IgG-index predicts neurological morbidity in patients with infectious central nervous system diseases

<p>Abstract</p> <p>Background</p> <p>Prognosis assessment of patients with infectious and neoplastic disorders of the central nervous system (CNS) may still pose a challenge. In this retrospective cross-sectional study the prognostic value of basic cerebrospinal fluid (CSF) parameters in patients with bacterial meningitis, viral meningoencephalitis and leptomeningeal metastases were evaluated.</p> <p>Methods</p> <p>White blood cell count, CSF/serum glucose ratio, protein, CSF/serum albumin quotient and Immunoglobulin indices for IgG, IgA and IgM were analyzed in 90 patients with bacterial meningitis, 117 patients with viral meningoencephalitis and 36 patients with leptomeningeal metastases in a total of 480 CSF samples.</p> <p>Results</p> <p>In the initial spinal tap, the IgG-index was the only independent predictor for unfavorable outcome (GOS < 5) in patients with infectious CNS diseases but not in patients with leptomeningeal metastases. The sensitivity and specificity of an IgG-index of 0.75 and higher for predicting unfavorable outcome was 40.9% and 80.8% in bacterial meningitis and 40% and 94.8% in viral meningoencephalitis, respectively. No significant associations between CSF parameters and outcome could be observed in follow-up CSF samples.</p> <p>Conclusion</p> <p>The present study suggests that in infectious CNS diseases an elevated IgG-Index might be an additional marker for the early identification of patients at risk for neurological morbidity.</p

Pharmacological Inhibition of Nicotinamide Phosphoribosyltransferase/Visfatin Enzymatic Activity Identifies a New Inflammatory Pathway Linked to NAD

Nicotinamide phosphoribosyltransferase (NAMPT), also known as visfatin, is the rate-limiting enzyme in the salvage pathway of NAD biosynthesis from nicotinamide. Since its expression is upregulated during inflammation, NAMPT represents a novel clinical biomarker in acute lung injury, rheumatoid arthritis, and Crohn's disease. However, its role in disease progression remains unknown. We report here that NAMPT is a key player in inflammatory arthritis. Increased expression of NAMPT was confirmed in mice with collagen-induced arthritis, both in serum and in the arthritic paw. Importantly, a specific competitive inhibitor of NAMPT effectively reduced arthritis severity with comparable activity to etanercept, and decreased pro-inflammatory cytokine secretion in affected joints. Moreover, NAMPT inhibition reduced intracellular NAD concentration in inflammatory cells and circulating TNFα levels during endotoxemia in mice. In vitro pharmacological inhibition of NAMPT reduced the intracellular concentration of NAD and pro-inflammatory cytokine secretion by inflammatory cells. Thus, NAMPT links NAD metabolism to inflammatory cytokine secretion by leukocytes, and its inhibition might therefore have therapeutic efficacy in immune-mediated inflammatory disorders

Testing for allergic disease: Parameters considered and test value

<p>Abstract</p> <p>Background</p> <p>Test results for allergic disease are especially valuable to allergists and family physicians for clinical evaluation, decisions to treat, and to determine needs for referral.</p> <p>Methods</p> <p>This study used a repeated measures design (conjoint analysis) to examine trade offs among clinical parameters that influence the decision of family physicians to use specific IgE blood testing as a diagnostic aid for patients suspected of having allergic rhinitis. Data were extracted from a random sample of 50 family physicians in the Southeastern United States. Physicians evaluated 11 patient profiles containing four clinical parameters: symptom severity (low, medium, high), symptom length (5, 10, 20 years), family history (both parents, mother, neither), and medication use (prescribed antihistamines, nasal spray, over-the-counter medications). Decision to recommend specific IgE testing was elicited as a "yes" or "no" response. Perceived value of specific IgE blood testing was evaluated according to usefulness as a diagnostic tool compared to skin testing, and not testing.</p> <p>Results</p> <p>The highest odds ratios (OR) associated with decisions to test for allergic rhinitis were obtained for symptom severity (OR, 12.11; 95%CI, 7.1–20.7) and length of symptoms (OR, 1.46; 95%CI, 0.96–2.2) with family history having significant influence in the decision. A moderately positive association between testing issues and testing value was revealed (β = 0.624, <it>t </it>= 5.296, <it>p </it>≤ 0.001) with 39% of the variance explained by the regression model.</p> <p>Conclusion</p> <p>The most important parameters considered when testing for allergic rhinitis relate to symptom severity, length of symptoms, and family history. Family physicians recognize that specific IgE blood testing is valuable to their practice.</p

Delineation of Diverse Macrophage Activation Programs in Response to Intracellular Parasites and Cytokines

Macrophages are a type of immune cell that engulf and digest microorganisms. Despite their role in protecting the host from infection, many pathogens have developed ways to hijack the macrophage and use the cell for their own survival and proliferation. This includes the parasites Trypanosoma cruzi and Leishmania mexicana. In order to gain further understanding of how these pathogens interact with the host macrophage, we compared macrophages that have been infected with these parasites to macrophages that have been stimulated in a number of different ways. Macrophages can be activated by a wide variety of stimuli, including common motifs found on pathogens (known as pathogen associated molecular patterns or PAMPs) and cytokines secreted by other immune cells. In this study, we have delineated the relationships between the macrophage activation programs elicited by a number of cytokines and PAMPs. Furthermore, we have placed the macrophage responses to T. cruzi and L. mexicana into the context of these activation programs, providing a better understanding of the interactions between these pathogens and macrophages

The anti-bacterial iron-restriction defence mechanisms of egg white; the potential role of three lipocalin-like proteins in resistance against Salmonella

Salmonella enterica serovar Enteritidis (SE) is the most frequently-detected Salmonella in foodborne outbreaks in the European Union. Among such outbreaks, egg and egg products were identified as the most common vehicles of infection. Possibly, the major antibacterial property of egg white is iron restriction, which results from the presence of the iron-binding protein, ovotransferrin. To circumvent iron restriction, SE synthesise catecholate siderophores (i.e. enterobactin and salmochelin) that can chelate iron from host iron-binding proteins. Here, we highlight the role of lipocalin-like proteins found in egg white that could enhance egg-white iron restriction through sequestration of certain siderophores, including enterobactin. Indeed, it is now apparent that the egg-white lipocalin, Ex-FABP, can inhibit bacterial growth via its siderophore-binding capacity in vitro. However, it remains unclear whether ex-FABP performs such a function in egg white or during bird infection. Regarding the two other lipocalins of egg white (Cal-γ and α-1-glycoprotein), there is currently no evidence to indicate that they sequester siderophores

Strengthening insights into host responses to mastitis infection in ruminants by combining heterogeneous microarray data sources

<p>Abstract</p> <p>Background</p> <p>Gene expression profiling studies of mastitis in ruminants have provided key but fragmented knowledge for the understanding of the disease. A systematic combination of different expression profiling studies via meta-analysis techniques has the potential to test the extensibility of conclusions based on single studies. Using the program Pointillist, we performed meta-analysis of transcription-profiling data from six independent studies of infections with mammary gland pathogens, including samples from cattle challenged <it>in vivo </it>with <it>S. aureus</it>, <it>E. coli</it>, and <it>S. uberis</it>, samples from goats challenged <it>in vivo </it>with <it>S. aureus</it>, as well as cattle macrophages and ovine dendritic cells infected <it>in vitro </it>with <it>S. aureus</it>. We combined different time points from those studies, testing different responses to mastitis infection: overall (common signature), early stage, late stage, and cattle-specific.</p> <p>Results</p> <p>Ingenuity Pathway Analysis of affected genes showed that the four meta-analysis combinations share biological functions and pathways (e.g. protein ubiquitination and polyamine regulation) which are intrinsic to the general disease response. In the overall response, pathways related to immune response and inflammation, as well as biological functions related to lipid metabolism were altered. This latter observation is consistent with the milk fat content depression commonly observed during mastitis infection. Complementarities between early and late stage responses were found, with a prominence of metabolic and stress signals in the early stage and of the immune response related to the lipid metabolism in the late stage; both mechanisms apparently modulated by few genes, including <it>XBP1 </it>and <it>SREBF1</it>.</p> <p>The cattle-specific response was characterized by alteration of the immune response and by modification of lipid metabolism. Comparison of <it>E. coli </it>and <it>S. aureus </it>infections in cattle <it>in vivo </it>revealed that affected genes showing opposite regulation had the same altered biological functions and provided evidence that <it>E. coli </it>caused a stronger host response.</p> <p>Conclusions</p> <p>This meta-analysis approach reinforces previous findings but also reveals several novel themes, including the involvement of genes, biological functions, and pathways that were not identified in individual studies. As such, it provides an interesting proof of principle for future studies combining information from diverse heterogeneous sources.</p

Adjunctive Dexamethasone Affects the Expression of Genes Related to Inflammation, Neurogenesis and Apoptosis in Infant Rat Pneumococcal Meningitis

Streptococcus pneumoniae is the most common pathogen causing non-epidemic bacterial meningitis worldwide. The immune response and inflammatory processes contribute to the pathophysiology. Hence, the anti-inflammatory dexamethasone is advocated as adjuvant treatment although its clinical efficacy remains a question at issue. In experimental models of pneumococcal meningitis, dexamethasone increased neuronal damage in the dentate gyrus. Here, we investigated expressional changes in the hippocampus and cortex at 72 h after infection when dexamethasone was given to infant rats with pneumococcal meningitis. Nursing Wistar rats were intracisternally infected with Streptococcus pneumoniae to induce experimental meningitis or were sham-infected with pyrogen-free saline. Besides antibiotics, animals were either treated with dexamethasone or saline. Expressional changes were assessed by the use of GeneChip® Rat Exon 1.0 ST Arrays and quantitative real-time PCR. Protein levels of brain-derived neurotrophic factor, cytokines and chemokines were evaluated in immunoassays using Luminex xMAP® technology. In infected animals, 213 and 264 genes were significantly regulated by dexamethasone in the hippocampus and cortex respectively. Separately for the cortex and the hippocampus, Gene Ontology analysis identified clusters of biological processes which were assigned to the predefined categories “inflammation”, “growth”, “apoptosis” and others. Dexamethasone affected the expression of genes and protein levels of chemokines reflecting diminished activation of microglia. Dexamethasone-induced changes of genes related to apoptosis suggest the downregulation of the Akt-survival pathway and the induction of caspase-independent apoptosis. Signalling of pro-neurogenic pathways such as transforming growth factor pathway was reduced by dexamethasone resulting in a lack of pro-survival triggers. The anti-inflammatory properties of dexamethasone were observed on gene and protein level in experimental pneumococcal meningitis. Further dexamethasone-induced expressional changes reflect an increase of pro-apoptotic signals and a decrease of pro-neurogenic processes. The findings may help to identify potential mechanisms leading to apoptosis by dexamethasone in experimental pneumococcal meningitis

Assessing the human immune system through blood transcriptomics

Blood is the pipeline of the immune system. Assessing changes in transcript abundance in blood on a genome-wide scale affords a comprehensive view of the status of the immune system in health and disease. This review summarizes the work that has used this approach to identify therapeutic targets and biomarker signatures in the field of autoimmunity and infectious disease. Recent technological and methodological advances that will carry the blood transcriptome research field forward are also discussed

Metamorphosis of Subarachnoid Hemorrhage Research: from Delayed Vasospasm to Early Brain Injury

Delayed vasospasm that develops 3–7 days after aneurysmal subarachnoid hemorrhage (SAH) has traditionally been considered the most important determinant of delayed ischemic injury and poor outcome. Consequently, most therapies against delayed ischemic injury are directed towards reducing the incidence of vasospasm. The clinical trials based on this strategy, however, have so far claimed limited success; the incidence of vasospasm is reduced without reduction in delayed ischemic injury or improvement in the long-term outcome. This fact has shifted research interest to the early brain injury (first 72 h) evoked by SAH. In recent years, several pathological mechanisms that activate within minutes after the initial bleed and lead to early brain injury are identified. In addition, it is found that many of these mechanisms evolve with time and participate in the pathogenesis of delayed ischemic injury and poor outcome. Therefore, a therapy or therapies focused on these early mechanisms may not only prevent the early brain injury but may also help reduce the intensity of later developing neurological complications. This manuscript reviews the pathological mechanisms of early brain injury after SAH and summarizes the status of current therapies

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]