Although littermates in altricial mammals usually experience highly similar environmental conditions during early life, considerable differences in growth and health can emerge among them. In a study ...on subadults of a European rabbit (Oryctolagus cuniculus) population with low MHC polymorphism, we tested whether litter-sibling differences in endoparasitic coccidia load and body mass at the end of the vegetation period were associated with within-litter differences in starting body mass (measured around 2 weeks prior to weaning) and in immune-genetic (MHC class II DRB) constitution. We hypothesized that siblings with a lighter starting mass might be more susceptible to endoparasite infections and thus, negative effects of a more unfavourable MHC constitution might be particularly pronounced in such individuals. Within-litter comparisons revealed that animals with a lighter starting mass reached a relatively lower body mass in autumn. Furthermore, there were indications for an allele-specific heterozygote advantage, as animals with heterozygous combinations of the allele Orcu-DRB*4 had relatively lower hepatic coccidia loads than their littermates with certain homozygous allele combinations. Consistent with our hypothesis, significantly higher hepatic coccidia loads and tendentially lower autumn body masses in homozygous compared to heterozygous individuals for the allele Orcu-DRB*4 were evident in initially lighter but not in heavier siblings, suggesting synergistic effects between an unfavourable MHC constitution and a light starting mass. Taken together, these effects might lead to notable differences in fitness among litter siblings, as a low body mass and a high endoparasite burden are key factors limiting young rabbits’survival during winter.
Large clinical trials testing hydrocortisone therapy in septic shock have produced conflicting results. Subgroups may benefit of hydrocortisone treatment depending on their individual immune ...response. We performed an exploratory analysis of the database from the international randomized controlled clinical trial Corticosteroid Therapy of Septic Shock (CORTICUS) employing machine learning to a panel of 137 variables collected from the Berlin subcohort comprising 83 patients including demographic and clinical measures, organ failure scores, leukocyte counts and levels of circulating cytokines. The identified theranostic marker was validated against data from a cohort of the Hellenic Sepsis Study Group (HSSG) (
= 246), patients enrolled in the clinical trial of Sodium Selenite and Procalcitonin Guided Antimicrobial Therapy in Severe Sepsis (SISPCT,
= 118), and another, smaller clinical trial (Crossover study,
= 20). In addition,
blood culture experiments and
experiments in mouse models were performed to assess biological plausibility. A low serum IFNγ/IL10 ratio predicted increased survival in the hydrocortisone group whereas a high ratio predicted better survival in the placebo group. Using this marker for a decision rule, we applied it to three validation sets and observed the same trend. Experimental studies
revealed that IFNγ/IL10 was negatively associated with the load of (heat inactivated) pathogens in spiked human blood and in septic mouse models. Accordingly, an
analysis of published IFNγ and IL10 values in bacteremic and non-bacteremic patients with the Systemic Inflammatory Response Syndrome supported this association between the ratio and pathogen burden. We propose IFNγ/IL10 as a molecular marker supporting the decision to administer hydrocortisone to patients in septic shock. Prospective clinical studies are necessary and standard operating procedures need to be implemented, particularly to define a generic threshold. If confirmed, IFNγ/IL10 may become a suitable theranostic marker for an urging clinical need.
OBJECTIVES:High physical activity levels are associated with wide-ranging health benefits, disease prevention, and longevity. In the present study, we examined the impact of regular physical exercise ...on the severity of organ injury and survival probability, as well as characteristics of the systemic immune and metabolic response during severe polymicrobial sepsis.
DESIGN:Animal study.
SETTING:University laboratory.
SUBJECTS:Male C57BL/6N mice.
INTERVENTIONS:Mice were trained for 6 weeks by treadmill and voluntary wheel running or housed normally. Polymicrobial sepsis in mice was induced by injection of fecal slurry. Subsequently, mice were randomized into the following groupshealthy controls, 6 hours postsepsis, and 24 hours postsepsis.
MEASUREMENTS AND MAIN RESULTS:Blood and organ samples were collected and investigated by measuring clinical chemistry variables, cytokines, plasma metabolites, and bacterial clearance. Organ morphology and damage were characterized by histological staining. Physical exercise improved survival and the ability of bacterial clearance in blood and organs. The release of pro- and anti-inflammatory cytokines, including interleukin-6 and interleukin-10, was diminished in trained compared to untrained mice during sepsis. The sepsis-associated acute kidney tubular damage was less pronounced in pretrained animals. By metabolic profiling and regression analysis, we detected lysophosphatidylcholine 14:0, tryptophan, as well as pimelylcarnitine linked with levels of neutrophil gelatinase-associated lipocalin representing acute tubular injury (corrected R = 0.910; p < 0.001). We identified plasma lysophosphatidylcholine 16:0, lysophosphatidylcholine 17:0, and lysophosphatidylcholine 18:0 as significant metabolites discriminating between trained and untrained mice during sepsis.
CONCLUSIONS:Regular physical exercise reduces sepsis-associated acute kidney injury and death. As a specific mechanism of exercise-induced adaptation, we identified various lysophosphatidylcholines that might function as surrogate for improved outcome in sepsis.
Although littermates in altricial mammals usually experience highly similar environmental conditions during early life, considerabledifferences in growth and health can emerge among them. In a study ...on subadults of a European rabbit (Oryctolaguscuniculus) population with low MHC polymorphism, we tested whether litter-sibling differences in endoparasitic coccidiaload and body mass at the end of the vegetation period were associated with within-litter differences in starting body mass(measured around 2 weeks prior to weaning) and in immune-genetic (MHC class II DRB) constitution. We hypothesized thatsiblings with a lighter starting mass might be more susceptible to endoparasite infections and thus, negative effects of a moreunfavourable MHC constitution might be particularly pronounced in such individuals. Within-litter comparisons revealedthat animals with a lighter starting mass reached a relatively lower body mass in autumn. Furthermore, there were indicationsfor an allele-specific heterozygote advantage, as animals with heterozygous combinations of the allele Orcu-DRB*4had relatively lower hepatic coccidia loads than their littermates with certain homozygous allele combinations. Consistentwith our hypothesis, significantly higher hepatic coccidia loads and tendentially lower autumn body masses in homozygouscompared to heterozygous individuals for the allele Orcu-DRB*4 were evident in initially lighter but not in heavier siblings,suggesting synergistic effects between an unfavourable MHC constitution and a light starting mass. Taken together, theseeffects might lead to notable differences in fitness among litter siblings, as a low body mass and a high endoparasite burdenare key factors limiting young rabbits’ survival during winter.
Introduction. Sepsis is the primary cause of death from infection. We wanted to improve the outcome of sepsis by stimulating innate immunity in combination with modulating the severity of ...inflammatory responses in rats. Method. Sepsis was induced by the injection of feces suspension (control). A 5-day course of G-CSF treatment was given before the septic insult (G-CSF). The inflammatory response was decreased using various doses of the LPS-blocking peptide LBPK95A (5 mg/kg=100% Combi group, 0.5 mg/kg=10% Combi group, and 0.05 mg/kg=1% Combi group). Survival rates were observed. Bacterial clearance, neutrophil infiltration, tissue damage, and the induction of hepatic and systemic inflammatory responses were determined 2 h and 12 h after the septic insult. Results. High-dose LBPK95A (100% Combi) reduced the survival rate to 10%, whereas low-dose LBPK95A (10% and 1% Combi) increased the survival rates to 50% and 80%, respectively. The survival rates inversely correlated with multiorgan damage as indicated by the serum levels of ALT and urea. G-CSF treatment increased the white blood cell counts, hepatic neutrophil infiltration, and bacterial clearance in the liver, lung, and blood. The blockade of the LPS-LBP interaction decreased neutrophil infiltration, led to increased white blood cell count, and decreased hepatic neutrophil infiltration, irrespective of dose. However, bacterial clearance improved in the 1% and 10% Combi groups but worsened in the 100% Combi group. G-CSF increased TNF-α and IL-6 levels. Irrespective of dose, the blockade of the LPS-LBP interaction was associated with low systemic cytokine levels and delayed increases in hepatic TNF-α and IL-6 mRNA expression. The delayed increase in cytokines was associated with the phosphorylation of STAT3 and AKT. Conclusion. Our results revealed that increasing innate immunity by G-CSF pretreatment and decreasing inflammatory responses using LBPK95A improved the survival rates in a rat sepsis model and could be a novel strategy to treat sepsis.
ABSTRACTThe effect of granulocyte colony-stimulating factor (G-CSF) on sepsis is discussed controversially in clinical studies. We previously demonstrated that G-CSF treatment induced ...lipopolysaccharide (LPS) sensitization via up-regulation of LPS-binding protein (LBP). We hypothesized that the futile effect of G-CSF-treatment in sepsis might be due to its ability to up-regulate LBP. Therefore, blockade of LBP may attenuate the G-CSF–induced LPS sensitization and protect animals from polymicrobial sepsis. Endogenous LBP levels were up-regulated by pretreatment with G-CSF, and the LBP protein was blocked by administration of a specific blocking peptide—LBPK95A. Polymicrobial sepsis was induced by intraperitoneal injection of feces slurry. Rats were monitored every 3 up to 72 h to observe the survival rate. Tissue injury, bacterial infiltration, local inflammatory response, and neutrophil infiltration at 0, 2, and 12 h after the septic insult were analyzed. The survival benefit of G-CSF pretreatment was improved when combined with LBPK95A treatment (control vs. G-CSF vs. combi36% vs. 56% vs. 93%; P < 0.05). Combined treatment of G-CSF and LBPK95A was associated with the minimal tissue damage. Treatment with LBPK95A significantly inhibited the neutrophil infiltration without interfering with the bacterial clearance. The G-CSF–induced inflammatory sensitization effect was inhibited by LBPK95A, indicated by the decrease of cytokines expression, and the activation of nuclear factor kappa B and signal transducer and activator of transcription 3 signaling pathway. In conclusion, these results suggested that the effect of prophylactic augmentation of the host’s response via G-CSF pretreatment was further enhanced by inhibition of the up-regulation of LBP.
Genes of the major histocompatibility complex (MHC) play a fundamental role in the vertebrate immune response and are amongst the most polymorphic genes in vertebrate genomes. It is generally agreed ...that the highly polymorphic nature of the MHC is maintained through host–parasite co‐evolution. Two nonexclusive mechanisms of selection are supposed to act on MHC genes: superiority of MHC heterozygous individuals (overdominance) and an advantage for rare MHC alleles. However, the precise mechanisms and their relative importance are still unknown. Here, we examined MHC dependent parasite load in European rabbits (Oryctolagus cuniculus) from a distinct population with low MHC diversity (three alleles, six genotypes). Using a multivariate approach, we tested for associations of individual MHC class II DRB constitution and the rabbits’ intestinal burden with nematodes and coccidia. Rabbits having a particular allele showed lower infestations with hepatic coccidia (E. stiedai). However, a comparison of all six genotypes in the population revealed that carriers of this allele only benefit when they are heterozygous, and furthermore, MHC heterozygosity in general did not affect individual parasite load. In conclusion, this study suggests an immunogenetic basis of European rabbit resistance to hepatic coccidiosis, which can strongly limit survival to maturity in this species. Our study gives a complex picture of MHC–parasite correlations, unveiling the limits of the classical hypotheses of how MHC polymorphism is maintained in natural systems.
Background
In patients with sepsis and renal failure, extracorporeal blood flow during renal replacement therapy may lead to the deposition of bacteria on artificial membranous surfaces, which might ...be suitable for the detection of pathogens. We studied whether discarded dialysis hemofilters can be used for the detection of bacteremia in patients with sepsis and renal failure.
Methods
Hemofilters of 16 ICU patients with sepsis were sampled. The hemofilters were incubated with soy broth and dehisced under sterile conditions. Samples were plated on blood agar and analyzed. Patient’s characteristics were assessed.
Results
Despite the use of antibiotics in 87.5 % (14/16), a true positive detection rate of 31.3 % (5/16) for bacteremia was found by using cultures from hemofilters. The overall true positive rate of blood cultures was significantly lower (10.7 %, 8/75,
p
= 0.048). Bacteria detected in hemofilters were similar to those found in blood cultures or by cultures from other sources of infection in 80 % (4/5).
Conclusions
Cultures from used hemofilters of patients with sepsis and renal failure provide the opportunity to identify pathogenic microorganisms as an add-on approach. Further studies should investigate whether this method is applicable in clinical practice to enhance the sensitivity of microbiological diagnostics.
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