Mécanismes physiopathologiques impliqués dans la dysfonction d'organes au cours du sepsis [Pathophysiological mechanisms of organ dysfunction in sepsis].

Sepsis is defined as the systemic inflammatory response to an infection. The occurrence of organ dysfunction increases the severity of sepsis. Complex interactions between multiple immunomodulating mediators and various cell populations, activated secondarily to the initial infectious insult, promote the development of organ dysfunction in sepsis. Although septic organ dysfunction has long been considered as the end result of chaotic, uncontrolled and deregulated inflammatory cascades, it might instead represent an adaptive response to avoid the occurrence of irreversible tissue damage and end-organ injury. In this article, we review the major mechanisms involved in organ dysfunction during sepsis, and also present the concept of organ dysfunction as an adaptive response to the septic process.

Histone deacetylase inhibitors impair innate immune responses

SUMMARYThe innate immune system plays a central role in host defenses against invading pathogens. Innate immune cells sense the presence of pathogens through pattern recognition receptors that trigger intracellular signaling, leading to the production of pro-inflammatory mediators like cytokines, which shape innate and adaptive immune responses. Both by excess and by default inflammation may be detrimental to the host. Indeed, severe sepsis and septic shock are lethal complications of infections characterized by a dysregulated inflammatory response.In recent years, members of the superfamily of histone deacetylases have been the focus of great interest. In mammals, histone deacetylases are broadly classified into two main subfamilies comprising histone deacetylases 1-11 (HDAC1-11) and sirtuins 1-7 (SIRT1-7). These enzymes influence gene expression by deacetylating histones and numerous non-histone proteins. Histone deacetylases have been involved in the development of oncologic, metabolic, cardiovascular, neurodegenerative and autoimmune diseases. Pharmacological modulators of histone deacetylase activity, principally inhibitors, have been developed for the treatment of cancer and metabolic diseases. When we initiated this project, several studies suggested that inhibitors of HDAC 1-11 have anti-inflammatory activity. Yet, their influence on innate immune responses was largely uncharacterized. The present study was initiated to fill in this gap.In the first part of this work, we report the first comprehensive study of the effects of HDAC 1- 11 inhibitors on innate immune responses in vitro and in vivo. Strikingly, expression studies revealed that HDAC1-11 inhibitors act essentially as negative regulators of basal and microbial product- induced expression of critical immune receptors and antimicrobial products by mouse and human innate immune cells like macrophages and dendritic cells. Furthermore, we describe a new molecular mechanism whereby HDAC1-11 inhibitors repress pro-inflammatory cytokine expression through the induction of the expression and the activity of the transcriptional repressor Μί-2β. HDAC1-11 inhibitors also impair the potential of macrophages to engulf and kill bacteria. Finally, mice treated with an HDAC inhibitor are more susceptible to non-severe bacterial and fungal infection, but are protected against toxic and septic shock. Altogether these data support the concept that HDAC 1-11 inhibitors have potent anti-inflammatory and immunomodulatory activities in vitro and in vivo.Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that plays a central role in innate immune responses, cell proliferation and oncogenesis. In the second part of this manuscript, we demonstrate that HDAC1-11 inhibitors inhibit MIF expression in vitro and in vivo and describe a novel molecular mechanism accounting for these effects. We propose that inhibition of MIF expression by HDAC 1-11 inhibitors may contribute to the antitumorigenic and anti-inflammatory effects of these drugs.NAD+ is an essential cofactor of sirtuins activity and one of the major sources of energy within the cells. Therefore, sirtuins link deacetylation to NAD+ metabolism and energy status. In the last part of this thesis, we report preliminary results indicating that a pharmacological inhibitor of SIRT1-2 drastically decreases pro-inflammatory cytokine production (RNA and protein) and interferes with MAP kinase intracellular signal transduction pathway in macrophages. Moreover, administration of the SIRT1-2 inhibitor protects mice from lethal endotoxic shock and septic shock.Overall, our studies demonstrate that inhibitors of HDAC1-11 and sirtuins are powerful anti-inflammatory molecules. Given their profound negative impact on the host antimicrobial defence response, these inhibitors might increase the susceptibility to opportunistic infections, especially in immunocompromised cancer patients. Yet, these inhibitors might be useful to control the inflammatory response in severely ill septic patients or in patients suffering from chronic inflammatory diseases.

Imaging of Lemierre Syndrome in children and young adultsA case-series analysis

Background / Purpose : Lemierre Syndrome (LS) is defined by a recent oro-pharangeal infection, the clinical presence or radiological demonstration of internal jugular vein (IJV) thrombosis and documented anaerobe germ, principally Fusobacterium necrophorum (Fn) leading to septicaemia and septic embolization. It is a rare infection described since 1900 and it nearly disappeared since the beginning of the antibiotic area. Even if it is seldom described in the literature, this infection is reappearing in the last 10 years, either because of the increase of antibiotic resistance or by modification of antibiotic prescription. The aim of this study is to describe the role of medical imaging in the diagnosis, staging and follow up of Lemierre syndrome, as well as to describe the ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI) findings of this rare disease. Patients and methods : Radiological and medical files of patients diagnosed with Lemierre syndrome in the past 6 years at CHUV hospital were analysed retrospectively. The CT scan, US, colour Doppler US (CDUS) and MRI examinations that were performed have been examined so as to define their specific imaging findings. Results IJV thrombosis was demonstrated in 2 cases by US, by CT in 6 cases and MRI in one case. Septic pulmonary emboli were detected by CT in 5 patients. Complications of the LS were depicted by MR in one case and by CT in 1 case. Conclusion : In the appropriate clinical settings, US, CT or MR evidence of IJV thrombosis and chest CT suggestive of septic emboli, should lead the physician to consider the diagnosis of LS. As a consequence, imaging allows a faster diagnosis and a more efficient treatment of this infection, which in case of insufficient therapy can lead to death.

Bacterial flagellin triggers cardiac innate immune responses and acute contractile dysfunction.

BACKGROUND: Myocardial contractile failure in septic shock may develop following direct interactions, within the heart itself, between molecular motifs released by pathogens and their specific receptors, notably those belonging to the toll-like receptor (TLR) family. Here, we determined the ability of bacterial flagellin, the ligand of mammalian TLR5, to trigger myocardial inflammation and contractile dysfunction. METHODOLOGY/PRINCIPAL FINDINGS: TLR5 expression was determined in H9c2 cardiac myoblasts, in primary rat cardiomyocytes, and in whole heart extracts from rodents and humans. The ability of flagellin to activate pro-inflammatory signaling pathways (NF-kappaB and MAP kinases) and the expression of inflammatory cytokines was investigated in H9c2 cells, and, in part, in primary cardiomyocytes, as well as in the mouse myocardium in vivo. The influence of flagellin on left ventricular function was evaluated in mice by a conductance pressure-volume catheter. Cardiomyocytes and intact myocardium disclosed significant TLR5 expression. In vitro, flagellin activated NF-kappaB, MAP kinases, and the transcription of inflammatory genes. In vivo, flagellin induced cardiac activation of NF-kappaB, expression of inflammatory cytokines (TNF alpha, IL-1 beta, IL-6, MIP-2 and MCP-1), and provoked a state of reversible myocardial dysfunction, characterized by cardiac dilation, reduced ejection fraction, and decreased end-systolic elastance. CONCLUSION/SIGNIFICANCE: These results are the first to indicate that flagellin has the ability to trigger cardiac innate immune responses and to acutely depress myocardial contractility.

Cardiopulmonary support and extracorporeal membrane oxygenation for cardiac assist.

BACKGROUND: Use of cardiopulmonary bypass for emergency resuscitation is not new. In fact, John Gibbon proposed this concept for the treatment of severe pulmonary embolism in 1937. Significant progress has been made since, and two main concepts for cardiac assist based on cardiopulmonary bypass have emerged: cardiopulmonary support (CPS) and extracorporeal membrane oxygenation (ECMO). The objective of this review is to summarize the state of the art in these two technologies. METHODS: Configuration of CPS is now fairly standard. A mobile cart with relatively large wheels allowing for easy transportation carries a centrifugal pump, a back-up battery with a charger, an oxygen cylinder, and a small heating system. Percutaneous cannulation, pump-driven venous return, rapid availability, and transportability are the main characteristics of a CPS system. Cardiocirculatory arrest is a major predictor of mortality despite the use of CPS. In contrast, CPS appears to be a powerful tool for patients in cardiogenic shock before cardiocirculatory arrest, requiring some type of therapeutic procedures, especially repair of anatomically correctable problems or bridging to other mechanical circulatory support systems such as ventricular assist devices. CPS is in general not suitable for long-term applications because of the small-bore cannulas, resulting in significant pressure gradients and eventually hemolysis. RESULTS: In contrast, ECMO can be designed for longer-term circulatory support. This requires large-bore cannulas and specifically designed oxygenators. The latter are either plasma leakage resistent (true membranes) or relatively thrombo-resistant (heparin coated). Both technologies require oxygenator changeovers although the main reason for this is different (clotting for the former, plasma leakage for the latter). Likewise, the tubing within a roller pump has to be displaced and centrifugal pump heads have to be replaced over time. ECMO is certainly the first choice for a circulatory support system in the neonatal and pediatric age groups, where the other assist systems are too bulky. ECMO is also indicated for patients improving on CPS. Septic conditions are, in general, considered as contraindications for ECMO. CONCLUSIONS: Ease of availability and moderate cost of cardiopulmonary bypass-based cardiac support technologies have to be balanced against the significant immobilization of human resources, which is required to make them successful.

Bacterial flagellin elicits innate immune defenses and cardiac dysfunction in vivo

Résumé Les agents pathogènes responsables d'infection entraînent chez l'hôte deux types de réponses immunes, la première, non spécifique, dite immunité innée, la seconde, spécifique à l'agent concerné, dite immunité adaptative. L'immunité innée, qui représente la première ligne de défense contre les pathogènes, est liée à la reconnaissance par les cellules de l'hôte de structures moléculaires propres aux micro-organismes (« Pathogen-Associated Molecular Patterns », PAMPs), grâce à des récepteurs membranaires et cytoplasmiques (« Pattern Recognition Receptors », PRRs) identifiant de manière spécifique ces motifs moléculaires. Les récepteurs membranaires impliqués dans ce processus sont dénommés toll-like récepteurs, ou TLRS. Lorsqu'ils sont activés par leur ligand spécifique, ces récepteurs activent des voies de signalisation intracellulaires initiant la réponse inflammatoire non spécifique et visant à éradiquer l'agent pathogène. Les deux voies de signalisation impliquées dans ce processus sont la voie des « Mitogen-Activated Protein Kinases » (MAPKs) et celle du « Nuclear Factor kappaB » (NF-κB), dont l'activation entraîne in fine l'expression de protéines de l'inflammation dénommées cytokines, ainsi que certaines enzymes produisant divers autres médiateurs inflammatoires. Dans certaines situations, cette réponse immune peut être amplifiée de manière inadéquate, entraînant chez l'hôte une réaction inflammatoire systémique exagérée, appelée sepsis. Le sepsis peut se compliquer de dysfonctions d'organes multiples (sepsis sévère), et dans sa forme la plus grave, d'un collapsus cardiovasculaire, définissant le choc septique. La défaillance circulatoire du choc septique touche les vaisseaux sanguins d'une part, le coeur d'autre part, réalisant un tableau de «dysfonction cardiaque septique », dont on connaît mal les mécanismes pathogéniques. Les bactéries à Gram négatif peuvent déclencher de tels phénomènes, notamment en libérant de l'endotoxine, qui active les voies de l'immunité innée par son interaction avec un toll récepteur, le TLR4. Outre l'endotoxine, la plupart des bactéries à Gram négatif relâchent également dans leur environnement une protéine, la flagelline, qui est le constituant majeur du flagelle bactérien, organelle assurant la mobilité de ces micro-organismes. Des données récentes ont indiqué que la flagelline active, dans certaines cellules, les voies de l'immunité innée en se liant au récepteur TLRS. On ne connaît toutefois pas les conséquences de l'interaction flagelline-TLRS sur le développement de l'inflammation et des dysfonctions d'organes au cours du sepsis. Nous avons par conséquent élaboré le présent travail en formulant l'hypothèse que la flagelline pourrait déclencher une telle inflammation et représenter ainsi un médiateur potentiel de la dysfonction d'organes au cours du sepsis à Gram négatif, en nous intéressant plus particulièrement àl'inflammation et à la dysfonction cardiaque. Dans la première partie de ce travail, nous avons étudié les effets de la flagelline sur l'activation du NF-κB et des MAPKs, et sur l'expression de cytokines inflammatoires au niveau du myocarde in vitro (cardiomyocytes en culture) et in vivo (injection de flagelline recombinante à des souris). Nous avons observé tout d'abord que le récepteur TLRS est fortement exprimé au niveau du myocarde. Nous avons ensuite démontré que la flagelline active la voie du NF-κB et des MAP kinases (p38 et JNK), stimule la production de cytokines et de chemokines inflammatoires in vitro et in vivo, et entraîne l'activation de polynucléaires neutrophiles dans le tissu cardiaque in vivo. Finalement, au plan fonctionnel, nous avons pu montrer que la flagelline entraîne une dilatation et une réduction aiguë de la contractilité du ventricule gauche chez la souris, reproduisant les caractéristiques de la dysfonction cardiaque septique. Dans la deuxième partie, nous avons déterminé la distribution du récepteur TLRS dans les autres organes majeurs de la souris (poumon, foie, intestin et rein}, et avons caractérisé dans ces organes l'effet de la flagelline sur l'activation du NF-κB et des MAPKs, l'expression de cytokines, et l'induction de l'apoptose. Nous avons démontré que le TLRS est exprimé de façon constitutive dans ces organes, et que l'injection de flagelline y déclenche les cascades de l'immunité innée et de processus apoptotiques. Finalement, nous avons également déterminé que la flagelline entraîne une augmentation significative de multiples cytokines dans le plasma une à six heures après son injection. En résumé, nos données démontrent que la flagelline bactérienne (a) entraîne une inflammation et une dysfonction importantes du myocarde et (b) active de manière très significative les mécanismes d'immunité innée dans les principaux organes et entraîne une réponse inflammatoire systémique. Par conséquent, la flagelline peut représenter un médiateur puissant de l'inflammation et de la dysfonction d'organes, notamment du coeur, au cours du choc septique déclenché par les bactéries à Gram négatif. Summary Pathogenic microorganisms trigger two kinds of immune responses in the host. The first one is immediate and non-specific and is termed innate immunity, whereas the second one, specifically targeted at the invading agent, is termed adaptative immunity. Innate immunity, which represents the first line of defense against invading pathogens, confers the host the ability to recognize molecular structures common to many microbial pathogens, ("Pathogen-Associated Molecular Patterns", PAMPs), through cytosolic or membrane-associated receptors ("Pattern Recognition Receptors", PRRs), the latter being represented by a family of receptors termed "toll-like receptors or TLRs". Once activated by the binding of their specific ligand, these receptors activate intracellular signaling pathways, which initiate the non-specific inflammatory response aimed at eradicating the pathogens. The two pathways implicated in this process are the mitogen-activated protein kinases (MAPK) and the nuclear factor kappa B (NF-κB) signaling pathways, whose activation elicit in fine the expression of inflammatory proteins termed cytokines, as well as various enzymes producing a wealth of additional inflammatory mediators. In some circumstances, the innate immune response can become amplified and dysregulated, triggering an overwhelming systemic inflammatory response in the host, identified as sepsis. Sepsis can be associated with multiple organ dysfunction (severe sepsis), and in its most severe form, with cardiovascular collapse, defming septic shock. The cardiovascular failure associated with septic shock affects blood vessels as well as the heart, resulting in a particular form of acute heart failure termed "septic cardiac dysfunction ", whose pathogenic mechanisms remain partly undefined. Gram-negative bacteria can initiate such phenomena, notably by releasing lipopolysaccharide (LPS), which activates innate immune signaling by interacting with its specific toll receptor, the TLR4. Besides LPS, most Gram-negative bacteria also release flagellin into their environment, which is the main structural protein of the bacterial flagellum, an appendage extending from the outer bacterial membrane, responsible for the motility of the microorganism. Recent data indicated that flagellin activate immune responses upon binding to its receptor, TLRS, in various cell types. However, the role of flagellin/TLRS interaction in the development of inflammation and organ dysfunction during sepsis is not known. Therefore, we designed the present work to address the hypothesis that flagellin might trigger such inflammatory responses and thus represent a potential mediator of organ dysfunction during Gram-negative sepsis, with a particular emphasis on cardiac inflammation and contractile dysfunction. In the first part of this work, we investigated the effects of flagellin on NF-κB and MAPK activation and the generation of pro-inflammatory mediators within the heart in vitro (cultured cardiomyocytes) and in vivo (injection of recombinant flagellin into mice). We first observed that TLRS protein is strongly expressed by the myocardium. We then demonstrated that flagellin activates NF-κB and MAP kinases (p38 and JNK), upregulates the transcription of pro-inflammatory cytokines and chemokines in vitro and in vivo, and stimulates the activation of polymorphonuclear neutrophils within the heart in vivo. Finally, we demonstrated that flagellin triggers acute cardiac dilation, and a significant reduction of left ventricular contractility, mimicking characteristics of clinical septic cardiac dysfunction. In the second part, we determined the TLRS distribution in other mice major organs (lung, liver, gut and kidney) and we characterized in these organs the effects of flagellin on NF-κB and MAPK activation, on the expression of pro-inflammatory çytokines, and on the induction of apoptosis. We demonstrated that TLRS protein is constitutively expressed and that flagellin activates prototypical innate immune responses and pro-apoptotic pathways in all these organs. Finally, we also observed that flagellin induces a significant increase of multiple cytokines in the plasma from 1 to 6 hours after its intravenous administration. Altogether, these data provide evidence that bacterial flagellin (a) triggers an important inflammatory response and an acute dysfunction of the myocardium, and (b) significantly activates the mechanisms of innate immunity in most major organs and elicits a systemic inflammatory response. In consequence, flagellin may represent a potent mediator of inflammation and multiple organ failure, notably cardiac dysfunction, during Gram-negative septic shock.

Management of a post-operative multi-resistant infectious spondylitis associated with a kyphotic deformity.

Anterior spinal infection (prevertebral abscess and/or discitis) after posterior instrumentation for vertebral fractures is a challenging complication, since a new implant may become necessary anteriorly, in a septic environment. Generally accepted management guidelines are yet to be established. The authors present a case of posterior instrumentation for fractures of T12 and L1, complicated after 9 months with an anterior infection (prevertebral abscess and discitis) with extended-spectrum beta-lactamase (ESBL) producing Escherichia coli (E. coli). This case is unique in that the multi-resistant organism was isolated only after the second stage of infection treatment, which consisted of anterior débridement and anterior implantation of titanium cages and rods. In this particular case, infection was controlled despite implantation of multiple cages, screws and rods, and fusion was achieved, by means of intravenous antibiotic treatment for 12 months. At the latest follow-up, 24 months post surgery, there was no evidence of infection. This problem case may be helpful for surgeons confronted with spinal deformities secondary to infections with multi-resistant organisms.

TRADD protein is an essential component of the RIG-like helicase antiviral pathway

Upon detection of viral RNA, the helicases RIG-I and/or MDA5 trigger, via their adaptor Cardif (also known as IPS-1, MAVS, or VISA), the activation of the transcription factors NF-kappaB and IRF3, which collaborate to induce an antiviral type I interferon (IFN) response. FADD and RIP1, known as mediators of death-receptor signaling, are implicated in this antiviral pathway; however, the link between death-receptor and antiviral signaling is not known. Here we showed that TRADD, a crucial adaptor of tumor necrosis factor receptor (TNFRI), was important in RIG-like helicase (RLH)-mediated signal transduction. TRADD is recruited to Cardif and orchestrated complex formation with the E3 ubiquitin ligase TRAF3 and TANK and with FADD and RIP1, leading to the activation of IRF3 and NF-kappaB. Loss of TRADD prevented Cardif-dependent activation of IFN-beta, reduced the production of IFN-beta in response to RNA viruses, and enhanced vesicular stomatitis virus replication. Thus, TRADD is not only an essential component of proinflammatory TNFRI signaling, but is also required for RLH-Cardif-dependent antiviral immune responses

Diagnostic value of soluble CD14 subtype (sCD14-ST) presepsin for the postmortem diagnosis of sepsis-related fatalities.

The first aim of this study was to assess the diagnostic performance of presepsin (sCD14-ST) in postmortem serum from femoral blood compared to procalcitonin (PCT) to detect sepsis-related fatalities. The second aim was to compare sCD14-ST levels found in postmortem serum to the values in pericardial fluid to investigate the usefulness of the latter as an alternative biological fluid. Two study groups were formed, a sepsis-related fatalities group and a control group. Radiology (unenhanced CT scans and postmortem angiographies), autopsies, histology, neuropathology, and toxicology as well as other postmortem biochemistry investigations were performed in all cases. Microbiological investigations on right cardiac blood were carried out exclusively in septic cases. The results of this study indicated that postmortem serum PCT and sCD14-ST levels, individually considered, allowed septic cases to be identified. Even though increases in both PCT and sCD14-ST concentrations were observed in the control cases, coherent PCT and sCD14-ST results in cases with suspected sepsis allowed the diagnosis to be confirmed. Conversely, no relevant correlation was identified between postmortem serum and pericardial fluid sCD14-ST levels in either the septic or control groups.

Effect of endotoxin on the angiotensin II receptor in cultured vascular smooth muscle cells.

1. In some tissues, a decrease in the number of cell surface receptors and alterations of the receptor coupling have been proposed as possible mechanisms mediating the deleterious effects of bacterial endotoxin in septic shock. 2. The effects of bacterial lipopolysaccharide (Escherichia coli 0111-B4; LPS) on vascular angiotensin II and vasopressin receptors have been examined in cultured aortic smooth muscle cells (SMC) of the rat by use of radioligand binding techniques. 3. In vascular SMC exposed to 1 micrograms ml-1 endotoxin for 24 h, a significant increase in angiotensin II binding was found. The change in [125I]-angiotensin II binding corresponded to an increase in the number of receptors whereas the affinity of the receptors was not affected by LPS. In contrast, no change in [3H]-vasopressin binding was observed. 4. The pharmacological characterization of angiotensin II binding sites in control and LPS-exposed cells demonstrated that LPS induced an increase in the AT1 subtype of the angiotensin II receptors. Receptor coupling as evaluated by measuring total inositol phosphates was not impaired by LPS. 5. The effect of LPS on the angiotensin II receptor was dose-, time- and protein-synthesis dependent and was associated with an increased expression of the receptor gene. 6. The ability of LPS to increase angiotensin II binding in cultured vascular SMC was independent of the endotoxin induction of NO-synthase. 7. These results suggest that, besides inducing factors such as cytokines and NO-synthase, endotoxin may enhance the expression of cell surface receptors. The surprising increase in angiotensin II binding in LPS exposed VSM cells may represent an attempt by the cells to compensate for the decreased vascular responsiveness. It may also result from a non-specific LPS-related induction of genes.

Analyse des épisodes de bactériémies chez les patients nécessitant une prise en charge aux soins intensifs

Introduction : Bacteremia are among the leading forms of severe infections requiring ICU management, and have been reported to be associated with important morbidity and mortality. Bloodstream infection (BSI) can be classified as hospital-acquired (HA), healthcare-associated (HCA) and community-acquired (CA). Each type has its own characteristics and outcome. Methods : We analyzed all consecutive episodes of bacteremia occurring in patients hospitalized in our mixed 32-bed ICU over a 12 month period (01.10.2009-30.09.2010). HA BSI were prospectively included in a multicenter study (EUROBACT). We adapted the case report form to analyze retrospectively all other cases of BSI. Chi-square tests were used for the categorical variables and ANOVA tests for the continuous variables. Results : Bacteremia occurred in 103 patients (120 bacteria) for an incidence-density of 49.3 episodes/1000 admissions. Among HA episodes, about one quarter of episodes was related to vascular accesses, including two thirds acquired outside of the ICU. Concerning HCA BSI, two-thirds originated from the urinary tract. In contrast, a respiratory origin was found in one third of CA episodes. Multiresistant microorganisms were more frequent in HA and HCA BSI. The overall mortality was 32%, as compared to 7.9% and 13.6% for the overall ICU and hospital mortality of other ICU patients over the same period, respectively. In a multivariate model, age (1.06 [1.02-1.11]), septic shock (3.11 [1.16-8.33]) and renal remplacement (7.81 [1.50, 14.93]) were significantly associated with a fatal outcome. Conclusion : Two-thirds of bacteremia documented among ICU patients were nosocomial and in contrast to those community-acquired, Gram-negatives represented the majority of them. However, CA bacteremia were associated with a higher rate of septic shock and death. The microbiological characteristics of HCA episodes were more similar to those HA, that is why it is important to individualize this category in order to adapt the antibiotics.

High-mobility group box-1 protein determination in postmortem samples.

The aims of this study were to assess whether high-mobility group box-1 protein can be determined in biological fluids collected during autopsy and evaluate the diagnostic potential of high-mobility group box-1 protein in identifying sepsis-related deaths. High-mobility group box-1 protein was measured in serum collected during hospitalization as well as in undiluted and diluted postmortem serum and pericardial fluid collected during autopsy in a group of sepsis-related deaths and control cases with noninfectious causes of death. Inclusion criteria consisted of full biological sample availability and postmortem interval not exceeding 6h. The preliminary results indicate that high-mobility group box-1 protein levels markedly increase after death. Concentrations beyond the upper limit of the calibration curve were obtained in undiluted postmortem serum in septic and traumatic control cases. In pericardial fluid, concentrations beyond the upper limit of the calibration curve were found in all cases. These findings suggest that the diagnostic potential of high-mobility group box-1 protein in the postmortem setting is extremely limited due to molecule release into the bloodstream after death, rendering antemortem levels difficult or impossible to estimate even after sample dilution.

A search for the origin of cadmium in the soil of the Swiss Jura

The top soil of a 14.5 km(2) region at la Chaux-de-Fonds in the Swiss Jura is exceptionally rich in cadmium. It contains an average of 1.3 mg per kg of soil. The spatial distribution of the metal has no simple pattern that could be explained by atmospheric deposition or agricultural practices. Thin soil contained most of its Cd at the surface; in thicker soil Cd is mainly concentrated between 60 and 80 cm depth. No specific minerals or soil fractions could account for these accumulation, and the vertical distribution of Cd is best explained by leaching from the topsoil and further adsorption within layers of nearly neutral pH. The local Jurassic sedimentary rocks contained too little Cd to account for the Cd concentrations in the soil. Alpine gravels from glacial till were too sparse in soils to explain such a spreading of Cd. Moreover this origin is contradictory with the fact that Cd is concentrated in the sand fraction of soils. The respective distributions of Fe and Cd in soils, and soil fractions, suggested that the spreading of iron nodules accumulated during the siderolithic period (Eocene) was not the main source of Cd. Atmospheric deposition, and spreading of fertiliser or waste from septic tanks seem the only plausible explanation for the Cd concentrations, but at present few factors allow us to differentiate between them.

Beyond Prejudice : conservation in the City : a case study from Switzerland

Conservation in the city is challenging because of a continued view that the urban realm is antithetical to nature. This was clearly the case when the first Swiss National Park was established at the beginning of the 20th century. New Swiss legislation brought new approaches to the establishment of natural parks, in particular by including human activities as a logical component in their development. In 2010, a Federal think tank discussed opportunities for launching a new kind of park: the Urban Natural Park. This paper reports an analysis of this discussion, together with the study of the literature dealing with conservation in the city and natural parks. It shows that a clear antagonism between city and nature still remains present, reflected in an implicit hierarchy hidden in the designation of natural parks: wild nature is nominated as the best nature; if not wild, the best nature is identified as rural; if neither wild nor rural, nature is thought not to be the concern of natural park policy. The Swiss Biodiversity Strategy implemented in 2012 is a recent recognition of the importance of urban nature for biodiversity conservation. This recognition, however, condemns urban nature to a special status, situated outside the usual framework of conservation management. I conclude by arguing that anti-urban bias must be addressed because it inhibits effective conservation strategy, prevents the identification of existing environmental qualities of cities and, eventually, has negative impacts on biological conservation outside the city because it fosters urban spreading.