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ABSTRACT: Patients with sepsis in the intensive care unit (ICU) are prone to develop Candida infections. Here, we investigated Candida-induced T-helper 17 (Th17) responses during experimental human endotoxemia and in patients with sepsis admitted to the ICU. Peripheral blood mononuclear cells were stimulated with Candida albicans. The Th17 response was significantly lower during endotoxemia, compared with baseline. Patients with gram-negative sepsis had a significantly lower Th17 response as compared to healthy controls. These data demonstrate that the Th17 response is deficient during endotoxin-related systemic inflammation, which likely represents an important risk factor for increased susceptibility to develop Candida infection in patients with sepsis.
The Journal of Infectious Diseases 09/2012; · 6.41 Impact Factor
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Evangelos J Giamarellos-Bourboulis,
Anna Norrby-Teglund,
Vassiliki Mylona,
Athina Savva,
Iraklis Tsangaris,
Ioanna Dimopoulou, Maria Mouktaroudi,
Maria Raftogiannis,
Marianna Georgitsi,
Anna Linner, [......],
Konstantinos Mandragos,
Androniki Marioli,
Jonas Sunden-Cullberg,
Anna Mega,
Athanassios Prekates,
Christina Routsi,
Charalambos Gogos,
Carl-Johan Treutiger,
Apostolos Armaganidis,
George Dimopoulos
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ABSTRACT: INTRODUCTION: Early risk assessment is the mainstay of management of patients with sepsis. APACHE II is the golden standard prognostic stratification system. A prediction rule is developed aimed to improve prognostication by APACHE II with the application of serum suPAR (soluble urokinase plasminogen activator receptor). METHODS: A prospective study cohort enrolled 1914 patients with sepsis including 62.2% with sepsis and 37.8% with severe sepsis/septic shock. Serum suPAR was measured in samples drawn after diagnosis by an enzyme-immunoabsorbent assay; in 367 patients sequential measurements were performed. After ROC analysis and multivariate logistic regression analysis a prediction rule for risk was developed. The rule was validated in a double-blind fashion by an independent confirmation cohort of 196 sepsis patients, predominantly severe sepsis/septic shock patients, from Sweden. RESULTS: Serum suPAR remained stable within survivors and non-survivors for 10 days. Regression analysis showed that APACHE II [greater than or equal to] 17 and suPAR [greater than or equal to] 12 ng/ml were independently associated with unfavorable outcome. Four strata of risk were identified: i) APACHE II <17 and suPAR <12 ng/ml with mortality 5.5%; ii) APACHE II < 17 and suPAR [greater than or equal to] 12 ng/ml with mortality 17.4%; iii) APACHE II [greater than or equal to] 17 and suPAR <12 ng/ml with mortality 37.4%; and iv) APACHE II [greater than or equal to] 17 and suPAR [greater than or equal to] 12 ng/ml with mortality 51.7%. This prediction rule was confirmed by the Swedish cohort. CONCLUSIONS: A novel prediction rule with four levels of risk in sepsis based on APACHE II score and serum suPAR is proposed. Prognostication by this rule is confirmed by an independent cohort.
Critical care (London, England) 08/2012; 16(4):R149. · 4.61 Impact Factor
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Eleni E Mylona, Maria Mouktaroudi,
Tania O Crisan,
Stamatoula Makri,
Aikaterini Pistiki,
Marianna Georgitsi,
Athina Savva,
Mihai G Netea,
Jos Wm van der Meer,
Evangelos J Giamarellos-Bourboulis,
Leo Ab Joosten
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ABSTRACT: INTRODUCTION: Monosodium urate monohydrate (MSU) crystals synergize with various toll-like receptor (TLR) ligands to induce cytokine production via activation of the NOD-like receptor (NLR) family, pyrin domain-containing 3 (NLPR3) inflammasome. This has been demonstrated in vitro using human cell lines or monocytes of healthy volunteers. In the present study, we have investigated the effect of MSU crystals and of their combination with TLR ligands in peripheral blood mononuclear cells (PBMC) of patients with gout. METHODS: PBMCs from 18 patients with primary gout and 12 healthy donors were exposed to MSU crystals in the presence or absence of saturated fatty acid C18:0 (free fatty acid, TLR2 ligand), palmitoyl-3-cystein (Pam3Cys, TLR1/2 ligand) and fibroblast stimulating factor-1 (FSL-1, TLR 2/6 ligand). Production of IL-1β, IL-6, IL-8, IL-17 and tumor necrosis factor alpha (TNFα) was determined by ELISA. mRNA transcripts of IL-1β were measured by real-time PCR. RESULTS: MSU crystals alone failed to induce IL-1β, IL-6 or TNFα in both patients and control groups, but a stronger synergy between MSU/Pam3Cys and MSU/C18:0 for the induction of IL-1β was found in patients with gout compared to healthy controls. IL-6, but not IL-8, followed the kinetics of IL-1β. No production of the neutrophil-recruiting IL-17 was detectable after stimulation of the patients' PBMCs with MSU in both the presence or absence of TLR ligands. No change of gene transcripts of IL-1β after stimulation with MSU and Pam3Cys or with MSU and C18:0 was found. A positive correlation was found between synergy in IL-1β production from PBMCs of patients between C18:0 and MSU crystals, as well as the annual number of attacks of acute gouty arthritis (rs: +0.649, P: 0.022). CONCLUSIONS: The synergy between MSU crystals and TLR-2 ligands is more prominent in patients with gout than in controls. This is likely mediated by the enhanced maturation of pro-IL-1β into IL-1β.
Arthritis research & therapy 07/2012; 14(4):R158. · 4.27 Impact Factor
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Aikaterini Spyridaki,
Maria Raftogiannis,
Anastasia Antonopoulou,
Thomas Tsaganos,
Christina Routsi,
Fotini Baziaka,
Vassiliki Karagianni, Maria Mouktaroudi,
Pantelis Koutoukas,
Aimilia Pelekanou,
Anastasia Kotanidou,
Stylianos E Orfanos,
Jos W M van der Meer,
Mihai G Netea,
Evangelos J Giamarellos-Bourboulis
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ABSTRACT: One recent, double-blind, randomized clinical trial with 200 patients showed that clarithromycin administered intravenously for 3 days in patients with ventilator-associated pneumonia (VAP) accelerated the resolution of pneumonia and decreased the risk of death from septic shock and multiple organ dysfunctions (MODS). The present study focused on the effect of clarithromycin on markers of inflammation in these patients. Blood was drawn immediately before the administration of the allocated treatment and on six consecutive days after the start of treatment. The concentrations of circulating markers were measured. Monocytes and neutrophils were isolated for immunophenotyping analysis and for cytokine stimulation. The ratio of serum interleukin-10 (IL-10) to serum tumor necrosis factor alpha (TNF-α) was decreased in the clarithromycin group compared with the results in the placebo group. Apoptosis of monocytes was significantly increased on day 4 in the clarithromycin group compared with the rate of apoptosis in the placebo group. On the same day, the expression of CD86 was increased and the ratio of soluble CD40 ligand (sCD40L) to CD86 in serum was unchanged. The release of TNF-α, IL-6, and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) by circulating monocytes after stimulation was greater in the clarithromycin group than in the placebo group. The expression of TREM-1 on monocytes was also increased in the former group. These effects were pronounced in patients with septic shock and MODS. These results suggest that the administration of clarithromycin restored the balance between proinflammatory versus anti-inflammatory mediators in patients with sepsis; this was accompanied by more efficient antigen presentation and increased apoptosis. These effects render new perspectives for the immunotherapy of sepsis.
Antimicrobial Agents and Chemotherapy 05/2012; 56(7):3819-25. · 4.84 Impact Factor
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ABSTRACT: Nosocomial infections are an emerging threat. Available solutions are limited due to the multidrug-resistance pattern of the pathogens. Macrolides modulate the immune function of the host and may be active in this setting.
Findings of in-vitro and experimental animal studies are presented. Clinical studies of community-acquired pneumonia (CAP) and ventilator-associated pneumonia (VAP) are described.
Macrolides decrease production of proinflammatory cytokines by circulating monocytes and by alveolar macrophages and decrease apoptosis of circulating lymphocytes in animal models of acute infections. They also inhibit gene expression of proteins participating in quorum sensing of Pseudomonas aeruginosa. Retrospective cohort studies indicate that addition of a macrolide significantly improves outcome in severe CAP. One randomized, double-blind, clinical study is available. This involves patients with VAP allocated to placebo or intravenous clarithromycin 1 g once daily for 3 days. Clarithromycin treatment significantly decreased time to resolution of VAP and time until weaning from mechanical ventilation. The described findings are promising for the use of macrolides in nosocomial infections.
Current Opinion in Infectious Diseases 04/2012; 25(2):205-10. · 4.93 Impact Factor
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Anastasia Antonopoulou,
Fotini Baziaka,
Thomas Tsaganos,
Maria Raftogiannis,
Pantelis Koutoukas,
Aikaterini Spyridaki, Maria Mouktaroudi,
Antigone Kotsaki,
Athina Savva,
Marianna Georgitsi,
Evangelos J Giamarellos-Bourboulis
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ABSTRACT: To identify the role of single nucleotide polymorphisms (SNPs) of the tumor necrosis factor (TNF) gene in the natural course of 2009 influenza A H1N1 virus infection.
Genomic DNA was isolated from 109 patients with an H1N1 infection and from 108 healthy volunteers. SNPs of the TNF gene were assessed after electrophoresis of the digested PCR products by restriction enzymes.
The frequency of the -238 A allele was significantly greater among patients than among controls. Viral pneumonia developed in 20 of 96 non-carriers of at least one -238 A allele (20.8%) and in seven of 13 carriers of at least one -238 A allele (53.8%, p=0.016). Logistic regression analysis showed that the most important factors associated with the development of pneumonia were the presence of an underlying disease (p=0.021, odds ratio (OR) 3.08) and the carriage of at least one -238 A allele (p=0.041, OR 3.74). Gene transcripts of the TNF gene were greater among non-carriers of the -238 A allele than among carriers of the -238 A allele.
The -238 A SNP allele of the TNF gene imposes on the course of 2009 H1N1 virus infection and is an independent risk factor for pneumonia.
International journal of infectious diseases: IJID: official publication of the International Society for Infectious Diseases 03/2012; 16(3):e204-8. · 2.17 Impact Factor
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Evangelos J Giamarellos-Bourboulis,
Frank L van de Veerdonk, Maria Mouktaroudi,
Maria Raftogiannis,
Anastasia Antonopoulou,
Leo A B Joosten,
Peter Pickkers,
Athina Savva,
Marianna Georgitsi,
Jos W M van der Meer,
Mihai G Netea
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ABSTRACT: Down-regulation of ex-vivo cytokine production is a specific feature in patients with sepsis. Cytokine downregulation was studied focusing on caspase-1 activation and conversion of pro-interleukin-1β into interleukin-1β (IL-1β).
Peripheral blood mononuclear cells were isolated from a) 92 patients with sepsis mainly of Gram-negative etiology; b) 34 healthy volunteers; and c) 5 healthy individuals enrolled in an experimental endotoxemia study. Cytokine stimulation was assessed in vitro after stimulation with a variety of microbial stimuli.
Inhibition of IL-1β in sepsis was more profound than tumour necrosis factor (TNF). Down-regulation of IL-1β response could not be entirely explained by the moderate inhibition of transcription. We investigated inflammasome activation and found that in patients with sepsis, both pro-caspase-1 and activated caspase-1 were markedly decreased. Blocking caspase-1 inhibited the release of IL-1β in healthy volunteers, an effect that was lost in septic patients. Finally, urate crystals, which specifically induce the NLPR3 inflammasome activation, induced significant IL-1β production in healthy controls but not in patients with sepsis. These findings were complemented by inhibition of caspase-1 autocleavage as early as two hours after lipopolysaccharide exposure in volunteers.
These data demonstrate that the inhibition of caspase-1 and defective IL-1 β production is an important immunological feature in sepsis.
Critical care (London, England) 01/2011; 15(1):R27. · 4.61 Impact Factor
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Oliver Kumpf,
Evangelos J Giamarellos-Bourboulis,
Alexander Koch,
Lutz Hamann, Maria Mouktaroudi,
Djin-Ye Oh,
Eicke Latz,
Eva Lorenz,
David A Schwartz,
Bart Ferwerda,
Christina Routsi,
Chryssanthi Skalioti,
Bart-Jan Kullberg,
Jos W M van der Meer,
Peter M Schlag,
Mihai G Netea,
Kai Zacharowski,
Ralf R Schumann
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ABSTRACT: It has been proposed that individual genetic variation contributes to the course of severe infections and sepsis. Recent studies of single nucleotide polymorphisms (SNPs) within the endotoxin receptor and its signaling system showed an association with the risk of disease development. This study aims to examine the response associated with genetic variations of TLR4, the receptor for bacterial LPS, and a central intracellular signal transducer (TIRAP/Mal) on cytokine release and for susceptibility and course of severe hospital acquired infections in distinct patient populations.
Three intensive care units in tertiary care university hospitals in Greece and Germany participated. 375 and 415 postoperative patients and 159 patients with ventilator associated pneumonia (VAP) were included. TLR4 and TIRAP/Mal polymorphisms in 375 general surgical patients were associated with risk of infection, clinical course and outcome. In two prospective studies, 415 patients following cardiac surgery and 159 patients with newly diagnosed VAP predominantly caused by Gram-negative bacteria were studied for cytokine levels in-vivo and after ex-vivo monocyte stimulation and clinical course.
Patients simultaneously carrying polymorphisms in TIRAP/Mal and TLR4 and patients homozygous for the TIRAP/Mal SNP had a significantly higher risk of severe infections after surgery (odds ratio (OR) 5.5; confidence interval (CI): 1.34 - 22.64; P = 0.02 and OR: 7.3; CI: 1.89 - 28.50; P < 0.01 respectively). Additionally we found significantly lower circulating cytokine levels in double-mutant individuals with ventilator associated pneumonia and reduced cytokine production in an ex-vivo monocyte stimulation assay, but this difference was not apparent in TIRAP/Mal-homozygous patients. In cardiac surgery patients without infection, the cytokine release profiles were not changed when comparing different genotypes.
Carriers of mutations in sequential components of the TLR signaling system may have an increased risk for severe infections. Patients with this genotype showed a decrease in cytokine release when infected which was not apparent in patients with sterile inflammation following cardiac surgery.
Critical care (London, England) 01/2010; 14(3):R103. · 4.61 Impact Factor
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ABSTRACT: To evaluate the long-term efficacy of etanercept for the management of hidradenitis suppurativa.
Analysis was based on the long-term follow-up (weeks 24-144) of 10 patients enrolled in a prospective open-label phase II study; etanercept was initially administered subcutaneously 50 mg once weekly for 12 weeks in 10 patients. Disease recurrence and the need to restart etanercept were recorded.
Three patients did not report any disease recurrence. A second course of treatment with etanercept was needed in seven patients. Favourable responses were found in five; two patients failed treatment.
The first treatment course achieved long-term disease remission in almost one-third of patients. The remaining needed a second treatment course but even in that case, their disease severity at restart was significantly lower compared with baseline.
Experimental Dermatology 09/2009; 19(6):538-40. · 3.54 Impact Factor
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Bart Ferwerda,
Santos Alonso,
Kathy Banahan,
Matthew B B McCall,
Evangelos J Giamarellos-Bourboulis,
Bart P Ramakers, Maria Mouktaroudi,
Pamela R Fain,
Neskuts Izagirre,
Din Syafruddin, [......],
Concepcion de la Rúa,
Robert Sauerwein,
Joost P H Drenth,
Bart-Jan Kullberg,
André J A M van der Ven,
Adrian V Hill,
Peter Pickkers,
Jos W M van der Meer,
Luke A J O'Neill,
Mihai G Netea
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ABSTRACT: Adequate responses by our innate immune system toward invading pathogens were of vital importance for surviving infections, especially before the antibiotic era. Recently, a polymorphism in Mal (Ser180Leu, TIRAP rs8177374), an important adaptor protein downstream of the Toll-like receptor (TLR) 2 and 4 pathways, has been described to provide protection against a broad range of infectious pathogens. We assessed the functional effects of this polymorphism in human experimental endotoxemia, and we demonstrate that individuals bearing the TIRAP 180L allele display an increased, innate immune response to TLR4 and TLR2 ligands, but not to TLR9 stimulation. This phenotype has been related to an increased resistance to infection. However, an overshoot in the release of proinflammatory cytokines by TIRAP 180L homozygous individuals suggests a scenario of balanced evolution. We have also investigated the worldwide distribution of the Ser180Leu polymorphism in 14 populations around the globe to correlate the genetic makeup of TIRAP with the local infectious pressures. Based on the immunological, clinical, and genetic data, we propose that this mutation might have been selected in West Eurasia during the early settlement of this region after the out-of-Africa migration of modern Homo sapiens. This combination of functional and genetic data provides unique insights to our understanding of the pathogenesis of sepsis.
Proceedings of the National Academy of Sciences 07/2009; 106(25):10272-7. · 9.68 Impact Factor
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ABSTRACT: To investigate whether angiopoietin-2 (Ang2) and vascular endothelial growth factor (VEGF) are implicated in the hypoxemic resuscitation from hemorrhagic shock.
Twenty rabbits were subjected to hemorrhagic shock after blood exsanguination; resuscitation was performed by infusion of the shed blood in ten rabbits under normoxemic conditions (NormoxRes) and in 10 under hypoxemic conditions (HypoxRes); four rabbits were subjected to sham operation. Serum was drawn at serial time intervals; serum was applied for stimulation of U937 monocytes.
Serum concentrations of Ang2 were higher in the NormoxRes group compared to the HypoxRes group at 90 min (p: 0.049) and at 120 min (p: 0.028). Serum concentrations of VEGF did not differ between groups. Concentrations of VEGF in the supernatants of U937 stimulated with sera of all groups were below detection limit. The wet to dry lung ratio of the HypoxRes group was significantly lower than the NormoxRes group (p<0.0001).
Hypoxemic resuscitation from hemorrhagic shock is a process accompanied by reduced serum levels of Ang2. These findings add significantly to our understanding of that experimental treatment strategy of resuscitation.
Cytokine 06/2009; 47(2):82-4. · 3.02 Impact Factor
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Evangelos J Giamarellos-Bourboulis,
Maria Raftogiannis,
Anastasia Antonopoulou,
Fotini Baziaka,
Pantelis Koutoukas,
Athina Savva,
Theodora Kanni,
Marianna Georgitsi,
Aikaterini Pistiki,
Thomas Tsaganos, [......],
Efthymia Giannitsioti,
Dimitra Kavatha,
Flora Kontopidou, Maria Mouktaroudi,
Garyfallia Poulakou,
Vissaria Sakka,
Periklis Panagopoulos,
Antonios Papadopoulos,
Kyriaki Kanellakopoulou,
Helen Giamarellou
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ABSTRACT: The pandemic by the novel H1N1 virus has created the need to study any probable effects of that infection in the immune system of the host.
Blood was sampled within the first two days of the presentation of signs of infection from 10 healthy volunteers; from 18 cases of flu-like syndrome; and from 31 cases of infection by H1N1 confirmed by reverse RT-PCR. Absolute counts of subtypes of monocytes and of lymphocytes were determined after staining with monoclonal antibodies and analysis by flow cytometry. Peripheral blood mononuclear cells (PBMCs) were isolated from patients and stimulated with various bacterial stimuli. Concentrations of tumour necrosis factor-alpha, interleukin (IL)-1beta, IL-6, IL-18, interferon (FN)-alpha and of IFN-gamma were estimated in supernatants by an enzyme immunoassay. Infection by H1N1 was accompanied by an increase of monocytes. PBMCs of patients evoked strong cytokine production after stimulation with most of bacterial stimuli. Defective cytokine responses were shown in response to stimulation with phytohemagglutin and with heat-killed Streptococcus pneumoniae. Adaptive immune responses of H1N1-infected patients were characterized by decreases of CD4-lymphocytes and of B-lymphocytes and by increase of T-regulatory lymphocytes (Tregs).
Infection by the H1N1 virus is accompanied by a characteristic impairment of the innate immune responses characterized by defective cytokine responses to S.pneumoniae. Alterations of the adaptive immune responses are predominated by increase of Tregs. These findings signify a predisposition for pneumococcal infections after infection by H1N1 influenza.
PLoS ONE 01/2009; 4(12):e8393. · 4.09 Impact Factor
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ABSTRACT: Based on the implication of soluble triggering receptor expressed on myeloid cells (sTREM-1) in the septic cascade, it was investigated whether it participates or not in posttraumatic systemic inflammatory response syndrome (SIRS).
Blood was sampled on days 1, 4, 7, and 15 from 69 patients with SIRS after multiple injuries and upon presentation of a septic complication. Concentrations of sTREM-1, tumor necrosis factor-alpha (TNFalpha), interleukin (IL)-6, IL-8, and interferon-gamma were determined by an enzyme immunoassay. Samples drawn on day 1 from 10 trauma patients without SIRS served as controls.
In 26 patients with SIRS without septic complication, sTREM-1, TNFalpha, and IL-8 remained stable over follow-up; IL-6 decreased and interferon-gamma increased on days 4 and 7 compared with day 1. TNFalpha was the only variable being higher upon advent of septic shock compared with patients without SIRS and upon presentation of SIRS, sepsis, and severe sepsis (p of comparisons with all subgroups <0.0001). Mortality of patients with sTREM-1 greater than 180 pg/mL was 5.3% compared with 28.0% of those with sTREM-1 lower than 180 pg/mL (p 0.035). sTREM-1 higher than 40 pg/mL had sensitivity 56.5% and specificity 91.7% for the differential diagnosis between SIRS and sepsis after multiple injuries.
This is the first study providing evidence about the participation of sTREM-1 in posttraumatic SIRS. Its levels are increased and remain constant over time in patients who did not develop any complications whereas it seems to behave as an anti-inflammatory mediator.
The Journal of trauma 12/2008; 65(6):1385-90. · 2.48 Impact Factor
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ABSTRACT: Recent studies suggest that crystals of monosodium urate (MSU), deposited in joints of patients with acute gouty arthritis, activate the NACHT domain, leucine-rich repeat and pyrin domain-containing protein (NALP)3 inflammasome. In the present study we have investigated whether production of proinflammatory cytokines by crystals was exacerbated during costimulation with Toll-like receptor (TLR) ligands.
Mononuclear cells of 22 healthy donors were stimulated by various concentrations of MSU crystals in the absence or presence of lipopolysaccharide (LPS), Pam3Cys and flagellin. Production of tumour necrosis factor alpha (TNFalpha), interleukin (IL)1 beta and IL6, as well as the intracellular concentrations of proIL1 beta were measured by ELISA. mRNA transcripts of TNFalpha and IL1 beta were assessed by real-time PCR. Stimulation experiments were also performed with peripheral blood mononuclear cells (PBMCs) of one patient carrying a NALP3 mutation.
MSU induced a moderate release of IL1 beta and IL6, but not of TNFalpha. Urate crystals amplified IL1 beta production stimulated by the TLR4 ligand LPS, while no synergy was apparent for IL6 production. In addition, no synergy between urate crystals and Pam3Cys (TLR2 ligand) or flagellin (TLR5 ligand) was apparent. The synergy between urate crystals and LPS was directed at the level of the NALP3 inflammasome, as it was present only when active IL1 beta was measured, but not at the level of IL1 mRNA or proIL1 beta. The synergy between LPS and MSU crystals ceased to exist in the presence of a caspase 1 inhibitor.
MSU crystals act in synergy with LPS for the induction of enhanced release of IL1 beta. Increased cleavage of proIL1 beta by urate-activated caspase 1 is proposed as the underlying mechanism.
Annals of the rheumatic diseases 05/2008; 68(2):273-8. · 8.11 Impact Factor
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Bart Ferwerda,
Matthew B B McCall,
Santos Alonso,
Evangelos J Giamarellos-Bourboulis, Maria Mouktaroudi,
Neskuts Izagirre,
Din Syafruddin,
Gibson Kibiki,
Tudor Cristea,
Anneke Hijmans, [......],
Reinout van Crevel,
Han G Brunner,
Djin-Ye Oh,
Ralf R Schumann,
Concepcion de la Rúa,
Robert Sauerwein,
Bart-Jan Kullberg,
André J A M van der Ven,
Jos W M van der Meer,
Mihai G Netea
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ABSTRACT: Infectious diseases exert a constant evolutionary pressure on the genetic makeup of our innate immune system. Polymorphisms in Toll-like receptor 4 (TLR4) have been related to susceptibility to Gram-negative infections and septic shock. Here we show that two polymorphisms of TLR4, Asp299Gly and Thr399Ile, have unique distributions in populations from Africa, Asia, and Europe. Genetic and functional studies are compatible with a model in which the nonsynonymous polymorphism Asp299Gly has evolved as a protective allele against malaria, explaining its high prevalence in subSaharan Africa. However, the same allele could have been disadvantageous after migration of modern humans into Eurasia, putatively because of increased susceptibility to severe bacterial infections. In contrast, the Asp299Gly allele, when present in cosegregation with Thr399Ile to form the Asp299Gly/Thr399Ile haplotype, shows selective neutrality. Polymorphisms in TLR4 exemplify how the interaction between our innate immune system and the infectious pressures in particular environments may have shaped the genetic variations and function of our immune system during the out-of-Africa migration of modern humans.
Proceedings of the National Academy of Sciences 11/2007; 104(42):16645-50. · 9.68 Impact Factor
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ABSTRACT: In an attempt to define the most important driver responsible for recurrence of cystitis in women, 181 records were retrospectively analysed among 1010 consecutive references in a tertiary centre for lower urinary tract infections (UTIs). All 181 women had more than three episodes of cystitis per year; 129 were under continuous prophylaxis and 52 were under postcoital prophylaxis. Analysis revealed that the most important factor affecting successful outcome of chemoprophylaxis was the compliance of patients (odds ratio 0.074; P<0.0001). Among women treated for >or=6 months, the most effective regimen was nitrofurantoin, with a success rate of 96.8% compared with 82.8% for trimethoprim/sulphamethoxazole and 72.3% for norfloxacin (P=0.046 between agents). Failure of chemoprophylaxis was observed in 51 women in total; in 26 of them resistance to the administered agent had developed. Results of this retrospective study revealed that the most important driver leading to failure of prophylaxis for recurrent lower UTIs was the lack of compliance of women with their medication. Nitrofurantoin was the most potent among the administered agents.
International Journal of Antimicrobial Agents 07/2007; 30(1):40-3. · 4.13 Impact Factor
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ABSTRACT: Triggering receptor expressed on myeloid cells (TREM-1) is a promoter of cytokine production triggered by microbial components. To investigate the significance of its soluble counterpart, sTREM-1, for the pathogenesis of peptic ulcer disease, sTREM-1 was compared with the proinflammatory mediators and the pathology score of gastritis.
Forty patients with dyspepsia were enrolled: 20 with peptic ulcer and 20 controls without any macroscopic abnormalities. All patients were examined by endoscopy; gastric juice was aspirated and biopsy specimens were collected from the antrum and corpus of the stomach. sTREM-1 was estimated by a hand-made enzyme immunoassay. Interleukin-8 was estimated by enzyme-linked immunosorbent assay and lipid peroxidation, indexed by malondialdehyde, by the thiobarbituric assay, after passage through a high-performance liquid chromatography system.
The median (+/-SE) of sTREM-1 of controls and patients with ulcer was 3.91+/-0.57 and 44.27+/-241.55 RU, respectively (P=0.006). The median (+/-SE) of interleukin-8 of controls and patients with ulcer was 1802.97+/-122.10 and 2030.66+/-64.44 pg/ml, respectively (P=0.023). sTREM-1 was positively correlated with the density of neutrophil and mononuclear infiltration scores and the total Sydney score (P=0.029, 0.043 and 0.041, respectively). sTREM-1 was positively correlated with interleukin-8 (P=0.042).
sTREM-1 might be an independent factor involving with the peptic ulcerative inflammatory process that is positively correlated with histopathological abnormalities of gastritis.
European Journal of Gastroenterology & Hepatology 05/2006; 18(4):375-9. · 1.76 Impact Factor
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ABSTRACT: Our aim was to define early changes of lymphocytes and of NK cells in severe sepsis and to correlate them with serum levels of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1).
Blood was sampled from 49 patients with proven highly suspected infection by Gram-negative pathogens, within 12 hours of the advent of severe sepsis, and was also sampled from six healthy volunteers. White blood cells were targeted with monoclonal antibodies and were analyzed by flow cytometry. The concentrations of sTREM-1 were estimated by ELISA.
The presence of CD3/CD4 cells was significantly lower (P < 0.0001) and that of NK cells significantly higher among patients with sepsis compared with controls (P = 0.011). The proportions (median +/- standard error) of ANNEXIN-V/CD4/CD3-positive cells, of ANNEXIN-V/CD8/CD3-positive cells and of ANNEXIN-V/CD14-positive cells of the patient population were 7.41 +/- 2.26%, 7.69 +/- 3.42% and 1.96 +/- 4.22%, respectively. Patients with NK cells >20% survived longer compared with those patients with NK cells < or =20% (P = 0.041), and patients with sTREM-1 concentrations >180 pg/ml survived longer compared with those patients with sTREM-1 concentrations < or =180 pg/ml (P = 0.042). A negative correlation was found between the percentages of ANNEXIN-V/CD4/CD3-positive cells and of CD3/CD4 cells (rs = -0.305, P = 0.049), and a positive correlation was found between the serum sTREM-1 concentration and the percentage of NK cells (rs = +0.395, P = 0.014). NK cells isolated from two healthy volunteers released sTREM-1 upon triggering with endotoxins.
Early severe sepsis is characterized by CD4-lymphopenia and increased NK cells, providing a survival benefit for the septic patient at percentages >20%. The survival benefit resulting from elevated NK cells might be connected to elevated serum levels of sTREM-1.
Critical care (London, England) 01/2006; 10(6):R166. · 4.61 Impact Factor
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ABSTRACT: The significance of lipid peroxidation as an independent factor leading to sepsis by multidrug-resistant Pseudomonas aeruginosa. Design experimental study.
Twenty-six rabbits were applied. They were divided into two groups; A (n=6) comprising controls, and B (n=20) comprising animals infected by the injection of 1x10(8) cfu/kg inoculum of the test pathogen into the left inner jugular vein. Six rabbits of group B were followed-up to estimate survival; all of the remaining were sacrificed. Blood was sampled for the determination of serum malondialdehyde (MDA) by the thiobarbiturate assay, total antioxidant status (TAS) by a chromogenic assay, tumor necrosis factor alpha by a bioassay on fibrosarcoma L929 cell line, and endotoxins (LPS) by the QCL-1000 LAL assay.
Mean survival of group B was 60.0+/-15.8 h. MDA was significantly higher in group B compared to group A at 30, 60, 120 and 150 min. TAS was statistically decreased in group B compared to group A at 30 and 60 min. Increases of MDA in group B were followed by reciprocal decreases of TAS (P of correlation <0.001). Hemodynamic instability was recorded in group B compared to group A 160 min after bacterial challenge.
Early alterations of oxidant/antioxidant balance occur in experimental sepsis by multidrug-resistant P. aeruginosa followed by hemodynamic instability. Results highlight the perspective of the administration of antioxidants as immunomodulatory treatment of sepsis in animal studies.
Prostaglandins Leukotrienes and Essential Fatty Acids 02/2005; 72(1):41-7. · 3.37 Impact Factor
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ABSTRACT: Recent in vitro and ex vivo studies disclosed an enhancement of the activity of antimicrobials on multidrug-resistant Pseudomonas aeruginosa by n-6 polyunsaturated fatty acids (PUFAS); therefore their effect was evaluated in experimental sepsis in 60 rabbits. Solutions of gamma-linolenic acid (GLA) and arachidonic acid (AA) were administered intravenously with ceftazidime and amikacin in rabbits with sepsis caused by one multidrug-resistant isolate. Therapy was started after bacterial challenge in five groups comprising 12 animals in each group: A, normal saline; B, antimicrobials; C, 99% ethanol and antimicrobials; D, GLA and antimicrobials; and E, AA and antimicrobials. Blood was sampled for the estimation of levels of endotoxins in serum (lipopolysaccharide), leukocytes, tumor necrosis factor alpha (TNF-alpha) and antimicrobials. Animals were sacrificed 210 min after bacterial challenge for tissue cultures. All animals had considerable endotoxemia and evolved leukopenia. The number of viable cells in blood, lung, and mesenteric lymph nodes was significantly reduced in groups D and E compared to that in other groups. Levels of antimicrobials in serum were inadequate to achieve bacterial killing due to the level of resistance. n-6 PUFAs did not influence TNF-alpha. It is concluded that intravenous coadministration of n-6 PUFAs and antimicrobials enhanced antimicrobial bacterial killing in experimental sepsis caused by multidrug-resistant P. aeruginosa.
Antimicrobial Agents and Chemotherapy 01/2005; 48(12):4713-7. · 4.84 Impact Factor
