Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine.

OBJECTIVE: Circulatory shock is a life-threatening syndrome resulting in multiorgan failure and a high mortality rate. The aim of this consensus is to provide support to the bedside clinician regarding the diagnosis, management and monitoring of shock. METHODS: The European Society of Intensive Care Medicine invited 12 experts to form a Task Force to update a previous consensus (Antonelli et al.: Intensive Care Med 33:575-590, 2007). The same five questions addressed in the earlier consensus were used as the outline for the literature search and review, with the aim of the Task Force to produce statements based on the available literature and evidence. These questions were: (1) What are the epidemiologic and pathophysiologic features of shock in the intensive care unit ? (2) Should we monitor preload and fluid responsiveness in shock ? (3) How and when should we monitor stroke volume or cardiac output in shock ? (4) What markers of the regional and microcirculation can be monitored, and how can cellular function be assessed in shock ? (5) What is the evidence for using hemodynamic monitoring to direct therapy in shock ? Four types of statements were used: definition, recommendation, best practice and statement of fact. RESULTS: Forty-four statements were made. The main new statements include: (1) statements on individualizing blood pressure targets; (2) statements on the assessment and prediction of fluid responsiveness; (3) statements on the use of echocardiography and hemodynamic monitoring. CONCLUSIONS: This consensus provides 44 statements that can be used at the bedside to diagnose, treat and monitor patients with shock

Identification of a Guanine Nucleotide Exchange Factor for Arf3, the Yeast Orthologue of Mammalian Arf6

Small G proteins of the Arf and Rab families are fundamental to the organisation and activity of intracellular membranes. One of the most well characterised of these G proteins is mammalian Arf6, a protein that participates in many cellular processes including endocytosis, actin remodelling and cell adhesion. Exchange of GDP for GTP on Arf6 is performed by a variety of guanine nucleotide exchange factors (GEFs), principally of the cytohesin (PSCD) and EFA6 (PSD) families. In this paper we describe the characterisation of a GEF for the yeast orthologue of Arf6, Arf3, which we have named Yel1 (yeast EFA6-like-1) using yeast genetics, fluorescence microscopy and in vitro nucleotide exchange assays. Yel1 appears structurally related to the EFA6 family of GEFs, having an N-terminal Sec7 domain and C-terminal PH and coiled-coil domains. We find that Yel1 is constitutively targeted to regions of polarised growth in yeast, where it co-localises with Arf3. Moreover the Sec7 domain of Yel1 is required for its membrane targeting and for that of Arf3. Finally we show that the isolated Yel1 Sec7 domain strongly stimulates nucleotide exchange activity specifically on Arf3 in vitro

Reassessment of the capacity of the HIV-1 Env cytoplasmic domain to trigger NF-κB activation

The cytoplasmic domain of lentiviral Envelopes (EnvCD) ensures Env incorporation into nascent virions and regulatesEnv trafficking to and from the plasma membrane. It has also been reported to promote transcription from the viralLTR both directly and indirectly. Noticeably, the HIV-1 and SIVmac239EnvCDs were described to trigger nucleartranslocation of NF-κB (Postler, Cell Host Microbes 2012). Given the paramount importance of identifying viral and host factors regulating HIV transcription, cellular signaling pathways and latency, and given that viral replicationcapacity is dependent on Env, we asked whether HIV EnvCDs from different HIV-1 subtypes differently modulatedNF-κB. To that aim, we evaluated the ability of primaryHIV-1 Envs from subtypes B and C to activate the NF-κB pathway.Primary subtype B and C Envs all failed to activate the NF-κB pathway. In contrast, when the EnvCD of HIV-1 Envs wasfused to the the CD8-αchain, it induced ~ 10-fold increase in NF-κB induction, and this increase was much stronger witha truncated form of the HIV EnvCD lacking the 76 C-terminal residues and containing the proposed TAK-1 bindingdomain. Our results indicate that the HIV-1 EnvCD is unlikely to trigger the NF-κB pathway in its native trimeric form

Preoperative scallop-by-scallop assessment of mitral prolapse using 2D-transthoracic echocardiography

<p>Abstract</p> <p>Background</p> <p>This study was conducted to assess the accuracy of harmonic imaging 2D-transthoracic echocardiography (2D-TTE) segmental analysis compared to surgical findings, in degenerative mitral regurgitation (MR).</p> <p>Methods</p> <p>Seventy-seven consecutive patients with severe degenerative MR were prospectively enrolled. Preoperative 2D-TTE with precise localization of prolapsing or flailing scallops/segments was performed. All patients underwent mitral valve surgical repair. Surgical reports (SR), including valve description, were used as references for comparisons. A postoperative control 2D-TTE was performed.</p> <p>Results</p> <p>Out of 462 scallops/segments studied, surgical inspection identified 102 prolapses or flails (22%), 92 of which had previously been detected by 2D-TTE (90.2% sensitivity, 100% specificity). Agreement between preoperative 2D-TTE segmental analysis and SR was 97.8% (k = 0.93; p < 0.0001). Sixty-nine out of 77 2D-TTE reports were completely concordant with SR (89.6% diagnostic accuracy). None of the 8 non-concordant 2D-TTE reports were in complete disagreement with SR. P2 scallop was always involved in posterior leaflet prolapse or flail and was described correctly by 2D-TTE in 68 out of 69 patients (98,7% agreement, k = 0,93; 98.5% sensitivity). The anterior leaflet was involved in 14 patients (18%); A2 segment was involved in all of those cases and was correctly detected by 2D-TTE in 13 (98,7% agreement, k = 0,95; 92,8% sensitivity). Antero-lateral and postero-medial para-commissural prolapse or flail had a lower prevalence (14% and 10% respectively), with 2D-TTE sensitivity respectively of 64% and 50%.</p> <p>Conclusions</p> <p>2D-TTE, performed by an experienced echo-lab, has very good diagnostic accuracy in localizing the scallops/segments involved in degenerative MR, particularly for the middle ones (P2-A2), which represent almost the totality of prolapses. More invasive, time consuming and expensive exams should be reserved to selected cases.</p