Septic cardiomyopathy

Depression of left ventricular (LV) intrinsic contractility is constant in patients with septic shock. Because most parameters of cardiac function are strongly dependent on afterload, especially in this context, the cardiac performance evaluated at the bedside reflects intrinsic contractility, but also the degree of vasoplegia. Recent advances in echocardiography have allowed better characterization of septic cardiomyopathy. It is always reversible providing the patient's recovery. Unlike classic cardiomyopathy, it is not associated with high filling pressures, for two reasons: improvement in LV compliance and associated right ventricular dysfunction. Although, it is unclear to which extent it affects prognosis, a hyperkinetic state is indicative of a profound and persistent vasoplegia associated with a high mortality rate. Preliminary data suggest that the hemodynamic response to a dobutamine challenge has a prognostic value, but large studies are required to establish whether inotropic drugs should be used to treat this septic cardiac dysfunction

Dual inhibition of HIV-1 replication by integrase-LEDGF allosteric inhibitors is predominant at the post-integration stage

BACKGROUND: LEDGF/p75 (LEDGF) is the main cellular cofactor of HIV-1 integrase (IN). It acts as a tethering factor for IN, and targets the integration of HIV in actively transcribed gene regions of chromatin. A recently developed class of IN allosteric inhibitors can inhibit the LEDGF-IN interaction. RESULTS: We describe a new series of IN-LEDGF allosteric inhibitors, the most active of which is Mut101. We determined the crystal structure of Mut101 in complex with IN and showed that the compound binds to the LEDGF-binding pocket, promoting conformational changes of IN which explain at the atomic level the allosteric effect of the IN/LEDGF interaction inhibitor on IN functions. In vitro, Mut101 inhibited both IN-LEDGF interaction and IN strand transfer activity while enhancing IN-IN interaction. Time of addition experiments indicated that Mut101 behaved as an integration inhibitor. Mut101 was fully active on HIV-1 mutants resistant to INSTIs and other classes of anti-HIV drugs, indicative that this compound has a new mode of action. However, we found that Mut101 also displayed a more potent antiretroviral activity at a post-integration step. Infectivity of viral particles produced in presence of Mut101 was severely decreased. This latter effect also required the binding of the compound to the LEDGF-binding pocket. CONCLUSION: Mut101 has dual anti-HIV-1 activity, at integration and post-integration steps of the viral replication cycle, by binding to a unique target on IN (the LEDGF-binding pocket). The post-integration block of HIV-1 replication in virus-producer cells is the mechanism by which Mut101 is most active as an antiretroviral. To explain this difference between Mut101 antiretroviral activity at integration and post-integration stages, we propose the following model: LEDGF is a nuclear, chromatin-bound protein that is absent in the cytoplasm. Therefore, LEDGF can outcompete compound binding to IN in the nucleus of target cells lowering its antiretroviral activity at integration, but not in the cytoplasm where post-integration production of infectious viral particles takes place

Echocardiography practice, training and accreditation in the intensive care: document for the World Interactive Network Focused on Critical Ultrasound (WINFOCUS)

Echocardiography is increasingly used in the management of the critically ill patient as a non-invasive diagnostic and monitoring tool. Whilst in few countries specialized national training schemes for intensive care unit (ICU) echocardiography have been developed, specific guidelines for ICU physicians wishing to incorporate echocardiography into their clinical practice are lacking. Further, existing echocardiography accreditation does not reflect the requirements of the ICU practitioner. The WINFOCUS (World Interactive Network Focused On Critical UltraSound) ECHO-ICU Group drew up a document aimed at providing guidance to individual physicians, trainers and the relevant societies of the requirements for the development of skills in echocardiography in the ICU setting. The document is based on recommendations published by the Royal College of Radiologists, British Society of Echocardiography, European Association of Echocardiography and American Society of Echocardiography, together with international input from established practitioners of ICU echocardiography. The recommendations contained in this document are concerned with theoretical basis of ultrasonography, the practical aspects of building an ICU-based echocardiography service as well as the key components of standard adult TTE and TEE studies to be performed on the ICU. Specific issues regarding echocardiography in different ICU clinical scenarios are then described

Depletion of lipoprotein lipase after heparin administration

The online version of this article, along with updated information and services, is located on th

Understanding Polycyclic Aromatic Hydrocarbon transfers at the catchment scale combining chemical and fallout radionuclides analyses

International audienceContamination of river water and sediment constitutes a major environmental issue for industrialized countries. Polycyclic Aromatic Hydrocarbons (PAHs) are a group of persistent organic pollutants characterized by two or more fused rings. In recent years, studies dealing with PAHs have grown in number. Some PAHs present indeed a high risk for environment and human health because of their carcinogenic and mutagenic properties. However, most of these studies focused on measuring PAH concentration in the different compartments of the environment (air, soil, sediment, water, etc.) In this context, there remains a lack of understanding regarding the various processes responsible for PAH transfers from one environmental compartment to another. Our study aims to quantify PAHs transfers at the catchment scale by combining chemical analysis with gamma spectrometry. Air, soil, river water and sediment samples (n=820) were collected in two upstream sub-catchments of the Seine River basin (France) during one year. Chemical analyses were carried out to determine PAHs concentrations in all samples. Furthermore, measurement of fallout radionuclides (Beryllium-7, Lead-210, Caesium-137) in both rainfall and river sediment provided a way to discriminate between freshly eroded sediment vs. resuspension of older material that previously deposited on the riverbed. This information is crucial to estimate PAH residence time and transfer velocities in the Seine River basin. The results show that the PAH behaviour varies from one subcatchment to the next. PAH transfers depend indeed on both the characteristics of the catchment (e.g. topography, presence of drained cropland in catchments) and the local anthropogenic pressures. A significant increase in atmospheric deposition of PAHs is observed during winter due to a larger number of sources (household heating). The 14-month study has also highlighted the seasonal variations of PAH fluxes, which are mainly related to the hydrological regimes (i.e. low flow vs. flood periods). The behaviour of the PAHs mainly depends on their molecular mass. The lightest ones tend to quickly migrate to rivers whereas the heaviest slowly accumulate in soils throughout the low-flow period. Then, an increase in PAH export associated with sediment is observed during the winter floods, when rivers are heavily loaded with suspended matter. The downstream exports of PAHs are controlled by the main erosion processes that occurred in the catchments. Results show that PAH fluxes are more important when material is mostly supplied to rivers by soil surface erosion processes than when they are delivered by gully or riverbank erosion. Despite the reduction in PAH emissions since the 1960s, there is still a significant storage of PAHs in the upstream part of the Seine River basin. In this context, WFD objectives are unlikely to be reached by 2015

Combining measurements and modelling to quantify the contribution of atmospheric fallout, local industry and road traffic to \PAH\ stocks in contrasting catchments

International audienceAbstract Various sources supply \PAHs\ that accumulate in soils. The methodology we developed provided an evaluation of the contribution of local sources (road traffic, local industries) versus remote sources (long range atmospheric transport, fallout and gaseous exchanges) to \PAH\ stocks in two contrasting subcatchments (46–614 km²) of the Seine River basin (France). Soil samples (n = 336) were analysed to investigate the spatial pattern of soil contamination across the catchments and an original combination with radionuclide measurements provided new insights into the evolution of the contamination with depth. Relationships between \PAH\ concentrations and the distance to the potential sources were modelled. Despite both subcatchments are mainly rural, roadside areas appeared to concentrate 20% of the contamination inside the catchment while a local industry was found to be responsible for up to 30% of the stocks. Those results have important implications for understanding and controlling \PAH\ contamination in rural areas of early-industrialized regions