Publications by authors named "Maria Mouktaroudi"

32 Publications

The association of TSH and thyroid hormones with lymphopenia in bacterial sepsis and COVID-19.

J Clin Endocrinol Metab 2021 Mar 13. Epub 2021 Mar 13.

Department of Internal Medicine, Division of Endocrinology, Radboud University Nijmegen, GA, Nijmegen, the Netherlands.

Context: Lymphopenia is a key feature of immune dysfunction in patients with bacterial sepsis and COVID-19 and associated with poor clinical outcomes, but the cause is largely unknown. Severely ill patients may present with thyroid function abnormalities, so-called non-thyroidal illness syndrome (NTIS), and several studies have linked TSH and the thyroid hormones thyroxine (T4) and triiodothyronine (T3) to homeostatic regulation and function of lymphocyte populations.

Purpose: To test the hypothesis that abnormal thyroid function correlates with lymphopenia in patients with severe infections.

Methods: Retrospective analysis of absolute lymphocyte counts, circulating TSH, T4, free T4 (FT4), T3, albumin and inflammatory biomarkers was performed in two independent hospitalized study populations: bacterial sepsis (n=224) and COVID-19 patients (n=161). A subgroup analysis was performed in patients with severe lymphopenia and normal lymphocyte counts.

Results: Only T3 significantly correlated (rho=0.252) with lymphocyte counts in patients with bacterial sepsis and lower concentrations were found in severe lymphopenic compared to non-lympopenic patients (n=56 per group). Severe lymphopenic COVID-19 patients (n=17) showed significantly lower plasma concentrations of TSH, T4, FT4 and T3 compared to patients without lymphopenia (n=18), and demonstrated significantly increased values of the inflammatory markers interleukin-6, C-reactive protein and ferritin. Remarkably, after one week follow-up, the majority (12/15) of COVID-19 patients showed quantitative recovery of their lymphocyte numbers, while TSH and thyroid hormones remained mainly disturbed.

Conclusion: Abnormal thyroid function correlates with lymphopenia in patients with severe infections, like bacterial sepsis and COVID-19, but future studies need to establish whether a causal relationship is involved.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgab148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989224PMC
March 2021

Disease severity-specific neutrophil signatures in blood transcriptomes stratify COVID-19 patients.

Genome Med 2021 01 13;13(1). Epub 2021 Jan 13.

Systems Medicine, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.

Background: The SARS-CoV-2 pandemic is currently leading to increasing numbers of COVID-19 patients all over the world. Clinical presentations range from asymptomatic, mild respiratory tract infection, to severe cases with acute respiratory distress syndrome, respiratory failure, and death. Reports on a dysregulated immune system in the severe cases call for a better characterization and understanding of the changes in the immune system.

Methods: In order to dissect COVID-19-driven immune host responses, we performed RNA-seq of whole blood cell transcriptomes and granulocyte preparations from mild and severe COVID-19 patients and analyzed the data using a combination of conventional and data-driven co-expression analysis. Additionally, publicly available data was used to show the distinction from COVID-19 to other diseases. Reverse drug target prediction was used to identify known or novel drug candidates based on finding from data-driven findings.

Results: Here, we profiled whole blood transcriptomes of 39 COVID-19 patients and 10 control donors enabling a data-driven stratification based on molecular phenotype. Neutrophil activation-associated signatures were prominently enriched in severe patient groups, which was corroborated in whole blood transcriptomes from an independent second cohort of 30 as well as in granulocyte samples from a third cohort of 16 COVID-19 patients (44 samples). Comparison of COVID-19 blood transcriptomes with those of a collection of over 3100 samples derived from 12 different viral infections, inflammatory diseases, and independent control samples revealed highly specific transcriptome signatures for COVID-19. Further, stratified transcriptomes predicted patient subgroup-specific drug candidates targeting the dysregulated systemic immune response of the host.

Conclusions: Our study provides novel insights in the distinct molecular subgroups or phenotypes that are not simply explained by clinical parameters. We show that whole blood transcriptomes are extremely informative for COVID-19 since they capture granulocytes which are major drivers of disease severity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-020-00823-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805430PMC
January 2021

Diabetes on sepsis outcomes in non-ICU patients: A cohort study and review of the literature.

J Diabetes Complications 2021 Jan 9;35(1):107765. Epub 2020 Oct 9.

Dept of Internal Medicine and Infectious Diseases, University Hospital of Patras, Greece.

Aims: We sought to determine whether primary outcomes differ between non-ICU septic patients with and without type 2 diabetes (T2D).

Methods: This study utilized the Hellenic Sepsis Study Group Registry, collecting nationwide data for sepsis patients since 2006, and classified patients upon presence or absence of T2D. Patients were perfectly matched for a) Sepsis 3 definition criteria (including septic shock) b) gender, c) age, d) APACHE II score and e) Charlson's comorbidity index (CCI). Independent sample t-test and chi-square t-test was used to compare prognostic indices and primary outcomes.

Results: Of 4320 initially included non-ICU sepsis patients, 812 were finally analysed, following match on criteria. Baseline characteristics were age 76 [±10.3] years, 46% male, APACHE II 15.5 [±6], CCI 5.1 [±1.8], 24% infection, 63.8% sepsis and 12.2% septic shock. No significant difference was noted between two groups in qSOFA, SOFA, or suPAR1 levels (p = 0.7, 0.1 & 0.3) respectively. Primary sepsis syndrome resolved in 70.9% of cases (p = 0.9), while mortality was 24% in 28-days time. Cause of death was similar between patients with and without T2D (sepsis 17.8% vs 15.8%, heart event 3.7% vs 3.2%, CNS event 0.5% vs 0.5%, malignancy 0.7% vs 2% respectively, p = 0.6).

Conclusions: DM does not appear to negatively affect outcomes in septic patients not requiring ICU.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jdiacomp.2020.107765DOI Listing
January 2021

Favorable Anakinra Responses in Severe Covid-19 Patients with Secondary Hemophagocytic Lymphohistiocytosis.

Cell Host Microbe 2020 07 14;28(1):117-123.e1. Epub 2020 May 14.

4(th) Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, 124 62 Athens, Greece. Electronic address:

Dysregulation of inflammation is hypothesized to play a crucial role in the severe complications of COVID-19, with the IL-1/IL-6 pathway being central. Here, we report on the treatment of eight severe COVID-19 pneumonia patients-seven hospitalized in intensive care units (ICUs) in Greece and one non-ICU patient in the Netherlands-with the interleukin-1 receptor antagonist Anakinra. All patients scored positive for the hemophagocytosis score (HScore) and were diagnosed with secondary hemophagocytic lymphohistocytosis (sHLH) characterized by pancytopenia, hyper-coagulation, acute kidney injury, and hepatobiliary dysfunction. At the end of treatment, ICU patients had less need for vasopressors, significantly improved respiratory function, and lower HScore. Although three patients died, the mortality was lower than historical series of patients with sHLH in sepsis. These data suggest that administration of Anakinra may be beneficial for treating severe COVID-19 patients with sHLH as determined by the HScore, and they support the need for larger clinical studies to validate this concept.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chom.2020.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221383PMC
July 2020

Paraneoplastic digital ischemia in clear-cell renal-cell carcinoma: Report of a case and review of the literature.

Urologia 2019 Aug 1;86(3):156-160. Epub 2018 Apr 1.

1 Hematology-Oncology Unit, Fourth Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Attikon Hospital, Athens, Greece.

Digital ischemia has been rarely associated, as a paraneoplastic syndrome, with renal cancer. Since it can severely compromise the patients' quality of life, early recognition is important, in order to optimally address it with currently available treatment options, such as tyrosine inhibitors. Digital ischemia may occur in the general population and it can be the result of other non-cancerous diseases; accordingly, a thorough and aggressive work-up is mandatory, together with appropriate therapeutic steps such as tyrosine kinase inhibitors, vasodilators, and antiaggregants. Herein, we report a 78-year-old male patient with a history of clear-cell renal-cell cancer, who presented in the emergency department with critical ischemia in the upper limbs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0391560318761289DOI Listing
August 2019

Deletion of hematopoietic Dectin-2 or CARD9 does not protect against atherosclerotic plaque formation in hyperlipidemic mice.

Sci Rep 2019 03 13;9(1):4337. Epub 2019 Mar 13.

Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands.

Inflammatory reactions activated by pattern recognition receptors (PRRs) on the membrane of innate immune cells play an important role in atherosclerosis. Whether the PRRs of the C-type lectin receptor (CLR) family including Dectin-2 may be involved in the pathogenesis of atherosclerosis remains largely unknown. Recently, the CLR-adaptor molecule caspase recruitment domain family member 9 (CARD9) has been suggested to play a role in cardiovascular pathologies as it provides the link between CLR activation and transcription of inflammatory cytokines as well as immune cell recruitment. We therefore evaluated whether hematopoietic deletion of Dectin-2 or CARD9 reduces inflammation and atherosclerosis development. Low-density lipoprotein receptor (Ldlr)-knockout mice were transplanted with bone marrow from wild-type, Dectin-2- or Card9-knockout mice and fed a Western-type diet containing 0.1% (w/w) cholesterol. After 10 weeks, lipid and inflammatory parameters were measured and atherosclerosis development was determined. Deletion of hematopoietic Dectin-2 or CARD9 did not influence plasma triglyceride and cholesterol levels. Deletion of hematopoietic Dectin-2 did not affect atherosclerotic lesion area, immune cell composition, ex vivo cytokine secretion by peritoneal cells or bone marrow derived macrophages. Unexpectedly, deletion of hematopoietic CARD9 increased atherosclerotic lesion formation and lesion severity. Deletion of hematopoietic CARD9 did also not influence circulating immune cell composition and peripheral cytokine secretion. Besides a tendency to a reduced macrophage content within these lesions, plasma MCP-1 levels decreased upon WTD feeding. Deletion of hematopoietic Dectin-2 did not influence atherosclerosis development in hyperlipidemic mice. The absence of CARD9 unexpectedly increased atherosclerotic lesion size and severity, suggesting that the presence of CARD9 may protect against initiation of atherosclerosis development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-40663-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416398PMC
March 2019

Angiopoietin-2 Levels as Predictors of Outcome in Mechanically Ventilated Patients with Acute Respiratory Distress Syndrome.

Dis Markers 2017 29;2017:6758721. Epub 2017 Aug 29.

Second Department of Critical Care Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece.

Pulmonary endothelium dysfunction is a key characteristic of ARDS. The aim of this study was to investigate endothelium-derived markers, such as angiopoietin-2 (Ang-2) and endothelial cell-specific molecule-1 (endocan), at the vascular and alveolar compartments as outcome predictors in ARDS. Fifty-three consecutive ARDS patients were studied. The primary outcome was 28-day mortality. Secondary endpoints were days of unassisted ventilation and days with organ failure other than ARDS, during the 28-day study period. Nonsurvivors presented higher lung injury scores and epithelial lining fluid (ELF) Ang-2 levels compared to survivors, with no significant differences in plasma Ang-2, endocan, and protein C concentrations between the two groups. In logistic regression analysis, ELF Ang-2 levels > 705 pg/ml were the only independent variable for 28-day mortality among the previous four. Plasma endocan values > 13 ng/pg were the only parameter predictive against days of unassisted ventilation during the 28-day study period. Finally, lung injury score > 2.25 and ELF Ang-2 levels > 705 pg/ml were associated with increased number of days with organ failure, other than ARDS. Our findings suggest that Ang-2 levels are increased in the alveolar compartment of ARDS patients, and this may be associated both with increased mortality and organ failure besides lung.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2017/6758721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5602490PMC
July 2018

Defective production of interleukin-1 beta in patients with type 2 diabetes mellitus: Restoration by proper glycemic control.

Cytokine 2017 02 3;90:177-184. Epub 2016 Dec 3.

4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece.

The underlying immune defect of susceptibility in diabetes mellitus type 2 to infections remains unknown. The qualitative changes in cytokine biosynthesis by circulating mononuclear cells (PBMCs) and its modulation by glycemic control were investigated. PBMCs were isolated from 39 patients and 25 controls. They were stimulated with purified ligands and heat-killed bacteria in the absence/presence of glucose and NLPR3 inflammasome ligands. Experiments were repeated after 3 and 6months. Cytokine production was measured in cell supernatants; pro-interleukin(IL)-1 β was measured in cell lysates. Gene expression of IL-1β and activity of caspase-1 were measured as well. Adequate release of interleukin (IL)-1β was found in 42.9% of patients compared to 90% of controls (p: 0.0001). This was related with down-regulation of the NLRP3 inflammasome since gene expression of IL-1β remained unaltered whereas both the ratio of IL-1β to the intracellular pro-IL-1β and the activity of caspase-1 was lower in patients than controls. Addition of glucose did not modify defective IL-1β production. IL-6 production was increased after stimulation with Pam3Cys, phytohemagglutinin and C. albicans. After proper glycemic control, release of IL-1β was increased and of IL-6 decreased; cells of patients with improved glycemic control responded better to LPS stimulation under increased concentrations of glucose. It is concluded that diabetes type 2 is characterized by defective production of IL-1β from circulating monocytes due to impaired activation of the NLRP3 inflammasome and increased production of the anti-inflammatory IL-6. Defects are restored with proper glycemic control.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cyto.2016.11.009DOI Listing
February 2017

Intravenous paracetamol as an antipyretic and analgesic medication: the significance of drug metabolism.

J Pharmacol Sci 2014 30;124(2):144-52. Epub 2014 Jan 30.

Fourth Department of Internal Medicine, University of Athens, Medical School, Greece.

One prospective, open-label, non-randomized study was conducted in 100 patients to define the antipyretic and analgesic effect of a new intravenous formulation of 1 g of paracetamol; 71 received paracetamol for the management of fever and 29 received paracetamol for pain relief after abdominal surgery or for neoplastic pain. Serial follow-up measurements of core temperature and of pain intensity were done for 6 h. Additional rescue medications were recorded for 5 days. Blood was sampled for the measurement of free paracetamol (APAP) and of glucuronide-APAP and N-sulfate-APAP by an HPLC assay. Defervescence, defined as core temperature below or equal to 37.1°C, was achieved in 52 patients (73.2%) within a median time of 3 h. Patients failing to become afebrile with the first dose of paracetamol became afebrile when administered other agents as rescue medications. Analgesia was achieved in 25 patients (86.4%) within a median time of 2 h. Serum levels of glucuronide-APAP were greater among non-responders to paracetamol. The presented results suggest that the intravenous formulation of paracetamol is clinically effective depending on drug metabolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1254/jphs.13133fpDOI Listing
October 2014

Effect of clarithromycin in patients with suspected Gram-negative sepsis: results of a randomized controlled trial.

J Antimicrob Chemother 2014 Apr 28;69(4):1111-8. Epub 2013 Nov 28.

4th Department of Internal Medicine, University of Athens, Medical School, 12462 Athens, Greece.

Background: A previous randomized study showed that clarithromycin decreases the risk of death due to ventilator-associated pneumonia and shortens the time until infection resolution. The efficacy of clarithromycin was tested in a larger population with sepsis.

Methods: Six hundred patients with systemic inflammatory response syndrome due to acute pyelonephritis, acute intra-abdominal infections or primary Gram-negative bacteraemia were enrolled in a double-blind, randomized, multicentre trial. Clarithromycin (1 g) was administered intravenously once daily for 4 days consecutively in 302 patients; another 298 patients were treated with placebo. Mortality was the primary outcome; resolution of infection and hospitalization costs were the secondary outcomes.

Results: The groups were well matched for demographics, disease severity, microbiology and appropriateness of the administered antimicrobials. Overall 28 day mortality was 17.1% (51 deaths) in the placebo arm and 18.5% (56 deaths) in the clarithromycin arm (P = 0.671). Nineteen out of 26 placebo-treated patients with septic shock and multiple organ dysfunctions died (73.1%) compared with 15 out of 28 clarithromycin-treated patients (53.6%, P = 0.020). The median time until resolution of infection was 5 days in both arms. In the subgroup with severe sepsis/shock, this was 10 days in the placebo arm and 6 days in the clarithromycin arm (P = 0.037). The cost of hospitalization was lower after treatment with clarithromycin (P = 0.044). Serious adverse events were observed in 1.3% and 0.7% of placebo- and clarithromycin-treated patients, respectively (P = 0.502).

Conclusions: Intravenous clarithromycin did not affect overall mortality; however, administration shortened the time to resolution of infection and decreased the hospitalization costs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jac/dkt475DOI Listing
April 2014

Deficient Candida-specific T-helper 17 response during sepsis.

J Infect Dis 2012 Dec 14;206(11):1798-802. Epub 2012 Sep 14.

Department of Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/infdis/jis596DOI Listing
December 2012

Risk assessment in sepsis: a new prognostication rule by APACHE II score and serum soluble urokinase plasminogen activator receptor.

Crit Care 2012 Aug 8;16(4):R149. Epub 2012 Aug 8.

Introduction: Early risk assessment is the mainstay of management of patients with sepsis. APACHE II is the gold standard prognostic stratification system. A prediction rule that aimed to improve prognostication by APACHE II with the application of serum suPAR (soluble urokinase plasminogen activator receptor) is developed.

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 ≥ 17 and suPAR ≥ 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 ≥ 12 ng/ml with mortality 17.4%; iii) APACHE II ≥ 17 and suPAR <12 ng/ml with mortality 37.4%; and iv) APACHE II ≥ 17 and suPAR ≥ 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/cc11463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3580738PMC
August 2012

Enhanced interleukin-1β production of PBMCs from patients with gout after stimulation with Toll-like receptor-2 ligands and urate crystals.

Arthritis Res Ther 2012 Jul 4;14(4):R158. Epub 2012 Jul 4.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/ar3898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3580550PMC
July 2012

Effect of clarithromycin in inflammatory markers of patients with ventilator-associated pneumonia and sepsis caused by Gram-negative bacteria: results from a randomized clinical study.

Antimicrob Agents Chemother 2012 Jul 7;56(7):3819-25. Epub 2012 May 7.

4th Department of Internal Medicine, University of Athens, Medical School, Athens, Greece.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/AAC.05798-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3393410PMC
July 2012

Role of tumor necrosis factor gene single nucleotide polymorphisms in the natural course of 2009 influenza A H1N1 virus infection.

Int J Infect Dis 2012 Mar 24;16(3):e204-8. Epub 2012 Jan 24.

4th Department of Internal Medicine, University of Athens Medical School, 1 Rimini Str., 124 62 Athens, Greece.

Objectives: 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.

Methods: 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.

Results: 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.

Conclusions: 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijid.2011.11.012DOI Listing
March 2012

Macrolides for the therapy of nosocomial infections.

Curr Opin Infect Dis 2012 Apr;25(2):205-10

4th Department of Internal Medicine, University of Athens, Medical School, Athens, Greece.

Purpose Of Review: 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.

Recent Findings: Findings of in-vitro and experimental animal studies are presented. Clinical studies of community-acquired pneumonia (CAP) and ventilator-associated pneumonia (VAP) are described.

Summary: 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/QCO.0b013e32834ff1b4DOI Listing
April 2012

Inhibition of caspase-1 activation in Gram-negative sepsis and experimental endotoxemia.

Crit Care 2011 18;15(1):R27. Epub 2011 Jan 18.

4th Department of Internal Medicine, University of Athens, Medical School, 1 Rimini Str, 12462 Athens, Greece.

Introduction: 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).

Methods: 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.

Results: 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.

Conclusions: These data demonstrate that the inhibition of caspase-1 and defective IL-1 β production is an important immunological feature in sepsis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/cc9974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3222063PMC
December 2011

Influence of genetic variations in TLR4 and TIRAP/Mal on the course of sepsis and pneumonia and cytokine release: an observational study in three cohorts.

Crit Care 2010 3;14(3):R103. Epub 2010 Jun 3.

Department of Anesthesiology, Intensive Care Medicine and Pain Management, Hanse-Klinikum Stralsund, Grosse Parower Strasse 47-53, Stralsund 18435, Germany.

Introduction: 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.

Methods: 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.

Results: 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.

Conclusions: 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/cc9047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2911747PMC
January 2011

Effect of the novel influenza A (H1N1) virus in the human immune system.

PLoS One 2009 Dec 23;4(12):e8393. Epub 2009 Dec 23.

4th Department of Internal Medicine, University of Athens, Medical School, Greece, Athens, Greece.

Background: 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.

Methodology/principal Findings: 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).

Conclusions/significance: 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0008393PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2792719PMC
December 2009

Epistaxis of patients admitted in the emergency department is not indicative of underlying arterial hypertension.

Rhinology 2009 09;47(3):260-3

ENT Department, General Hospital of Athens O Evagelismos, Athens, Greece.

Objective: To assess the association between epistaxis and arterial hypertension.

Methods: A prospective study was conducted in 80 patients admitted in the emergency department, 42 with epistaxis and 38 well-matched controls. Blood pressure was measured upon admission and by continuous 24-hour ambulatory monitoring on the following days.

Results: Estimated values upon admission did not differ between groups. A definitive diagnosis of hypertension was set in 18 patients admitted for epistaxis (42.9%) and in 11 controls (28.9%, p = NS). Systolic pressures during the 24-hour recording period, systolic pressures during day and diastolic pressures during night were significantly higher among patients admitted for epistaxis than among controls.

Conclusions: Although studies with larger series of patients are mandatory, epistaxis does not seem to result from underlying arterial hypertension.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4193/Rhin08.157DOI Listing
September 2009

Long-term efficacy of etanercept in hidradenitis suppurativa: results from an open-label phase II prospective trial.

Exp Dermatol 2010 Jun 16;19(6):538-40. Epub 2009 Sep 16.

Objective: To evaluate the long-term efficacy of etanercept for the management of hidradenitis suppurativa.

Methods: 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.

Results: 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.

Conclusions: 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1600-0625.2009.00967.xDOI Listing
June 2010

Hypoxemic resuscitation after hemorrhagic shock is accompanied by reduced serum levels of angiopoietin-2.

Cytokine 2009 Aug 18;47(2):82-4. Epub 2009 Jun 18.

3rd Department of Critical Care, University of Athens Medical School, Greece.

Background: To investigate whether angiopoietin-2 (Ang2) and vascular endothelial growth factor (VEGF) are implicated in the hypoxemic resuscitation from hemorrhagic shock.

Methods: 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.

Results: 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).

Conclusions: 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cyto.2009.05.013DOI Listing
August 2009

Functional and genetic evidence that the Mal/TIRAP allele variant 180L has been selected by providing protection against septic shock.

Proc Natl Acad Sci U S A 2009 Jun 9;106(25):10272-7. Epub 2009 Jun 9.

Department of Internal Medicine and Nijmegen Institute for Infectious Inflammation and Immunity, Radboud University Nijmegen Medical Center, HB, Nijmegen, The Netherlands.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.0811273106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2700915PMC
June 2009

Evidence for the participation of soluble triggering receptor expressed on myeloid cells-1 in the systemic inflammatory response syndrome after multiple trauma.

J Trauma 2008 Dec;65(6):1385-90

4th Department of Internal Medicine, University of Athens Medical School, Athens, Greece.

Background: 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).

Methods: 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.

Results: 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.

Conclusions: 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TA.0b013e31814699ccDOI Listing
December 2008

TLR4 polymorphisms, infectious diseases, and evolutionary pressure during migration of modern humans.

Proc Natl Acad Sci U S A 2007 Oct 9;104(42):16645-50. Epub 2007 Oct 9.

Department of Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.0704828104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2034238PMC
October 2007

The significance of compliance for the success of antimicrobial prophylaxis in recurrent lower urinary tract infections: the Greek experience.

Int J Antimicrob Agents 2007 Jul 24;30(1):40-3. Epub 2007 Apr 24.

4th Department of Internal Medicine, University of Athens, Medical School, Athens, Greece.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijantimicag.2007.02.017DOI Listing
July 2007

Early changes of CD4-positive lymphocytes and NK cells in patients with severe Gram-negative sepsis.

Crit Care 2006 ;10(6):R166

4th Department of Internal Medicine, University of Athens, Medical School, 1 Rimini Str, Athens, Greece.

Introduction: 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).

Methods: 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.

Results: 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.

Conclusion: 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/cc5111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1794479PMC
March 2007

Soluble triggering receptor expressed on myeloid cells (sTREM-1): a new mediator involved in the pathogenesis of peptic ulcer disease.

Eur J Gastroenterol Hepatol 2006 Apr;18(4):375-9

Department of Gastroenterology, Sismanoglion General Hospital of Athens, Greece.

Objectives: 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.

Methods: 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.

Results: 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).

Conclusions: sTREM-1 might be an independent factor involving with the peptic ulcerative inflammatory process that is positively correlated with histopathological abnormalities of gastritis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/00042737-200604000-00010DOI Listing
April 2006

The significance of oxidant/antioxidant balance for the pathogenesis of experimental sepsis by multidrug-resistant Pseudomonas aeruginosa.

Prostaglandins Leukot Essent Fatty Acids 2005 Jan;72(1):41-7

Department of Biological Chemistry, Medical School, University of Athens, Greece.

Objective: The significance of lipid peroxidation as an independent factor leading to sepsis by multidrug-resistant Pseudomonas aeruginosa. Design experimental study.

Methods: 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.

Results: 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.

Conclusions: 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.plefa.2004.09.003DOI Listing
January 2005

n-6 polyunsaturated fatty acids enhance the activities of ceftazidime and amikacin in experimental sepsis caused by multidrug-resistant Pseudomonas aeruginosa.

Antimicrob Agents Chemother 2004 Dec;48(12):4713-7

4th Department of Internal Medicine, Medical School, University of Athens, Athens, Greece.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/AAC.48.12.4713-4717.2004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC529197PMC
December 2004