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1.  Fluid resuscitation should respect the endothelial glycocalyx layer 
Critical Care  2014;18(6):707.
Endothelial glycocalyx degradation induced by fluid overload adds to the concern of a detrimental effect of uncontrolled fluid resuscitation and the risk of unnecessary fluid infusion. As a consequence, the use of new tools for monitoring response to fluids appears promising. From that perspective, the monitoring of plasma concentration of glycocalyx degradation markers could be useful.
doi:10.1186/s13054-014-0707-6
PMCID: PMC4331386  PMID: 25629597
2.  Abrogated transforming growth factor beta receptor II (TGFβRII) signalling in dendritic cells promotes immune reactivity of T cells resulting in enhanced atherosclerosis 
European Heart Journal  2012;34(48):3717-3727.
Aims
The importance of transforming growth factor beta (TGFβ) as an immune regulatory cytokine in atherosclerosis has been established. However, the role of TGFβ signalling in dendritic cells (DCs) and in DC-mediated T cell proliferation and differentiation in atherosclerosis is unknown.
Methods and results
Here, we investigated the effect of disrupted TGFβ signalling in DCs on atherosclerosis by using mice carrying a transgene resulting in functional inactivation of TGFβ receptor II (TGFβRII) signalling in CD11c+ cells (Apoe−/−CD11cDNR). Apoe−/−CD11cDNR mice exhibited an over two-fold increase in the plaque area compared with Apoe−/− mice. Plaques of Apoe−/−CD11cDNR mice showed an increase in CD45+ leucocyte content, and specifically in CD3+, CD4+ and CD8+ cells, whereas macrophage content was not affected. In lymphoid organs, Apoe−/−CD11cDNR mice had equal amounts of CD11c+ cells, and CD11c+CD8+ and CD11c+CD8− subsets, but showed a subtle shift in the CD11c+CD8− population towards the more inflammatory CD11c+CD8−CD4− DC subset. In addition, the number of plasmacytoid-DCs decreased. Maturation markers such as MHCII, CD86 and CD40 on CD11chi cells did not change, but the CD11cDNR DCs produced more TNFα and IL-12. CD11c+ cells from CD11cDNR mice strongly induced T-cell proliferation and activation, resulting in increased amounts of effector T cells producing high amounts of Th1 (IFN-γ), Th2 (IL-4, IL-10), Th17 (IL-17), and Treg (IL-10) cytokines.
Conclusion
Here, we show that loss of TGFβRII signalling in CD11c+ cells induces subtle changes in DC subsets, which provoke uncontrolled T cell activation and maturation. This results in increased atherosclerosis and an inflammatory plaque phenotype during hypercholesterolaemia.
doi:10.1093/eurheartj/ehs106
PMCID: PMC3869966  PMID: 22613345
Atherosclerosis; Inflammation; TGFβ; Dendritic cell
3.  Multiplex PCR performed of bronchoalveolar lavage fluid increases pathogen identification rate in critically ill patients with pneumonia: a pilot study 
Background
In critically ill patients with pneumonia, accurate microorganism identification allows appropriate antibiotic treatment. In patients undergoing bronchoalveolar lavage (BAL), direct examination of the fluid using Gram staining provides prompt information but pathogen identification accuracy is low. Culture of BAL fluid is actually the reference, but it is not available before 24 to 48 h. In addition, pathogen identification rate observed with direct examination and culture is decreased when antibiotic therapy has been given prior to sampling. We therefore assessed, in critically ill patients with suspected pneumonia, the performance of a multiplex PCR (MPCR) to identify pathogens in BAL fluid. This study is a prospective pilot observation.
Methods
We used a MPCR detecting 20 types of microorganisms. Direct examination, culture, and MPCR were performed on BAL fluid of critically ill patients with pneumonia suspicion. The final diagnosis of infective pneumonia was retained after the medical chart was reviewed by two experts. Pathogen identification rate of direct examination, culture, and MPCR in patients with confirmed pneumonia was compared.
Results
Among the 65 patients with pneumonia suspicion, the diagnosis of pneumonia was finally retained in 53 cases. Twenty nine (55%) were community-acquired pneumonia and 24 (45%) were hospital acquired. Pathogen identification rate with MPCR (66%) was greater than with culture (40%) and direct examination (23%) (p =0.01 and p <0.001, respectively). When considering only the microorganisms included in the MPCR panel, the pathogen identification rate provided by MPCR reached 82% and was still higher than with culture (35%, p <0.001) and direct examination (21%, p <0.001). Pathogen identification rate provided by MPCR was not modified in the case of previous antibiotic treatment (66% vs. 64%, NS) and was still better than with culture (23%, p <0.001).
Conclusions
The results of this pilot study suggest that in critically ill patients, MPCR performed on BAL fluid could provide higher identification rate of pathogens involved in pneumonia than direct examination and culture, especially in patients having received antimicrobial treatment.
doi:10.1186/s13613-014-0035-7
PMCID: PMC4273674  PMID: 25593751
Multiplex PCR; SeptiFast®; Bronchoalveolar lavage; Antibiotic therapy; Prior antibiotic treatment; Community-acquired pneumonia; Hospital-acquired pneumonia; Ventilator-acquired pneumonia
4.  B lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction 
Nature medicine  2013;19(10):1273-1280.
Acute myocardial infarction is a severe ischemic disease responsible for heart failure and sudden death. Here, we show that after acute myocardial infarction in mice, mature B lymphocytes selectively produce Ccl7 and induce Ly6Chi monocyte mobilization and recruitment to the heart, leading to enhanced tissue injury and deterioration of myocardial function. Genetic (Baff receptor deficiency) or antibody-mediated (CD20- or Baff-specific antibody) depletion of mature B lymphocytes impeded Ccl7 production and monocyte mobilization, limited myocardial injury and improved heart function. These effects were recapitulated in mice with B cell–selective Ccl7 deficiency. We also show that high circulating concentrations of CCL7 and BAFF in patients with acute myocardial infarction predict increased risk of death or recurrent myocardial infarction. This work identifies a crucial interaction between mature B lymphocytes and monocytes after acute myocardial ischemia and identifies new therapeutic targets for acute myocardial infarction.
doi:10.1038/nm.3284
PMCID: PMC4042928  PMID: 24037091
5.  Alteration of skin perfusion in mottling area during septic shock 
Background
Mottling score has been reported to be a strong predictive factor during septic shock. However, the pathophysiology of mottling remains unclear.
Methods
In patients admitted in ICU for septic shock, we measured on the same area the mean skin perfusion by laser Doppler, the mottling score, and variations of both indices between T1 (6 hours after vasopressors were started) and T2 (24 hours later).
Results
Fourteen patients were included, SAPS II was 56 [37–71] and SOFA score at T1 was 10 [7–12]. The mean skin surface area analyzed was 4108 ± 740 mm2; 1184 ± 141 measurements were performed over each defined skin surface area. Skin perfusion was significantly different according to mottling score and decreased from 37 [31–42] perfusion units (PUs) for a mottling score of [0–1] to 22 [20–32] PUs for a mottling score of [2–3] and 23 [16–28] for a score of [4–5] (Kruskal-Wallis test, P = 0.05). We analyzed skin perfusion changes during resuscitation in each patient and together with mottling score variations between T1 and T2 using a Wilcoxon signed-rank test. Among the 14 patients included, mottling score increased (worsened) in 5 patients, decreased (improved) in 5 patients, and remained stable in 4 patients. Baseline skin perfusion at T1 was arbitrarily scored 100%. Mean skin perfusion significantly decreased in all the patients whose mottling score worsened from 100% baseline to 63.2 ± 10.7% (P = 0.001), mean skin perfusion significantly increased in all patients whose mottling score improved from 100% baseline to 172.6 ± 46.8% (P = 0.001), and remained stable in patients whose mottling score did not change (100.5 ± 6.8%, P = 0.95).
Conclusions
We have shown that mottling score variations and skin perfusion changes during septic shock resuscitation were correlated, providing additional evidence that mottling reflects skin hypoperfusion.
doi:10.1186/2110-5820-3-31
PMCID: PMC3848827  PMID: 24040941
Septic shock; Microcirculation; Mottling; Intensive care medicine
6.  Comparison of superior vena cava and femoroiliac vein pressure according to intra-abdominal pressure 
Background
Previous studies have shown a good agreement between central venous pressure (CVP) measurements from catheters placed in superior vena cava and catheters placed in the abdominal cava/common iliac vein. However, the influence of intra-abdominal pressure on such measurements remains unknown.
Methods
We conducted a prospective, observational study in a tertiary teaching hospital. We enrolled patients who had indwelling catheters in both superior vena cava (double lumen catheter) and femoroiliac veins (dialysis catheter) and into the bladder. Pressures were measured from all the sites, CVP, femoroiliac venous pressure (FIVP), and intra-abdominal pressure.
Results
A total of 30 patients were enrolled (age 62 ± 14 years; SAPS II 62 (52–76)). Fifty complete sets of measurements were performed. All of the studied patients were mechanically ventilated (PEP 3 cmH20 (2–5)). We observed that the concordance between CVP and FIVP decreased when intra-abdominal pressure increased. We identified 14 mmHg as the best intra-abdominal pressure cutoff, and we found that CVP and FIVP were significantly more in agreement below this threshold than above (94% versus 50%, P = 0.002).
Conclusions
We reported that intra-abdominal pressure affected agreement between CVP measurements from catheter placed in superior vena cava and catheters placed in the femoroiliac vein. Agreement was excellent when intra-abdominal pressure was below 14 mmHg.
doi:10.1186/2110-5820-2-21
PMCID: PMC3424143  PMID: 22742667
Intensive unit care; Central venous pressure; Superior vena cava; Femoroiliac vena; Intra-abdominal pressure
7.  Continuous insulin administration via complex central venous catheter infusion tubing is another risk factor for blood glucose imbalance. A retrospective study 
Background
We assessed the potential impact of infusion tubing on blood glucose imbalance in ICU patients given intensive insulin therapy (IIT). We compared the incidence of blood glucose imbalance in patients equipped, in a nonrandomized fashion, with either conventional tubing or with a multiport infusion device.
Methods
We retrospectively analyzed the nursing files of 35 patients given IIT through the distal line of a double-lumen central venous catheter. A total of 1389 hours of IIT were analyzed for occurrence of hypoglycemic events [defined as arterial blood glucose below 90 mg/dL requiring discontinuation of insulin].
Results
Twenty-one hypoglycemic events were noted (density of incidence 15 for 1000 hours of ITT). In 17 of these 21 events (81%), medication had been administered during the previous hour through the line connected to the distal lumen of the catheter. Conventional tubing use was associated with a higher density of incidence of hypoglycemic events than multiport infusion device use (23 vs. 2 for 1,000 hours of IIT; rate ratio = 11.5; 95% confidence interval, 2.71–48.8; p < 0.001).
Conclusions
The administration of on-demand medication through tubing carrying other medications can lead to the delivery of significant amounts of unscheduled products. Hypoglycaemia observed during IIT could be related to this phenomenon. The use of a multiport infusion device with a limited dead volume could limit hypoglycemia in patients on IIT.
doi:10.1186/2110-5820-2-16
PMCID: PMC3409028  PMID: 22697362
Hypoglycemia; Intensive care unit; Infusion tubing; Central venous catheter; Intensive insulin therapy
8.  B cell depletion reduces the development of atherosclerosis in mice 
The Journal of Experimental Medicine  2010;207(8):1579-1587.
B cell depletion significantly reduces the burden of several immune-mediated diseases. However, B cell activation has been until now associated with a protection against atherosclerosis, suggesting that B cell–depleting therapies would enhance cardiovascular risk. We unexpectedly show that mature B cell depletion using a CD20-specific monoclonal antibody induces a significant reduction of atherosclerosis in various mouse models of the disease. This treatment preserves the production of natural and potentially protective anti–oxidized low-density lipoprotein (oxLDL) IgM autoantibodies over IgG type anti-oxLDL antibodies, and markedly reduces pathogenic T cell activation. B cell depletion diminished T cell–derived IFN-γ secretion and enhanced production of IL-17; neutralization of the latter abrogated CD20 antibody–mediated atheroprotection. These results challenge the current paradigm that B cell activation plays an overall protective role in atherogenesis and identify new antiatherogenic strategies based on B cell modulation.
doi:10.1084/jem.20100155
PMCID: PMC2916123  PMID: 20603314
9.  TGF-β activity protects against inflammatory aortic aneurysm progression and complications in angiotensin II–infused mice 
Complicated abdominal aortic aneurysm (AAA) is a major cause of mortality in elderly men. Ang II–dependent TGF-β activity promotes aortic aneurysm progression in experimental Marfan syndrome. However, the role of TGF-β in experimental models of AAA has not been comprehensively assessed. Here, we show that systemic neutralization of TGF-β activity breaks the resistance of normocholesterolemic C57BL/6 mice to Ang II–induced AAA formation and markedly increases their susceptibility to the disease. These aneurysms displayed a large spectrum of complications on echography, including fissuration, double channel formation, and rupture, leading to death from aneurysm complications. The disease was refractory to inhibition of IFN-γ, IL-4, IL-6, or TNF-α signaling. Genetic deletion of T and B cells or inhibition of the CX3CR1 pathway resulted in partial protection. Interestingly, neutralization of TGF-β activity enhanced monocyte invasiveness, and monocyte depletion markedly inhibited aneurysm progression and complications. Finally, TGF-β neutralization increased MMP-12 activity, and MMP-12 deficiency prevented aneurysm rupture. These results clearly identify a critical role for TGF-β in the taming of the innate immune response and the preservation of vessel integrity in C57BL/6 mice, which contrasts with its reported pathogenic role in Marfan syndrome.
doi:10.1172/JCI38136
PMCID: PMC2810071  PMID: 20101093

Results 1-9 (9)