Antiplatelet therapy for patients undergoing coronary artery bypass surgery.

Considerable variation in the use and duration of antiplatelet medications during the perioperative and postoperative care of patients undergoing coronary artery bypass grafting (CABG) reflects the limited number of studies focused directly on these patients as well as the variation in the results reported. In this review we highlight the incidence and mechanisms of graft closure as well as the evidence in support of antiplatelet therapy that is balanced by the impact of antiplatelet therapy on the risk of bleeding to provide recommendations for the use of this therapy in patients undergoing CABG. Low-dose acetylsalicylic acid (ASA; ≤ 160 mg daily) reduces the incidence of perioperative myocardial infarction, acute renal injury, and mortality without increasing the risk of bleeding and so is recommended both before and after CABG. The use of dual antiplatelet therapy with ASA plus a P2Y12 antagonist adds a greater risk of bleeding. While additional studies are required, we can make the following recommendations: because of increased bleeding and mortality when patients are treated with clopidogrel preoperatively, CABG should be delayed for five days. Because of increased bleeding when patients are treated with ticagrelor preoperatively, CABG should be delayed for three days. Because of increased bleeding when patients are treated with prasugrel preopera-tively, CABG should be delayed for seven days. For patients who had a coronary stent placed preoperatively or had an acute coronary syndrome preoperatively, resumption of therapy with their P2Y12 antagonist postoperatively for 12 months reduces the subsequent incidence of cardiovascular events.

Atrial Septostomy: A Contemporary Review.

Pulmonary arterial hypertension (PAH) is a rare disease, but it boasts significant morbidity and mortality. Although remarkable achievements have been made in the medical treatment of PAH, there is a role for invasive or surgical procedures in patients with progressive disease despite optimal medical therapy or with no access to such therapy. Atrial septostomy creates a right-to-left intracardiac shunt to decompress the overloaded right ventricle. Despite significant advances to validate and improve this palliative procedure, as well as recent reports of improved outcomes, it is only slowly being adopted. This article aims to detail the history, indications, contraindications, procedural techniques, and outcomes of atrial septostomy. We will also shed light on some of the newer interventions, inspired by the same physiological concept, that are being evaluated as potential palliative modalities in patients with PAH.

NKp30 ligation induces rapid activation of the canonical NF-kappaB pathway in NK cells.

Studies of patients with congenital immunodeficiency due to mutation of the NF-kappaB essential modulator (NEMO) gene have demonstrated that NEMO integrity is required for NK cell cytotoxicity. Thus, we have studied the physiology of NF-kappaB activation in NK cells during the cytolytic program. In resting ex vivo human NK cells or cell lines, IkappaB was degraded after 10 min exposure to PMA and ionomycin, or TNF and was maximally degraded by 30 min. Ligation of several NK cell activation receptors including NKp30 induced a similar response and was blocked by pretreatment with the proteosome inhibitor MG132. There was no short-term effect on p100 processing, the signature of noncanonical NF-kappaB activation. NK cell IkappaB degradation corresponded to increases in nuclear NF-kappaB as detected by EMSA. Supershift of stimulated NK cells and fluorescence microscopy of individual NK cells in cytolytic conjugates demonstrated that the p65/p50 heterodimer was the primary NF-kappaB used. NF-kappaB function was evaluated in NK92 cells transduced with a kappaB GFP reporter, and their conjugation with K562 cells or ligation of NKp30 ligation resulted in rapid GFP accumulation. The latter was prevented by the Syk inhibitor piceatannol. Thus, NK cell activation signaling specifically induces transcriptional activation and synthesis of new NF-kappaB dependent proteins during the initiation of cytotoxicity.

Superantigen presentation by airway smooth muscle to CD4+ T lymphocytes elicits reciprocal proasthmatic changes in airway function.

Microbial products serving as superantigens (SAgs) have been implicated in triggering various T cell-mediated chronic inflammatory disorders, including severe asthma. Given earlier evidence demonstrating that airway smooth muscle (ASM) cells express MHC class II molecules, we investigated whether ASM can present SAg to resting CD4(+) T cells, and further examined whether this action reciprocally elicits proasthmatic changes in ASM responsiveness. Coincubation of CD4(+) T cells with human ASM cells pulsed with the SAg, staphylococcal enterotoxin A (SEA), elicited adherence and clustering of class II and CD3 molecules at the ASM/T cell interface, indicative of immunological synapse formation, in association with T cell activation. This ASM/T cell interaction evoked up-regulated mRNA expression and pronounced release of the Th2-type cytokine, IL-13, into the coculture medium, which was MHC class II dependent. Moreover, when administering the conditioned medium from the SEA-stimulated ASM/T cell cocultures to isolated naive rabbit ASM tissues, the latter exhibited proasthmatic-like changes in their constrictor and relaxation responsiveness that were prevented by pretreating the tissues with an anti-IL-13 neutralizing Ab. Collectively, these observations are the first to demonstrate that ASM can present SAg to CD4(+) T cells, and that this MHC class II-mediated cooperative ASM/T cell interaction elicits release of IL-13 that, in turn, evokes proasthmatic changes in ASM constrictor and relaxant responsiveness. Thus, a new immuno-regulatory role for ASM is identified that potentially contributes to the pathogenesis of nonallergic (intrinsic) asthma and, accordingly, may underlie the reported association between microbial SAg exposure, T cell activation, and severe asthma.