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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.
Sphingolipids are characterized by a broad range of bioactive properties. Particularly, the development of insulin resistance, a major pathophysiological hallmark of Type 2 Diabetes mellitus (T2D), has been linked to ceramide signaling. Since vitamin D supplementation may slow down T2D progression by improving glucose concentrations and insulin sensitivity, we investigated whether vitamin D supplementation impacts on plasma sphingolipid levels in T2D patients. Thus, plasma samples of 59 patients with non-insulin-requiring T2D from a placebo-controlled, randomized, and double-blind study were retrospectively analyzed. Once per week, patients received either 20 drops of Vigantol oil, corresponding to a daily dose of 1904 IU/d vitamin D (verum: n = 31), or a placebo oil consisting of medium chain triglycerides (placebo: n = 28). Blood samples were taken from all of the participants at three different time points: 1) at the beginning of the study (baseline), 2) after 6 months supplementation, and 3) after an additional 6 months of follow-up. Plasma sphingolipids were measured by high-performance liquid chromatography tandem mass spectrometry. At baseline and 6 months follow-up, no significant differences in plasma sphingolipid species were detected between the placebo and verum groups. After 6 months, vitamin D supplementation significantly enhanced plasma C18dihydroceramide (dhCer; N-stearoyl-sphinganine (d18:0/18:0)) and C18ceramide (Cer; N-stearoyl-sphingosine (d18:1/18:0)) levels were observed in the verum group compared to the placebo group. This was accompanied by significantly higher 25-hydroxyvitamin D3 (25(OH)D3) blood levels in patients receiving vitamin D compared to the placebo group. Taken together, vitamin D supplementation induced changes of the C18 chain-length-specific dhCer and Cer plasma levels in patients with T2D. The regulation of sphingolipid signaling by vitamin D may thus unravel a novel mechanism by which vitamin D can influence glucose utilization and insulin action. Whether this acts favorably or unfavorably for the progression of T2D needs to be clarified.
Background: The pro-inflammatory status of the elderly triggers most of the age-related diseases such as cancer and atherosclerosis. Atherosclerosis, the leading cause world wide of morbidity and death, is an inflammatory disease influenced by life-style and genetic host factors. Stimuli such as oxLDL or microbial ligands have been proposed to trigger inflammation leading to atherosclerosis. It has recently been shown that oxLDL activates immune cells via the Toll-like receptor (TLR) 4/6 complex. Several common single nucleotide polymorphisms (SNPs) of the TLR system have been associated with atherosclerosis. To investigate the role of TLR-6 we analyzed the association of the TLR-6 SNP Pro249Ser with atherogenesis.
Results: Genotyping of two independent groups with CAD, as well as of healthy controls revealed a significant association of the homozygous genotype with a reduced risk for atherosclerosis (odds ratio: 0.69, 95% CI 0.51-0.95, P = 0.02). In addition, we found a trend towards an association with the risk of restenosis after transluminal coronary angioplasty (odds ratio: 0.53, 95% CI 0.24-1.16, P = 0.12). In addition, first evidence is presented that the frequency of this protective genotype increases in a healthy population with age. Taken together, our results define a role for TLR-6 and its genetic variations in modulating the inflammatory response leading to atherosclerosis.
Conclusions: These results may lead to a better risk stratification, and potentially to an improved prophylactic treatment of high-risk populations. Furthermore, the protective effect of this polymorphism may lead to an increase of this genotype in the healthy elderly and may therefore be a novel genetic marker for the well-being during aging.
Sphingosine 1-phosphate (S1P) signaling influences numerous cell biological mechanisms such as differentiation, proliferation, survival, migration, and angiogenesis. Intriguingly, our current knowledge is based solely on the role of S1P with an 18-carbon long-chain base length, S1P d18:1. Depending on the composition of the first and rate-limiting enzyme of the sphingolipid de novo metabolism, the serine palmitoyltransferase, other chain lengths have been described in vivo. While cells are also able to produce S1P d20:1, its abundance and function remains elusive so far. Our experiments are highlighting the role of S1P d20:1 in the mouse central nervous system (CNS) and human glioblastoma. We show here that S1P d20:1 and its precursors are detectable in both healthy mouse CNS-tissue and human glioblastoma. On the functional level, we focused our work on one particular, well-characterized pathway, the induction of cyclooxygenase (COX)-2 expression via the S1P receptor 2 (S1P2). Intriguingly, S1P d20:1 only fairly induces COX-2 expression and can block the S1P d18:1-induced COX-2 expression mediated via S1P2 activation in the human glioblastoma cell line LN229. This data indicates that S1P d20:1 might act as an endogenous modulator of S1P signaling via a partial agonism at the S1P2 receptor. While our findings might stimulate further research on the relevance of long-chain base lengths in sphingolipid signaling, the metabolism of S1P d20:1 has to be considered as an integral part of S1P signaling pathways in vivo.
Immunosuppression is a typical hallmark of cancer and frequently includes perturbations of the NKG2D tumor recognition system as well as impaired signaling by other activating NK cell receptors. Several in vitro studies suggested that sustained engagement of the NKG2D receptor, as it is occurring in the tumor microenvironment, not only impairs expression and function of NKG2D but also impacts signaling by other activating NK receptors. Here, we made use of a transgenic mouse model of ubiquitous NKG2D ligand expression (H2-Kb-MICA mice) to investigate consequences of chronic NKG2D engagement in vivo for functional responsiveness by other activating NK receptors such as NKp46 and Ly49D. Unexpectedly, we found no evidence for an impairment of NKp46 expression and function in H2-Kb-MICA mice, as anticipated from previous in vitro experiments. However, we observed a marked downregulation and dysfunction of the activating receptor Ly49D in activated NK cells from H2-Kb-MICA mice. Ly49D shares the adaptor proteins DAP10 and DAP12 with NKG2D possibly explaining the collateral impairment of Ly49D function in situations of chronic NKG2D engagement. Altogether, our results demonstrate that persistent engagement of NKG2D in vivo, as often observed in tumors, can selectively impair functions of unrelated NK receptors and thereby compromise NK responsiveness to third-party antigens.
Background: Mild therapeutic hypothermia following cardiac arrest is neuroprotective, but its effect on myocardial dysfunction that is a critical issue following resuscitation is not clear. This study sought to examine whether hypothermia and the combination of hypothermia and pharmacological postconditioning are cardioprotective in a model of cardiopulmonary resuscitation following acute myocardial ischemia. Methodology/Principal Findings: Thirty pigs (28–34 kg) were subjected to cardiac arrest following left anterior descending coronary artery ischemia. After 7 minutes of ventricular fibrillation and 2 minutes of basic life support, advanced cardiac life support was started according to the current AHA guidelines. After successful return of spontaneous circulation (n = 21), coronary perfusion was reestablished after 60 minutes of occlusion, and animals were randomized to either normothermia at 38°C, hypothermia at 33°C or hypothermia at 33°C combined with sevoflurane (each group n = 7) for 24 hours. The effects on cardiac damage especially on inflammation, apoptosis, and remodeling were studied using cellular and molecular approaches. Five animals were sham operated. Animals treated with hypothermia had lower troponin T levels (p<0.01), reduced infarct size (34±7 versus 57±12%; p<0.05) and improved left ventricular function compared to normothermia (p<0.05). Hypothermia was associated with a reduction in: (i) immune cell infiltration, (ii) apoptosis, (iii) IL-1beta and IL-6 mRNA up-regulation, and (iv) IL-1beta protein expression (p<0.05). Moreover, decreased matrix metalloproteinase-9 activity was detected in the ischemic myocardium after treatment with mild hypothermia. Sevoflurane conferred additional protective effects although statistic significance was not reached. Conclusions/Significance: Hypothermia reduced myocardial damage and dysfunction after cardiopulmonary resuscitation possible via a reduced rate of apoptosis and pro-inflammatory cytokine expression.
Creatinine and proteinuria are used to monitor kidney transplant patients. However, renal biopsies are needed to diagnose renal graft rejection. Here, we assessed whether the quantification of different urinary cells would allow non-invasive detection of rejection. Urinary cell numbers of CD4+ and CD8+ T cells, monocytes/macrophages, tubular epithelial cells (TEC), and podocalyxin(PDX)-positive cells were determined using flow cytometry and were compared to biopsy results. Urine samples of 63 renal transplant patients were analyzed. Patients with transplant rejection had higher amounts of urinary T cells than controls; however, patients who showed worsening graft function without rejection had similar numbers of T cells. T cells correlated with histological findings (interstitial inflammation p = 0.0005, r = 0.70; tubulitis p = 0.006, r = 0.58). Combining the amount of urinary T cells and TEC, or T cells and PDX+ cells, yielded a significant segregation of patients with rejection from patients without rejection (all p < 0.01, area under the curve 0.89–0.91). Urinary cell populations analyzed by flow cytometry have the potential to introduce new monitoring methods for kidney transplant patients. The combination of urinary T cells, TEC, and PDX-positive cells may allow non-invasive detection of transplant rejection.
Background. Colorectal cancers (CRC) shed DNA into blood circulation. There is growing evidence that the analysis of circulating tumor DNA can be effectively used for monitoring of disease, to track tumor heterogeneity and to evaluate response to treatment. Case Presentation. Here, we describe two cases of patients with advanced CRC. The first case is about a patient with no available tissue for analysis of RAS mutation status. Liquid biopsy revealed RAS-wild-type and the therapy with anti-EGFR (epidermal growth factor receptor) monoclonal antibody cetuximab could be initiated. In the second case, the mutational profile of a patient with initial wild-type RAS-status was continually tracked during the course of treatment. An acquired KRAS exon 3 mutation was detected. The number of KRAS mutated fragments decreased continuously after the discontinuation of the therapy with EGFR-specific antibodies. Conclusion. Liquid biopsy provides a rapid genotype result, which accurately reproduces the current mutation status of tumor tissue. Furthermore, liquid biopsy enables close monitoring of the onset of secondary resistance to anti-EGFR therapy.
Genetic or pharmacological ablation of toll-like receptor 2 (TLR2) protects against myocardial ischemia/reperfusion injury (MI/R). However, the endogenous ligand responsible for TLR2 activation has not yet been detected. The objective of this study was to identify HMGB1 as an activator of TLR2 signalling during MI/R. C57BL/6 wild-type (WT) or TLR2(-/-)-mice were injected with vehicle, HMGB1, or HMGB1 BoxA one hour before myocardial ischemia (30 min) and reperfusion (24 hrs). Infarct size, cardiac troponin T, leukocyte infiltration, HMGB1 release, TLR4-, TLR9-, and RAGE-expression were quantified. HMGB1 plasma levels were measured in patients undergoing coronary artery bypass graft (CABG) surgery. HMGB1 antagonist BoxA reduced cardiomyocyte necrosis during MI/R in WT mice, accompanied by reduced leukocyte infiltration. Injection of HMGB1 did, however, not increase infarct size in WT animals. In TLR2(-/-)-hearts, neither BoxA nor HMGB1 affected infarct size. No differences in RAGE and TLR9 expression could be detected, while TLR2(-/-)-mice display increased TLR4 and HMGB1 expression. Plasma levels of HMGB1 were increased MI/R in TLR2(-/-)-mice after CABG surgery in patients carrying a TLR2 polymorphism (Arg753Gln). We here provide evidence that absence of TLR2 signalling abrogates infarct-sparing effects of HMGB1 blockade.
Purpose: Student circus artists train as both artists and athletes with their bodies holding the key to professional success. The daily training load of student circus artists is often associated with maximum physical and psychological stress with injuries posing a threat to a potential professional career. The purpose of this study is the differentiated analysis and evaluation of work accidents in order to initiate the development of injury preventive programs.
Methods: The 17 years of data were obtained from standardized anonymous work accident records of the Berlin State Accident Insurance (UKB) as well as a State Artist Educational School (n = 169, Male: 70; Female: 99) from student artists. Evaluation and descriptive statistics were conducted with Excel 2007 and PASW Statistics 18.
Results: The injury risk seems to be relatively low (0.3 injuries/1000h). There are gender specific differences as to the location of injuries. Only 7% of the accidents demand a break of more than 3 days. Injury patterns vary depending on the activity and the employment of props/equipment. 75.2% of work accidents have multifactorial and 24.8% exogenous causes.
Conclusions: Because physical fitness is all important in the circus arts there are numerous options for injury prevention programs that should be realized subject to gender-specific differences. Follow-ups on chronic complaints and a more individual approach are indispensable due to the very specific activities in the circus arts.