. Six conscious sheep received renal arterial infusion of either vehicle or aldosterone (3 μg/h). Forty hours after commencement of infusion ouabain was infused into the renal artery at 400 μg/h for 60min. A second infusion of ouabain was administered on the 6th day of aldosterone treatment. 3. In the absence of aldosterone, the effects on sodium excretion produced by ouabain infusion at 400 μg/h into the renal artery were variable and not statistically significant. Ouabain infusion after 40 h of aldosterone treatment increased sodium excretion from 40 ± 14 to 676 ± 69 μmol/min in the second hour following cessation of ouabain infusion (P< 0.001). Ouabain infusion after 6 days of aldosterone treatment increased sodium excretion similarly. Ouabain-stimulated sodium excretion was significantly greater during aldosterone treatment compared to vehicle treatment (P<0.05). In contrast, no enhancement of effect was observed after acute treatment with aldosterone. 4. These results demonstrate potentiation of the natriuretic response to ouabain infusion by chronic mineralocorticoid treatment and suggest a potential role of endogenous digitalislike factor in the physiological control of sodium homeo stasisaldo sterone, endogenous digitalis-like factor, ouabain, sodium excretion.     

Legitimizing surrogacy in Israel

Recently the Israeli Parliament passed legislation regarding all aspects of assisted reproductive techniques, including surrogacy. The main points of this legislation are presented and discussed. The most important aspects are: (i) a public committee authorizes and supervises every single case; (ii) only full surrogacy is permitted; (iii) the agreement is not commercial, reasonable expenses can be paid to the surrogate mother under the supervision of the Approving Committee; (iv) the surrogate mother must be single or divorced; (v) under certain conditions the surrogate mother can withdraw from the agreement; (vi) the child is under the tutelage of a social worker, representing the state, from birth until the completion of the adoption procedure. The religious, social and legal status of surrogate pregnancies worldwide are discussed.      

Progressive platelet activation with storage: evidence for shortened survival of activated platelets after transfusion

Platelets are known to become activated during storage, but it is unclear whether such activation affects recovery or survival after platelet concentrate (PC) transfusion. With the use of flow cytometry to determine the percentage of platelets expressing the alpha-granule membrane protein 140 (GMP-140), a known adhesive ligand appearing on the platelet surface after activation, several studies were conducted. These investigations evaluated 1) the occurrence of significant platelet activation over time in PCs (n = 46) stored under standard blood bank conditions; 2) the correlation between platelet activation and platelet recovery in normal subjects after PC storage (n = 12), as assessed by the recovery of Indium-labeled platelets; and 3) the recovery of activated and unactivated platelets in thrombocytopenic cancer patients transfused with standard PCs (n = 11). It was determined 1) that an increasing duration of storage of PC was associated with increasing platelet activation as measured by the percentage of platelets expressing GMP-140, progressing from a mean of 4 +/- 2 percent (SD) on the day of collection to a mean of 25 +/- 8 percent by 5 days of storage: 2) that, in normal subjects, posttransfusion recovery of autologous platelets stored for 2 to 4 days and then labeled with In111 was inversely correlated with the percentage of activated platelets in the transfused PC (r = -0.55, p = 0.05); and 3) that, when thrombocytopenic patients were transfused with standard PCs, the recovery of the activated platelets in the transfused PCs averaged only 38 +/- 15 percent of the number predicted by the absolute platelet increment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Complications Associated with Pectoral Implantation of Cardioverter Defibrillators

Pectoral placement of ICD pulse generators is now routine after downsizing of these devices. However, the safety of this approach is not well documented. The aim of this study was to evaluate complications in a large cohort of patients undergoing initial pectoral ICD implantation. The subjects for this study were 1,000 consecutive patients receiving a Medtronic Jewel ICD at 93 centers worldwide. Cumulative follow-up for all patients was 634 patient-years, with 64.9% of patients followed for 6 months or longer. The complications evaluated were erosion, pocket hematoma, seroma, wound infection, dehiscence, device migration, lead fracture, and dislodgment. In this series, 1.8% of patients experienced a pocket complication with only 3 (0.3%) erosions and 2 (0.2%) infections. Lead complications were observed in 2.1% of subjects, most commonly early dislodgment of the RV lead. We conclude that pectoral implantation of a downsized ICD system can be performed with a low rate of complications. However, careful attention to anchoring techniques and close early monitoring is important given the 1.7% rate of lead dislodgment that occurred primarily during the first month following implantation.