Involvement of matrix metalloproteinases in chronic Q fever.

OBJECTIVES: Chronic Q fever is a persistent infection with the intracellular Gram-negative bacterium Coxiella burnetii, which can lead to complications of infected aneurysms. Matrix metalloproteinases (MMPs) cleave extracellular matrix and are involved in infections as well as aneurysms. We aimed to study the role of MMPs in the pathogenesis of chronic Q fever. METHODS: We investigated gene expression of MMPs through microarray analysis and MMP production with ELISA in C. burnetii-stimulated peripheral blood mononuclear cells (PBMCs) of patients with chronic Q fever and healthy controls. Twenty single nucleotide polymorphisms (SNPs) of MMP and tissue inhibitor of MMP genes were genotyped in 139 patients with chronic Q fever and 220 controls with similar cardiovascular co-morbidity. Additionally, circulating MMPs levels in patients with chronic Q fever were compared with those in cardiovascular controls with and without a history of past Q fever. RESULTS: In healthy controls, the MMP pathway involving four genes (MMP1, MMP7, MMP10, MMP19) was significantly up-regulated in C. burnetii-stimulated but not in Escherichia coli lipopolysaccharide -stimulated PBMCs. Coxiella burnetii induced MMP-1 and MMP-9 production in PBMCs of healthy individuals (both p<0.001), individuals with past Q fever (p<0.05, p<0.01, respectively) and of patients with chronic Q fever (both p<0.001). SNPs in MMP7 (rs11568810) (p<0.05) and MMP9 (rs17576) (p<0.05) were more common in patients with chronic Q fever. Circulating MMP-7 serum levels were higher in patients with chronic Q fever (median 33.5 ng/mL, interquartile range 22.3-45.7 ng/mL) than controls (20.6 ng/mL, 15.9-33.8 ng/mL). CONCLUSION: Coxiella burnetii-induced MMP production may contribute to the development of chronic Q fever.

Intact interferon-γ response against Coxiella burnetii by peripheral blood mononuclear cells in chronic Q fever.

OBJECTIVES: Q fever is caused by Coxiella burnetii, an intracellular bacterium that infects phagocytes. The aim of the present study was to investigate whether the C. burnetii-induced IFN-γ response is defective in chronic Q fever patients. METHODS: IFN-γ was measured in supernatants of C. burnetii-stimulated peripheral blood mononuclear cells (PBMCs) of 17 chronic Q fever patients and 17 healthy individuals. To assess IFN-γ responses, expression profiles of IFN-γ-induced genes in C. burnetii-stimulated PBMCs were studied in six patients and four healthy individuals. Neopterin was measured in PBMC supernatants (of eight patients and four healthy individuals) and in sera (of 21 patients and 11 healthy individuals). In a genetic association study, polymorphisms in genes involved in the Th1-cytokine response were analysed in a cohort of 139 chronic Q fever patients and a cohort of 220 control individuals with previous exposition to C. burnetii. RESULTS: IFN-γ production by C. burnetii-stimulated PBMCs from chronic Q fever patients was significantly higher than in healthy controls. Many IFN-γ response genes were strongly upregulated in PBMCs of patients. Neopterin levels were significantly higher in PBMC supernatants and sera of patients. The IL12B polymorphisms rs3212227 and rs2853694 were associated with chronic Q fever. CONCLUSIONS: IFN-γ production, as well as the response to IFN-γ, is intact in chronic Q fever patients, and even higher than in healthy individuals. Polymorphisms in the IL-12p40 gene are associated with chronic Q fever. Thus, a deficiency in IFN-γ responses does not explain the failure to clear the infection. The genetic data suggest, however, that the IL-12/IFN-γ pathway does play a role.

[Modulation of transcriptomic signature of the infected host: a new therapeutic strategy for the management of severe viral infections? Example of the flu]. / La modulation de la signature transcriptomique de l'hôte infecté : une nouvelle stratégie thérapeutique dans les viroses graves ? Exemple de la grippe.

During the last decades, emergence and reemergence of viruses were responsible for epidemic and pandemic infectious diseases, with variable degrees of severity. Current preventive strategies are not sufficient at all, and available therapeutic drugs are very limited. Indeed, genetic variations of viruses can impair the efficacy of antiviral compounds by the apparition of resistance. Moreover, current delay needed for de novo development of drugs does not allow a rapid response in case of important epidemic or pandemic events. In this context, new therapeutic approaches are necessary. An innovative concept is to repurpose already marketed compounds that can reverse the host cellular transcriptomic response to the infection. By targeting the host, these molecules exhibit a broad-spectrum activity and are potentially effective even against new emergent strains. This strategy implements the characterization of specific host gene expression profiles, the in silico screening of drugs, and their validation in in vitro and in vivo models, until their evaluation in clinical trials. Here, we will present this approach, with the example of the flu.

Isoproterenol infusion and microcirculation in septic shock.

INTRODUCTION: Our study primarily aimed at investigating the effect of isoproterenol infusion on tissue oxygen saturation in patients with septic shock. The secondary aim was to assess the relation between cardiac index, central venous oxygen saturation and tissue oxygen saturation. METHODS: This retrospective study was conducted from December 2010 to March 2012. We included 14 consecutive patients with septic shock treated with isoproterenol. All patients were monitored by cardiac index and tissue oxygen saturation. From medical charts, routine hemodynamic data were extracted one hour before and six hours after the onset of isoproterenol infusion. RESULTS: From baseline to H6, tissue oxygen saturation levels rise from 78 [72-82]% to 85 [78-88]% (p = 0.03). Isoproterenol infusion was associated with an increase of central venous oxygen saturation (from 67 [65-74]% to 84 [77-86]%, p = 0.02) and cardiac index (from 2.9 [2.7-3.1] L/min/m² to 3.9 [3.0-4.4] L/min/m², p = 0.006). Tissue oxygen saturation was correlated neither to cardiac index (p = 0.14, R(2) = 0.08) nor to central venous oxygen saturation (p = 0.19, R(2) = 0.10). CONCLUSIONS: Use of isoproterenol was associated with an increase of tissue oxygen saturation. This increase was not correlated to cardiac index, suggesting a decoupling between macrocirculation and microcirculation.

[Lung ultrasound: clinical applications and perspectives in intensive care unit]. / Échographie pleuropulmonaire: applications cliniques et perspectives en réanimation.

OBJECTIVE: To describe the use of lung ultrasound in clinical practice and the new opportunities offered by this technology in intensive care unit (ICU) patients. METHOD: Review of signs identified by lung ultrasound and systematic analysis of data published within the last 5 years on its use in ICU. The literature has been extracted from the database Pubmed™. Specific keywords were used to select relevant publications. Clinical studies published in French and English languages were assessed. RESULTS: Lung ultrasound serves to diagnose, quantify, drain and monitor pleural effusions. In patients with acute respiratory failure, lung ultrasound participates to the diagnosis, the implementation of treatments and their follow-up. It helps to manage patients with pneumonia and acute lung injury. Finally, the investigation of the interstitial edema brings information about hemodynamics that can serve to manage our patients. CONCLUSION: Lung ultrasound is an easy, non-invasive, and non-irradiant technology. It brings lot of useful information at the patient's bedside.

HLA-DR and B7-2 (CD86) monocyte expressions after major cancer surgery: profile in sepsis.

AIM: HLA-DR monocyte expression may be affected by major surgery. A potential mechanism for monocyte activation is the engagement of costimulatory receptors (B7-2 or CD-86). The aim of the present study was to determine the possible role of monocyte HLA-DR and B7-2 molecules in the occurrence of postoperative sepsis after major cancer surgery. METHODS: This was an observational study in 25 consecutive patients undergoing major elective surgery. Flow cytometry measures were used to determine the expression of HLA-DR and its costimulatory receptors before (day 0) and after surgery (day 1 and day 2). RESULTS: After surgery, the rate of monocytes expressing HLA-DR decreased significantly in all the patients. As compared with day 0, the rate of monocytes expressing B7-2 decreased in all the patients (P<0.03). In the septic group, it remained significantly decreased postoperatively. In the non-septic group, it reached baseline levels at day 2. CONCLUSION: Results suggest a key role for costimulatory molecules in modulating inflammatory response in the context of subsequent postoperative sepsis after major cancer surgery. These molecules may be involved, in association with HLA-DR, in postoperative monocyte dysfunction.

[Role of genetics in anaesthesia-related variability]. / Rôle de la génétique dans la variabilité interindividuelle en anesthésie.

OBJECTIVE: This review discusses variability among patients in anesthesia, due to genetic polymorphisms. DATA SOURCES: Articles in French and English languages were retrieved from PubMed database. The initial request was "anesth* and (genotyp* or polymorphism* or genetic*)". STUDY SELECTION: Original articles, general reviews and one case report. Letters were excluded. DATA EXTRACTION: Rare genetic diseases were excluded from the scope of this review. We stressed on frequent genetic polymorphisms that may have a daily impact in anesthesiology. DATA SYNTHESIS: Most results were related to pain studies. We selected various examples to describe how genetic polymorphisms impacts the pharmacology of a given drug, and what are the clinical consequences. CONCLUSION: There is a growing field of pharmacogenetic related evidences in anesthesiology. The results from various animal and human studies underline the genetic origin of variability among individuals. How anaesthesists have to integrate these parameters for their daily practice is still unclear, but pharmacogenetic will obviously be a leading field of anesthesia research in the future.

[Venous oximetry: physiology and therapeutic implications]. / Oxymétrie veineuse : physiologie et implications thérapeutiques.

OBJECTIVES: The aims of this review are to point out the determinants of oxygen saturation of the haemoglobin of mixed venous blood (SvO(2)), to specify the correlations existing between SvO(2) and central venous saturation in superior vena cava (ScvO(2)), to determine and finally to locate the current place of venous oximetry in clinical practice. DATA SOURCES: A PubMed database research in English and French languages published until December 2006. The keywords were mixed venous blood oxygen saturation; oxygen consumption; oxygen delivery; oxygen extraction; tissue hypoxia; central venous oxygen saturation. DATA EXTRACTION: Data in selected articles were reviewed, clinical and basic science research relevant information was extracted. DATA SYNTHESIS: The SvO(2) reflects the peripheral extraction of oxygen (O(2)), O(2) delivery and consumption. Its value is related to four determinants: the O(2) consumption (VO(2)), cardiac flow (CF), haemoglobin level (Hb) and O(2) saturation of the haemoglobin of arterial blood (SaO(2)). ScvO(2) is more easily measurable than SvO(2). Under physiological conditions its value is 2 to 3% lower than that of SvO(2). In the critically ill patient, its value is 5% higher than that SvO(2). In most patients, changes in ScvO(2) values parallel those in SvO(2). The clinical interest of the monitoring of venous oximetry was underlined in cases of severe sepsis and septic shock, and during the perioperative period of major surgery. CONCLUSION: The management of patients in critical states with therapeutic goals integrating the monitoring of venous oximetry may reduce the morbidity and mortality of patients undergoing major surgery or hospitalised in the intensive care unit.

[How about blood pressure in brain injury?]. / Comment moduler la pression artérielle en cas de lésion cérébrale ?

One of the goals of the medical management of head injured patients is to get a cerebral perfusion pressure between 60 and 70 mmHg. To reach such a goal, catecholamines are used after fluid challenge. Systemic effects of catecholamines depend on their affinity for the receptors alpha and beta. The topical application of norepinephrine (alpha predominant) induced a vasoconstriction on large cerebral arteries only. Cerebral blood flow increased in the pericontusionnal area, suggesting a loss of autoregulation. The topical application of dopamine at low concentration relaxed large cerebral arteries. Dopamine increased cerebral blood flow in the pericontusional area but data suggest a possible raise in the volume of contusion. Four human comparative studies have been published. The first study, which was not randomized, showed an intracranial pressure increase associated with dopamine. Two randomized clinical trials, published by the same group, demonstrated a better predictability with norepinephrine. The fourth study did not find any difference regarding cerebral haemodynamics. In conclusion, the quality of data on the effects of catecholamines on cerebral haemodynamics of head injured patients do not make it possible to conclude about their use.

[Selective digestive decontamination: the light as changed from red to green]. / La décontamination digestive sélective: le feu est passé du rouge au vert.

OBJECTIVES: To study the efficacy of selective digestive decontamination (SDD) for the prevention of nosocomial infections, particularly pneumonia, as well as its impact on the emergence of multiresistant bacteria. DATA SOURCES: Data collected from the Pubmed: original articles, review articles and editorial published on SDD. The keywords were: selective digestive decontamination, pneumonia, intensive care unit, infection. DATA SELECTION: Ten randomized clinical trials performed since 1995 in mechanically ventilated adult patients hospitalized in intensive care unit. RESULTS: The rationale for the use of SDD consists on the parenteral administration of a short course of antibiotic associated with the topical use of non-absorbable antibiotics directed against Gram negative bacteria. Five randomized studies described a reduction in the incidence of pneumonia associated with SDD. Only one study has showed a decrease in mortality rate. The other five studies, which present some methodological limitations, concluded the lack of efficacy of SDD. Regarding the emergence of multiresistant bacteria, the literature underlines the role of environment. The use of SDD seems to trigger the resistance in endemic areas, while these are softened in the units with a good control of their ecology. CONCLUSION: The data from the literature provide arguments to use SDD in targeted patient populations like multiple traumas in intensive care units, which have a low rate of multiresistant bacteria.