[Left ventricular migrating thrombus detected by intraoperative transesophageal echocardiography].

Transesophageal echocardiography (TEE) helps detecting intra-cavity thrombus size, mobility and fragility, which are of great importance in surgical removal of the thrombus. Thrombus characteristics may render surgical thrombectomy incomplete, raising the risk of catastrophic embolization. A 50-year-old man, suffering from congestive heart failure, developed a mobile thrombus in the left ventricle (LV). He was scheduled for a LV thrombectomy. TEE showed two thrombi on the apical side of the left ventricle, measuring 2.1 x 1.3 cm and 2.1 x 1.0 cm each. A surgical removal of these thrombi was performed under cardiopulmonary bypass (CPB). Just before separation from CPB, TEE detected a high echogenic mass in the LV Surgical re-explorations found residual thrombi, whose size, figure and echo signal strength resembled papillary muscles. This experience leads us to advocate repeated search for thrombi using TEE scans, in order to facilitate complete removal of thrombi prior to closing the ventriculotomy, and prior to weaning from CPB.

HIV-1 proteins preferentially activate anti-inflammatory M2-type macrophages.

HIV-1 proteins, including Tat, gp120, and Nef, activate macrophages (MΦ), which is consistent with the fact that HIV-1 infection is characterized by sustained immune activation. Meanwhile, MΦ are functionally classified into two types: proinflammatory M1-MΦ and anti-inflammatory M2-MΦ. We show that HIV-1 proteins, particularly Nef, preferentially activate M2-MΦ. Extracellular Tat, gp120, and Nef activated MAPK and NF-κB pathways in human peripheral blood monocyte-derived MΦ. However, the activation was marked in M-CSF-derived M2-MΦ but not GM-CSF-derived M1-MΦ. Nef was the most potent activator, and its signaling activation was comparable to that by TNF-α. Indeed, Nef was internalized more rapidly by M2-MΦ than by M1-MΦ. The myristoylation and proline-rich motif of Nef were responsible for the observed signaling activation. Consistent with the activation of MAPK/NF-κB pathways, Nef stimulated the production of a number of proinflammatory cytokines/chemokines by M2-MΦ. However, Nef reduced the expression of CD163 and phagocytosis, the characteristic markers of M2-MΦ, indicating that Nef drives an M2-like to M1-like phenotypic shift. Because the differentiation of most tissue MΦ depends on M-CSF and its receptor, which is the essential axis for the anti-inflammatory M2-MΦ phenotype, the current study reveals an efficient mechanism by which HIV-1 proteins, such as Nef, induce the proinflammatory MΦ.

HIV-1 Nef perturbs the function, structure, and signaling of the Golgi through the Src kinase Hck.

The interaction between HIV-1 Nef and the Src kinase Hck in macrophages has been shown to accelerate the progression to AIDS. We previously showed that Nef disturbed the N-glycosylation/trafficking of Fms, a cytokine receptor essential for maintaining macrophages in an anti-inflammatory state, in an Hck-dependent manner. Here, we show the underlying molecular mechanism of this effect. Using various Hck isoforms and their mutants and Golgi-targeting Hck mutants, we confirmed that Hck activation at the Golgi causes the Nef-induced Fms N-glycosylation defect. Importantly, we found that both the co-expression of Nef and Hck and the expression of a Golgi-targeted active Hck mutant caused alterations in the distribution of GM130, a Golgi protein that was shown to be required for efficient protein glycosylation. Moreover, the activation of Hck at the Golgi caused strong serine phosphorylation of the GM130-interacting Golgi structural protein GRASP65, which is known to induce Golgi cisternal unstacking. Using pharmacological inhibitors, we also found that the activation of Hck at the Golgi followed by the activation of the MAP kinase ERK-GRASP65 cascade is involved in the Fms N-glycosylation defect. These results suggest that Nef perturbs the structure and signaling of the Golgi by activating Hck at the Golgi, and thereby, induces the N-glycosylation/trafficking defect of Fms, which is in line with the idea that Src family kinases are crucial Golgi regulators.