The potential for immunoglobulins and host defense peptides (HDPs) to reduce the use of antibiotics in animal production

Abstract Innate defense mechanisms are aimed at quickly containing and removing infectious microorganisms and involve local stromal and immune cell activation, neutrophil recruitment and activation and the induction of host defense peptides (defensins and cathelicidins), acute phase proteins and complement activation. As an alternative to antibiotics, innate immune mechanisms are highly relevant as they offer rapid general ways to, at least partially, protect against infections and enable the build-up of a sufficient adaptive immune response. This review describes two classes of promising alternatives to antibiotics based on components of the innate host defense. First we describe immunoglobulins applied to mimic the way in which they work in the newborn as locally acting broadly active defense molecules enforcing innate immunity barriers. Secondly, the potential of host defense peptides with different modes of action, used directly, induced in situ or used as vaccine adjuvants is described

Plasma cytokine levels predict response to corticosteroids in septic shock

Purpose: To investigate if plasma cytokine concentrations predict a beneficial response to corticosteroid treatment in septic shock patients. Methods: A cohort of septic shock patients in whom a panel of 39 cytokines had been measured at baseline (n = 363) was included. Patients who received corticosteroids were propensity score matched to non-corticosteroid-treated patients. An optimal threshold to identify responders to corticosteroid treatment for each cytokine was defined as the concentration above which the odds ratio for 28-day survival between corticosteroid- and non-corticosteroid-treated patients was highest. Results: Propensity score matching partitioned 165 patients into 61 sets; each set contained matched corticosteroid- and non-corticosteroid-treated patients. For 13 plasma cytokines threshold concentrations were found where the odds ratio for survival between corticosteroid- and non-corticosteroid-treated patients was significant (P <0.05). CD40 ligand was associated with the highest odds ratio and identified 21 % of the patients in the propensity score matched cohort as responders to corticosteroid treatment. Combinations of triplets of cytokines with a significant odds ratio, using the thresholds identified above, were tested to find a higher proportion of responders. IL3, IL6, and CCL4 identified 50 % of the patients in the propensity score matched cohort as responders to corticosteroid treatment. The odds ratio for 28-day survival was 19 (95 % CI 3.5–140, P = 0.02) with a concentration above threshold for a least one of these cytokines. Conclusion: Plasma concentration of selected cytokines is a potential predictive biomarker to identify septic shock patients that may benefit from treatment with corticosteroids

Small Acute Increases in Serum Creatinine Are Associated with Decreased Long-Term Survival in the Critically Ill

Rationale: Long-term outcomes after acute kidney injury (AKI) are poorly described. Objectives: We hypothesized that one single episode of minimal (stage 1) AKI is associated with reduced long-term survival compared with no AKI after recovery from critical illness. Methods: A prospective cohort of 2,010 intensive care unit (ICU) patients admitted to the ICU between years 2000 and 2009 at a provincial tertiary care hospital. Development of AKI was determined according to the KDIGO classification and mortality up to 10 years after ICU admission was recorded. Measurements and Main Results: Of the 1,844 eligible patients, 18.4% had AKI stage 1, 12.1% had stage 2, 26.5% had stage 3, and 43.0% had no AKI. The 28-day, 1-year, 5-year, and 10-year survival rates were 67.1%, 51.8%, 44.1%, and 36.3% in patients with mild AKI, which was significantly worse compared with the critically ill patients with no AKI at any time (P < 0.01). The unadjusted 10-year mortality hazard ratio was 1.53 (95% confidence interval, 1.2-2.0) for 28-day survivors with stage 1 AKE compared with critically ill patients with no AKI. Adjusted 10-year mortality risk was 1.26 (1.0-1.6). After propensity matching stage 1 AKI with no AKE patients, mild AKE was still significantly associated with decreased 10-year survival (P =0.036). Conclusions: Patients with one episode of mild AKI have significantly lower long-term survival rates than critically ill patients with no AKI. Close medical follow-up of these patients may be warranted and mechanistic research is required to understand how AKI influences long-term events

Bioinformatics Advance Access published February 10, 2004 Automated ordering of fingerprinted clones

Motivation: A considerable amount of human intervention is currently required to produce high quality fingerprint based physical maps for genomic studies. Results: An algorithm has been developed and implemented to automatically order fingerprinted clones within contigs. The resulting software, named CORAL (Clone ORdering ALgorithm), has been tested on maps that have previously been manually edited and on maps derived from in silico simulations. The fingerprint map and DNA sequence of the human genome has provided an additional test to CORAL. Measurements suggest that CORAL performs significantly better than the software currently used by most laboratories to order fingerprinted clones at throughputs far exceeding those that can be achieved manually. Availability: Available on request from the authors. Contact

The specific organism : Not bacterial gram type: Drives the inflammatory response in septic shock

Background and Hypothesis: The inflammatory response was targeted by unsuccessful therapies but ignored pathogen. We hypothesized that the inflammatory response differs according to organism in human septic shock. Materials and Methods: We measured 39 cytokines at baseline and 24 h in patients (n = 363) in the Vasopressin and Septic Shock Trial (VASST). We compared cytokine profiles (cytokine functional class) at baseline and at 24 h by organism and used hierarchical clustering to classify cytokines according to 28-day outcomes. Results: In 363 patients, 88 and 176 patients had at least 1 species isolated from blood and other sites, respectively. Cytokine levels differed significantly according to organism: Neisseria meningitidis and Streptococcus pneumoniae had the highest (baseline and at 24 h), while Enterococcus faecalis (blood) had the lowest mean cytokine levels. N. meningitidis and Klebsiella pneumoniae had significantly higher cytokine levels at baseline versus 24 h (p = 0.01 and 0.02, respectively); E. faecalis had significantly higher cytokine levels at 24 h versus baseline. Hierarchical clustering heat maps showed that pathogens elicited similar cytokine responses not related to the functional cytokine class. Conclusion: The organism type induces different cytokine profiles in septic shock. Specific gram-positive and gram-negative pathogens stimulated similar plasma cytokine-level patterns

A Systems Biology Approach to the Analysis of Subset-Specific Responses to Lipopolysaccharide in Dendritic Cells

<div><p>Dendritic cells (DCs) are critical for regulating CD4 and CD8 T cell immunity, controlling Th1, Th2, and Th17 commitment, generating inducible Tregs, and mediating tolerance. It is believed that distinct DC subsets have evolved to control these different immune outcomes. However, how DC subsets mount different responses to inflammatory and/or tolerogenic signals in order to accomplish their divergent functions remains unclear. Lipopolysaccharide (LPS) provides an excellent model for investigating responses in closely related splenic DC subsets, as all subsets express the LPS receptor TLR4 and respond to LPS in vitro. However, previous studies of the LPS-induced DC transcriptome have been performed only on mixed DC populations. Moreover, comparisons of the in vivo response of two closely related DC subsets to LPS stimulation have not been reported in the literature to date. We compared the transcriptomes of murine splenic CD8 and CD11b DC subsets after in vivo LPS stimulation, using RNA-Seq and systems biology approaches. We identified subset-specific gene signatures, which included multiple functional immune mediators unique to each subset. To explain the observed subset-specific differences, we used a network analysis approach. While both DC subsets used a conserved set of transcription factors and major signalling pathways, the subsets showed differential regulation of sets of genes that ‘fine-tune’ the network Hubs expressed in common. We propose a model in which signalling through common pathway components is ‘fine-tuned’ by transcriptional control of subset-specific modulators, thus allowing for distinct functional outcomes in closely related DC subsets. We extend this analysis to comparable datasets from the literature and confirm that our model can account for cell subset-specific responses to LPS stimulation in multiple subpopulations in mouse and man.</p></div

Expression of canonical transcription factor-target TLR4-dependent pathways mediating the LPS response in CD8 and CD11b DCs.

<p>Transcription factor-target over-representation analysis of LPS-induced genes in CD8 and CD11b DCs.</p><p>1. The ratio of odds (Odds-Ratio) that a transcription factor-associated pathway is enriched in the selected DC subset was calculated as the odds of differentially expressed genes being regulated by the transcription factor divided by the odds of non-differentially expressed genes being regulated by the same transcription factor.</p><p>2. P-values are adjusted to control for multiple comparisons.</p><p>*denotes not significant (p>0.05).</p

Comparison of steady-state spleen DC subsets.

<p>(A) Steady-state splenic DCs were magnetic bead-enriched for CD19⁻B220⁻CD3⁻Gr-1⁻Ter119⁻CD11c⁺ cells. MHCII⁺CD11c⁺ cells (circled) were then sorted for CD8 (blue gate) and CD11b (orange gate) subsets and RNA prepared and analysed by RNA-Seq. (B) Heatmap showing the relative expression of the 50 most commonly defined and validated markers for CD8 and CD11b subsets. Data are presented as fold changes (CD11b/CD8), all of which were statistically significant with an associated p-value <0.05. Orange denotes genes that were increased in CD11b DCs while blue denotes genes that were decreased in CD11b DCs (and thus increased in CD8 DCs. (C) Overlap between genes that were significantly differentially expressed between CD8 and CD11b DCs in our dataset and in 9 previously published microarray datasets derived from splenic DC subsets (datasets 1–9 listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100613#pone.0100613.s006" target="_blank">Table S1</a>). The significance of overlap between the gene list from our dataset and those from each of the published datasets was calculated using a hypergeometric test to assess the consistency/quality of our results. Data are presented as 1/p-value on a log scale with all overlaps reaching a significance cut-off <0.05.</p